The Psychiatric Dimensions of Sleep Medicine

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Foreword

Teofilo Lee-Chiong, Jr., MD Section of Sleep Medicine National Jewish Medical and Research Center University of Colorado Health Sciences Center 1400 Jackson Street Room J232 Denver, CO 80206, USA

Teofilo Lee-Chiong, Jr., MD Consulting Editor

A bidirectional relationship exists between the sciences of psychiatry and sleep medicine. Indeed, symptoms of psychiatric disorders are modified by and, more importantly, can lead to sleep disruption. The association of insomnia and the risk of a new psychiatric disorder, specifically major depression, developing is well described. Furthermore, psychiatric disorders can give rise to complaints of insomnia (eg, bipolar disorder, depression, generalized anxiety disorder, obsessive–compulsive disorder, panic disorder, personality disorders, posttraumatic stress disorder, and schizophrenia) or excessive daytime sleepiness (eg, atypical depression and seasonal affective disorder). Certain parasomnias, such as nightmares and sleep terrors, may be more prevalent in patients with psychiatric illnesses. Finally, the medications used to manage psychiatric disorders, including many antidepressant and antipsychotic agents, can affect sleep quality, duration, and architecture. The clinical course of schizophrenia may be complicated by sleep disturbance, sleep-initiation and sleep-maintenance, insomnia, reversal of day– night sleep patterns, or alternating phases of sleeplessness and sleepiness. Since some antipsychotic

E-mail address: [email protected]

agents can cause sedation, insomnia may also develop following discontinuation of these medications. During exacerbations of psychotic symptoms, prolonged periods of waking may be maintained and terminated only by exhaustion. Conversely, rebound sleepiness can occur during the waning phase of schizophrenia or during residual schizophrenia. Insomnia is common among persons suffering from mood disorders, and there is generally a correlation between the severity of both conditions. Sleep disturbances and changes in sleep architecture (ie, increase in sleep onset latency or reductions in sleep efficiency, N3 sleep, and REM sleep latency) may both precede or persist after remission of major depressive episodes. Insomnia can be especially severe during a manic episode. Excessive daytime sleepiness, along with an increase in the requirement for sleep, may be seen during the depressive phase of a bipolar disorder, seasonal affective disorder, or atypical depression. In seasonal affective disorder, major depressive episodes occur during the fall and winter, when patients may complain of daytime sleepiness, fatigue, and decreased energy levels; during spring and summer,

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some patients’ moods improve, but they may experience hypomanic symptoms. Patients with atypical depression may present with lethargy, increase in appetite, weight gain, sensation of heaviness in the extremities, sensitivity to rejection, and excessive sleepiness. Anxiety disorders, including acute stress disorder, generalized anxiety disorder, and posttraumatic stress disorder, commonly manifest with insomnia, frequent nighttime awakenings, recurring anxiety dreams, or excessive daytime sleepiness. It is important to distinguish generalized anxiety disorder from psychophysiologic insomnia in which anxiety is chiefly restricted to the issues related to sleep disturbance and insomnia. Patients with posttraumatic stress disorder may describe

re-experiences of the original event in frequent distressing dreams, nightmares, and sleep terrors. In panic disorder, panic attacks can occur during sleep, typically in the transition between light NREM sleep and N3 sleep, but occasionally from REM sleep; awakenings can be accompanied by sympathetic activation and delayed return to sleep. Sleep panic attacks can be triggered by sleep deprivation. Finally, other psychiatric disorders can also profoundly affect sleep, including insomnia in somatization disorders, obsessive–compulsive personality disorder, and anorexia nervosa; excessive sleepiness in bulimia; and greater rates of obstructive sleep apnea and periodic limb movement disorder in attention deficit hyperactivity disorder.

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SLEEP MEDICINE CLINICS Sleep Med Clin 3 (2008) xv–xvi

Preface

Karl Doghramji, MD Thomas Jefferson University Sleep Disorders Center 211 South Ninth Street, Suite 500 Philadelphia, PA 19107, USA E-mail address: [email protected] Karl Doghramji, MD Guest Editor

Sleep has been of great interest to mankind throughout the centuries. It was not, however, a focus of scientific exploration until the 1900s when Sigmund Freud advanced the notion, in The Interpretation of Dreams, that dreams are a window into the mysteries of the mind. Freud’s primary interest was, no doubt, understanding the thoughts and feelings that reside in the unconscious mind and which motivate human behavior and lead to psychic conflict. Sleep and dreams represented a means towards that end. However, by necessity, Freud’s interests led him to advance a number of theoretical formulations regarding the psychological processes that govern dream production and sleep maintenance. Whereas Freud and the field of psychoanalysis that he championed remained focused on the psychological aspects of sleep, later psychiatrists delved into sleep’s physiological bases. Hans Berger, a German psychiatrist, was the first to record and describe human electroencephalographic wave forms in 1924. This established the technological foundation for the milestone discovery of rapid eye movement (REM) sleep by Aesrinsky and Kleitman in 1953. The subsequent surge in research into

electrophysiological sleep formed the foundation upon which much of the field of sleep medicine, as we know it today, is based. It is fitting that we begin this issue of the Sleep Medicine Clinics with a review of the history of sleep medicine by a sleep researcher who is widely regarded as the father of this field, Dr. William Dement. Dr. Dement’s initial interest in sleep research was engendered through the exploration of dreams, dreaming, and psychiatric conditions. Today, the clinical practice of sleep medicine subsumes scientific knowledge and clinical conditions that also belong to the mainstay of other medical specialties. These include psychiatry, psychology, neurology, pulmonary medicine, otolaryngology, and pediatrics. The goal of this issue of Sleep Medicine Clinics is to explore those disorders that are shared with the field of psychiatry for the sleep medicine practitioner. We begin with a clarification of the psychological underpinnings of sleep and dreaming and demonstrate how these broaden our understanding of the parasomnias and depressive disorders. We then explore the many facets of insomnia—clearly the most commonly expressed sleep-related complaint—through a review

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of its clinical presentation and evaluation and of its management through pharmacological and nonpharmacological means. We also explore excessive daytime somnolence and fatigue, which affect the majority of patients presenting to sleep medicine clinics, and review the clinical characteristics and management techniques of the emotional conditions that feature these two complaints. We then discuss the parasomnias, long considered to be disorders of primarily emotional origin, and review their neurophysiological underpinnings. Psychotic, mood, and anxiety disorders feature complaints surrounding sleep and wakefulness, and patients with these disorders turn to sleep medicine practitioners for assistance. The next few articles focus on

the clinical manifestations of these syndromes and the nature, significance, and clinical management of disturbed sleep in these disorders. We also discuss special issues that confront children, seniors, and women. We conclude with a chapter on seasonal affective disorder and review guidelines for phototherapy, a therapeutic measure with applications in a myriad of sleep disorders. I am indebted to the contributing authors of this issue: luminaries in the field of sleep medicine and highly respected for their research and clinical work. Without them, a project of this scope would have been impossible. I am also grateful to my family—Laurel Jeanne, Mark, and Leah—for their loving support.

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History of Sleep Medicine William C. Dement, -

MD, PhD

Professional organizations Complications of obstructive sleep apnea Discipline identity and discipline overlap Minimal penetration of the mainstream educational system

There have been a number of accounts of the history of sleep medicine. Perhaps the most notable was developed by a group of sleep specialists for the inaugural issue of the Journal of Clinical Sleep Medicine [1]. Insofar as the history of anything is known, it is what it is and cannot be changed, although possibly it can be reinterpreted and expanded. This article may have some novelty from the perspective of the author’s participation in the field from 1952 until present, spiced with some information not achieving publication in scientific journals, or even the occasional autobiographic material [2]. It is assumed that the first life forms evolved in equatorial climates rather than the poles. This being the case, early life forms were continuously exposed to the consequences of the earth’s rotation. This exposure almost certainly induced some sort of 24-hour rest-activity cycle. With diversity and ecologic specialization, it is likely that some organisms became nocturnal primarily for safety and to avoid daytime predators. Presumably, at the end of eons of evolution primates and human beings arrived whose interaction with the environment was primarily visual. This interaction must have fostered the evolution of the 24-hour sleep-wake cycle. Interest in sleep almost certainly goes back to the dawn of history. It is in marked contrast that sleep research and particularly the diagnosis and treatment

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Final thoughts References

of sleep disorders began so recently. It may be that the major obstacle was the need for investigators and clinicians to stay awake at night. Until the advent of the electric light, working at night had none of the practicality that it currently possesses. The recognition of the important specific sleep disorders (eg, obstructive sleep apnea) may have some partial roots in antiquity. Although human beings have been concerned about their sleep for centuries, there had not been a specific focus on problems of sleep and particularly the development of specific characterizations of individual sleep disorders. It is difficult to select highlights over the last hundred or so years; however, there is some consensus. A very important early step was the discovery of the electrical activity of the central nervous system by Richard Caton in 1875. The German psychiatrist Hans Berger was the first to describe human brain waves in reports published in the late 1920s. In the 1930s, a group at Harvard described different patterns of sleeping brain waves, and in particular described what are now known as ‘‘sleep spindles,’’ ‘‘K-complexes,’’ and ‘‘high amplitude slow waves.’’ By this time, it had also been found that the resting awake human adult had a very prominent 8 to 12 cycle per second nearly continuous oscillation from the occipital surface of the skull, which disappeared at the onset of sleep. Further advances in understanding the mechanisms of sleep and

Department of Psychiatry and Behavioral Sciences, Sleep Disorder/Sleep Center, 701 Welch Road, #2226, Stanford, CA 94305–5744, USA E-mail address: [email protected] 1556-407X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

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wakefulness were delayed by the hostilities up to and during World War II, and to some extent, the Korean War and events associated with the Cold War. Appropriately, the discovery that many say initiated the modern era of sleep research and sleep medicine was made in the laboratory of a man whose focus was on the study of human sleep, University of Chicago Professor of Physiology Nathaniel Kleitman. Slow rolling eye movements during sleep had been described much earlier. Kleitman decided that this slow activity might be an excellent measure of the depth of sleep. He based this hypothesis on the somewhat disproportionately large areas of the brain devoted to the execution of eye movements and the demanding nuances of visual following and focusing. A graduate student in Kleitman’s department, Eugene Aserinksy, was put to work studying the aforementioned slow rolling eye movements during sleep. Initially, Aserinsky simply looked at the eyes of sleeping subjects (eg, direct visual observation). He soon came across the fact, however, of the existence of a corneoretinal potential difference with the cornea consistently about 70 mV positive to the retina. Aserinsky then concluded that eye movements could be recorded electrographically and proceeded to do so with the use of an ink-writing oscillograph. In the course of observing slow eye movements, Aserinsky occasionally saw what appeared to be electrical artifacts. In 1952, I was a sophomore medical student at the University of Chicago. I approached Kleitman and asked if I could work in his laboratory. He immediately gave me the assignment of helping Aserinsky. My somewhat tedious task was to sit by the bed of the sleeping subject (only one subject at a time was studied) and look at the eyes with a flashlight when Aserinsky saw the ‘‘electrical artifacts.’’ After a few observations, it became clear that the electrical artifacts were actually the changes in electropolarity as the eyeballs moved rapidly (very different from the previously described slow movements). Because the periods of eye movements were associated with an elevated heart rate, Kleitman wondered if they might represent dreaming. To test this notion, 20 normal men were used in several series of experiments. These observations [3] were subsequently published in 1953 and marked what some have said represents the true beginning of the modern era of sleep research and sleep medicine. Subjects were wakened when eye movement potentials appeared in the electrooculogram. In the original observations, rapid eye movements (REM) were not seen

in four of the subjects [3]. Nonetheless, when the occurrence and detail of dream recall reports from REM awakenings were compared with dream recall reports from awakenings when REM were not present, the differences were highly significant. In 1953, any interest in sleep by health professionals was engendered mainly by the theories of Sigmund Freud, specifically about the meaning of dreams. Accordingly, the interest was only in the phenomenon of dreaming, with sleep as the necessary background state. Freud’s work resulted in the creation of a clinical and scientific discipline known as ‘‘psychoanalysis,’’ and the technique of dream interpretation was a very important part of its therapeutic and theoretic approach to psychiatric problems. The discovery of an objective measure of dreaming was extremely interesting. Aserinsky’s initial observations described previously were performed using a four-channel ink writing oscillograph to record brain waves and eye movements, and because electroencephalogram (EEG) paper at the time was fairly expensive, sample recordings were made about every 10 or 15 minutes. No continuous all-night recordings were performed in the first wave of eye movement observations. My first independent study was performed at the Illinois Manteno State Hospital, in a special research ward that housed approximately 5000 chronic schizophrenics1. No antipsychotic medications were available at the time, but electroconvulsive shock therapy was occasionally used. Because Freud believed that dreams were the safety valve of the mind, it was hypothesized that for some reason this safety valve was not available in schizophrenics and dreaming erupted into the waking state giving rise to the symptomatology of psychosis. During the summer and fall of 1953, I studied 17 schizophrenics and 13 medical students. All had periods of REM during sleep [4]. Because of my intense interest in dreams and dreaming at the time, I decided to carry out a more complete description of all-night sleep by recording brain waves and eye movements continuously all through the night rather than sampling. To do this, a relatively slow paper speed was used but REM potentials were very easy to identify at any paper speed. One purpose was further to expand and quantify the description of these REM periods. During my junior and senior years in medical school, I performed a total of 126 all-night recordings on 33 subjects and, by means of a unique categorization of sleeping EEG patterns, scored the sleep

1 In 1983, I was driving from Chicago to southern Illinois on a route that took me past the Manteno State Hospital. Permission was given for me to visit the buildings and grounds. They were eerily deserted, but quite familiar, including the building that housed the sleep recordings.

History of Sleep Medicine

recordings in their entirety. When these 126 allnight records were examined, I found that there was a predictable sequence of patterns over the course of the night that had been hinted at in Aserinsky’s study but entirely overlooked in all previous EEG studies of sleep. Furthermore, all subjects without exception showed periods of REM [5]. Although this sequence of regular variations has now been observed thousands of times in hundreds of laboratories, the original description remains essentially unchanged. The following is from my chapter in the 4th edition of Principles and Practice of Sleep Medicine [6]. The usual sequence was that after the onset of sleep, the EEG progressed fairly rapidly to stage 4 (record dominated by high amplitude slow waves) which persisted for varying amounts of time generally about 30 minutes, and then a lightening of sleep indicated by EEG changes took place. Whereas the progression from wakefulness to stage 4 at the beginning of the cycle was almost invariable through a continuum of change, the lightening was usually abrupt and often coincided with a body movement or a series of body movements. After the termination of stage 4, there was generally a short period of stage 2 (low amplitude EEG with sleep spindles) or stage 3 which gave way to stage 1 and rapid eye movements. When the first eye movement period ended, the EEG again progressed through a continuum of change through stage 3 or 4, which persisted for a time and then lightened, often abruptly, with body movement to stage 2 which again gave way to stage 1 and the second rapid eye movement period. This cyclic variation of EEG patterns occurred repeatedly throughout the night at intervals of 90 to 100 minutes from the end of one eye movement period to the end of the next. The regular occurrences of REM periods and dreaming strongly suggested that dreams did not occur in response to chance disturbances.

Despite these observations, sleep was still considered to be a single organismic state of being. In our 1957 paper, Kleitman and I characterized the EEG during REM periods ‘‘as emergent stage 1 in contrast to descending stage 1 at the onset of sleep’’ [5]. The percentage of total sleep time occupied by REM periods was between 20% and 25%. The periods of REM tended to be shorter in the early cycles of the night. This typical pattern of all-night sleep has been seen over and over in normal humans of both genders in widely varying environments and cultures and across the lifespan. By the time I graduated from medical school, the data allowed me to assume that all male adults in the human population had a characteristic sleep architecture that consisted of alternating periods of REM sleep and non-REM sleep. The latter name was consistent with the much greater interest in

REM periods. Although it seemed unlikely, in the absence of data it remained a possibility that these REM periods did not occur in females. Accordingly, it was necessary to study at least one woman. Kleitman was somewhat reluctant to have a woman sleeping all night in his laboratory and insisted on having a chaperone. I recruited a chaperone, who came to Kleitman’s sleep laboratory on the same evening as the first female subject and promptly went to sleep on a cot in Kleitman’s office. The first female subject did indeed have periods of REM during sleep that were essentially the same as the male subjects. In 1955, Kleitman temporarily left the University of Chicago to spend a sabbatical leave in Europe. Alone in the sleep laboratory, I recorded several more females without a chaperone and satisfied myself that the characteristic sleep architecture was present in all human adults regardless of gender. Because of the corneal bulge, it is very easy to see the eyeballs rotate under the closed lids. It had been assumed that dreaming might not occur until several years after birth. It was also assumed that the ability of the human brain to experience the subjective world of dreaming was not necessarily a requirement for the occurrence of the REM. In 1956, I went to the newborn nursery at the University of Chicago Hospital and observed sleeping 1-day old infants. I saw the characteristic binocularly synchronous REMs enough times to assume that newborn sleep includes REM periods. In subsequent studies, Howard Roffwarg and I found that nearly 50% of the sleep time in newborns consisted of REM periods [7]. These observations have been subsequently confirmed by many others. Assuming that all human sleep contained REM periods, the next question was what about animals? In the Department of Physiology at the University of Chicago, research was being performed on cats. Although cats were somewhat unwilling to sleep under laboratory circumstances, enough observations were eventually accumulated to be certain that a state of sleep analogous to REM sleep in humans did occur with regularity in cats [8]. The technique of electrodes implanted directly into the brain of animals had been developed in 1956; my studies of sleep in cats used pins inserted into the scalp. When cats were awake, the recordings were dominated entirely by the electromyographic activity of the cats’ prominent temporal muscles. During periods of REM sleep, this electromyographic activity completely disappeared and the brain wave patterns were easy to observe. In addition, it was noteworthy that in these observations, the brain wave patterns during eye movement periods in the cat were essentially identical with EEG patterns recorded during wakefulness. These patterns were of low amplitude with higher

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frequencies. The assertion by me, however, that an ‘‘activated’’ EEG could be associated with unambiguous sleep was considered to be absurd. I must admit that I did not fully appreciate the significance of the absence of muscle potentials during the REM periods. It remained for the French scientist, Michel Jouvet, who began working in Lyon, France, in 1959 to insist on the importance of electromyographic suppression in his early studies [9], the first of which was published in 1959. I left Chicago in 1957 to take a post at the Mt. Sinai Medical Center in New York City. There I collaborated with others to study muscle activity during sleep. We monitored the electrically induced H reflex during sleep and found it to be completely suppressed in REM periods [10]. As the decade of the 1960s began, the concept of sleep as a single organismic state with different levels was giving way to the concept of the duality of sleep. In all other mammals that were studied in addition to humans, it was found that overall sleep consisted of two entirely different alternating organismic states: REM sleep and non-REM sleep. An enormous amount of data was accumulated supporting the duality concept; microelectrode studies of single neurons in the brain during sleep, more complex studies of motor atonia, and finally the seminal work of Jouvet and Mounier [11] showing that electrolytic lesions in the pontine reticular formation of the cat brain eliminated REM sleep, but left non-REM sleep intact. Sleep research, emphasizing all-night sleep recordings, burgeoned in the 1960s. This research was the legitimate precursor of sleep medicine and particularly of its core clinical test, polysomnography. Other than the early studies in schizophrenic patients at the Manteno State Hospital, very little interest in other clinical applications had been manifested until investigators noted a significantly shortened REM latency in association with endogenous depression. In the ensuing years, this phenomenon has been well investigated. Other important harbingers of sleep medicine were the following: (1) the observation of sleep-onset REM periods in individuals afflicted with narcolepsy, (2) an interest in epileptic seizures during sleep, and (3) sleep studies to evaluate benzodiazepine medications for the treatment of insomnia. The latter application represents the first time the sleep laboratory and all-night polysomnography were used as part of efficacy protocols to evaluate sedative hypnotics. In 1959, my colleague at the Mt. Sinai Hospital, Dr. Charles Fisher, saw a patient who was referred with the diagnosis of narcolepsy. At Fisher’s suggestion, I arranged to record all-night sleep in this patient. Within several seconds after the patient fell

asleep, he was showing the dramatically characteristic REM sleep and electromyographic suppression. Simultaneously, observations were performed on a single patient by Vogel [12] at the University of Chicago, the results of which were published in 1960. In a subsequent collaborative study between the University of Chicago and the Mt. Sinai Hospital, nine patients underwent all-night sleep recordings and the important sleep-onset REM periods were described and reported in a 1963 publication [13]. It is noteworthy that patients were diagnosed with narcolepsy when they showed a characteristic set of symptoms reported in 1880 by Gelineau (sleep attacks, hypnagogic hallucinations, sleep paralysis, and cataplexy). The latter term was applied to sudden attacks of muscular atonia experienced by the narcoleptic patients usually precipitated by strong emotion. Subsequent studies showed that sleepy patients who did not report having attacks of cataplexy also did not show sleep-onset REM periods. Conversely, sleepy individuals who reported the occurrence of attacks of cataplexy always had sleep-onset REM periods. It was clear that the best explanation for the strange attacks of muscle atonia was the normal motor inhibitory mechanism of REM sleep occurring in a precocious or abnormal manner [14]. Most of the aforementioned research was performed after I moved to Stanford University in January 1963. My plans to carry out this research were initially hampered by the fact that not a single narcoleptic patient could be identified at the Stanford University Medical Center. Finally, in desperation, I placed an advertisement in the local daily newspaper. More than 100 people responded! About 50 of these respondents were bona fide narcoleptics having daytime sleepiness and cataplexy and hypnagogic hallucinations and sleep paralysis. The response to this advertisement was a seminal event in the future development of sleep disorders medicine. None of the narcoleptics had been previously diagnosed and I was forced to assume responsibility for their clinical management for them to participate in the research project. As the months passed, I and a research colleague became responsible for managing and taking care of over 100 individuals with narcolepsy. Mostly this involved visiting with the patients at regular intervals and adjusting their medications, which consisted mainly of methylphenidate or dextroamphetamine. Providing this patient care was the harbinger of the modern sleep disorders clinic. I was managing sleep disorders patients and in addition performing diagnostic recordings to demonstrate the pathognomonic sleep-onset REM periods. In 1964, I formally launched the Stanford University Narcolepsy Clinic. It was set up as a true fee-for-service

History of Sleep Medicine

enterprise. Most of the patients were unable to pay their bills, however, and insurance companies denied payment because the diagnostic recordings of narcolepsy patients were deemed ‘‘experimental.’’ Accordingly, this unique clinic was closed because of financial bankruptcy. One of the most important landmarks in the history of sleep disorders medicine occurred in Europe around this time. Obstructive sleep apnea was discovered independently by Gastaut, Tassinari, and Duron in France and by Jung and Kuhlo in Germany. Both groups reported their findings in 1965. Scholars have found hints in earlier works, even biblical, that suggest obstructive sleep apnea was being described. The aforementioned European reports, however, were the first clear-cut recognition and description that had a direct continuity to sleep disorders medicine as it is known today. There is no evidence that the pulmonary medicine community in the United States understood the importance of these European reports. What should have been an almost inevitable discovery by the pulmonary medicine community or perhaps by the ear-nose-throat surgery community did not occur because there was no interest in either specialty for meticulously observing respiration during sleep. The well-known and frequently cited study of Burwell and colleagues [15], although impressive in a literary sense in its evoking of the somnolent boy Joe from the Papers of the Pickwick Club by Charles Dickens, erred badly in attributing the somnolence of their obese patients to hypercapnea. The frequent citing of this paper further reduced the likelihood that sleep apnea would be discovered by the pulmonary medicine community. To this day, evidence that hypercapnea causes true somnolence is completely lacking, although high levels of PCO2 are certainly associated with impaired cerebral function. Nonetheless, the term ‘‘pickwickian syndrome’’ became an instant neologistic success and may have played a role in stimulating an interest in this syndrome by the European neurologists who were also interested in sleep. In the 1960s, a small group of French neurologists began specializing in clinical neurophysiology and electroencephalography. An individual trained in France, Alberto Tassinari, joined the Italian neurologist Elio Lugaresi, in Bologna. These scientists then performed a crucial series of clinical sleep investigations that provided a complete description of the sleep apnea syndrome including the first observations of the occurrence of sleep apnea in nonobese patients, a description of the cardiovascular correlates, and a clear identification of the importance of snoring and hypersomnolence as diagnostic indicators. These pioneering studies are recounted in Lugaresi’s book, Hypersomnia with

Periodic Apneas [16]. Henri Gastaut and Elio Lugaresi were prompted to organize an international symposium in 1967, the proceedings of which were published as Abnormalities of Sleep in Man. These proceedings encompassed issues across a full range of pathologic sleep in humans. The meeting took place in Bologna and the papers presented covered many of what are now major topics in the sleep medicine field: insomnia, sleep apnea, narcolepsy, and periodic leg movements during sleep. It was an epochal meeting from the point of view of the clinical investigation of sleep. The only major issues not represented were clear concepts of clinical practice models and accurate estimates of the high population prevalence of sleep disorders. The event, however, finally triggered a serious international interest in sleep apnea syndromes. Another extremely important meeting was organized by Lugaresi in 1972. An account of this meeting is included in Lugaresi’s 1978 book [16]. Despite all the laudatory clinical research, the concept of the all-night sleep recording as a clinical diagnostic test did not occur. An all-night diagnostic test, particularly if it was conducted on out-patients, was completely unprecedented. In addition, the cost of all-night polysomnographic recording was already quite high without adding the cost of hospitalization, although the latter would have legitimized a patient spending the entire night in a testing facility. It should also be clear that in 1970, only a tiny number of people understood that the complaint of daytime sleepiness represented something that had clinical significance. Even narcolepsy, which had been fully characterized as an interesting and disabling clinical syndrome, was not recognized as such in the larger medical community. The extreme neglect of patients with narcolepsy (we documented a mean of 15 years from onset of the characteristic symptoms of narcolepsy until recognition and accurate diagnosis by a clinician, and patients having seen a mean of 5.5 different physicians during the 15 years), however, well justified creating a medical specialty dedicated to such patients. The evaluation of efficacy in the development of sedative hypnotics had quite reasonably begun to include all-night sleep recordings. When a pharmaceutical company wanted to evaluate a new hypnotic compound, it was necessary to recruit volunteer subjects for the research who manifested objective signs of insomnia. Recruiting insomniacs typically involved giving clinical advice and staying in touch. For these reasons, it became obvious to me early in 1970 that there needed to be a new clinical discipline that specialized in the diagnosis and treatment of individuals afflicted with one or other

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of the then known sleep disorders. In the summer of 1970, with as much fanfare as we could muster, we announced the opening of the Stanford University Sleep Disorders Clinic and organized a press conference to publicize this event. Only one reporter attended the press conference, and he turned out to be more interested in the issue of whether or not children should sleep with their parents. In the early months and probably the first year or so of the existence of the Stanford University Sleep Disorders Clinic, there were very few referrals from community physicians. For quite some time, we were unable to achieve more than five or six referrals per week. The all-night diagnostic sleep recordings were done on the side by technologists who at the time were funded by research projects. I and my sleep colleague, Dr. Vincent Zarcone, were also paid largely by research grants. One of the current giants of sleep medicine, Dr. Christian Guilleminault, a French neurologist and psychiatrist, had come to the sleep center as a research fellow and was doing basic research in the summer of 1970. He returned to France later in the year. Because most of our patients in the early days turned out to be afflicted with narcolepsy, we believed in the need to have a neurologist on the clinical staff. In the summer of 1971, Dr. Zarcone and I recruited Dr. Guilleminault to return to Stanford, which he did, arriving in January of 1972. Until his arrival, the Stanford group had not routinely used respiratory and cardiac sensors in their all-night sleep studies. Beginning in 1972, these measurements became a routine part of the all-night diagnostic test, which was finally dubbed ‘‘polysomnography’’ in 1974. During 1972, the search for sleep abnormalities in patients with sleep-related complaints continued. We also attempted to conceptualize the pathophysiologic process as both an entity and as the cause of the presenting symptom. With this approach, a number of phenomena seen during sleep were rapidly linked to the fundamental sleeprelated presenting complaints. Toward the end of 1972, the basic concepts and protocols of sleep disorders medicine were sculpted sufficiently to offer a day-long course through Stanford University’s Division of Postgraduate Medicine. This course was offered under the title ‘‘The Diagnosis and Treatment of Sleep Disorders.’’ The topics covered were normal sleep architecture; the diagnosis and treatment of insomnia with drug-dependent insomnia, pseudoinsomnia, central sleep apnea, and periodic leg movement as diagnostic entities; and the diagnosis and treatment of excessive daytime sleepiness or hypersomnia with narcolepsy, non-REM narcolepsy, and obstructive sleep apnea as diagnostic entities.

Professional organizations In 1964, the Stanford University Sleep Research Program hosted the fourth annual meeting of persons interested in sleep research. This was still somewhat informal, but before the occasion a small group met with the idea of creating some sort of professional organization. The first suggestion for the name of such an organization was the Association for the Study of Sleep, until someone noticed the acronym. Finally, because of the interest in both the physiology of sleep and the phenomenon of dreaming, it was agreed that the organization should be named the Association for the Psychophysiological Study of Sleep (APSS). Every since, there have been annual meetings of the APSS without exception. By 1975, there were five centers diagnosing and treating patients with sleep-related complaints. Following the launching of the Stanford University Sleep Disorders Clinic, the second such clinic was initiated by the late Dr. Elliot Weitzman who spent a sabbatical year, 1974 to 1975, at Stanford. In a 1976 meeting at O’Hare Airport in Chicago, the Association of Sleep Disorders Centers (ASDC) was formally organized. The charter members were from medical schools at Stanford, Montefiore, Baylor, Cincinnati, and Pittsburgh. The APSS continued to meet annually, and at a certain point the issue of sponsoring a scientific journal arose. The journal Sleep was sponsored jointly by the APSS, the European Society for Sleep Research, and the ASDC. The first issue appeared in September 1978. Because the sleep disorders discipline was clearly established and growing, the first president of the ASDC and secretary began to think about achieving more notice from the National Institutes of Health and some support from the US Congress. In a first visit to Washington, Dr. Merrill Mitler encountered a Washington lobbyist, Mr. Harley Dirks, who had been chief of staff for the Chairman of the Senate Appropriations Committee. After leaving his congressional position, Mr. Dirks established the Health and Medicine Council of Washington, which is now headed by his son, Mr. Dale Dirks. In 1986, to increase the lobbying clout of the sleep organizations, it was decided to meld them into one overall organization. This entailed the difficulty that two of the organizations consisted of individual members, whereas the third consisted of member centers. A fourth organization was temporarily created called the Clinical Sleep Society to facilitate this process and after several organizing meetings, the Association of Professional Sleep Societies came into being. There was, however, a problem with leadership and finances such that the

History of Sleep Medicine

organizations almost immediately separated into a loose coalition renamed the Associated Professional Sleep Societies. I was elected president of the ASDC for four consecutive 3-year terms, after which it was decided that a 1-year presidency would suffice and more managerial responsibility should devolve to the Executive Director. The first formal national office of the APSS and what is now the American Academy of Sleep Medicine was located in Rochester, Minnesota; it was later moved to a less out of the way location in Westbrook, Illinois, a suburb of Chicago. A fourth professional society came into being in 1991 to serve the interests of dentists, called the Academy of Dental Sleep Medicine. In addition, under the aegis of the American Academy of Sleep Medicine, several tax exempt foundations were formed. The first examination by what is now the American Board of Sleep Medicine was administered in 1977. Today, there are more than 7000 individual members of the professional sleep societies, more than 1400 accredited sleep disorder centers, and more than 10 scientific journals around the world devoted to sleep disorders, sleep research, and biologic rhythms.

Complications of obstructive sleep apnea The disability and cardiovascular complications of severe obstructive sleep apnea are very serious. In the early years of sleep medicine, treatment options were limited to weight loss and chronic tracheostomy. Chronic tracheotomy dramatically ameliorated the symptoms and complications of the illness. Many patients with severe obstructive sleep apnea, however, nonetheless strongly resisted being treated by means of chronic tracheostomy. In addition, the broader medical community was extremely skeptical about the use of chronic tracheostomy mainly because of ignorance about the sleep disorders field. Securing the proper management was a major challenge, as illustrated by the case history of one of the first patients referred to the Stanford Clinic, a 10-year-old boy, Raymond M. The overall difficulties are illustrated in a personal account by Dr. Christian Guilleminault. Raymond M. was a 10 1⁄2 -year-old boy referred to the pediatrics clinic in 1971 for evaluation of unexplained hypertension which had developed progressively over the preceding 6 months. There was a positive family history of high blood pressure, but never so early in life. Raymond was hospitalized and had determination of renin, angiotensin, and aldosterone, renal function studies including contrast radiographs, and extensive cardiac evaluation. All results had been normal except that his blood pressure oscillated between 140-170/90-100.

It was noticed that he was somnolent during the daytime and Dr. S. suggested that I see him for this ‘unrelated’ symptom. I reviewed Raymond’s history with his mother. Raymond had been abnormally sleepy ‘all his life.’ However, during the past two to three years, his schoolteachers were complaining that he would fall asleep in class and was at times a ‘behavioral problem’—not paying attention, hyperactive, and aggressive. His mother confirmed that he had been a very loud snorer since he was very young, at least since age two, perhaps before. Physical examination revealed an obese boy with a short neck and a very narrow airway. I recommended a sleep evaluation which was accepted. An esophageal balloon and measurement of end tidal CO2 was added to the usual array. His esophageal pressure reached 80 to 120 cm H2O, he had values of 6% end tidal CO2, apneic events lasted between 25 and 65 sec, and the apnea index was 55. His SaO2 [arterial oxygen saturation] was frequently below 60%. I called the pediatric resident and informed him that the sleep problem was serious. I also suggested that the sleep problem might be the cause of the as yet unexplained hypertension. The resident could not make sense of my information and passed it to the attending physician. I was finally asked to present my findings at the weekly pediatric case conference which was led by Dr. S. I came with the recordings, showed the results, and explained why I believed that there was a relationship between the hypertension and the sleep problem. There were a lot of questions. They simply could not believe it. I was asked what treatment I would recommend, and I suggested a tracheostomy. I was asked how many patients had this treatment in the United States, and how many children had ever been treated with tracheostomy. When I had to answer ‘zero’ to both questions, the audience was somewhat shocked. It was decided that such an approach was doubtful at best, and completely unacceptable in a child. However, they did concede that if no improvement was achieved by medical management, Raymond would be reinvestigated, including sleep studies. This was Spring 1972. In the Fall, he was, if anything, worse in spite of vigorous medical treatment. At the end of 1972, Raymond finally had his tracheostomy. His blood pressure went down to 90/60 within 10 days, and he was no longer sleepy. During the five years we were able to follow Raymond, he remained normotensive and alert, but I had to fight continuously to prevent outside doctors from closing his tracheostomy. I don’t know what happened to him since.

Discipline identity and discipline overlap In July of 1981 I wrote a note for the ASDC newsletter. The title was ‘‘Does Somnology (a.k.a Sleep

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Medicine) Exist?’’ It was patterned after an analogous discussion titled ‘‘Does Gerontonology Exist?’’, which appeared elsewhere. A dozen criteria defining the existence of a clinical scientific discipline were posed. They were paraphrased by me and answered. In 1981, the title of someone who practiced sleep medicine was ‘‘clinical polysomnographer,’’ a name of which no one was particularly fond. The criteria are presented below, slightly updated for this article. 1. Does clinical polysomnography and sleep research have the broad academic organization to provide career lines for teachers and researchers? No. Tenured appointments are controlled by departments. As far as I know, no medicinal school has a department of sleep medicine. 2. Does society provide support for sleep research? Although there are a fair number of federal grants for sleep research, they are not easy to obtain. Certainly, there is no official large government mandate for such funding. There is, however, a small Center for Sleep Disorders Research (2 FTEs) in the National Heart, Lung, and Blood Institute. 3. Is there a student demand for courses? Although the need is great, the demand is small. It is increasing, however, as are applications to sleep centers for postgraduate training. 4. Is there a demand for graduates? Yes, definitely. Many institutions interested in starting sleep disorders centers need trained and experienced sleep specialists to serve as medical directors; the dearth of well-trained people actually hampers development of the field. Questions five through seven concern a would-be discipline’s relation to its subject matter. 5. Does sleep research study some distinct part of nature? Yes. Sleep research is concerned with the sleeping organism, the determinants of sleep, the mechanisms of sleep, the circadian rhythm of sleep and wakefulness and its determinants, the role of sleep in waking function, and the pathology of all systems and mechanisms responsible for the sleep-wake cycle. Certainly, sleep research overlaps with other disciplines. Sleep-induced respiratory disturbances concern pulmonary specialists. Many sleep disorders have significant hemodynamic impact, of interest to cardiologists. Hypersomnia is still considered to be a neurologic problem. Sleep research provides the umbrella or the forum in which professionals from different areas can share their findings and forge new diagnostic and therapeutic approaches. 6. Is there at least a social group to be studied? Not applicable.

7. Is there at minimum a social problem to be studied? Not applicable unless it is the impact of waking sleepiness in all components of society. The last set of questions concerns the internal criteria or maturity of the discipline. 8. Does the work of sleep researchers share a unique method? Certainly. Polysomnography, sleep scoring, characterization of sleep patterns, and sleep deprivation studies all are good examples of approaches unique to the field. 9. Does sleep research have a theory? Yes. Although there are many questions as yet unanswered, several models have been developed that generate testable hypotheses. 10. Can the knowledge of the field be linked in an integrated whole? The answer is now ‘‘yes.’’ Although there is minor disagreement about what might be regarded as common knowledge within the discipline, there are now several textbooks. 11. Do scholars, teachers, and practitioners find it useful to share interaction? As with any field investigating widespread and serious medical disorders, the answer to this question is an unqualified ‘‘yes.’’ The overall answer to these questions is ‘‘yes.’’ Clearly, sleep research qualifies as a full-fledged academic discipline concerned with, for example, physiology during sleep, sleep mechanisms, state regulation and sequencing in the organism, chronobiology as it relates to sleep and wakefulness rhythms, sleepiness and alertness and related variables, and the diagnosis and treatment of pathologies in all of these areas. Unlike many newcomers to the medical mainstream, sleep medicine is not the child of a single parent discipline. Rather, clinical and basic sleep research have been the foster children of many disciplines but have been the favored children of none. In the early days, we were passed from hand to hand as then current findings had practical significance for other specialties. Early research on REM deprivation provided models for psychosis and depression. Sleep apnea syndromes, sleep-induced gastroesophageal reflux with secondary laryngospasm, and general sleep-related respiratory load increase have intrigued those in pulmonary medicine. REM sleep-related penile tumescence is of great diagnostic value to urologists in the study of impotence. Pediatricians work with sleep specialists to unravel sudden infant death syndrome and the impact of sleep disturbances on normal development. REM sleep muscle inhibition and sleeprelated changes in the balance of the autonomic and parasympathetic nervous system concern practitioners caring for patients already compromised

History of Sleep Medicine

(eg, those with poliomyelitis, familial dysautonomia, muscular dystrophy, diabetes, and so forth). Those concerned with biologic rhythms share an interest in the important circadian rhythms of sleep and wakefulness.

Minimal penetration of the mainstream educational system The clinical scientific discipline of sleep medicine has not yet been widely embraced by academic medicine. Although such surveys are difficult, it is likely that there are fewer than five tenured professorships in American medical schools designated specifically for sleep research and sleep medicine. There does not exist in any medical school a department of sleep medicine. There are, however, at least a few divisions of sleep medicine, eg, at Harvard University in the Department of Medicine, at the University of Pennsylvania in the Department of Medicine, at Stanford University in the Department of Psychiatry, and at the University of Michigan in the Department of Neurology. An unsuccessful proposal was made by one medical school to establish a division in its department of ear, nose, and throat surgery. At the undergraduate level, there is very little systematic teaching about sleep knowledge, circadian rhythms, dreaming, and sleep disorders in the nearly 4000 colleges and universities. In a very recent survey of Stanford undergraduates, fewer than 2% had received systematic teaching about sleep before matriculating. The first sleep disorders clinic did not exist before 1970 and until the invention of continuous positive airway pressure for the treatment of sleep apnea, the standard treatment using chronic tracheostomy posed a major obstacle to the rapid expansion of the diagnosis and treatment of sleep apnea. The discipline of sleep medicine did not become truly viable until the 1980s. Unfortunately, clinicians have now reached a time when expansion and growth in many components of society has flattened or slowed. The number of medical schools in America today is essentially the same as it was four decades ago, and no undergraduate department of psychology or human biology offers a well-organized and complete teaching program involving the sleep-related disciplines.

Final thoughts The need for an effective societal understanding of sleep-related issues is great and urgent. It is possible that the entire human race has not achieved its full behavioral and intellectual capacity because of chronic sleep deprivation and the accumulation of

sleep debt. Extrapolating from the report by Young and coworkers [17] in 1993, there are at least 30 million victims of obstructive sleep apnea in the United States. It is not inconceivable that new cases are developing at a rate that is higher than the rate of cases that are identified and effectively treated. The complaint of insomnia is extremely widespread and the underlying causes are reasonably well characterized. Sleep medicine in all its ramifications is a field that should take its destiny into its own hands as much as possible. We must penetrate the educational system. We must prevail on elected representatives to do more for the field both at the national and the state levels. If both patients and sleep professionals can be mobilized, the numbers are there to achieve many things. There are still far too many sleep-related accidents, far too many undiagnosed and untreated victims of sleep disorders, and many individuals continue to organize their lives based more on mythologic beliefs than the true facts of sleep and wakefulness.

References [1] Shepard J, Buysse D, Chesson A, et al. History of the development of sleep medicine in the United States. J Clin Sleep Med 2005;1:61–82. [2] Dement W, Vaughan C. Promise of sleep. New York: Delacorte Press, Random House Inc.; 1999. [3] Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science 1953;118:273–4. [4] Dement W. Dream recall and eye movements during sleep in schizophrenics and normals. J Nerv Ment Dis 1955;122:263–9. [5] Dement W, Kleitman N. Cyclic variations in EEG during sleep and their relation to eye movements, body motility, and dreaming. Electroencephalogr Clin Neurophysiol 1957;9:673–90. [6] Kryger M, Roth T, Dement W. Principles and practice of sleep medicine. Philadelphia: WB Saunders Co.; 1994. [7] Roffwarg H, Muzio J, Dement W. Ontogenetic development of the human sleep-dream cycle. Science 1966;152:604–19. [8] Dement W. The occurrence of low voltage, fast, electroencephalogram patterns during behavioral sleep in the cat. Electroencephalogr Clin Neurophysiol 1958;10:291–6. [9] Jouvet M, Michel F, Courjon J. Sur un stade d’activite electrique cerebrale rapide au cours du sommeil physiologique. C R Seances Soc Biol Fil 1959;153:1024–8 [in French]. [10] Hodes R, Dement W. Depression of electrically induced reflexes (H-reflexes) in man during low voltage EEG sleep. Electroencephalogr Clin Neurophysiol 1964;17:617–29. [11] Jouvet M, Mounier D. Effects des lesions de la formation reticulaire pontique sur le sommeil

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du chat. C R Seances Soc Biol Fil 1960;154: 2301–5 [in French]. [12] Vogel G. Studies in psychophysiology of dreams. III: The dream of narcolepsy. Arch Gen Psychiatry 1960;3:421–8. [13] Rechtschaffen A, Wolpert E, Dement W, et al. Nocturnal sleep of narcoleptics. Electroencephalogr Clin Neurophysiol 1963;15:599–609. [14] Dement W, Rechtschaffen A, Gulevich G. The nature of the narcoleptic sleep attack. Neurology 1966;16:18–33.

[15] Burwell CS, Robin ED, Whaley RD, et al. Extreme obesity associated with alveolar hypoventilation: a pickwickian syndrome. Am J Med 1956;21: 811–8. [16] Lugaresi E, Coccagna G, Mantovani M. Hypersomnia with periodic apneas. New York: Spectrum; 1978. [17] Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328: 1230–5.

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The Contribution of the Psychology of Sleep and Dreaming to Understanding Sleep-Disordered Patients Rosalind Cartwright, -

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A brief history The first twenty years The focus on sleep disorders Current theories of dreaming and the psychology of sleep circa 2007 Non–rapid eye movement parasomnia: sleepwalking What makes a sleepwalker walk? Sleepwalking in obstructive sleep apnea

This article reviews the major psychologic functions occurring during sleep and the evidence that patients who present with disorders of sleep have specific psychologic dysfunctions related to the type and degree of their sleep disturbance. Although there are individual differences in the degree to which people are aware of sleep thoughts and dreams, mental activity is actually continuous throughout the waking, sleeping, and dreaming cycles. The neurologic mechanism responsible for this is the cooperation recently identified between the slow wave sleep (SWS) of the first hour and the following rapid eye movement (REM) sleep. As sleep begins, the neural networks that were activated during the waking experience are reactivated and remain active until REM sleep occurs. At that point, the coded representation of that experience is matched to similar older memories, and this combination is displayed as a dream. This is the explanation of how normal sleep is basic to

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Rapid eye movement parasomnia: nightmares Dream enactment in rapid eye movement behavior disorder Major depression Summary Future research References

‘‘learning’’ the overnight improvement in mood and performance. The organization of new experience, and retention of it in long-term memory, allows waking behavior to be more adaptive. The selection of which experiences are to be saved relates to their emotional relevance to the selfsystem. The replay of these initiates a hippocampal-neocortical dialog during which negative emotion, generated in response to experience that challenges the sense of self, is downregulated in an across-the-night, sequential processing. If there is a persistent sleep disorder the learning process and mood regulation process is less efficient or stopped altogether. The study of sleep disorders provides insights into this regular nocturnal updating of the self-program, and of the specific psychologic effects of interrupted sleep or abnormalities in the timing of the cycles. The application of these findings to understanding and treating these patients is discussed.

Department of Behavioral Sciences, Rush University Medical Center, 1653 West Congress Parkway, Chicago, IL 60612, USA E-mail address: [email protected] 1556-407X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

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A brief history Academic psychology did not recognize dreaming as a legitimate area of study until the early 1950s, when publications from Kleitman’s laboratory announced there is a regularly occurring active brain state in sleep, dubbed ‘‘rapid eye movement’’ sleep, which is a reliable indicator of when a distinctive type of mental behavior, dreaming, is ongoing [1,2]. A way was opened to access the psychology of sleep on-line. At that time psychology was still struggling to be recognized as an independent empiric science devoted to the understanding of human behavior through the methods of hypothesis testing and controls. As a new science, psychology staked out the areas that defined its turf: learning and memory, motivation, and emotion. The idea that these basic aspects of behavior were also operating during sleep, or that they were affected by sleep, was not then considered credible. After all, the sleeper was unconscious and experimental psychologists could neither observe their mental activity directly, nor could they rely on the sleepers’ morning memory to be a reliable data source. As a result, the formal study of psychology, with few exceptions, ignored the 8 hours of sleep until the methods of sleep recording made this investigation scientifically feasible. Freud’s Interpretation of Dreams [3], originally published in 1900, called attention to the importance of the unconscious as a strong influence on the motives that drive behavior and the accompanying emotions. Freud not only illustrated the many ways the unconscious plays a role in waking behavior, but he pointed to dreaming as the path by which one could tap into this important information [3]. Armed with the guidepost of the strong correlation between REM sleep and dreaming, psychologists set out to test the validity of Freud’s premise, that adding information from dreaming enhances one’s understanding of human behavior and why it is that even some smart people do not ‘‘learn from experience’’ and continue to make self-destructive behavior choices.

The first twenty years Despite the drawbacks of the unnatural situation of sleeping in a laboratory, early studies of dreaming managed to address important questions: At what age does the child begin to dream and how does that relate to their waking cognitive development? [4]; Are dreams the normal equivalent of the hallucinations of psychosis? [5]; Do dreams have inherent meaning or is this added to random images as an awakening takes place [6]; Do dreams tell a connected story from REM to REM across the night?

[7]; Why do some dreams repeat over and over? [8]. Some of the more difficult questions addressing the major topics of psychology (what is the role of sleep in learning, memory, and motivation; and is sleep a place where emotion is regulated [9]) remained controversial and only recently have been addressed with more advanced methodology.

The focus on sleep disorders Something else occurred to divert psychologists from the basic studies. The years 1975 to 2000 saw the emphasis shift from research into the nature and function of normal sleep to that of pathology. That in turn led to the advent of specialized clinical facilities to diagnose and treat those whose sleep was dysfunctional. This development resulted in a tremendous increase in public awareness of the role of sleep in both physical and mental health and an expansion of the disciplines involved in the applied area of clinical sleep medicine [10]. Studies of the mind were left behind; the very existence of mind was denied. It was deemed a fuzzy concept no longer necessary in the age of brain imaging. Some clinical research on the psychologic aspects of sleep and dreaming continued, however, and is now ready to be integrated to better the understanding and treatment of patients who present with problems of sleep.

Current theories of dreaming and the psychology of sleep circa 2007 Although early studies had noted that there was some mental activity that could be retrieved from sleep onset and in sleep stages other than REM [11], most of the research of the first 50 years was focused on REM-related dreaming. This article begins with the legacy from that work, the consensus on one major dream function, before moving to the newer view of the influence of waking states of mind on the mental activity of non-REM (NREM) sleep and on the following dream production in REM and the effect of sleep on tomorrow’s behavior, the full 24-hour perspective on continuous mental activity. Many of the research-based investigators of dreaming [12–17] all place emotion as the key to understanding dreams and their relation to why one generally feels better in the morning. This is referred to as the ‘‘mood regulatory function of dreaming.’’ Hartmann [13] states: ‘‘overall dreaming makes connections more broadly than waking in nets of the mind, and the connections are not made randomly but guided by the dreamer’s emotional concerns.’’ Breger [14] links presleep emotion to postsleep waking adaptation: ‘‘(dreaming) serves

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a unique function in the assimilation and mastery of aroused material into the solutions embedded in existing memory systems.’’ From my own research [17] I have concluded that ‘‘dreaming has an active self-regulatory role in emotional modulation.’’ How this self-regulating dream function adds to an understanding of four sleep disorders is explored next: sleepwalking (an NREM parasomnia); nightmares and dream enactment (both are REM parasomnias); and major depression (insomnia associated with a mental disorder). These illustrate how specific deficits in the integrity of sleep relate to failures to regulate mood and to change behavior. Fig. 1 is a model of mental activity throughout night, drawn from reports from normal volunteers awakened in various sleep stages at different times of the night. Freud identified three parallel levels of ongoing mental activity: (1) conscious, (2) preconscious, and (3) unconscious. If one superimposes the results from awakening studies, the model predicts that aspects of the presleep waking thoughts (level 1) are picked up and mingled with the longer-term preconscious emotional concerns of the sleeper (level 2). The mental activity retrieved from the first NREM episode depends on the strength of the emotion evoked in waking and carried into sleep by the reactivation mechanism. As REM sleep is turned on, this activation is ‘‘mapped onto previously stored memories’’ (level 3), matched to a neocortical network with similar feelings. As the first REM period ends and NREM sleep is resumed, some memory bits continue to be carried forward into the next NREM sleep. This process continues throughout the night. The evidence supporting this continuity model has recently been summarized by Ribeiro and Nicolelis [18] and Giuditta and coworkers [19] and is next examined as it applies in several sleep disorders.

Non–rapid eye movement parasomnia: sleepwalking The continuation of motives and emotions from waking into the first cycle of SWS can be seen

most clearly in the behavior of adult sleepwalkers. This disorder has been difficult to study in the laboratory because of its unpredictability and lack of any distinctive marker of its presence using the standard sleep stage scoring of the polysomnogram (PSG) [20]. What is well established is that the sleepwalker is not acting out a dream. The walk actually begins with an abrupt arousal out of SWS in the first third of the night, not out of REM sleep [21]. Nor can the patient clarify why they were doing what they did, because they have little or no memory of the event. At best they report a sense of urgency. Although this disorder is relatively common in young children with an equal prevalence in both genders, the frequency of these episodes wanes or stops all together during adolescence as SWS is reduced in amount and in the amplitude of the delta waves. There can be a resurgence of this disorder in young adulthood under certain conditions, however, and when it does the prevalence is much higher in males.

What makes a sleepwalker walk? The strongest predisposing factor is genetics. Those with a family tree loaded with many relatives affected with sleepwalking or sleep terrors are at increased risk for this disorder [22]. Twin studies in Sweden [23] find that monozygotic twins are concordant for sleepwalking at six times the rate of dyzygotic twins. Genetic testing by HLA typing shows sleepwalkers more often display a DQB1 marker than do controls [24], although this marker is also found in those affected by narcolepsy and REM behavior disorder. All three of these disorders have in common some motor control dysfunction. More promising is new evidence that scoring the PSG by spectral analysis for the presence of delta frequency activity rather than by the usual sleep stage criteria finds sleepwalkers differ from controls in having less delta activity at the beginning of the night [25–27]. Fig. 2 shows the reduced delta activity in the first sleep cycle of sleepwalkers compared Fig. 1. R. Cartwright graph.

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Fig. 2. The reduced delta activity in the first sleep cycle of sleepwalkers compared with controls. (From Guilleminault C, Poyares D, Abat F, et al. Sleep and wakefulness in somnambulism: a spectral analysis study. J Psychosom Res 2001;51:411–16; with permission.)

with controls [25]. Another feature of the PSG is that sleepwalkers have multiple arousals from delta sleep in the first two sleep cycles, making this sleep time very unstable. An episode of adult sleepwalking typically begins with an abrupt arousal during this unstable first hour of sleep, when the brain is simultaneously partially asleep and partially awake. One imaging study caught a 16-year-old habitual sleepwalker shortly after he had a behavioral arousal during a PSG study [28]. The single-photon emission CT showed a 25% increase in blood flow in the posterior cingulate cortex and decreases in the frontoparietal cortices. In this mixed state, a sleepwalker is able to perform complex motor behaviors, including driving a car sometimes for long distances, but is not able to recognize faces, even those of loved ones. This suggests that the area of the brain identified with face recognition, the fusiform gyrus, is not active [29]. Once an episode is over, which may take as long as an hour, the sleepwalker typically returns to sleep spontaneously, although this may be in a strange or even dangerous location. If startled by a touch or sound while in this state a sleepwalker may become swiftly aggressive, however, behaving as if they are in a fight or flight survival mode. In a large epidemiologic study the rate of those adults reporting that they currently have episodes of aggressive sleepwalking was 2.1%, much higher than expected [30]. These vary in severity from benign to lethal, such as jumping out a window or thrusting an arm through a glass door. There are many behaviors other than aggression that have been recently reported performed without

conscious awareness, or any later memory, following an arousal from SWS within the first 3 hours of sleep. Some sleepwalkers eat, and even prepare food; often these are strange combinations of foods, such as raw bacon with chocolate bar sandwiches. Others attempt to rescue someone from an imaginary danger, such as pulling their wife out of bed because the mattress is thought to be on fire. Recently, there have been patients who have presented because of inappropriate sexual behavior, such as lying on top of a sleeping child. Exploring new territory is another sleepwalking behavior, as it was in the 15 year old who climbed a 130-foot crane. All of these are instances of basic motives necessary for our survival: eating, procreating, fighting or fleeing in response to danger, protecting the family, and exploring new territory. All show these remain active during SWS, the realm of the unconscious. If not for the arousal that aborts the transmission into REM, the activation of these drives would most likely be expressed in dream imagery and down-regulated by morning. In addition to a genetic predisposition, it takes added factors for an overt episode of sleepwalking to occur. The most powerful of these is sleep deprivation. When a genetically vulnerable person has inadequate amounts of sleep over an extended period of weeks, because of either an internal or external arousing stimulus, sleepwalking is highly likely to occur. Sleep deprivation increases the drive for more SWS. Recently this has been used to stimulate sleepwalking under laboratory conditions. The study required both sleepwalkers and controls to undergo 25 hours of sleep deprivation before

The Contribution of the Psychology of Sleep and Dreaming

a PSG test. All the sleepwalkers had one or more episodes, whereas none occurred in the controls [31]. Under home sleep conditions, the degree of sleep loss patients report having before a sleepwalking episode occurs is usually more chronic. This protocol, a combination of acute sleep deprivation beforehand, videotaping of any events during the sleep study, and power density scoring of the PSG, can now be used to confirm this diagnosis in the laboratory. This will be important in future forensic cases when sleepwalking is invoked by the defense in the case of a serious assault. In one such case, which received widespread media attention [32], PSG studies were ordered by the court, but were conducted before the publication of the work showing the usefulness of power density scoring and the triggering effect of prior sleep deprivation. Although the studies demonstrated that K.P., a tall, well built, 23 year old, had very little delta sleep and many abrupt arousals whenever SWS was reached, he made no attempt to sleepwalk in the laboratory and so these tests were inconclusive. There was, however, other evidence that supported the argument that he may have been sleepwalking. K.P. had a strong family history of sleepwalking detailed by a court-appointed expert, and was known to be a sleepwalker as a child. He was also experiencing an ongoing major stress that resulted in extended loss of sleep, and he no memory for the event that brought him to trial. The back story of this case reveals the psychology of this event. K.P. a high school graduate, married, with a new first baby, had begun to gamble on horse races and quickly found himself in serious debt. Without his wife’s knowledge he continued to bet and lose many thousands of dollars. He emptied their joint bank account, took out an additional home loan, and then embezzled from his employer. When this was discovered he was fired. Over the next 4 months he became increasingly immobilized; he stopped seeking work and seeing his friends; and did not visit his in-laws, with whom he had a close relationship. His mother-in-law called him her Gentle Giant. His sleep quality was so poor he often did not go to bed at all but stayed on the couch watching television. The violent episode started late on a Saturday night. That afternoon he and his wife had quarreled about his behavior. She insisted he seek help and that he accompany her the following day for a Sunday visit to her parents. This would mean revealing his financial crisis to them, which he dreaded and had avoided. His in-laws were modest people, not able to help him financially, and had trusted him to care for their daughter. Now that he was unable to find work and was at risk of losing their home, he feared he would be seriously diminished in their

eyes. He did promise his wife that he would go with her next day. That night he fell asleep on the couch while watching television and, as he reported, ‘‘I woke up over the body of a woman.’’ He did not recognize this as his mother-in-law, whom he had stabbed to death, nor did he remember that he had driven 15 km to their house, attacked his sleeping father-in-law, and killed the mother-in-law with a knife from her kitchen. When I interviewed K.P. while he awaited trial, he asked me in a bewildered voice really wanting an answer: ‘‘Why would I do that, when I had everything to lose and nothing to gain?’’ He was right: this episode made no rational sense. It was an emotionally driven, complex set of responses to an identity crisis. He fell asleep with the visit on his mind. He was determined to go, to carry through on his promise to his wife, but once there was the threat of exposing himself to her parents as a failure. This prospect mobilized his drive to survive by attacking those who would destroy a positive part of his self-system. He would no longer be the beloved Gentle Giant. The jury’s task was to decide if the ensuing aggression was committed when he was in a nonconscious state. Their verdict was to acquit on the grounds that he was in a state of ‘‘noninsane automatism.’’ Because his arousal from NREM sleep aborted REM, he lost the opportunity for dreaming to perform a dampening of his rage, and no mood regulation took place.

Sleepwalking in obstructive sleep apnea Cases of NREM parasomnia precipitated by the sleep loss associated with obstructive sleep apnea are not common but three cases have been published; two of these involved serious violence [33–35]. In all three the obstructive sleep apnea was assessed to be severe by laboratory studies and also showed the reduced delta and increased number of arousals typical of obstructive sleep apnea and of patients diagnosed with NREM parasomnia. In the case published by Nofzinger and Wettstein [33] a man shot his wife to death following an arousal from sleep. In this case the sleep expert testified for the prosecution. He argued that sleepwalking was unlikely because obstructive sleep apnea is common but there had been no reports of the disrupted sleep being associated with violence. Also it did not help the defendant’s case that he may have had conscious ‘‘motivation’’ for this act. The police found a note written by the wife in her handbag stating that she intended to leave him. The jury found him guilty and he was convicted. The second case [34] was one of a night terror during a PSG study while continuous positive airway pressure was being titrated. A return of SWS in which

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a desaturation occurred prompted an abrupt arousal. The patient jumped up and stood on the bed in a state of fear but no aggression was involved. In the third case [35], a 54-year-old woman with a 5-year history of weight gain and excessive daytime sleepiness awoke one morning to find her hands bloody. She then found more blood on a kitchen cutting board. The remains of her cat were found by the trash can. She was diagnosed with severe obstructive sleep apnea and treated with continuous positive airway pressure and had no further episodes. What her motivation was for dissecting the cat could not be explored because she lived alone and had complete amnesia for this act. A desaturation episode may have triggered an arousal into a sleepwalk to the kitchen where perhaps the cat interrupted her by a touch or sound, but that is a guess. Two other studies indicate that mild breathing disorders are more common in those who have a history of sleepwalking than they are in matched controls [36,37]. In the Guilleminault study [37], a surgical intervention to improve the respiration, a tonsillectomy, or opening the nasal passages eliminated the sleepwalking in a group of children with a history of sleepwalking.

Rapid eye movement parasomnia: nightmares Patients suffering from chronic nightmares present another opportunity to examine the impact of a sleep disorder on the psychologic function of dreaming. In contrast to the NREM parasomnias, the definition of nightmares includes an abrupt arousal from REM sleep, usually toward the end of the night, into a fully awake state with a clear memory of a highly emotional dream. The dream scenario usually involves a fear-invoking situation in which the dreamer has a strong sense of powerlessness. This may explain why they are more common in young children and become less frequent as youngsters acquire more coping skills. Adult nightmares have been studied extensively where they are found to be associated with psychopathology [38–41]. Nightmare frequency increases suicide potential in the depressed [42], and is a defining symptom of posttraumatic stress disorder following major disasters and personal traumas, such as physical abuse and rape [43–46]. Epidemiologic studies show a high prevalence of nightmares in adults, particularly in inner city women. Between 2% and 6% of the general population report experiencing nightmares at least once per week. Here too, the family and twin studies [47] implicate a genetic basis for this disorder. A variety of explanatory theories link the

neurobiology of fear to a psychologic trait of poor capacity to regulate stress [48,49]. In a recent review [48] the authors propose there is a common link between emotion-evoking dream imagery and the profound lack of muscle tone characteristic of REM sleep. Being scared to death, while literally unable to move the major muscles, mimics the situation in the behavioral treatment called ‘‘desensitization.’’ In this program, visually imagining the fear-evoking memory while awake is coupled with training in physical relaxation [50]. The parallel in sleep is that the exposure from REM to REM over 1 or more nights to the feared stimulus while the atonia prevents a motor response ‘‘wears out’’ the arousal response. In chronic nightmares, however, the negative affect exceeds the capacity of REM to sustain sleep. This may be because there is no match in memory to the current stressful event to help disperse the affect load and an arousal occurs instead that prevents completion of the dream. It is the failure to complete the dream that is responsible for the repeated bad dream scenario rather than its extinction. Evidence supporting this model comes from three sources. 1. Nightmares are more common in those identified as having anxiety disorders, neuroticism, schizophrenia-spectrum symptoms, posttraumatic stress disorder, and maladaptive coping. 2. The usual flattening of emotion indicators during fearful dreams (low heart rate, respiratory rate, and low eye movement counts during REM) are even lower in the sleep just before a nightmare arousal [41]. 3. The usual reduction in negative mood following the morning awakening fails to occur for the nightmare sufferer [49].

Dream enactment in rapid eye movement behavior disorder REM behavior disorder is another sleep disorder in which there is a failure to maintain REM sleep. These patients not only have abrupt arousals from REM with vivid recall of a fearful dream, they also act it out [51]. Swinging at imaginary intruders they punch holes in the bedroom walls, upset lamps, hurt themselves, and damage property. Their sleep recordings show bursts of muscle activity in the chin leads during REM sleep and other indicators of a failure of motor control: bruxism (tooth grinding), hypnic jerks, and periodic leg movements are all common throughout the sleep in the PSGs of these patients. When this disorder was originally described it was most often identified in the elderly who also had some neurodegenerative disease, primarily Parkinson’s disease. Then,

The Contribution of the Psychology of Sleep and Dreaming

younger patients meeting the diagnostic criteria began to be seen in sleep centers, when no clinical Parkinson’s disease symptoms were apparent. Longitudinal follow-up of these patients showed it might be decades later before the neurologic symptoms were documented in waking [52]. Although rare, a milder form of one REM behavior disorder symptom called ‘‘dream enactment’’ has been documented in healthy young adults. It is possible that these may also be at risk for the later appearance of Parkinson’s disease. Again, there is a mixed picture of psychologic precipitating factors on top of a genetic vulnerability caused by a flaw in the REM motor inhibition system. One young patient, a recently married medical student, presented with a self-diagnosis of dream enactment with a 3-month history. He described his sleep episodes as now occurring three to six times per night on 5 or 6 nights a week. A typical recent event began with an abrupt sit up in bed in a fearful state imagining an anaconda in the bed. He described himself as screaming to his wife ‘‘you grab the tail, I’ll grab the head.’’ His PSG recording showed multiple bursts of activity in the submental muscle and periodic leg movements during REM sleep. Clearly, he needed some insight into the added stress his marriage just 3 months ago imposed while he was preparing for his second-year board examination. He also needed some help with stress management. The breakthrough of muscle activity during REM is usually successfully treated with a small dose of clonazepam at bedtime. In the case of this patient where the psychologic function of sleep was so clearly disturbed the treatment also needed to include the rules of good sleep hygiene, especially the importance of avoiding sleep deprivation and training in relaxation techniques.

variables: the expression of negative emotion and the inclusion in the dream story aspects of both the present life event and older memory images [54]. Twenty men and women who met depression criteria and 10 nondepressed divorcing controls all had their dreams collected from each REM period on three occasions over a 5-month period. At the follow-up visit, 12 of the depressed were in remission without any intervening psychotherapy or pharmacologic treatment and 8 remained depressed. All controls remained free of depression symptoms. The major difference between the depressed who improved and those who did not was the degree to which the dreams integrated fragments of the recent emotional experience with older memories relating to the same emotion associated with the divorce [54]. One example of this is a dream reported by a depressed woman who when awakened from REM gave this report: ‘‘My ex-spouse appeared at my parent’s home where I was having my 16th birthday party. He embarrassed me by exposing himself.’’ The dreams of those who were in remission by the end of the study were longer than those who did not change. They were also more complex and included multiple characters and shifts of scene. This heightened dream complexity was characteristic of their REM reports from the start of the study [55]. Their remission could be predicted from the dream-like quality of their reports on the first night of REM awakenings. They seemed to be putting things together in new ways,‘‘changing their minds’’ during sleep. Those who failed to remit without treatment had short rather stark dreams or no recall at all. These are the depressed that require some treatment intervention, antidepressant medication, psychotherapy, or a therapy directed to dream change [56].

Major depression In major depression the sleep marker in the PSG is in the timing of the onset of the first REM period of the night. The number of minutes of sleep before the first REM episode, normally about 90 minutes, is most often reduced to less than 65 minutes displacing the SWS [53] or is skipped lengthening the first NREM cycle. This robust finding suggests dreams too may be abnormal. In a series of studies volunteers, all of whom were undergoing the same negative emotional experience (the breakup of a first marriage), were followed longitudinally tracking the early REM marker and their dreams. The aim was to examine whether those who met depression criteria would restore mood regulation over time (wake in a better morning mood and remit from depression) following a change in dream scenarios. The focus was on two dream

Summary This article has looked into how one psychologic function of sleep applies to expand the understanding of a number of sleep disorders. Overall, this function integrates new waking experience relevant to the organized self-system, and modulates negative emotion invoked by experience that threatens this program. The reactivation mechanism supports the update of the ‘‘underlying strategies that guide behavior’’ [57] and thereby prepares for more appropriate responses to any challenges the next day. In sleepwalking the arousal out of SWS aborts REM and so stops this process at the beginning of the night’s sleep. In nightmare disorder the reactivation matches some current experience to a reminder of an earlier threat to the self-structure. The dream constructed in the late night sleep, when REM is

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most intense, has the additive effect of the old and new threats leading to a spontaneous awakening delaying any modification of the underlying selfsystem. In dream enactment dreams are acted out in response to an overload of new challenges to a system with a genetic deficit in sustaining sleep motor atonia. All these are examples of a failure to sustain sleep because of a high level of some disturbing affect in those with an inherited biologically weakened motor control system either in early NREM sleep, late night REM sleep, or both. In major depression the problem is not primarily one of sustaining sleep but of its timing. The early REM displaces the SWS responsible for the reactivation of relevant waking experience. The REM dream content is either empty or at best simple and bland and is not functional for change in morning mood.

Future research There is still much work to be done to understand with more precision all of the interactions of brain and behavior in the different organizational states humans cycle through each 24-hour period. 1. The evidence of a role for genetics in several sleep disorders needs further work. As yet there has been no application of the newer SNIPS technique to differentiate between narcolepsy, REM behavior disorder, and sleepwalking, all of which have a common DBQ1 marker using HLA typing. 2. There is likely a genetic differentiation within the group of adult sleepwalkers between those who are and those who are not violent [58]. This should be addressed with better genetic testing. 3. The question of why the male gender is so dominant in adult sleepwalkers also is a topic for further study. 4. Besides the evidence that sleep deprivation and zolpidem are precipitating factors in NREM parasomnias, there is controversy about the role of substances, such as caffeine and alcohol [59–61], which lighten the first NREM sleep and so challenge the old model that it is increased SWS with high thresholds for arousal that are responsible for this disorder rather than low thresholds and the reduced delta activity. Further work exploring the effect of these and other sleep medications is needed to test their potential as triggers for sleepwalking in prone individuals. 5. There is also controversy about the continuity of cognition, motivation, and emotion throughout the sleep-wake cycle based on the data from sleep interruptions across the night. This method may induce continuity because of the memory of what was reported when awakened.

New protocols are needed to control for this experimental artifact. 6. There is evidence that there are individual differences in both the speed and amount of overnight improvement in behavior within normal subjects related to sleep variables other than number of arousals or timing of cycles. The eye movement density is one predictor of learning ability [62]. Further work on the role of more specific sleep variables, such as sleep spindles and K complexes, on learning and memory is indicated [63]. These are a few of the topics for future research to clarify the proposition put forth here: that when sleep is intact, of adequate length, and undisturbed by abnormal arousals, information from waking continues to be actively carried forward through neural circuits allowing it to be sorted, stored, and tempers cooled. Sleep likely performs several psychologic functions. This article focuses on the REM and dream function, for which there is the most data. This explores how sleep processes waking experience that has a negative emotional impact. Recent work studying how more neutral experimental learning tasks effect sleep and subsequent performance is providing information about specific changes in sleep characteristics that take place as one learns. Correcting sleep disorders has the potential of restoring the neuropsychologic system to the fine balance between stability and flexibility of behavior characteristic of humans at their best.

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[29] Cartwright R. Sleepwalking violence: a sleep disorder, a legal dilemma and a psychological challenge. Am J Psychiatry 2004;161:1149–58. [30] Ohayon M, Guilleninault C, Priest R. Night terrors, sleep walking and confusional arousals in the general population: their frequency and relationship to other sleep and mental disorders. J Clin Psychiatry 1999;60:268–76. [31] Pilon M, Zadra A, Adam B, et al. 25 hours of sleep deprivation increases the frequency and complexity of somnambulistic episodes in adult sleepwalkers. Sleep 2005;28:A257. [32] Broughton R, Billings R, Cartwright R, et al. Homocidal somnambulism: a case report. Sleep 1994;17:915–25. [33] Nofzinger E, Wettstein R. Homicidal behavior and sleep apnea: a case report and a medicolegal discussion. Sleep 1995;18:776–82. [34] Pressman M, Meyer T, Kendrick-Mohamed J. Night terrors in an adult precipitated by sleep apnea. Sleep 1995;8:773–5. [35] Lateef O, Wyatt J, Cartwright R. A case of non-REM parasomnia that resolved with treatment of obstructive sleep apnea. Chest 2005; 28:461S. [36] Espa F, Dauvillers Y, Ondze B. Arousal reactions in sleep-walking in adults: the role of respiratory events. Sleep 2002;25:871–5. [37] Guilleminault C, Palombini L, Pelayo R, et al. Sleepwalking and sleep terrors in prepubertal children: what triggers them? Pediatrics 2003; 111:17–25. [38] Spoormaker VI, Schredl M, Bout JV. Nightmares: from anxiety symptom to sleep disorder. Sleep Med Rev 2005;10:19–31. [39] Levin R. Nightmares and schizotypy. Psychiatry 1998;61:206–16. [40] Zadra A, Donderi DC. Nightmares and bad dreams: their prevalence and relationship to well-being. J Abnorm Psychol 2000;109:273–81. [41] Nielsen T, Zadra A. Nightmares and other common dream disturbances. In: Kryger M, Roth T, Dement W, editors. Principles and practice of sleep medicine. 4th edition. Philadelphia: Elsevier Saunders; 2005. p. 926–35. [42] Agargun M, Cartwright R. REM sleep, dream variables and suicidality in depressed patients. Psychiatry Res 2003;119:33–9. [43] Ohayon M, Morselli P, Guilleminault C. Prevalence of nightmares and their relationship to psychopathology and daytime functioning in insomnia subjects. Sleep 1997;20:340–8. [44] Mellman T, Pigeon W. Dreams and nightmares in posttraumatic stress disorder. In: Kryger M, Roth T, Dement W, editors. Principles and practice of sleep medicine. 4th edition. Philadelphia: Elsevier Saunders; 2005. p. 573–8. [45] Mellman T, David D, Bustemente V. Dreams in the acute aftermath of trauma and their relationship to PTSD. J Trauma Stress 2001;14: 241–7.

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Insomnia: Prevalence, Impact, Pathogenesis, Differential Diagnosis, and Evaluation Evelyn Mai, -

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MD,

Daniel J. Buysse,

Insomnia prevalence Insomnia impact Insomnia and psychiatric conditions Insomnia and medical conditions Socioeconomic impact of insomnia Insomnia pathogenesis Insomnia evaluation

Insomnia is the most common sleep disorder affecting millions of people as either a primary or comorbid condition. Insomnia has been defined as both a symptom and a disorder, and this distinction may affect its conceptualization from both research and clinical perspectives. Whether insomnia is viewed as a symptom or a disorder, however, it nevertheless has a profound effect on the individual and society. The burden of medical, psychiatric, interpersonal, and societal consequences that can be attributed to insomnia underscores the importance of understanding, diagnosing, and treating the disorder.

Insomnia prevalence The prevalence of insomnia varies depending on the specific case definition. Broadly speaking, insomnia has been viewed as a symptom and as a disorder in its own right. Insomnia has also been defined by subtypes based on frequency; duration (acute

MD*

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Patient interview Physical and mental status examination Collateral sources interview Objective data Summary References

versus chronic); and etiology. This picture is further complicated by considerations of insomnia as either a comorbid condition; as a symptom of a larger sleep, medical, or psychiatric disorder; or as a secondary disorder [1]. An illustration of this idea is the overlap between insomnia and depression. Do insomnia and depression coexist in an individual as separate disorders? Is insomnia only one symptom in the larger context of depression? Did insomnia secondarily developed as a distinct disorder from a primary depressive disorder? The three main diagnostic manuals, International Classification of Sleep Disorders (ICSD-2) [2], Diagnostic and Statistic Manual (DSM IV-TR) [3], and International Classification of Disease (ICD-10) [4], vary in their approach to defining insomnia (Box 1). ICSD-2 subdivides insomnia into descriptive, etiologic categories. Examples include adjustment insomnia (insomnia temporally related to an identifiable stressor) and psychophysiologic

Supported by National Institutes of Health grants MH24652 and AG20677. Sleep Medicine Institute, University of Pittsburgh, 3811 O’Hara Street, Pittsburgh, PA 15213, USA * Corresponding author. Department of Psychiatry, E-1127 WPIC, 3811 O’Hara Street, Pittsburgh, PA 15213. E-mail address: [email protected] (D.J. Buysse). 1556-407X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

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Box 1:

Insomnia diagnostic categories

ICSD-2 insomnia categories Adjustment insomnia (acute insomnia) Psychophysiologic insomnia Paradoxical insomnia Idiopathic insomnia Insomnia caused by mental disorder Inadequate sleep hygiene Behavioral insomnia of childhood Insomnia caused by drug or substance Insomnia caused by medical condition Insomnia not caused by substance or known physiologic conditions, unspecified (nonorganic insomnia) Physiologic (organic) insomnia, unspecified ICD-10 insomnia categories Nonorganic insomnia Nonorganic disorder of the sleep-wake schedule DSM-IV-TR insomnia categories Primary insomnia Insomnia related to axis I or II category

insomnia (increased arousal and conditioned sleep difficulty) (Box 2) [2]. These categories also contain insomnia caused by a mental disorder, substance, or medical condition. The DSM IV-TR separates out primary insomnia (insomnia symptoms associated with distress or daytime impairment) from other ‘‘dyssomnias,’’ such as a breathing-related sleep disorder [3]. ICD-10 uses the broadest approach, categorizing insomnia based on underlying pathology: nonorganic insomnia and nonorganic disorder of the sleep-wake schedule (see Box 2) [4]. Duration of insomnia (at least 1 month of symptoms) is noted in ICSD-2 and DSM IV-TR; however, frequency of symptoms is broached only in ICD-10. As a result of these differences in insomnia case definitions, estimates of insomnia prevalence have varied widely, from 10% to 40% [5–12]. This problem is demonstrated by the findings of a prevalence study from South Korea. When insomnia was defined by frequency (symptoms occurring at least 3 nights per week), 17% of randomly selected subjects from the population qualified for the diagnosis. If the symptom of difficulty maintaining sleep was the defining factor, 11.5% of the sample was affected. Using the more stringent criteria from DSM-IV, however, 5% of the sample qualified for the diagnosis [13]. Similar disparities were shown in a prevalence study from France [14]. According to a 2005 statement by the National Institutes of Health, insomnia has a prevalence of 10% if the definition necessitates daytime distress or impairment

Box 2:

Insomnia definition

ICSD-2 general criteria for insomnia 1. A complaint of difficulty initiating sleep, difficulty maintaining sleep, or waking up too early or sleep that is chronically unrestorative or poor in quality. In children, the sleep difficulty is often reported by the caretaker and may consist of observed bedtime resistance or inability to sleep independently. 2. The above sleep difficulty occurs despite adequate opportunity and circumstances for sleep. 3. At least one of the following forms of daytime impairment related to the nighttime sleep difficulty is reported by the patient: fatigue or malaise; attention, concentration or memory impairment; social or vocational dysfunction or poor school performance; mood disturbance or irritability; daytime sleepiness; motivation, energy, or initiative reduction; proneness for errors or accidents at work or while driving; tension, headaches, or gastrointestinal symptoms in response to sleep loss; concerns or worries about sleep. DSM-IV-TR criteria for primary insomnia 1. The predominant complaint is difficulty initiating or maintaining sleep, or nonrestorative sleep, for at least 1 month. 2. The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. 3. The sleep disturbance does not occur exclusively during the course of narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, or a parasomnia. 4. The disturbance does not occur exclusively during the course of another mental disorder (eg, major depressive disorder, generalized anxiety disorder, a delirium). 5. The disturbance is not caused by the direct physiologic effects of a substance (eg, a drug of abuse, a medication) or a general medical condition. ICD-10 criteria for nonorganic insomnia A condition of unsatisfactory quantity or quality of sleep, which persists for a considerable period of time, including difficulty falling asleep, difficulty staying asleep, or early final wakening. Insomnia is a common symptom of many mental and physical disorders, and should be classified here in addition to the basic disorder only if it dominates the clinical picture.

Insomnia

[15]. Given all the information available, the prevalence of insomnia symptoms may be estimated at 30% and specific insomnia disorders at 5% to 10% [16]. Several risk factors for insomnia have been identified. Female gender, advanced age, depressed mood, snoring, low levels of physical activity, comorbid medical conditions, nocturnal micturation, regular hypnotic use, onset of menses, previous insomnia complaints, and high level of perceived stress have all been implicated as risk factors; the first three factors in particular (female gender, advanced age, and depressed mood) are consistent risk factors [7,17–22]. Precipitants of insomnia have also been studied. Bastien and colleagues [23] examined precipitating factors of insomnia and found that family, work or school, and health events proved to be the most common precipitants [23]. Another study of psychosocial stressors in Japan demonstrated that employees with greater intragroup conflict and job dissatisfaction had greater risk for insomnia [24]. Knowledge of both risk factors and possible precipitants of insomnia can help to guide the evaluation and treatment of insomnia. Questions about psychosocial stressors at home and at work in high-risk individuals, such as those experiencing depression or who are female or elderly, can help to shape and direct patient care.

Insomnia impact Insomnia and psychiatric conditions An estimated 40% of individuals with insomnia have a comorbid psychiatric condition [7,25]. In a review of epidemiologic studies, Taylor and colleagues [26] found that insomnia predicted depression, anxiety, substance abuse or dependence, and suicide [26]. The correlation between insomnia and later development of depression within 1 to 3 years is particularly strong [27]. Johnson and colleagues [28] found that in a community sample of adolescents, in 69% of cases insomnia preceded comorbid depression, whereas an anxiety disorder preceded insomnia 73% of the time [28]. In a large group of subjects aged 15 to 100 years, insomnia either appeared before (>40%) or at the same time (>22%) as mood disorders. This study also found that insomnia appeared at the same time as (>38%) or after (34%) anxiety disorders [29]. As further evidence of morbidity, individuals with insomnia complaints in the last year but without any previous psychiatric history were shown to have an increased risk of first-onset major depression, panic disorder, and alcohol abuse the following year when compared with controls [30]. Furthermore, adolescents who completed suicide

were found to have higher rates of insomnia in the week preceding death than community-control adolescents [31,32]. Taken as a whole, these findings underscore the impact of insomnia on the individual while suggesting a possible relationship between insomnia and psychiatric disorders. The nature of this relationship has yet to be established. Insomnia could be an early symptom, part of a prodrome, of a depressive or anxiety disorder. Similarly, insomnia might also exist as a separate, comorbid disorder that either gave rise to or developed from a psychiatric condition. In either case the need to address insomnia and psychiatric disorders together remains important.

Insomnia and medical conditions Associations between insomnia and a variety of medical conditions have also been established. Taylor and colleagues [33] found that in a communitybased sample chronic insomniacs reported more heart disease, hypertension, chronic pain, and increased gastrointestinal, neurologic, urinary, and breathing difficulties. The converse was also shown to be true, in which subjects with hypertension, chronic pain, breathing, gastrointestinal, and urinary problems complained of insomnia more often than noninsomniacs [33]. Others have also found increased odds ratios for insomnia in a variety of medical conditions, ranging from congestive heart failure to hip impairment [34]. Ancoli-Israel [35] emphasized the different ways that insomnia and chronic medical conditions may relate to each other: sleep complaints may function as a symptom of a disorder, such as congestive heart failure and Cheyne-Stokes respiration gastroesophageal reflux disease and increased arousals. In other cases, insomnia may be a component of the etiology of a disorder, such as diabetes mellitus [35]. The connection between cardiovascular disease and insomnia bears specific attention. After adjusting for age and coronary risk factors, a risk ratio of 1.5 to 3.9 between difficulty falling asleep and coronary heart disease has been demonstrated [36]. Men who experienced difficulty falling asleep were also shown to have a threefold risk of death secondary to coronary heart disease [37]. The relationship between chronic pain and insomnia is also of particular clinical relevance. In one study, more than 40% of insomniacs reported having at least one chronic painful physical condition. Moreover, chronic pain was in turn associated with shorter sleep duration and decreased ability to resume sleep following arousal [38]. Tang and colleagues [39] found that 53% of chronic pain patients had scores suggestive on the Insomnia

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Severity Index of clinical insomnia versus 3% of subjects without pain [39].

Socioeconomic impact of insomnia In addition to psychiatric and medical comorbidities, insomnia is associated with substantial personal and societal consequences. One study that examined the effect of insomnia on primary care patients found insomniacs had double the number of days with restricted activity because of illness [11]. Another study showed that more insomniacs rated their quality of life as poor (22%) compared with subjects without any sleep complaints (3%) [32]. Insomnia has also been shown to have a detrimental effect on health-related quality of life to the same degree as chronic disorders, such as depression and congestive heart failure [40]. When the economic costs that encompass health care use, workplace effects of absenteeism, accidents, and increased alcohol consumption secondary to insomnia were considered, the annual cost was estimated to be between $35 to $107 billion a year [41,42]. Insomnia has not been found to be associated with increased risk of death [43]. Health care use, as defined by increased office visits and rates of hospitalization, is consistently higher in insomniacs than in subjects without sleep complaints [44,45]. The direct costs incurred through inpatient, outpatient, pharmacy, and emergency room usage are greater in insomniacs regardless of age [46]. An evaluation of the direct health care costs of insomnia in 1995 placed estimates at $13.9 billion in the United States and $2.1 billion in France [47,48]. Function in the workplace is also negatively affected. Insomniacs miss work twice as often as good sleepers, with absenteeism particularly prominent in men and blue-collar workers [49]. The extra cost of work absenteeism secondary to insomnia, through decreased productivity and salary replacement, is then brought to bear on employers [50].

Insomnia pathogenesis Insomnia is often believed to arise from a state of hyperarousal. In the physiologic hyperarousal model, an elevated level of alertness throughout the day and night makes it difficult to sleep. In support of this theory, insomniacs have been found to have an increased whole body metabolic rate when compared with normal sleepers [51,52]. They also score higher than normal sleepers on a Hyperarousal Scale, and even during the day when complaining of fatigue, insomniacs still take a longer time to fall asleep [53,54]. On functional neuroimaging, insomniacs show increased cerebral glucose metabolism during sleep

and wake states [55]. On electroencephalography, insomniacs demonstrate increased beta activity and lower delta activity [56,57]. From an endocrine perspective, insomniacs, like patients with major depressive disorder, demonstrate corticotropinreleasing factor hyperactivity, suggesting a role for hypothalamic-pituitary-adrenal axis dysfunction [58].

Insomnia evaluation The cornerstone of the insomnia evaluation is a detailed history obtained during the patient interview. Although the approach to the interview may vary depending on the practitioner, key points should be covered to ensure a thorough evaluation. Additional assessment tools, such as the sleep-wake diary, actigraphy, and in specific cases polysomnography, can supplement the information obtained in the interview. A list of diagnoses and comorbid conditions to consider during the insomnia evaluation can be found in Box 3.

Patient interview Detailed information about the nature of the complaint is necessary, such as if insomnia is related to sleep onset, sleep maintenance, early morning awakening, nonrestorative sleep quality, or a combination of these problems. Information obtained here may help to guide the diagnosis, such as a sleep-onset complaint resulting from restless legs syndrome as opposed to an early morning awakening presenting as part of a depressive disorder. Additional information about the onset, course and duration, current presentation, frequency, severity, and precipitating or alleviating factors also helps to define the problem. In particular, a lifelong course with an onset in the absence of medical and psychiatric comorbidities may suggest a primary insomnia as opposed to a secondary insomnia that develops in late adulthood in the context of chronic pain. The sleep schedule, including bedtime, sleep latency, number and length of nighttime awakenings, sleep reinitiation time, wake time, time spent in bed, and total sleep time, should be reviewed. A patient’s preferred bedtime may not coincide with actual bedtime, as in a circadian rhythm disorder. Similarly, nighttime awakenings caused by nightmares from posttraumatic stress disorder as opposed to awakenings from nocturia caused by prostate enlargement suggest different disorders. The daytime routine with a review of work schedule, eating and exercise times, and duration and timing of naps is also important. Eating and exercise times that occur in close temporal relation to bedtimes may inhibit the patient’s ability to fall asleep. Moreover, naps of long duration that occur

Insomnia

Box 3: Insomnia differential diagnosis and common comorbidities Medical conditions Cardiovascular: congestive heart failure, arrhythmia, coronary artery disease Pulmonary: chronic obstructive pulmonary disease, asthma Neurologic: stroke, Parkinson’s disease, neuropathy traumatic brain injury Gastrointestinal: gastroesophageal reflux Renal: chronic renal failure Endocrine: diabetes, hyperthyroidism Rheumatologic: rheumatoid arthritis, osteoarthritis, fibromyalgia, headaches Sleep disorders Restless legs syndrome Periodic limb movement disorder Sleep apnea Circadian rhythm disorder Parasomnias Nocturnal panic attacks Nightmares Rapid eye movement behavior disorder Psychiatric conditions Depression Anxiety Panic disorder Posttraumatic stress disorder Medications Decongestants Antidepressants Corticosteroids b-Agonists b-Antagonists Stimulants Statins Substances Caffeine Alcohol Nicotine Cocaine Data from Buysse DJ. Sleep disorders and psychiatry. Arlington (VA): American Psychiatric Publishing, American Psychiatric Publishing Review of Psychiatry; 2005; and Sateia MJ, Doghramji K, Hauri PJ, et al. Evaluation of chronic insomnia. An American Academy of Sleep Medicine review. Sleep 2000;23:243–308.

in the late afternoon or evening may have a similar negative effect on sleep latency and continuity. A discussion of daytime functioning and associated symptoms includes daytime sleepiness; fatigue; difficulty with memory and concentration; depression; anxiety; irritability; impairment at work, school, or home; and overall quality of life. A report of daytime impairment and patient distress may underscore the severity of symptoms, and highlight the need aggressively to treat insomnia.

In this area, collateral report from family, teachers, or coworkers may prove helpful if the patient is unaware of the extent of his or her symptoms. Safety issues, such as the negative effect on driving and work performance in potentially hazardous areas, should be broached and may provide an opportunity for patient education. Sleep conditions and routines should be discussed, such as the conditions of the room used for sleep (eg, effect of light, temperature, and noise); use of television, computer, or radio both in the prebedtime routine and during periods of nighttime awakenings; the effect of anxiety during sleep latency and sleep reinitiation periods; and the presence of clock-watching before and during sleep times. Too much noise or light exposure in the sleeping room may inhibit sleep initiation. Similarly, clock-watching with each nighttime awakening may only further heighten an already raised level of anxiety. Specific difficulty falling asleep at home but not while out of town may suggest insomnia related to the bedroom environment. Previous treatments tried and their effects and side effects should be discussed. Treatments may include over-the-counter, homeopathic, herbal, or prescription medications and behavioral therapies. In addition to providing information on potential treatments that may not have yet been offered to the patient, information obtained in this area may provide a sense of the kind of treatment for which the patient is looking. Symptoms of other sleep disorders that could be affecting the complaint include such conditions as restless legs syndrome, periodic limb movement disorder, sleep apnea, and sleep phase syndromes. These should be considered as possible contributors to insomnia. One should review comorbid medical conditions that could play a role in the presentation. General categories to consider include cardiovascular, pulmonary, neurologic, gastrointestinal, renal, endocrine, and rheumatologic. Review of underlying psychiatric conditions and psychosocial stressors should be included. Eliciting symptoms of depression, bipolar disorder, anxiety, panic (including nocturnal panic attacks), and psychosis can help to clarify the diagnostic picture while emphasizing the need to obtain or continue psychiatric care. A review of substance use, including nicotine, alcohol, and caffeine, should cover amount, frequency, and time of day the substance is used because all of these substances may contribute to an insomnia complaint. Patient education about the effects of nicotine, alcohol, and caffeine on sleep should also be undertaken if it seems that substance use has a negative effect on sleep quality.

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Fig. 1. Sleep diary.

Finally, one should undertake a review of family history of sleep, medical, and psychiatric disorders.

Physical and mental status examination The physical examination may reveal signs consistent with sleep apnea (obesity, enlarged neck circumference, crowded oropharynx) and thyroid, cardiac, respiratory, and neurologic disorders. The mental status examination may yield information about the patient’s mood, affect, level of alertness, and ability to attend.

Collateral sources interview Interview the patient’s bed partner or family members, if possible, to elicit symptoms of which the patient may be unaware. This part of the evaluation may also help to corroborate and expand on the patient’s original description. Revelation about respiratory symptoms (snoring, apneas, or gasping) could suggest a sleep-disordered breathing etiology, whereas report of repeated limb movements may move the diagnosis toward restless legs syndrome or periodic limb movement disorder.

Objective data Actigraphy Actigraphy helps to characterize rest-activity patterns and may have some use as an objective measure when used in conjunction with a sleep-wake dairy and formal interview. For insomniacs actigraphy can provide information about circadian rhythms and sleep patterns [59]. Compared with polysomnography, however, actigraphy in

insomniacs has had variable results: it has been found to overestimate and underestimate total sleep time [60–62]. Another study found that actigraphy was well validated by polysomnography with respect to number of awakenings, wake time after sleep onset, total sleep time, and sleep efficiency [63]. When using actigraphy, increasing the duration of recording to more than 7 days may improve the reliability of sleep time estimates [64]. Polysomnography Polysomnography is not routinely used in the evaluation of insomnia; the onus of the diagnosis lies instead on the patient interview. According to 2003 practice parameters established by the American Academy of Sleep Medicine, specific cases may apply when polysomnography is warranted. These cases include suspicion of sleep-related breathing disorders or periodic limb movement disorders, uncertain initial diagnosis, treatment failure, and arousals leading to violent behavior [65]. Sleep diaries Sleep diaries recorded over 1 to 2 weeks can help track a patient’s sleep-wake patterns. Information including actual sleep-wake times, duration of time in bed, and day-to-day variability in sleepwake times can be gathered from the diaries (Fig. 1).

Summary Insomnia is thought to result from a state of hyperarousal. As a result of this elevated state of alertness,

Insomnia

sleep may prove difficult. Formulating a clinical definition of insomnia has proved a challenge. Nevertheless, some enduring characteristics of insomnia include difficulty with sleep initiation or maintenance, early morning awakening, and nonrestorative sleep in the setting of daytime impairment or distress in the setting of adequate sleep opportunity. With these characteristics in mind the prevalence of insomnia is thought to be approximately 10%. The evaluation of insomnia emphasizes the interview, during which information about the specific complaint, comorbid sleep, medical or psychiatric conditions, family histories, medication, and substance use may be gathered. Additional information from collateral sources, sleep diaries, actigraphy, and polysomnography may also prove useful. Insomnia is a disorder that has far-reaching effects: medical, psychiatric, personal, and societal consequences have all been linked with insomnia. The cost of insomnia can be measured not just in dollars, but also in impaired quality of life from comorbid conditions and impaired interpersonal relationships.

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SLEEP MEDICINE CLINICS Sleep Med Clin 3 (2008) 175–187

Efficacy and Safety of Sleep-Promoting Agents Thomas Roth, -

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a,b,c,

PhD

*, Timothy Roehrs,

Efficacy of hypnotics Defining hypnotic efficacy Assays of hypnotic efficacy Therapeutic end points Patient populations Duration of efficacy Safety of benzodiazepine receptor agonists Psychomotor impairment Cognitive impairment Discontinuation effects Liability for abuse Falls Idiosyncratic side effects

The management of insomnia has been affected dramatically by advances in the understanding of the pathophysiology and morbidity of insomnia, by new applications for behavioral treatments of insomnia, and by the development of new therapeutic targets for the pharmacologic management of insomnia [1]. Insomnia encompasses one or more of the following symptoms: difficulty initiating sleep, difficulty maintaining sleep, waking up too early, or sleep that is chronically nonrestorative or of poor quality [2]. These difficulties with sleep occur despite the individual’s having adequate opportunity and circumstances for sleep. In addition to the reported difficulties with sleep, the diagnosis of

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a,c

PhD

Drugs used for insomnia therapy On-label use Off-label use Self-treatment Special populations Elderly persons Patients who have primary sleep disorders Persons who have hepatic/renal impairments Alcohol and substance abusers References

insomnia requires a patient’s report of daytime impairment or distress related to the nighttime sleep difficulty. These impairments may include, but are not limited to, problems such as fatigue, memory impairment, mood disturbances, increased risk for errors and accidents, tension headaches, and gastrointestinal symptoms in association with the difficulty with sleep [3]. Most diagnostic systems require these symptoms to be present three or more times per week and to have been present for at least a month. Data presented at a recent state of the science conference on insomnia [1] demonstrate clearly that clinicians need to treat insomnia as a primary disorder rather than as a symptom secondary to

a Sleep Disorders and Research Center, Henry Ford Hospital, 2799 West Grand Boulevard, CFP-3, Detroit, MI 48202, USA b Department of Psychiatry, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA c Department of Psychiatry and Behavioral Neuroscience, Wayne State University, School of Medicine, 2751 East Jefferson, Suite 400, Detroit, MI 48207, USA * Corresponding author. Sleep Disorders and Research Center, Henry Ford Hospital, 2799 West Grand Boulevard, CFP-3, Detroit, MI 48202. E-mail address: [email protected] (T. Roth).

1556-407X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

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an underlying condition. Clinicians historically have regarded insomnia as a consequence of another disorder, because in most cases insomnia is not present in isolation (primary insomnia) but rather coexists with another medical, psychiatric, or sleep disorder (comorbid insomnia). In this view these other conditions do not cause insomnia; rather, they precipitate it in vulnerable individuals. Clinically it is important to recognize that many patients who have these other conditions do not report insomnia, that the insomnia often predates the comorbid condition, that treating the comorbid condition does not always reverse the insomnia, and that treating the insomnia has benefits in the management of comorbidities such as pain and depression.

Efficacy of hypnotics Defining hypnotic efficacy The efficacy of any treatment is determined by its ability to reverse the signs and symptom of a condition. Insomnia is a symptom-based diagnosis. Specifically, the symptoms of insomnia include difficulty in falling asleep or in staying asleep and the experience of nonrefreshing sleep. To meet the diagnostic criteria for insomnia, these symptoms should be associated with daytime impairment or daytime distress. Finally, these difficulties with sleep and associated impairment in daytime function should be present for at least 3 nights a week for at least a month.

Assays of hypnotic efficacy The efficacy of hypnotics is determined objectively by polysomnography (PSG) and by patient reports of nocturnal sleep (postsleep questionnaires or diaries). In addition, a variety of measures are used to evaluate daytime function. Finally, global ratings of efficacy are determined by evaluations of overall sleep by the patient and by clinicians.

Therapeutic end points The therapeutic end points of hypnotics are improvements in the patient’s ability to fall asleep and stay asleep and in the refreshing quality of sleep. For sleep induction the primary end point is the speed of falling asleep. In PSG studies the accepted measure is the time need to achieve 10 consecutive minutes of uninterrupted sleep (ie, latency to persistent sleep). In patient reports, subjects simply are asked, ‘‘How long did it take you to fall asleep last night?’’ This subjective assay usually is collected in the morning, 1 to 2 hours after arising, and is averaged over some period of time, typically a week. It is preferable to collect this information by using a method that time stamps the entries (eg, an

interactive voice response system or electronic diary) to prevent patients from filling out all the estimates at a single time point. For sleep maintenance, the accepted PSG end point is the number of minutes that the patient is awake after sleep onset (WASO) before getting out of bed. It includes the times the patient woke in the middle of the night well as early morning awakening. Another measure of sleep maintenance is the number of times the patient woke during the night before the final awakening. Three measures are used for patient reports. The first is the question, ‘‘How long were you awake during the night?’’ This question is parallel to the WASO measure. Often, however, the patient response to ‘‘How long did you sleep last night?’’ is a better correlate of WASO and thus is used more frequently. Finally, subjects are asked how many times they awake during the night. In PSG measurement, sleep duration (total sleep time) is evaluated by the number of minutes that the subject was asleep expressed as a percentage of the time that the subject was in bed. This ratio of total sleep time to total time in bed is termed ‘‘sleep efficiency.’’ Although total sleep time and its derivative, sleep efficiency, are important, they do not provide direct information about whether the medication is facilitating sleep onset or sleep maintenance. That is, a 30-minute reduction in sleep latency and a 30-minute reduction in WASO have the same effect on total sleep time. The final end point in sleep efficacy is the refreshing quality of sleep. All sleep diaries ask questions such as, ‘‘How would you rate the quality of your sleep?’’ or ‘‘How refreshing was your sleep?’’ Although these questions have great face validity, their validity in demonstrating an improvement in the symptom of nonrefreshing sleep has not been established to date. This lack of validation is a challenge, because there is no accepted PSG measure of sleep quality. In evaluating hypnotics, measures of daytime function have been used primarily to measure the residual effects of hypnotics. Attempts to show improvement in a variety of tasks in association with improved sleep have failed, in great part because almost all studies evaluating daytime function in insomniacs have failed to identify impairment. Thus it is difficult to find a cognitive or psychomotor task that shows improvement after an improved nights’ sleep. In contrast, there are assays of daytime function that show promise. It has been shown that measures of fatigue, daytime sleepiness, work productivity, quality of life, and disability are improved with the pharmacologic management of insomnia [4]. Such improvement is a critical element of insomnia therapy and needs to be a primary therapeutic end point in future studies. These end points probably have been neglected because historically

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clinical trials in insomnia were of short duration, and longer treatment periods were need to reverse some of these morbidities. The overall efficacy of treatment needs to be evaluated with a patient and/or a clinician global impression. In these evaluations the rater typically uses a five-point scale to determine the degree to which the treatment has made the insomnia symptom complex better or worse.

example, in studying patients who have insomnia comorbid with depression, sleep and daytime function were measured, and the rating of depression was evaluated [6]. In most of these studies the results seem to indicate that treating the insomnia has positive effects on the comorbid condition; however, hypnotics are not indicated for the treatment of these comorbid conditions.

Duration of efficacy Patient populations Most studies are conducted in patients who have primary insomnia [1]. It is accepted that most cases of insomnia are not primary insomnia but rather insomnia that is comorbid with other conditions [2]. Studying primary insomnia, however, allows evaluation of the therapeutic effect of the medication without the confounding elements of concurrent disease and the medications used to treat it. These studies are conducted in adults and in elderly populations. There is a need to study insomnia in elderly, because the therapeutic dose often is lower and the incidence of side effects is greater in these patients. Studies also have evaluated the effect of drugs in normal volunteers undergoing an experimental challenge that produces transient insomnia [5]. These experimental manipulations, which include changing the sleep environment (sleeping in a laboratory or with noise in the background), changing the timing of sleep (as occurs with jet travel across multiple time zones), and decreasing homeostatic drive by requiring the subject to nap in the afternoon or consuming caffeine or other stimulants, produce a variety of sleep disturbances that can be corrected with effective sleep agents. More recently it has been become clear that most individuals who have insomnia have a comorbid condition and, more importantly, that the course of the insomnia and the course of the comorbid condition interact. Therefore efficacy studies also are being conducted in comorbid insomnia [6,7]. The most common comorbid conditions are those associated with a psychiatric disorder (eg, comorbid depression and anxiety) and/or a medical disorder (eg, comorbid disorders associated with pain and with dyspnea). In menopausal women it also is important to evaluate the effect of sleep agents on sleep induction and continuity and on the occurrence of menopause-related hot flashes during the night. In these studies a sample of patients meeting the diagnostic criteria for insomnia and for a comorbid disorder are recruited. Typically the subjects are allowed to take a medication for the comorbid condition in combination with the hypnotic (or placebo). To evaluate efficacy, the traditional sleep end points are assayed, and the signs and symptoms of the comorbid condition are evaluated also. For

Until recently the clinical lore was that insomnia was a symptom; therefore, the underlying condition should be treated in the long term, and hypnotic therapy should be undertaken only as a shortterm solution. As a result, hypnotic efficacy trials were conducted only on a short-term basis; the duration of most trials was 4 weeks or less. With the realization that insomnia is a chronic disorder and data showing that many insomniacs use hypnotics on a long-term basis, long-term trials of hypnotic are being conducted routinely [1]. Almost all sleep medications recently marketed or under development undergo efficacy trials for nightly use for 3 to 12 months [8]. These longer trials allow the evaluation of daytime function, which requires a longer therapeutic trial to demonstrate potential benefit.

Safety of benzodiazepine receptor agonists The drug class of choice for pharmacotherapy of insomnia is the benzodiazepine receptor agonists (BzRAs). This class includes all but one of the indicated hypnotics. The major side effects associated with BzRAs are psychomotor and cognitive (ie, anterograde amnesia) impairment, discontinuation effects, and the risk of dependence [9]. Some of these side effects are mediated by the primary pharmacodynamic activity of BzRAs—sedation—and thereby relate directly to the pharmacokinetic properties of specific BzRAs. Other side effects can be attributed to both the drug’s pharmacokinetics and the specificity of its receptor selectivity. Finally, drug dosage and duration of use may determine other of the side effects; drug dosage is the major determinant of all these side effects.

Psychomotor impairment Psychomotor impairment has been demonstrated in laboratory performance tests and actual roadway driving by slowed reaction times, response errors, tracking errors, lapses of attention, and driving deviations. At peak plasma concentrations, impairment relates directly to drug concentration (dose and time since ingestion). For example, the effects of daytime administration of 0.125, 0.25, and 0.50 mg triazolam, of 5, 10, and 20 mg zolpidem,

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and of 15, 30, and 60 mg temazepam were compared [10]. The drugs were chosen for their differences in pharmacokinetics and receptor selectivity, with temazepam being longer acting than zolpidem, and triazolam and zolpidem being more receptor selective than triazolam and temazepam. At peak concentration, zolpidem, triazolam, and temazepam each produced orderly dose-related impairments of psychomotor performance, learning, and recall. Their differential receptor selectivity (ie, zolpidem’s greater selectivity for gammaaminobutyric acid type A [GABAA] alpha 1 receptors) did not produce differing patterns of impairment at peak concentrations. The duration of impairment relates to both the half-life and dose. The time-course of impairment for the drugs in the study described previously revealed a 6-hour duration of impairment relative to placebo with temazepam (60 mg) and a 3-hour duration impairment with zolpidem (20 mg), although these drug doses had comparable impairing effects at their peak [10]. When the BzRAs are administered before sleep, and the impairment extends to the morning following the nighttime administration, the impairment is referred to as ‘‘residual effects’’ (ie, a prolongation of the therapeutic effect of the drug). Residual effects are not the same as a rebound effect; with residual effects, plasma concentrations of drug are still present, whereas rebound occurs after the plasma concentration has reached zero. Thus, the primary determinant of residual effects is the duration of drug action, which is determined by half-life of the drug and secondarily by the dose of the drug (eg, higher doses and longer half-lives extend the duration of action). Studies using performance, driving, and Multiple Sleep Latency Test (MSLT) assessments show differences in residual effects between short- and long-acting drugs and between doses of the same drug. A classic early study in healthy elderly persons compared the daytime residual effects of triazolam (0.25 mg) and flurazepam (15 mg) administered before sleep [11]. Both drugs produced a comparable 1-hour increase in total sleep time, but flurazepam, a long-acting drug, resulted in greater daytime sleepiness as evaluated by the MSLT on the following day, whereas triazolam, a short-acting drug, reduced sleepiness as evaluated by the MSLT. Also next-day vigilance performance was impaired with flurazepam, but triazolam had no effect on vigilance. The likelihood of residual effects is determined by the time of drug administration relative to the time of arising versus the pharmacokinetics of the drug. This point is illustrated in a study that compared the residual effects of zolpidem (10 mg), which has a short half-life (2.5–4.5 hours)

and of zaleplon (10 mg), which has an ultra-short half-life (1 hour) after middle-of-the-night administration (at 3:00, 4:00, 5:00, or 6:00 AM) before an 8:00 AM awakening or 2 to 5 hours after administration [12]. Zolpidem showed residual effects on digit symbol substitution and immediate and delayed memory recall after all the middle-of-thenight administrations, but no effects were observed with zaleplon, even when administered at 6 AM, 2 hours before awakening. Consequently, given the distinct pharmacokinetics for various hypnotics, the Food and Drug Administration labels may include the caution that 8 hours should be devoted to sleep when using the medication.

Cognitive impairment Cognitive impairment, typically anterograde amnesia, is another major side effect of BzRAs. Anterograde amnesia is memory failure for information presented after consumption of the drug. It is determined by the pharmacokinetics and dose of the drug: the plasma concentration at the time of information input determines the degree of amnesia (ie, memory consolidation failure). At peak plasma concentrations, very orderly dose-dependent amnesic effects have been demonstrated for BzRAs [10]. The amnesia is related in part to the sedative effects of the BzRAs, because the degree of the amnesic effects parallels the sedative effects as measured by the MSLT [13]. That failed consolidation of the newly acquired material is the cause of the amnesia was supported by a study in which the drug-induced rapid return to sleep was delayed for 15 minutes (ie, wakefulness was maintained for 15 minutes), and memory was preserved [14]. The extent to which the sedative effects mediate the amnesic effects has been disputed extensively, however. Several studies have attempted to dissociate the two effects by using drugs that have different effects on sedation and memory or by using the antagonist, flumazenil; results have been equivocal [15,16]. The problem with these studies is that sedation is self-reported rather than assessed objectively. Amnesia also is associated with the receptor selectivity of the BzRAs. The BzRAs act as allosteric modulators of GABAA receptors, and gene knockin studies have identified and characterized the pharmacologic profiles of various GABAA receptor subunits. Animal data indicate the alpha 1 receptor subtype mediates both the sleep and amnesic effects of the BzRAs [17]. When the first nonbenzodiazepine hypnotics were introduced, it was hypothesized that amnesia could be avoided because of the receptor selectivity of zolpidem. As noted previously, however, zolpidem, which is selective for the alpha 1 receptor, did not differ from the nonselective BzRAs in its amnesic effects

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[10]. The subsequent animal studies revealed that the alpha 1 receptor subtype mediates both sedation and memory. All BzRAs produce dosedependent anterograde amnesia, and no studies have demonstrated differences among the various drugs when sedative potency is controlled. Long-term BzRA use purportedly is associated with cognitive impairment, particularly in elderly persons. The results of studies assessing cognitive function in elderly chronic BzRA users are equivocal, with some studies reporting impairment and others finding minimal or no impairment [18–20]. It is difficult to make definitive conclusions, because these reports are cross-sectional and retrospective in nature with a number of possible confounds, and determining the appropriate controls for these studies is problematic. Furthermore, most of the information is from patients who have anxiety disorders who are using long-acting BzRAs. The relevance of these data to current best clinical practice for insomnia pharmacotherapy (ie, short-acting non-benzodiazepine hypnotics) is questionable.

Discontinuation effects The most prominent discontinuation effect of the BzRAs in clinical use is rebound insomnia [21]. Rebound insomnia is disturbed sleep for 1 to 2 nights relative to baseline after even 1 to 2 nights of previous BzRA use. In the short term, rebound insomnia does not seem to increase in severity with the duration of nightly use. It was reported first with the 0.5 mg dose, but not the 0.25 mg dose, of the short-acting drug triazolam [21]. Although proper multiple-dose studies exploring the threshold dose for rebound in other hypnotics have not been conducted, rebound is likely to occur after high doses (ie, beyond minimally effective doses) of all short- and intermediate-acting BzRAs. This prediction is based on the multiple-dose studies of daytime performance impairment that have compared various drugs with triazolam and have found comparable impairment at triazolam doses that produce rebound [10]. Rebound is not likely with any long-acting drugs because of the gradual decline in plasma concentrations inherent in their pharmacology. Clinically rebound can be minimized with short- and intermediate-acting drugs by tapering the dose gradually over a few nights. Rebound insomnia is an exacerbation of the original symptom (ie, insomnia) and thus differs from recrudescence, which is the return of the original symptom at its original severity. It is not a withdrawal syndrome (ie, expression of new symptoms), at least in the available short-term studies (ie, 2 weeks and less), which induced rebound but in which no other new symptoms were

observed [21]. The extent to which duration of use and dosage might combine to increase the likelihood of rebound, even at clinical doses, with long-term use, is not known fully. A recent study assessed rebound insomnia after 6 months of nightly use of eszopiclone at its clinical dose (3 mg) [22]. No increase in self-reported sleep latency or WASO relative to baseline was observed for 14 days after eszopiclone was discontinued. It has been suggested that the experience of rebound insomnia leads to continued chronic use of the hypnotic. A study directly tested that notion and showed that the experience of rebound insomnia did not alter the subsequent likelihood of a patient’s self-administering triazolam (0.25 mg) [23].

Liability for abuse With long-term use there is concern about dependence, because physical and behavioral dependence have been reported with long-term daytime anxiolytic use of therapeutic doses of BzRAs [24]. Systematic information regarding the risk of dependence with long-term therapeutic use of BzRA hypnotics at clinical doses is very limited, however. Epidemiologic studies indicate that most patients use hypnotics for 2 weeks or less [25,26]. Two recent placebo-controlled, double-blind studies of eszopiclone (3 mg) reported no evidence of physical or behavioral dependence after 6 months of nightly use [22,27]. These studies, however, did not directly test the risk of physical and behavioral dependence. Short-term studies directly testing the risk of behavioral dependence of BzRA hypnotics suggest they carry a low risk of behavioral dependence [28,29]. The risk of behavioral dependence was tested directly by using color-coded capsules to assess the self-administration of active drug versus self-administration of placebo. After sampling each color-coded capsule, patients chose a capsule based on its color over 7 to 14 subsequent nights. Self-administration of hypnotics by insomniacs was not associated with dose escalation with repeated use when insomniacs were given the opportunity to self-administer multiple capsules [29], did not increase with rebound insomnia [23], did not generalize to daytime use [30], and varied as a function of the nature and severity of the patient’s sleep disturbance [28]. This evidence indicates that the insomnia patients’ self-administration of hypnotics in these studies is therapy-seeking behavior and not drug seeking or abuse. These conclusions hold true for insomniacs and normal controls but not for individuals who have a history of drug abuse. One important question is the extent to which receptor subtype selectivity may influence the risk of abuse of the BzRAs. One assessment failed to find differential receptor subtype selectivity as

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a factor in the risk of abuse among drugs used as hypnotics [31]. For example, the risk of abuse of the alpha-1 receptor–selective drug zolpidem did not differ from that of various nonselective BzRAs. Few studies, however, have compared multiple doses of multiple drugs, and thus the rating had to be made across a variety of methodologies and data sources. The rating also included drug toxicities and thus was not specific to what is more narrowly defined as drug-abuse liability.

Falls The use of psychotropic medication has been reported to be associated with an increased risk of falls, particularly in elderly persons. A number of studies done in hospitalized, nursing home, and residential care patients have reported an association between the use of psychotropic medication and falls, but antidepressants seem to carry the highest risks for falls [32–37]. The BzRAs typically reported in these studies as being associated with risk of falls are all long-acting drugs used as daytime sedatives. The extent to which BzRA hypnotics used to treat insomnia, particularly the short-acting drugs, are associated with falls is not known fully. These studies did not control for the presence of insomnia, a known risk factor for falls in the elderly. Several recent studies controlling for insomnia have found the risk of falls associated with these medications is the same as, or even less than, the risk with untreated insomnia [36,37].

Idiosyncratic side effects Reports of idiosyncratic side effects associated with BzRA hypnotics have appeared periodically in the public press. These reports of ‘‘global amnesia,’’ somnambulism, and sleep-related eating disorders are problematic because they raise unnecessary concern among patients and their physicians. These reports are not peer reviewed, generally are not documented independently, are subject to confirmation bias, and overrepresent the real risk. Peer-reviewed case reports of idiosyncratic side effects associated with BzRA use also have appeared in the scientific and medical literature. One must view these reports with caution. Although case reports do provide more accurate information that includes contributing factors, they do not have the evidence level of placebo-controlled information. The real risk is unknown, because the rate of exposure is not known: the number of prescriptions written and the doses consumed at the time of the event are unknown, and consequently the incidence of the events cannot be determined. Transient global amnesia has been reported in association with the use of triazolam by otherwise healthy individuals [38,39]. The memory loss was

for all autobiographical events transpiring over an 8- to 12-hour period. In some of these cases in which clinical doses were used, prior stress, sleep deprivation, and a virus may have contributed to the amnesia. In other cases, supraclinical doses and alcohol ingestion probably were contributory factors. It is unlikely that this phenomenon is unique to triazolam, because similar kinds of amnesia are produced by the intravenous administration of other BzRAs. Somnambulism has been reported with zolpidem and zaleplon [40,41]. These episodes of somnambulism have occurred in individuals taking two to three times the clinical doses of the drug, in individuals who have a prior history of somnambulism, and in individuals who have experienced prior traumatic head injury. Zolpidem-associated somnambulism also has been reported in combination with antidepressant treatment [42]. Somnambulism is believed to be associated with partial arousals from sleep. Although BzRAs increase somnambulism, alcohol and sleep deprivation also produce partial arousals and increase somnambulism. Finally, there have been recent case reports involving sleep-related eating disorder and psychotropic medications, including BzRAs [43–48]. It is disputed whether sleep-related eating disorder is a disorder of partial arousal from sleep with altered levels of consciousness or is the psychiatric disorder of nocturnal eating with awareness and recall [46,48]. Sleep-related eating disorder is hypothesized to share a common pathophysiology with somnambulism. Zolpidem was reported to exacerbate sleep-related eating disorder and in several cases to induce it de novo [46]. In some of these cases doses of zolpidem greater than 10 mg were being used, and in other cases there was use of sedating antidepressants. Sleep-related eating disorder also has been reported with triazolam [47,49]. A common thread links much of this case-report information: excessive hypnotic activity or sleep drive. The excessive hypnotic activity can occur as a result of high doses, clinical doses in vulnerable individuals (ie, those who have a past history of sleep disorders or brain injury), the combination of clinical or high doses with prior sleep deprivation caused by stress or illness, or the combination of clinical or high doses with the prior consumption of alcohol. The behaviors described in these case reports also share a commonality. They all are symptoms of excessive hypnotic activity or excessive sleepiness. Patients who have primary sleep disorders report amnesia and memory difficulties associated with excessive daytime sleepiness. Sleep deprivation produces intense slow-wave sleep, and abrupt arousal from slow-wave sleep after prior sleep deprivation is known to be associated with

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sleep inertia, behavior of which individuals have little consciousness or little memory. Patients who have excessive sleepiness are known to engage in automatic behavior. Sleep deprivation also is known to induce somnambulism in individuals who have a previous history of somnambulism. Thus, this information from case reports is not quite as idiosyncratic as it first might seem. This information relates to the known effects of high doses of BzRAs and to the effects of other manipulations of sleep, such as sleep-phase reversal, sleep deprivation, sleep fragmentation, and the consumption of alcohol and other sedating drugs. Clinically, two points should be emphasized. First, excessive sleep drive and hypnotic activity produced by high doses (doses above the approved clinical doses), a combination of sedating drugs, or the combination of prior sleep deprivation and a sedating drug in vulnerable individuals should be avoided. Thus, the dose used, the concurrent use of other sedating drugs, and the time in bed after drug ingestion should be monitored carefully. Second, by most indications these side effects are rare when the medications are used appropriately. One study of adverse reactions to sedative hypnotics over a 3-year period found the median frequency of report adverse reactions was 0.01%, or 1 in 10,000 doses [50]. In double-blind, placebo-controlled trials no reports of such adverse events associated with the BzRAs have been reported.

Drugs used for insomnia therapy A variety of drugs from different drug classes are prescribed for insomnia pharmacotherapy, and insomniacs also report self-treating their insomnia with alcohol and with over-the-counter (OTC) and herbal agents. The drugs currently approved for pharmacotherapy of insomnia are listed in Table 1. As noted earlier, with one exception, the BzRAs are the drug class of choice for insomnia pharmacotherapy. The BzRAs share a common mechanism of action; the one non-BzRA, ramelteon, has a unique mechanism, stimulation of the melatonin MT1 receptor. The BzRAs differ in their receptor-binding specificity, time to maximum concentration, and half-life.

On-label use The term ‘‘benzodiazepine receptor agonists’’ is derived from the recognized mechanism of action of these drugs, which involves occupation of benzodiazepine receptors on the GABAA receptor complex, resulting in the opening of chloride ion channels and facilitation of GABA inhibition [51]. Some of these drugs, described in Table 1,

Table 1: Drug

Insomnia treatment medications Half-life (in hours)

BzRAs Estazolam 8–24 Flurazepam 48–120 Quazepam 48–120 Temazepam 8–20 Triazolam 2–4 Non-BzRAs Imidazopyridine Zolpidem 1.5–2.4 Zolpidem 2.8–2.9 extended-release Pyrazolopyrimidine Zaleplon w1 Pyrrolopyrazine Eszopiclone 5–7 MT agonist Ramelteon 1–2.6

Available dose (in mg) 1, 2 15, 30 7.5, 15 7.5, 15, 22.5, 30 0.125, 0.25

5, 10 6.25, 12.5

5, 10 1, 2, 3 8

have a benzodiazepine chemical structure (ie, estazolam, flurazepam, quazepam, temazepam, triazolam); others (ie, zaleplon, zolpidem, zolpidem CR, eszopiclone) do not. The one non-BzRA, remelteon, acts as an agonist at MT1 receptors in the super-chiasmatic nucleus (SCN). The SCN contains high concentrations of MT1 and MT2 receptors; the MT1 receptors are thought to attenuate the SCN’s alerting signal, and the MT2 receptors are thought to synchronize the circadian clock [52,53]. The binding affinity of the BzRAs for most GABAA receptor subtypes is similar. In contrast, the affinity of the non-BzRAs for the receptor subtype with an alpha-1 subunit is much higher than for other subtypes [54]. Because receptors with alpha-1 subunits mediate sedation, amnesia, and some of the anticonvulsant properties, but not anxiolysis or myorelaxation, it is possible that these more selective drugs will have hypnotic effects with fewer side effects [54]. This conjecture remains to be demonstrated definitely, however. The other major difference among BzRAs is in their pharmacokinetics: some have an ultra-short half-life, others have a short or an intermediate half-life, and some have a long half-life. Drugs that have an intermediate and long half-life are likely to produce residual daytime sedation, whereas zaleplon, which has an ultra-short halflife, is indicated only for sleep induction, not for sleep maintenance. The non-BzRA, remelteon, also is indicated only for sleep induction. All theindicated hypnotics in short- and intermediate-term studies have been shown to reduce sleep latency and most, excepting zaleplon and remelteon,

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increase total sleep time as assessed by patient reports, by nocturnal PSGs, or both. The development of tolerance to the hypnotic effects of these drugs has been an area of dispute. Tolerance classically is defined as the reduction of a drug effect with repeated administration of a constant dose or the need to increase the dosage to sustain a specific level of effect. Despite speculations in the medical literature, tolerance to the hypnotic effects of BzRAs did not develop in most studies, at least at the therapeutic doses for the periods of time that have been studied. Investigations that often are cited as evidence for the development of tolerance (eg, the study by Mitler and colleagues [55]) show gradual improvement over time in the placebo group versus a constant effect in the drug group, resulting in loss of statistical significance. The sleep in the active drug groups does not worsen with time with a stable dose of drug, as the definition of tolerance requires. Thus, one cannot conclude that tolerance has developed. It is likely that unspecified changes have occurred over time with placebo, such as spontaneous remission, regression to the mean (if there are sleep disruption entry criteria), sleep hygiene influences inherent in protocol adherence, Hawthorne effects, and true placebo effects. Several recent large-sample outpatient studies have shown continued hypnotic efficacy of eszopiclone (3 mg) for 6 months and more of nightly administration [8,56]. Chronic primary insomnia is defined as difficulty initiating or maintaining sleep or as nonrestorative sleep that is associated with some type of daytime impairment. One would expect that improved nighttime sleep would result in improved daytime function. Few studies, however, have documented impaired daytime function in primary insomniacs objectively, and consequently improved daytime function associated with improved nighttime sleep has been an elusive outcome. Among other things, the problem relates to an incomplete understanding of the pathophysiology of primary insomnia. In the 6-month eszopiclone studies, however, patient reports of daytime alertness, ability to function during the day, and physical sense of well being were improved relative to placebo [8,56].

Off-label use Sedating antidepressants The most frequently prescribed medications for the treatment of primary insomnia are sedating antidepressants, trazodone, amitriptyline, and mirtazepine being the leading three [57]. Unfortunately, little is known about their mechanism of action for hypnotic effects or their efficacy and safety as hypnotics. The transmitter systems altered by the three leading sedating antidepressants differ.

Trazodone antagonizes serotonin 2a (5HT2a), 5HT2c, and alpha1-adrenergic receptors and also inhibits 5HT reuptake [58,59]. Amitriptyline blocks acetylcholine and histamine binding and inhibits reuptake of norepinephrine and 5HT [60–62]. Mirtazepine antagonizes alpha1-adrenergic, 5HT2a, 5HT2c, and 5HT3 receptors, and is a strong histamine receptor type 1 (H1) antagonist [63,64]. Amitriptyline and mirtazepine share antihistaminergic activity, which may produce hypnotic effects. The hypnotic activity of trazodone may occur through 5HT2a, 5HT2c, and/or alpha1-adrenergic mechanisms. To the authors’ knowledge, the data concerning the hypnotic efficacy of sedating antidepressant agents in primary insomniacs are limited to two studies of trazodone, two studies of trimipramine, and two studies of doxepin [65–68]. Amitriptyline and mirtazepine have not been studied in primary insomnia. Trazodone (150 mg) in ‘‘poor sleepers’’ (participants were not further characterized) over 3 weeks reduced WASO and stage 1 sleep and increased stage 3 to 4 sleep relative to a placebo baseline, but it did not increase total sleep time or reduce sleep latency [65]. In well-defined primary insomniacs, trazodone (50 mg), compared with zolpidem (10 mg) and parallel placebo, reduced self-reported sleep latency and increased sleep duration only during the first week of the 2-week study; zolpidem, however, continued to reduce sleep latency during the second week of the study [66]. One of the trimipramine studies failed to find a significant improvement of PSG-defined sleep measures with a mean dose of 100 mg taken for 1 month, although self-rated sleep did show improvement relative to placebo [67]. The second trimipramine study found an increase in total sleep time and sleep quality relative to a baseline with a average 166-mg dose taken for 1 month [68]. This study, however, did not include a parallel placebo group. Doxepin (25–50 mg) taken nightly for 1 month by primary insomniacs improved total sleep time and WASO on both nights 1 and 28 relative to a parallel placebo group [69]. Lower doses of doxepin (1, 3, and 6 mg), with less likelihood of anticholinergic side effects, were studied recently in primary insomniacs [70]. Taken for 2 nights in a crossover design, 1, 3, and 6 mg of doxepin increased total sleep time and reduced WASO relative to placebo. The side-effect profile of the sedating antidepressants may be more problematic, particularly compared with the BzRAs,. The safety data for sedating antidepressants have been compiled from studies of patients who have primary depression using antidepressant doses. As a case in point, in the 25- to

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50-mg doxepin study cited previously, two of the four insomniacs who discontinued doxepin treatment did so because of significant adverse events [69], but no serious adverse events were reported in the study of low-dose doxepin [70]. With that proviso, the margin of safety is much narrower with antidepressants than with BzRAs and, because the half-life of most of these drugs is 9 to 30 hours, the likelihood of daytime residual effects is enhanced. Anticholinergic side effects are reported with many of the tricyclic antidepressants, including amitriptyline and trimipramine. For example, in the previously cited study of trimipramine in primary insomniacs, dizziness, dry mouth, headache, and nausea were more frequent than with the comparator drug, lormetazepam [67]. With trazodone, orthostatic hypotension, weakness, and lightheadedness are common; cardiac conduction abnormalities have been reported in patients who have pre-existing heart disease; and, although rare, priapism is a potentially serious side effect [71–74]. Antipsychotics The antipsychotics quetiapine and olanzapine also are used frequently as hypnotics in people who have primary insomnia. Unlike the sedating antidepressants, almost no information is available about the efficacy and safety of their use as hypnotics in primary insomnia. Any sedative effects with these drugs may result from their antihistaminic activity. These drugs also have adrenergic, muscarinic, dopaminergic, and serotonergic activity. Activity at these multiple transmitter systems increases the likelihood of side effects. Anxiolytics Anxiolytics, including clonazepam, alprazolam, and lorazepam, also were among the 16 drugs most frequently reported as being used to treat insomnia [57]. Furthermore, the anxiolytics are prescribed as hypnotics for a longer initial period of treatment, and the prescriptions are refilled more frequently [75]. The mechanism of action of these drugs is the same as for the hypnotic BzRAs. To the authors’ knowledge, however, there are no studies of their hypnotic efficacy in primary insomnia. Clonazepam has been studied as a second-line treatment for periodic limb movement disorder and as a primary treatment for various parasomnia disorders [76,77]. Having the same mechanism of action, these drugs have side effect profiles similar to those of the hypnotic BzRAs. The half-lives of clonazepam and lorazepam are longer than 6 hours, and thus they are likely to produce residual effects. Alprazolam is chemically similar to triazolam and has a short half-life.

Self-treatment In the general population relatively few people who have insomnia receive medical treatment; one study reported that 5% received treatment [78]. Persons who have insomnia do use other available substances to treat their condition. Population-based studies have reported that 10% to 28% of respondents report using alcohol as a sleep aid, and 10% to 29% use OTC sleep aids [75,78–80]. Alcohol Reported studies of the effects of alcohol on sleep conducted in healthy normal persons have used high alcohol doses, doses that raise alcohol breath concentrations above 0.05% [81]. These doses disrupt sleep, at least during the second half of the night. Insomniacs, however, report using low doses, one to two drinks before sleep [79]. The use of lowdose alcohol as a sleep aid is potentially dangerous for two reasons. Low-dose alcohol initially improves the sleep of insomniacs, which is why they self-administer it as a sleep aid [82]. Within 6 nights, however, tolerance develops, sleep is worsened beyond baseline, and larger alcohol doses are selfadministered to achieve the sleep effect [83,84]. Also, in one population-based study, insomniacs who reported using alcohol as a sleep aid reported greater levels of daytime sleepiness than those who used prescription or OTC drugs for sleep [26]. Over-the-counter sleep aids The active component of most all OTC sleep aids is an H1 antihistamine, typically diphenhydramine (25 mg). Several studies of diphenhydramine (25–50 mg) have shown hypnotic effects for several nights of administration, but these were not parallel, placebo-controlled studies [85,86]. There is limited placebo-controlled evidence that diphenhydramine has hypnotic efficacy, and it has been shown that tolerance to the sedative effects of diphenhydramine develops rapidly [87]. Herbals According to the 2002 National Health Interview Survey of the general population, 17% of respondents reported insomnia within the past year, and approximately 5% of persons who had experienced insomnia reported using various alternative treatments, mostly herbals, for their insomnia [88]. There is a paucity of rigorous scientific investigation of the efficacy and safety of the use of herbals to treat insomnia. The herbal that has received the most investigation is valerian. Valerian is a root occurring in several species (ie, Valeriana officinalis, Valeriana wallichii, Valeriana edulis), which is extracted and prepared by different methods, producing differing chemical constituents in the final

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product [89]. The mechanism of action for valerian’s hypnotic effect is not certain, although one study suggests that valerian has agonistic activity at the adenosine A1 receptor [90]. A recent systematic review identified 29 controlled trials of the efficacy of valerian in insomniacs and concluded that, regardless of preparation, valerian did not improve self-rated or PSG-rated sleep relative to placebo [89]. The failure to find efficacy occurred although the placebo condition in more than half the studies did not control for the distinctive, unpleasant odor of valerian. Another herbal taken for a variety of conditions, including depression, anxiety, and sleep disturbances, is St John’s Wort [91]. St John’s Wort is a flowering herb that also is available in a number of different preparations, although the active ingredient is thought to be hyperforin [91]. Hyperforin inhibits reuptake of serotonin, norepinephrine, dopamine, L-glutamate, and GABA. Trials of its efficacy in depression have been conducted, but there are no trials in primary insomnia. The results of the two studies of its hypnotic activity in healthy normal persons are equivocal [91].

Special populations Elderly persons Treating insomnia in the elderly is complex for two reasons: the normal change in drug pharmacokinetics associated with aging, and the increased frequency of primary sleep disorders in elderly persons. A number of age-related changes in gastrointestinal structure and function have been documented that affect the absorption of drugs, and age-related changes in body morphology alter drug distribution [92]. Better known is the agingassociated change in liver function that alters drug metabolism. Drugs that are metabolized primarily by conjugation are potentially safer for aged patients or patients who have liver disease. The characteristic pharmacokinetics of oxidated drugs are altered in elderly people and in patients who have liver disease by increasing the area under the plasmaconcentration curve. This alteration occurs in some drugs (eg, triazolam) by increasing the peak plasma concentration and in others (eg, flurazepam) by extending the duration of significant blood levels. The reduced recommended dose for most hypnotics when treating elderly patients is related, in part, to these kinetic changes. The second issue in treating insomnia in the elderly relates to the increased frequency of primary sleep disorders in elderly persons, a welldocumented phenomenon [92]. The issue of use

of hypnotics in persons who have primary sleep disorders is discussed in the next section.

Patients who have primary sleep disorders There is a potential negative effect of drugs used as hypnotics in insomniacs who have the primary sleep disorders of sleep-related breathing disturbances and periodic leg movements. Among the drugs most frequently prescribed for treatment of insomnia are the sedating antidepressants, one of which is the tricyclic, amitriptyline. The tricyclics are reported to exacerbate periodic leg movements, although the risk factors, mechanisms, and doserelations for this effect are unclear [92,93]. On the other hand, BzRA hypnotics improve periodic leg movements by reducing the arousals associated with the leg movements. Drugs that have a sedative effect, including the BzRAs, have the potential to exacerbate sleeprelated breathing disturbances. The early data were scientifically weak and somewhat equivocal. The evidence now suggests that hypnotics do not induce sleep-related breathing disturbance in people without such disturbance, do produce a small increase in people who have occasional apnea and hypopnea, and exacerbate sleep-related breathing in patients who have clear obstructive sleep apnea syndrome [92].

Persons who have hepatic/renal impairments Because most hypnotics undergo hepatic metabolism, advanced liver disease requires the use of a lower dose or avoidance of these medications. The alteration of the pharmacokinetics of hypnotics in cases of compromised liver function was discussed earlier in this article.

Alcohol and substance abusers Although the risk of developing dependence on BzRAs and other sedative drugs is low, most patients who have a history of alcoholism or drug abuse should not receive BzRAs in outpatient settings without close supervision. The BzRAs also should be used cautiously by moderate users of alcohol because the additive sedative effects with hypnotics narrow the wide margin of safety. Sleep-related eating disorder in association with hypnotic use is often reported after prior alcohol consumption, suggesting additive sedative effects evoke the eating disorder. Given the persisting sleep disturbance of alcoholism and the proven risk of relapse associated with the sleep disturbance, treating that disturbance is clinically important. No alternative to the BzRAs has emerged, however. GABA agonists, specifically gabapentin, have shown some promise, but in studies to date their use either has improved sleep but

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not drinking outcomes or has improved drinking outcomes but not sleep [94]. Selective 5HT2A receptor antagonists such as ritanserin, eplivanserin, and several others are being investigated as hypnotics because of their capacity of enhance slow-wave sleep [94]. Like the BzRAs, these drugs have not shown strong effects on sleep induction.

[14]

[15]

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[65] Montgomery I, Oswald I, Morgan K, et al. Trazodone enhances sleep in subjective quality but not in objective duration. Br J Clin Pharmacol 1983;16:139–44. [66] Walsh JK, Erman M, Erwin CW, et al. Subjective hypnotic efficacy of trazodone and zolpidem in DSM-III-R primary insomnia. Hum Psychopharmacol 1998;13:191–8. [67] Riemann D, Voderholzer U, Cohrs S, et al. Trimipramine in primary insomnia: results of a polysomnographic double-blind controlled study. Pharmacopsychiatry 2002;35:165–74. [68] Hohagen F, Montero RF, Weiss E, et al. Treatment of primary insomnia with trimipramine: an alternative to benzodiazepine hypnotics? Eur Arch Psychiatry Clin Neurosci 1994;244(2):65–72. [69] Hajak G, Rodenbeck A, Voderholzer U, et al. Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study. J Clin Psychiatry 2001;62:453–63. [70] Roth T, Rogowski R, Hull S. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep 2007;30:1555–61. [71] Golden RN, Dawkins K, Nicholas L. Trazadone and nefazodone. In: Schatzberg A, Nemeroff C, editors. The American psychiatric textbook of psychopharmacology. Washington, DC: American Psychiatric Textbook, Inc.; 2004. p. 315–25. [72] Levenson JL. Prolonged QT interval after trazodone overdose. Am J Psychiatry 1999;156: 969–70. [73] Haria M, Fitton A, McTavish D. Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders. Drugs Aging 1994;4:331–55. [74] Carson CC III, Mino RD. Priapism associated with trazodone therapy. J Urol 1988;139: 369–70. [75] Roehrs T, Roth T.‘Hypnotic’ prescription patterns in a large managed-care population. Sleep Med 2004;5:463–6. [76] Montplaisir J, Allen RP, Walters AS, et al. Restless legs syndrome and periodic leg movements during sleep. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. 4th edition. Philadelphia: Elsevier Saunders; 2005. p. 839–52. [77] Mahowald MW, Schenck CH. REM sleep parasomnias. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. 4th edition. Philadelphia: Elsevier Saunders; 2005. p. 897–916. [78] Ancoli-Israel S, Roth T. Characteristics of insomnia in the United States: results of the 1991 National Sleep Foundation Survey. I. Sleep 1999;22:S347–53.

[79] Gallup. Sleep in America. Princeton (NJ): Gallup Organization; 1995. p. 1–78. [80] Johnson EO, Roehrs T, Roth T, et al. Epidemiology of alcohol and medication as aids to sleep in early adulthood. Sleep 1998;21:178–86. [81] Roehrs T, Roth T. Sleep, sleepiness, sleep disorders and alcohol use and abuse. Sleep Med Rev 2001;5:287–97. [82] Roehrs T, Papineau K, Rosenthal L, et al. Ethanol as a hypnotic in insomniacs: self administration and effects of sleep and mood. Neuropsychopharmacology 1999;20:279–86. [83] Roehrs T, Blaisdell B, Cruz N, et al. Tolerance to hypnotic effects of ethanol in insomniacs. [abstract]. Sleep 2004;27:A52. [84] Roehrs TA, Blaisdell B, Richardson GS, et al. Insomnia as a path to alcoholism: dose escalation [abstract]. Sleep 2003;26:A307. [85] Kudo Y, Kurihara M. Clinical evaluation of diphenhydramine hydrochloride for the treatment of insomnia in psychiatric patients: a double-blind study. J Clin Pharmacol 1990; 30:1041–8. [86] Rickels K, Morris RJ, Newman H, et al. Diphenhydramine in insomniac family practice patients: a double-blind study. J Clin Pharmacol 1983;23(5–6):234–42. [87] Richardson GS, Roehrs TA, Rosenthal L, et al. Tolerance to daytime sedative effects of H1 antihistamines. J Clin Psychopharmacol 2002;22: 511–5. [88] Pearson NJ, Johnson LL, Nahin RL. Insomnia, trouble sleeping, and complementary and alternative medicine. Arch Intern Med 2006;166: 1775–82. [89] Taibi DM, Landis CA, Petry H, et al. A systematic review of valerian as a sleep aid: safe but not effective. Sleep Med Rev 2007;11:209–30. [90] Muller CE, Schumacher B, Brattstrom A, et al. Interactions of valerian extracts and a fixed valerian-hop extract combination with adenosine receptors. Life Sci 2002;71:1939–49. [91] Clinical Practice Review Committee, American Academy of Sleep Medicine. Oral nonprescription treatment for insomnia: an evaluation of products with limited evidence. J Clin Sleep Med 2005;1:173–87. [92] Roehrs T, Roth T. Drugs, sleep disorders, and aging. Clin Geriatr Med 1989;5:395–404. [93] Schweitzer PK. Drugs that disturb sleep and wakefulness. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. 4th edition. Philadelphia: Elsevier Saunders; 2005. p. 499–518. [94] Brower KJ. Insomnia, alcoholism and relapse. Sleep Med Rev 2003;7:523–39.

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Nonpharmacologic Strategies in the Management of Insomnia: Rationale and Implementation Paul B. Glovinsky, PhDa,b,*, Chien-Ming Yang, PhDc, Boris Dubrovsky, PhDd, Arthur J. Spielman, PhDa,d -

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Neurophysiologic models of insomnia Psychologic and behavioral factors affecting sleep Dysfunctional sleep cognitions Behaviors adversely affecting sleep Emotional arousal The 3P model of insomnia Evaluation of insomnia Cognitive behavioral interventions for insomnia

As a physician, you probably offer a fair amount of support and encouragement along with more specific recommendations. Whether you are exhorting your patients to diet, exercise, or more assiduously monitor blood sugar, the underlying message they are likely to hear is that they should be making more of an effort. This advice is not necessarily regrettable, because trying harder is generally beneficial when coping with chronic illness; however, the situation grows trickier when dealing with insomnia. Trying harder to sleep often proves counterproductive. Natural sleep can occasionally be coerced into making an appearance, for example, by

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Sleep hygiene education Stimulus control instructions Sleep restriction therapy Relaxation training Cognitive therapy Chronotherapy Light therapy Selecting and delivering cognitive behavioral treatments References

prolonged sleep deprivation, but typically the prospects for sleep dissipate when too much force is applied. Patients who plant themselves in bed hoping to net an adequate amount of sleep even if it takes all night and half the morning usually end up with sleep that is unsatisfying and broken. The same is true of those who obsess over the ingredients of a good night, searching for a fail-safe recipe. The best way to fall asleep and stay asleep is not to think so much about it. This prescription is easy enough for good sleepers to follow but not so for those who have been plagued by months or years of sleep

a

Department of Psychology, The City College of New York NAC 7/120, 138th Street and Convent Avenue, New York, NY 10031, USA b St. Peter’s Sleep Center, Pine West Plaza # 1, Washington Avenue Ext., Albany, NY 12205, USA c Department of Psychology, National Chengchi University, 64, Sec. 2, Chih-Nan Road, Taipei, Taiwan 116 d Center for Sleep Disorders Medicine and Research, New York Methodist Hospital, 519 Sixth Street, Brooklyn, NY 11215, USA * Corresponding author. St. Peter’s Sleep Center, Pine West Plaza # 1, Washington Avenue Ext., Albany, NY 12205. E-mail address: [email protected] (P.B. Glovinsky). 1556-407X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

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difficulties. These poor sleepers have learned to their chagrin not only that their sleep is unreliable but also that they can conjure up a night of sleeplessness ‘‘out of thin air’’ merely by imagining it might happen. This article surveys cognitive behavioral treatments for insomnia (CBT-I), providing a basic review of their theoretic rationale and practical strategies for their implementation. Substantial evidence demonstrates that CBT-I offers effective and sustained benefits for patients contending with insomnia, regardless of whether the sleep disturbance is of a primary nature [1–4] or secondary to a psychiatric or medical disorder [5–10]. The current evidence-based view is that non-drug treatments are at least as effective as pharmacologic remedies [11–14]. Demonstrated efficacy notwithstanding, CBT-I can present as a motley group of interventions. In the text to follow, we discuss therapies that involve altering bedtime schedules, initiating worry journals, making rounds between the bed and an easy chair, muscle relaxation, bright light exposure, mental imagery, and more. Is the only attribute that binds such an array the fact that they are nonpharmacologic? We submit that the therapies have something more substantial in common, that is, CBT-I represents efforts to counter the unreliable and evanescent nature of sleep, especially as it is experienced by veteran insomniacs, by recruiting from among a wide range of processes known to affect sleep—be these physiologic, cognitive, behavioral, environmental, or social—and aligning them in the service of sleeping well. In their roundabout approach, CBT-I presents a contrast with pharmacologic treatments, which act directly on neurotransmitters subserving sleep to increase the propensity of falling and staying asleep. Of course sleeping pills do require modest cooperation from patients (in terms of maintaining behavioral and cognitive quiescence) to work effectively. Typically, poor sleepers who have just taken a hypnotic are able to do their part in this regard. Instead of becoming more keyed up as night falls, they can relax as they perceive the balance tipping in favor of sleep. They may even relish the sense that the impending slide is a fait accompli, that is, this time out they will not be able to sabotage their own prospects. An unheralded but important psychologic effect of sleeping pills, therefore, is that they allow poor sleepers to cede control of the mission to sleep. Although beneficial in the short run, this consequence of resorting to sleeping pills is a core component of the psychologic dependence that can accrue with long-term use. Poor sleepers tend to attribute whatever sleep they have accumulated to the pill itself,

shortchanging their own contributions. Anticipatory anxiety and pharmacologically based withdrawal symptoms often collude to produce ‘‘rebound insomnia’’ when such patients refrain from sleeping pills, confirming the need for continued use. CBT-I is useful in transitioning patients away from sleeping pill dependency, because it provides means by which these patients can improve their sleep by dint of their own efforts. Given that CBT-I draws upon wide-ranging models of sleep/wake functioning, we feel it appropriate to review these explanatory models. A deeper understanding is not only of academic interest but also clinically useful, providing a sturdy theoretic framework with which to buttress treatment recommendations. In contrast to sleeping pills, CBT-I is not coated with face validity. These treatments may be met with initial skepticism on the part of patients because they typically involve interventions that run counter to current practices. Success often hinges on fostering patience in the weeks before the beneficial effects of treatment become apparent. This goal is best accomplished by accompanying your seemingly outlandish advice with a solid theoretic rationale. The following sections provide a brief overview of strategies for evaluating insomnia, with the aim of helping one elicit clinical material than can guide the choice of treatment. Readers interested in more in-depth treatment of this topic are referred to several comprehensive reviews [15–17]. We then describe the practical application of CBT-I, highlighting critical issues and potential pitfalls.

Neurophysiologic models of insomnia Insomnia can be construed as a disruption of the balance between three major neural systems regulating sleep: (1) a homeostatic system that with each passing hour of wakefulness increases the propensity to sleep; (2) a circadian process that generates a biologic rhythm of sleep and wake tendency irrespective of recent sleep history; and (3) an arousal system that promotes wakefulness, countering the homeostatic sleep drive [18–20]. The homeostatic system works to maintain an adequate amount of total sleep over successive nights. The level of sleep drive present on the basis of this homeostatic mechanism is at any given time determined by prior durations of sleep and wakefulness. If an individual’s sleep is curtailed, this leads to an augmented sleep drive and an increased likelihood of accumulating extra recovery sleep during subsequent time in bed, thereby restoring the balance. Oversleeping and napping by contrast reduce the homeostatic sleep drive, leading to shorter or lighter stints of sleep.

Nonpharmacologic Management of Insomnia

The circadian system is based on an internal clock in the hypothalamus that generates a rhythm of sleepiness and alertness independent of prior sleep history. Studies of animals and humans have identified the genetic basis of this cycle [21,22]. The typical endogenous circadian cycle in human beings has a period of slightly over 24 hours [23,24]; there is an innate tendency for our bedtimes and rising times to slowly drift later around the clock. This propensity is often revealed during vacation periods, when we are not as constrained by externally imposed schedules. Exposure to environmental time cues, especially daylight or other bright light, can stabilize an endogenous circadian rhythm that would otherwise ‘‘free run.’’ The arousal system counteracts the sleep drive through the promotion of alertness. Activated by internal thoughts and emotions as well as by external stimulation, it can be viewed as a mobilizing system intended to arouse the organism when it is at risk. In contrast to the homeostatic mechanism that gradually strengthens the sleep drive as our waking hours pass, alertness can soar in a moment, as required in an emergency. Although this arrangement may be adaptive from an evolutionary standpoint, it works against the prospects for sleep in insomnia patients, whose careful preparations for sleep can be overturned in an instant by an errant thought. Several models highlighting the role of arousal as a cause of insomnia have been proposed [25,26]. Individuals with insomnia have been shown to have elevated autonomic activity, indicated by a higher metabolic rate, body temperature, heart rate, urinary cortisol and adrenaline excretion, skin conduction, and muscle tension [27,28], as well as increased cognitive processing around sleep onset or during sleep as reflected by faster electroencephalographic frequencies [29–31]. Recent studies using event-related potentials [32] and PET imaging [33] further demonstrate a relative inability to lower general attentional or arousal processes as well as impairment in the sleep-specific inhibitory process associated with sleep initiation in patients with insomnia. Difficulty sleeping can arise from inherited anomalies pertaining to each of the three systems subserving sleep and wakefulness described previously. Some individuals possess an inherently weak homeostatic sleep drive. Others are under the sway of atypical circadian clocks. For example, persons who have clocks that are strongly biased toward sleep phase delay may comfortably follow a ‘‘night owl’’ pattern under typical circumstances but be at greater risk for sleep initiation difficulties when stressed. Although persons who have hyperaroused ‘‘type A’’ constitutions may benefit from

that makeup during waking hours in terms of productivity, their sleep may be especially vulnerable to disruption. In addition to inherited predispositions, insomnia may be learned. Formerly good sleepers can engage in maladaptive behavioral practices that lead to a weakened sleep drive, an attenuated circadian sleep/wake cycle, or hyperarousal at bedtime. For example, the freedom from work-imposed sleep schedules that comes with retirement can lead to irregular sleep patterns and eventually to insomnia even as the stakes regarding performance the next day have been reduced.

Psychologic and behavioral factors affecting sleep Although the three physiologically based systems described previously interact to create a stable sleep/wake cycle under ideal conditions, this outcome is by no means assured because sleep is so susceptible to interruption by psychologic and behavioral factors. Sleep is readily deferred (at least in the short run) in the aftermath of emotionally charged experiences, to complete tasks deemed sufficiently important, or to maintain vigilance in the face of real or perceived threats. This tilt toward wakefulness renders sleep, in the minds of chronically poor sleepers, vulnerable and capricious.

Dysfunctional sleep cognitions Several studies have provided evidence that anxious or dysphoric thoughts are likely to inhibit sleep [34–39]. Insomnia is clearly associated with worrying that has a ‘‘real world’’ basis or with exposure to traumatic events; however, even neutral cognitions such as planning for the week ahead can interfere with sleep. Sometimes it is not so much the content as the form of thinking that proves deleterious. Many patients insist they are not particularly worried about anything. Rather, their minds simply ‘‘will not shut off’’; they may race instead from thought to thought or incessantly replay an advertising jingle. A special case obtains when concern centers on sleep itself. A string of poor nights provides fodder for lamenting the past and worrying about the future. Recalling long hours of nocturnal wakefulness and consequent daytime listlessness and anticipation of more of the same is a surefire way to avert sleep. A similar pattern may be seen if patients harbor unreasonable expectations about sleep. Poor sleepers who feel that their insomnia is ‘‘inevitable’’ and will necessarily lead to dire health consequences may become frenzied by bedtime. The sleeplessness that predictably follows only cements their original premonitions. Directly challenging

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dysfunctional thinking about sleep through education and cognitive therapy has been shown to improve sleep [40,41].

Behaviors adversely affecting sleep The impact of evening activity on subsequent sleep quality is underappreciated. Poor sleepers are often surprised to learn that they need at least 4 hours in which to wind down before sleep. They cannot expect to work an evening shift, finish up an assignment brought home from the office, or play in an evening basketball league and still fall asleep at a relatively early hour. Even seemingly relaxing activities such as calling friends or surfing the Web may prove sufficiently stimulating to preclude sleep. Poor sleepers should strive instead to disengage from real world concerns, be they work related or social, in the hours before bedtime. A particularly pernicious set of behaviors originates in the desire to compensate for poor sleep or its daytime effects [42]. It is common to hear that patients will sleep into the morning following a disrupted night when their schedules allow or take an afternoon nap. These responses may bring short-term relief from the effects of sleep loss but at the cost of reducing the amount of sleep drive available to induce sleep at bedtime, or of disrupting the circadian processes that regulate sleep and wakefulness. Box 1 lists common daily life practices that may interfere with sleep in these ways.

Emotional arousal Transient insomnia in the face of acute stress is a nearly universal experience resulting directly from autonomic nervous system activation and hormone release subserving the ‘‘fight or flight’’ reaction [27]; however, some individuals are more vulnerable to chronic sleep disruption than others [43]. Persons who internalize conflicts through self-inhibition, denial, or suppression seem to be more susceptible to sleeplessness [44]. The need for perfection and the need to maintain control are associated with insomnia, just as are more predictable psychologic traits such as a predisposition to anxiety and depression [44–47]. Arousal can also be a learned response, appearing in specific contexts such as the approach of bedtime or entry into the bedroom after repeated pairings of these contexts with the experience of sleeplessness. Once such associative links are established, bedtime with its attendant rituals begins to offer contextual cues for arousal rather than sleep [48]. Fig. 1 offers a schematic representation of how behavioral and psychologic factors influence sleep through the mediation of the three neural systems described above.

The 3P model of insomnia The waxing and waning of the various physiologic, psychologic, and behavioral factors contributing to insomnia and their interaction can complicate clinical assessment of the disorder. We have introduced a model that has proven useful for understanding the genesis of a particular case of insomnia and focusing treatment efforts. Termed the 3P model, it groups etiologic factors temporally into predisposing characteristics, precipitating events, and perpetuating attitudes and practices [49]. Predisposing characteristics are often present for years before chronic insomnia takes hold. Many are thought to be congenital, such as tendencies toward physiologic or cognitive hyperarousal, or innate preferences for activity in the evening versus the morning. The 3P model allows for acquired predisposing factors as well. For example, residual pain following an injury may not in itself be accompanied by chronic insomnia, but it can lower the threshold for the disorder’s appearance. Precipitating events within the 3P model correspond to what patients are wont to label as the ‘‘cause’’ of insomnia. Appearing just before or concurrently with the sleep disturbance, typical precipitating events lead to a few nights or even weeks of poor sleep in just about everyone. They may be as dire as divorce or serious illness or elating as a newborn. Precipitating events may also be fairly innocuous, such as the acquisition of a new mattress or the introduction of flexible starting times on the job. The disruption associated with a precipitating event usually subsides with the passage of time, and sleep generally regroups in turn. By the time people have labeled themselves ‘‘poor sleepers’’ and presented this complaint to their physician, the precipitating events identified as triggers of their sleeplessness are often long resolved. This can be a source of consternation. A patient may appear years after a divorce and demonstrate convincingly that she has moved on with her life yet still be unable to count on a good night’s sleep. In this case, perpetuating attitudes and practices, the third component of the 3P model, have likely become predominant. As we have seen, the experience of sleep disturbance on a chronic basis becomes self-sustaining. Poor sleepers begin to associate bedtime and their bedrooms with an anxious hyperaroused state, and they settle for short-term relief from the effects of sleep loss through ultimately maladaptive measures such reliance on caffeine or frequent napping (Fig. 2). Perpetuating factors are what telescope acute sleep disruption into chronic insomnia; as such, they often present the most opportune targets for behavioral treatment. Their presence is actually grounds

Nonpharmacologic Management of Insomnia

Box 1:

Daily life behaviors and sleep-related habits that may interfere with sleep

Practices that reduce homeostatic drive at bedtime Daily life behaviors  Insufficient activity during the day  Lying down to rest during the day Sleep-related habits    

Napping, nodding, and dozing off during the day or evening In a trance, semi-awake in the evening Spending too much time in bed Extra sleep on weekends

Practices that disrupt circadian regularity Daily life behaviors  Insufficient morning light exposure, leading to a phase delay in circadian rhythm  Early morning light exposure, producing early morning awakening due to a phase advance in circadian rhythm Sleep-related habits  Irregular sleep-wake schedule  Sleeping in in the morning during weekends Practices that enhance the level of arousal Daily life behaviors      

Consuming caffeine excessively or too late in the day Smoking in the evening Alcohol consumption in the evening Exercising in the late evening Late evening meal or fluid intake (may cause nocturnal acid reflux or frequent urination) Getting home late, leaving insufficient time to wind down

Sleep-related habits         

Evening apprehension regarding sleep Preparations for bed are arousing No regular pre-sleep ritual Distressing pillow talk Watching TV, reading, or engaging in other sleep-incompatible behaviors in bed before lights out, or falling asleep with TV or radio left on Trying too hard to sleep Clock watching during the night Staying in bed during prolonged awakenings, or lingering in bed awake in the morning Non-conducive sleep environment, such as bed partner snoring, noises, direct morning sunlight, or pets in the bedroom

Adapted from Yang CM, Spielman AJ, Glovinsky PB. Nonpharmacologic strategies in the management of Insomnia. Psychiatr Clin North Am 2006;29(4):900; with permission.

for optimism. When patients have become disheartened by the entanglement of their sleep with seemingly intractable problems such as chronic illness or the loss of financial security, addressing perpetuating factors can yield moderate improvement relatively quickly. The other factors in the 3P model should not be overlooked. Because predisposing characteristics increase the risk of developing insomnia, any mitigation of their contribution would be helpful. A similar notion holds true for precipitating events.

These stressors pile onto the patient’s preexisting propensity for sleep disturbance, eventually breaching the threshold for insomnia. Addressing triggers of sleep loss such as marital strife or performance anxiety directly with targeted treatments can roll back the level of sleep disturbance to a subclinical state. Box 2 lists factors contributing to insomnia categorized according to the 3P model, with each category further subdivided by the three processes governing sleep and wakefulness.

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Psychological/Behavioral Factors

Neurophysiological Systems

Homeostatic System

Behavioral Practices Sleep Cognition

Circadian System

Sleep

Emotional Arousal Arousal System

Fig. 1. A conceptual model illustrating how psychologic/behavioral factors influence sleep through the mediation of neurophysiologic mechanisms. (Adapted from Yang CM, Spielman AJ, Glovinsky PB. Nonpharmacologic strategies in the management of insomnia. Psychiatr Clin North Am 2006;29(4):898; with permission.

Evaluation of insomnia The complex nature of insomnia presents a diagnostic challenge for physicians practicing under rigorous time constraints. There is a lot of territory to cover, and it can be difficult to elicit a balanced and well-articulated history. Patients may readily provide a summary such as ‘‘I can’t fall asleep’’ or ‘‘I keep waking up through the night,’’ or review a blow-by-blow account of last night’s fiasco, but

they often have a harder time making sense of their sleeplessness in terms that facilitate diagnosis and treatment. The physician’s task will be considerably eased by the adoption of a structured interview and the use of sleep logs. Although a semi-structured interview for insomnia has been published [50] and others are in development, one may have to use an abridged version in daily practice. A comprehensive evaluation will elicit the chief nocturnal sleep complaints, daytime

Fig. 2. The 3P model of insomnia, in this case illustrating the major contributions of precipitating and perpetuating factors and the minor contribution of predisposing factors. (Adapted from Spielman AJ, Yang CM, Glovinsky PB. Assessment techniques for insomnia. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. 4th edition. Philadelphia: Elsevier Saunders; 2005. p. 1405; with permission.)

Nonpharmacologic Management of Insomnia

Box 2:

Common contributing factors associated with the development of insomnia

Predisposing factors Homeostatic process  Abnormality or weakness of the neurophysiologic system that generates sleep Circadian process  Extreme circadian type as a trait (eg, ‘‘owls’’ predisposed to activity in the late evening or ‘‘larks’’ inclined to the early morning)  Less flexible circadian system Arousal system  Anxiety-prone and depressive personality traits as well as tendencies toward neuroticism and somatization lead to a higher level of emotional and physiologic arousal  Personality traits associated with sustained level of arousal, such as perfectionism and excessive need for control  Heightened or more sensitive physiologic arousal system Precipitating factors Homeostatic process  Lack of, or decrease of, daytime activities, such as retirement Circadian process  Change of sleep-wake schedule, such as jet lag or starting a night shift job Arousal system  Life stressors or events leading to emotional and physiologic distress Perpetuating factors Homeostatic process  Increased resting in bed  Discharge of the sleep drive by sleeping outside of the nocturnal sleep period through planned daytime naps or inadvertent dozing  Reduced daytime activities Circadian process  Sleeping in during weekend to catch up on sleep Arousal system  Dysfunctional beliefs and attitudes about sleep that lead to increased emotional arousal and worries over sleep loss  Conditioning between bedtime cues and arousal Adapted from Yang CM, Spielman AJ, Glovinsky PB. Nonpharmacologic strategies in the management of insomnia. Psychiatr Clin North Am 2006;29(4):900; with permission.

consequences, life circumstances at the onset of the sleep disorder and during its subsequent course, typical weekday and weekend sleep patterns, beliefs about sleep and the likely effects of sleeplessness, behavioral changes that have been made to compensate for poor sleep, any concurrent sleep disorders, prior treatments, general medical status, medication and substance use, family history, and assessments of psychologic and social functioning. Both underlying sleep patterns and the extent of variability masking those patterns can best be appreciated by the use of a nightly sleep log kept for 1 or 2 weeks. We favor a graphic log for its ability to quickly convey copious amounts of temporal

information as well as any changes occurring from week to week. Patients clock retiring and rising times (at night and for daytime naps), estimate how long it took to first fall asleep, and indicate the duration and distribution of subsequent sleep and waking episodes. The night’s pattern is supplied in the morning as a holistic impression rather than by fastidiously watching the clock. Patients rate sleep quality and, when getting into bed the next night, their level of fatigue during the day just passed. Other variables of interest such as caffeine and alcohol intake, exercise, the phase of the menstrual cycle, light exposure, and medication use may also be logged. Besides aiding clinicians in assessing

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I leave my bed in the middle of the night,’’ your patient might protest, ‘‘then I’ll be losing sleep for sure.’’ A common objection is that the treatments do not provide short-term relief. It is useful to anticipate negative attitudes and to counter them with clear rationales for treatment while at the same time lowering expectations. Declare at the outset that improvement will likely take a few weeks rather than a few nights, and contrast this against the months or years that your patient’s insomnia has resisted the strategies deployed thus far. It is also helpful to aim for an early victory. For example, total sleep time is not so readily extended through CBT-I. Even sleeping pills yield only about 30 minutes more sleep on average over placebo in clinical trials. Nevertheless, prolonged sleep latencies can be reduced fairly quickly with several of the treatments described in the next sections. This outcome should not go unheralded.

a complex and protean problem, sleep logs offer patients a wider perspective. They learn that their sleep’s appearance is not totally random, that their worst nights are, in fact, not representative, and, hopefully, that over time sleep does respond to recommended interventions, even if that improvement is not apparent every night (Fig. 3). If the physician’s assessment suggests that a physiologic sleep disorder such as obstructive sleep apnea or periodic leg movements may be contributing to sleep disruption, referral for nocturnal polysomnographic recording would be indicated. One may also decide that other medical or psychiatric co-morbidities warrant additional evaluation. Even so, CBT-I may proceed apace, because concurrent treatment of predisposing, precipitating, and perpetuating factors often proves most effective.

Cognitive behavioral interventions for insomnia

Sleep hygiene education

Most patients will accept and tolerate CBT-I [51]. Similar to the prevailing view among clinicians, they typically conceive of these treatments in terms of what they are not, that is, that they are nonpharmacologic. Not having a pill to swallow may be considered a plus in that there is no danger of drug dependency; however, the treatments may also be viewed as counterintuitive, requiring too much effort, and of dubious efficacy. ‘‘Why should EXAMPLE: Into bed

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Caffeine

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1 = Benadryl, 50 mg

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Instruction regarding proper sleep hygiene is a frontline approach to correcting maladaptive behaviors that may have been identified from perusal of Box 1. Sleep hygiene is premised on the notion that practically every decision we make in our waking lives affects sleep. Sometimes the issues are straightforward, such as when a double espresso is habitual after dinner. Others are more open to debate, such as whether one can really ‘‘wind down’’ with a video game

Asleep

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Medication 1 ______________ Dosage _________

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Medication 2 ______________

Dosage _________

Alcohol Day 1 ___________2 __________3 ___________4 __________5 __________6 __________ 7__________ Fig. 3. A sample sleep log.

Nonpharmacologic Management of Insomnia

before bed, or whether carving out a home office in the bedroom is such a good idea. Clinicians and patients often discount sleep hygiene education, albeit, for different reasons. Clinicians tend to regard the guidelines as self-evident, assuming that someone who has had trouble sleeping for years would know to silence the TV and banish the golden retriever from bed. Patients may acknowledge that sleep hygiene directives are generally beneficial but just not applicable in their case. They have tried following the rules to no avail. Years of trial and error have honed their tactics, and even if their sleep is still disrupted, it only gets worse when they forego a nightcap or sleep in a room that is too dark. It should not surprise the physician to discover that simply handing out a list of ‘‘Good Sleep Hygiene Practices’’ does not trigger an epiphany. Sleep hygiene really does require education, a process of building upon general principles to help patients arrive at an understanding of how their thoughts and actions affect their prospects for sleep. They must also learn not to expect a payoff within a night or two after instituting the recommendations. Improved sleep hygiene by itself is often insufficient to uproot chronic insomnia, although it should render sleeplessness more amenable to other CBT-I.

Stimulus control instructions Stimulus control instructions were one of the first behavioral interventions specifically developed to treat insomnia [48]. They target the maladaptive association between bedtime cues and conditioned arousal that strengthens each time the act of going to bed leads to a sleepless night. Stimulus control instructions treatment accomplishes this by banishing from the bed behaviors that are incompatible with sleep, such as eating, watching TV, reading, or just worrying about being unable to sleep. An exception is made for sex. Patients are instructed to get out of bed if not asleep after about 20 minutes and to sit in a chair reading, listening to music, or engaged in some other only mildly stimulating activity, returning to bed when they feel sleepy. See Box 3 for detailed instructions. Initially, patients may accrue considerable sleep loss following the 20-minute rule, which will enhance the sleep drive and eventually foster more rapid sleep onset. Patients should be forewarned that this sleep loss may also lead to daytime deficits. Repeated association of bedroom cues with rapid sleep onset rather than with tossing and turning, such as before treatment, is said to bring sleep under the ‘‘stimulus control’’ of the bedroom environment. Stimulus control instructions treatment may raise several objections from patients. As noted previously, they may argue that the treatment guarantees

Box 3:

Stimulus control instructions

1. Go to sleep only when you feel sleepy. 2. Do not use your bed or bedroom for anything except sleep (sexual activity is the only exception). 3. If you have not fallen asleep within approximately 20 minutes, get up and go into another room. Engage in relaxing activities, such as non–work-related light reading, and go back to bed when you feel sleepy or ready for sleep. 4. If you cannot fall back to sleep, repeat step 3. 5. Set the alarm for the same time each morning. Adapted from Bootzin RR. Stimulus control treatment for insomnia. Proc Am Psychol Assoc 1972;7:395.

sleep loss, and that there would be at least a chance of their returning to sleep if they stayed in bed. Some patients become wide awake when they read. Others may grow despondent sitting up alone while everyone else is fast asleep. It may help to remind patients that their experiences with stimulus control instructions are properly compared with a night spent tossing and turning in bed rather than to some idealized sleep experience. One might also point out that their current pattern already entails sleep loss, along with frustration and helplessness. Stimulus control instructions, by contrast, puts more control in their hands. Although the treatment cannot make sleep appear on command, it does allow patients to put their own stamp on the wakefulness they experience at night (see Box 3).

Sleep restriction therapy Sleep restriction therapy addresses both the weakened homeostatic sleep drive and attenuated circadian sleep/wake cycle characteristic of chronic insomnia. Restricting time in bed to prescribed hours leads to the gradual accumulation of significant sleep debt and, in so doing, replenishes the sleep drive [52]. It also ensures that sleep consistently appears in the same relatively narrow time slot rather than being strewn in snippets across a wide span of nighttime and perhaps daytime hours. The regular timing of sleep begins to reestablish the circadian sleep/wake cycle. It also allays the anticipatory anxiety that perpetuates chronic sleeplessness. Sleep restriction therapy is applied following a 1or 2-week log of baseline sleep. The estimated total sleep time averaged across the log is initially used to set time in bed. For example, a patient who retires for nearly 9 hours but who reports sleeping for

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only 6 of these would be assigned 6 hours in bed and asked to refrain from napping and oversleeping on weekends. The exact times of retiring and rising should factor in work and social obligations while at the same time taking note of when patients are most likely to be awake. Patients who generally have difficulty falling asleep should be assigned a relatively late bedtime, whereas those who log broken sleep toward morning should rise early. We set a lower limit of about 5 hours to avoid severe sleep loss, even when patients claim they hardly sleep at all. In our original formulation of sleep restriction therapy, the time in bed was adjusted weekly based on subjective sleep efficiency (total sleep time/time in bed  100%) according to the following rules: (1) for a mean sleep efficiency greater than 90% (85% in seniors), increase the time in bed by 15 minutes; (2) for a mean sleep efficiency less than 85% (80% in seniors), decrease the time in bed by 15 minutes; and (3) for a mean sleep efficiency greater than 85% and less than 90% (80% to 85% in seniors), keep the time in bed the same [53]. More recently, we have employed an alternative approach that, following acute restriction, progressively increases the time in bed each week as long as the patient’s subjectively estimated wake time in bed is 45 minutes or less [54]. Fifteen-minute increments in the time in bed are preferred to give the sleep drive adequate time to build, but 30 minutes might be added if daytime sleepiness becomes too pronounced. This variation of sleep restriction therapy is often better tolerated, avoiding the dispiriting effect of reducing bedtime yet again after the initial curtailment (Box 4). Sleep restriction therapy can be a trying experience for patients, often on account of daytime sleepiness. While acknowledging that this can be a significant problem and issuing precautions regarding driving or operating dangerous machinery, one should also underscore that the sleepiness is direct evidence of a strengthened sleep drive which, when harnessed properly, will be at the service of nocturnal sleep. For patients whose insomnia reflects chronic hyperarousal, the mere appearance of sleepiness, even if initially ill timed, may be welcomed as a sign that the homeostatic mechanism is still viable. Patients may also object that using an alarm clock to curtail precious sleep is inane, that they are at a loss for things to do during the extra hours of wakefulness, or that they experience a ‘‘second wind’’ by the time their assigned bedtimes roll around. Such objections might be countered by drawing patients’ attention to the shorter sleep latencies and more consistent sleep that begin to appear on their logs, improvements arising in part because

Box 4:

Sleep restriction therapy

From the information provided on a sleep log completed for at least 1 week, set the initial time in bed equal to the reported average total sleep time. To avoid severe sleep deprivation, the minimum time in bed is 5 hours. Version 1 A. Increase the time in bed by 15 to 30 minutes when the average reported sleep efficiency (sleep efficiency 5 average sleep time/time in bed  100%) for 5 days is R90% (85% in older individuals). B. When the sleep efficiency from 5 days documented on a sleep log is <85% (80% in older individuals), decrease the time in bed by 15 minutes. C. When the sleep efficiency from 5 days documented on a sleep log is R85% and <90% (R80 to <85% in older individuals), keep the time in bed the same. Version 2 After the original restriction, increase the time in bed progressively by 15 or 30 minutes each week, contingent upon a subjective total wake time of 45 minutes or less, until the patient is spending 7 hours in bed. Further changes are based on daytime functioning, fatigue, and sleepiness. Adapted from Yang CM, Spielman AJ, Glovinsky PB. Nonpharmacologic strategies in the management of insomnia. Psychiatr Clin North Am 2006;29(4):903; with permission.

sleep is not allowed to run its course in the morning. With sleep restriction therapy, there may not be any fully satisfying nights of sleep, but there are also fewer awful nights. Night-to-night variability in sleep length and quality is replaced by predictable strings of relatively short but consolidated sleep. This change, in turn, lessens anticipatory anxiety about what the coming night will bring. Patients who experience a second wind are probably allowing themselves to dip too close to sleep in the early evening out of boredom, perhaps ‘‘zoning out’’ in front of the TV, and should be counseled to become more intellectually engaged or, if need be, physically active after dinner. Because they will be likely staying up quite late while undergoing sleep restriction therapy, there will still be plenty of time in which to wind down before getting into bed.

Relaxation training We have discussed how insomnia can be brought about by maladaptive behaviors and thoughts. Mental and physical repose, on the other hand, facilitate sleep. Several classic cognitive behavioral

Nonpharmacologic Management of Insomnia

treatments for tension and anxiety have proved useful in the management of insomnia. These treatments include progressive relaxation, which reduces tension by sequentially tensing and relaxing the main muscle groups [55,56]; autogenic training, which promotes relaxation by inducing sensations of warmth and heaviness [56]; guided imagery, which provides a safe path for the mind to follow, keeping it from straying into potentially dangerous territory [57]; and biofeedback, helpful in teaching patients to recognize and maintain calmer behavioral and mental states [58,59]. It takes time and practice to learn how to relax. Patients can quickly grow frustrated at their inability to attain such a seemingly fundamental state. Initial practice should not take place at bedtime when the stakes are too high. Relaxation scripts and inductions recorded on tapes or CDs may be helpful. In any case, do not let the declaration ‘‘I just can’t relax’’ go unchallenged. Emphasize that the ability to achieve physical and mental equilibrium is an acquired skill much like riding a bicycle. Once mastered, relaxation is useful precisely because the state can be induced on cue. If sleep is not quickly forthcoming, a restful state can be summoned before agitation sets in and really ruins the night. Restfulness is also pleasant in its own right, besides serving as an effective staging ground for sleep (Box 5).

Cognitive therapy The dysfunctional thinking about sleep so often found in cases of entrenched insomnia can be classified into five categories: (1) misconceptions concerning the causes of insomnia, (2) misplaced concerns regarding its consequences, (3) unrealistic sleep expectations, (4) diminished perceptions of control, and (5) mistaken beliefs about the predictability of sleep [60]. Directly challenging such misguided beliefs and attitudes through cognitive therapy has been demonstrated to bring about improvements in sleep [37,40]. One such therapy, cognitive restructuring, involves identifying specific dysfunctional thoughts and replacing them with more realistic assessments and positive ideas [60]. A spirit of objectivity is fostered, with clinician and patient as co-investigators. For example, a patient may assume that he requires at least 8 hours of sleep to stay awake the next day. This claim might be evaluated using sleep logs and repeated assessments on a simple sleepiness scale. The opportunity might be taken to provide education about how our circadian rhythms and arousal system counter the effects of moderate sleep loss. Another patient may arrive at your office frantically clutching an Internet printout headlining research on mortality and sleep. It may be useful to retrieve

Box 5: Relaxation training (progressive muscle relaxation, autogenic training, slow deep abdominal breathing, guided imagery) 1. Explain the rationale for the specific technique. 2. The clinician demonstrates the technique for the patient during an office visit. 3. The patient then practices the technique at home once or twice a day (for about 10 minutes) in between office visits. 4. The clinician’s instructions and demonstration can be recorded, or commercial tapes can be used to facilitate the practice at home. 5. It may take a few weeks of practice before the patient develops the skill required. 6. The patient is told not to use the technique for sleep until a moderate level of skill in performing the technique is achieved. Adapted from Yang CM, Spielman AJ, Glovinsky PB. Nonpharmacologic strategies in the management of insomnia. Psychiatr Clin North Am 2006;29(4):910; with permission.

the original journal article and place the findings in context, noting similarities and differences with the patient’s own circumstances. Keeping a ‘‘worry journal’’ is another way to address distressing thoughts that often preoccupy the minds of would-be sleepers. In the evening before the buffer period begins, the authors have patients sit down and predict which issues and problems are most likely to snag their descent into sleep during the coming night, listing these on the left side of their journal. On the right side, they are free to formulate a credible solution, come up with a ‘‘quick fix,’’ or just find a good way to procrastinate. The goal here is not one of problem solving but rather of getting off the hook. The journal is then closed for the night. Committing a problem to paper, affixed permanently on page 5, and paired with even a flimsy solution has the effect of inoculating the mind against this same problem racing around it later on (Box 6).

Chronotherapy Because the endogenous circadian pacemaker typically has a period slightly longer than 24 hours, sleep has a propensity to drift progressively later around the clock. To be able to fall asleep around the same time each night, we must advance our sleep phase a few minutes every cycle. Persons who have internal clocks that run particularly slow or that are especially hard to advance can reach a point where it habitually takes hours to fall asleep. This problem, in turn, leads to difficulty arising in the morning and

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Box 6:

Cognitive therapy

1. Discuss with patients their general beliefs regarding sleep and their sleep problems. Subjective rating scales such as the Dysfunctional Beliefs and Attitudes Scale [60] can be used to help with the evaluation of patients’ sleep cognitions. 2. Identify counterproductive beliefs. 3. Enlist the patient as a co-investigator to help gather data that will test and refute the dysfunctional beliefs. 4. Provide correct information to address the specific dysfunctional beliefs. Adapted from Yang CM, Spielman AJ, Glovinsky PB. Nonpharmacologic strategies in the management of insomnia. Psychiatr Clin North Am 2006;29(4):910; with permission.

tardiness for school or work. Sleep latencies are appreciably shorter on weekends or during vacations, when bedtimes are very late and oversleeping well past noon is not uncommon. When this sleep pattern is associated with adverse psychosocial consequences, a circadian rhythm sleep disorder known as delayed sleep phase disorder may be diagnosed [61]. This condition is relatively common in adolescents and young adults [62]. A specialized treatment for delayed sleep phase disorder known as chronotherapy takes advantage of the slightly slow circadian clock, which makes sleep amenable to shifting later [63]. Chronotherapy involves a progressive delay of bedtime, generally 3 hours per night, bringing sleep around the clock to the desired earlier bedtime. The process is analogous to traveling nearly all the way around the world in a westward direction, only to end up slightly east of one’s point of departure. Before beginning chronotherapy, patients should adhere for 1 week to a slightly restricted bedtime schedule, starting when they are typically able to fall asleep, for example, from 3 AM to 10 AM. Their times of retiring and rising are then delayed by 3 hours until they approach the desired bedtime. For example, after the first phase delay, patients would be following a 6 AM to 1 PM schedule (perhaps a typical weekend pattern) and after the second, a 9 AM to 4 PM schedule. For the first time in years, patients may wish to go to bed early. They should be discouraged from doing so, with others in the household enlisted to help keep them on track. We have found it useful to ‘‘apply the brakes’’ by limiting the last few phase shifts to 1 hour, because there is a risk of overshooting the mark and resuming a late pattern. Continuing with our example, after bedtimes of 12 noon, 3 PM, 6 PM, and 9 PM, with 7 hours of allotted time in bed at each step,

patients might then follow a slightly extended 10 PM to 6 AM schedule for a full week before finally settling into an 11 PM to 7 AM routine (Box 7). Chronotherapy does not counter the patient’s innate phase delay tendencies, and it provides no bulwark against further slippage once the target is reached; however, it can provide relief in what had been deemed an intractable situation. This improvement can endure if patients reschedule their days as well as nights, that is, when they eat, work, and play. Whereas 10 PM was previously ‘‘prime time’’ for activities of all sorts, it will have to signal the start of the wind-down period if sleep is to follow shortly. For several days under chronotherapy, patients will have no chance of meeting school or work obligations. If the treatment cannot coincide with a vacation, teachers or supervisors will have to sign off on the absence. The middle phase is most problematic in terms of compliance, when patients are asked to retire in the afternoon and early evening. There is also resistance against leading such a regimented life. Patients ask if they will ever again be able to enjoy a late night out with friends. You might assure them that if they can come to see 2 AM rather than 6 AM as ‘‘late’’ and limit oversleeping to an hour or so rather than sleeping into the afternoon, such outings can be accommodated.

Light therapy Light is the most important influence on circadian rhythms. Typically, bright outdoor light stabilizes or ‘‘entrains’’ rhythms that might otherwise free run. Exposure to sunlight can also shift the phase of these rhythms, a phenomenon that lets us adapt

Box 7:

Chronotherapy

1. The patient chooses a retiring time and arising time that can be adhered to for 1 to 2 weeks. 2. The patient completes a sleep log daily. 3. The retiring time and arising time are delayed by 2 or 3 hours each day until they are within 1 hour of the desired sleep schedule. 4. For 1 week, the retiring and arising time are maintained within 1 hour of the desired schedule. 5. The retiring time and arising time are delayed by 1 hour to the desired schedule. 6. The patient should not sleep later than the scheduled arising time to help avoid relapse. Adapted from Yang CM, Spielman AJ, Glovinsky PB. Nonpharmacologic strategies in the management of insomnia. Psychiatr Clin North Am 2006;29(4):912; with permission.

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to new time zones following jet travel. For the past 20 years, artificial bright light has been used to reset circadian rhythms in individuals who never leave the ground. The size and direction of the phase shift depend on the intensity and timing of the exposure [64,65]. Morning light exposure in individuals following a nocturnal sleep schedule will tend to advance the circadian sleep phase. It counters our inherent drift toward a later phase, helping maintain a 24-hour period. Evening light exposure, by contrast, suppresses the expected melatonin secretion and tends to delay the circadian sleep phase. Light exposure upon awakening is now the treatment of choice for most patients with a delayed sleep phase [66]. Because the magnitude of the phase shift is greatest when exposure occurs just after the circadian temperature nadir (approximately 2 hours before habitual awakening in most individuals), there should be as little delay as possible between arising and light exposure. Initially, patients should keep typical bedtimes, even if that means arising at midday. As treatment proceeds, bedtimes and rising times are progressively shifted, perhaps an hour earlier each week, with light exposure also shifting to immediately follow awakening (Box 8). As is true for chronotherapy, bright light treatment for delayed sleep phase disorder is abetted by the rescheduling of waking activities to complement earlier sleep times. Light therapy has the advantage that patients adhere to progressively earlier rising times over the course of treatment; therefore, they are more likely to comply with a fixed schedule at its conclusion. It should be cautioned that bright light treatment has been noted to precipitate manic episodes in bipolar patients [67]. Bright light therapy can be administered with artificial light boxes or natural sunlight. Traditional commercial devices use low UV fluorescent bulbs and special reflectors to provide illuminances of 2500 to 10,000 lux at the eye when obliquely placed about 1.5 to 3 ft away. Exposure times are typically about 60 minutes, during which patients can have breakfast, read, or watch TV. Patients should not stare directly into the light. If obtaining much brighter outdoor light (75,000 lux or more on clear summer days) is feasible, good results can be had with exposure times as short as 30 minutes. Cloudy days are sufficiently bright to maintain progress; patients should be counseled to obtain light exposure on a consistent basis. Recently, it has been discovered that the circadian system responds specifically to light in the shorter, deep blue wavelengths of the visible spectrum. It relies on dedicated receptors in the retina with a peak sensitivity at about 470 nanometers [68–70]. Some manufacturers have devised light boxes emitting less intense blue light, allowing shorter durations of

Box 8:

Light therapy

Sleep schedule Patients can shift their circadian phase by a half hour to an hour each week with little difficulty with the help of light exposure. Each week of treatment, the wake-up time is progressively shifted to an earlier time for patients with a delayed circadian sleep phase; in contrast, the retiring time is gradually shifted to a later time for patients with an advanced circadian sleep phase. For patients with a delayed sleep-wake pattern, bright light exposure is administered in the morning as close to the patient’s scheduled arising time as possible. In contrast, for patients with an advanced sleep-wake pattern, bright light should be administered in the early evening, a couple of hours before their scheduled bedtime. The source of bright light can be an artificial light therapy device or natural outdoor sunlight. Illuminance of approximately 2500 lux or more at eye level usually is required to obtain successful results. A 1- to 2-hour period of treatment each day is optimal. Scheduling constraints may necessitate a shorter exposure duration or less frequent exposure that will result in slower treatment response. Adapted from Yang CM, Spielman AJ, Glovinsky PB. Nonpharmacologic strategies in the management of insomnia. Psychiatr Clin North Am 2006;29(4):913; with permission.

exposure. It is important to follow their instructions carefully, because overexposure to blue light can be especially hazardous to the eye. Because light exposure before bedtime delays the sleep phase, blocking exposure to the blue wavelengths of evening light with special sunglasses can be helpful for patients contending with a delayed sleep phase, especially during summer months when the photoperiod is prolonged [71]. Blue-blocking glasses (with lenses that render the world in amber shades) may be worn from about 6 PM to sunset (except when driving at dusk for reasons of safety). The glasses might also be worn by persons who spend hours in front of computer screens during the evening. Evening bright light exposure has been used to treat patients (more often the elderly) whose circadian sleep phases are advanced [72,73]. These patients typically complain of evening sleepiness with inadvertent dozing, as well as early morning awakenings. Light boxes are generally employed because outdoor evening light is not available during much of the year. Because evening light is delivered further from the temperature nadir, it is generally less potent in effecting phase shifts;

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therefore, exposure times toward the longer end of the recommended range may be required. An ophthalmic consultation may be advisable in the elderly population before using bright light treatment. The use of blue-blocking sunglasses in the morning hours may also be helpful in promoting a phase delay. As light treatment progresses, bedtime schedules are shifted later to accommodate the gradual shift in sleep phase.

Selecting and delivering cognitive behavioral treatments CBT-I are effective, producing moderate-to-large effect sizes in controlled studies [1–4]. Currently, most behavioral medicine practitioners tend to employ a combination of treatments. Multi-component CBT and CBT in combination with hypnotics have been proved to be superior to hypnotic use alone in long-term follow-up [3,11,12]. The authors advocate an initial choice of treatment based on the predominant insomnia complaint and an analysis based on the 3P model, with special attention given to perpetuating factors [54]. If sleep has a broken pattern, with short periods of sleep and wakefulness in succession, or if the time in bed is excessive relative to the amount of sleep actually obtained, sleep restriction therapy may be the initial treatment of choice. Stimulus control instructions are especially useful when prolonged periods of wakefulness are seen, whether in the form of difficulty falling asleep or staying asleep, or when patients report getting a second wind upon climbing into bed, evidence that the bedroom has become associated with arousal rather than sleep. Dysfunctional thinking that interferes with sleep is best addressed directly with cognitive treatments, whereas relaxation training is of particular benefit when hyperarousal is deemed a critical predisposing factor. Circadian rhythm disorders are most effectively addressed with light therapy, with chronotherapy reserved for severe cases of delayed sleep phase disorder in which patients are not falling asleep until near sunrise or later. CBT-I can be delivered individually or in groups; in either situation, treatment usually takes 4 to 8 weeks. Recently, an abbreviated two-session program was reported to be effective in a primary care setting [74]. Treatments for insomnia have also been delivered through structured bibliotherapy [75], self-help books [54,76,77], telephone consultations [78,79], and the Internet [80]. Although not all formats have been demonstrated to be effective, the ongoing effort to disseminate CBT-I reflects an acknowledged need to bring these wellestablished treatments to the millions who suffer from chronic insomnia, despite a dearth of experts

in the field. There are also initiatives underway to train nurses, mental health counselors, and others to deliver CBT-I in primary care settings, efforts that have already shown promise [81].

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SLEEP MEDICINE CLINICS Sleep Med Clin 3 (2008) 205–215

Sleepiness and Fatigue in Patients with Psychiatric Disorders Chad C. Hagen, -

-

a,

MD

*, Jed E. Black,

Sleepiness and fatigue Psychiatric diagnosis Cognitive disorders Attention Deficit-Hyperactivity Disorder (ADHD) Dementia Mood disorders

-

-

Fatigue and daytime sleepiness are common complaints in the patient with a psychiatric diagnosis. Although both psychiatric illness and psychotropic medications may cause sleepiness and fatigue, when complaints of sleepiness or fatigue arise in these patients other potential etiologies must be considered. Patients with a psychiatric disorder and comorbid sleepiness or fatigue warrant appropriate evaluation to determine whether a primary sleep disorder is accounting for, contributing to, or complicating the treatment of a presumed psychiatric disorder. A review of cognitive and mood effects secondary to sleep fragmentation and deprivation are beyond the scope of this article, but it is well-demonstrated that fatigue and sleepiness arise from processes that compromise the efficiency of sleep or restrict a person from an adequate sleep duration. These include conditions such as periodic limb movement disorder, sleep-related breathing disorders, chronobiological or circadian rhythm sleep disorders, insomnia, and neurologic or medical conditions adversely effecting sleep

b

MD

Depression Bipolar disorder Anxiety disorders Post traumatic stress disorder Generalized anxiety disorder Emerging circadian findings Psychiatric medications References

quantity or quality. If sleepiness, decreased vigilance, or fatigue is secondary to a sleep disorder, then they should not be used to support a psychiatric diagnosis such as depression, attention-deficit hyperactivity disorder, or generalized anxiety disorder. Indeed such sleep disorders commonly exacerbate comorbid psychiatric conditions and often render primary psychiatric syndromes more treatment refractory. Insufficient sleep is the most common explanation for sleepiness and fatigue in the general population. Sleep-disordered breathing accounts for most cases of sleepiness and fatigue that present to sleep disorders clinics. Other causes of sleepiness such as circadian misalignment, insufficient or disrupted sleep, head trauma, narcolepsy, and idiopathic hypersomnia should be considered in all patients complaining of excessive daytime sleepiness (EDS) or fatigue. Lack of an understanding of these conditions not only leads to misdiagnosis or lack of recognition, but often also results in gross mismanagement. Examples include the use of

a Sleep Disorders Program, CR-139, Department of Psychiatry, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239-3098, USA b Stanford Sleep Disorders Center, Department of Psychiatry and Behavioral Sciences, 401 Quarry Rd., #3301, Stanford, CA 94305, USA * Corresponding author. E-mail address: [email protected] (C.C. Hagen).

1556-407X/08/$ – see front matter. ª Chad C. Hagen and Jed E. Black.

sleep.theclinics.com

doi:10.1016/j.jsmc.2008.01.013

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antipsychotic medications in a patient with narcolepsy-related hypnagogic hallucinations or antidepressant therapy for patients with a complaint of hypersomnolence related to a primary sleep disorder that is misdiagnosed as depression. This article summarizes psychiatric disorders and treatments that are associated with EDS or fatigue, and the role of the sleep physician in addressing these complaints in the patient with comorbid sleep and psychiatric disorders.

Sleepiness and fatigue A patient with EDS often struggles to maintain wakefulness in monotonous situations, whereas a patient with the complaint of fatigue may experience listlessness and lethargy with or without EDS and the tendency to fall asleep. There is considerable overlap between these two presentations, and both complaints may indicate a significant problem. EDS has been easier to define as a specific physiologic state by measuring a patient’s capacity to fall asleep or capacity to remain awake in sedentary situations throughout the day. Fatigue, however has remained more difficult to isolate and quantify and may represent numerous chronic or acute physiologic or psychologic processes. The American Academy of Sleep Medicine defines EDS in the International Classification of Sleep Disorders (ICSD) as ‘‘a complaint of difficulty in maintaining desired wakefulness or a complaint of excessive amount of sleep’’ [1]. It also notes that while sleepiness may be more objectively defined, it is still essentially a subjective report of difficulty maintaining the alert awake state, usually accompanied by an increased propensity for rapid entrance into sleep when the individual is sedentary [1]. The second edition of the ICSD describes strategies for quantifying the capacity to stay awake or the tendency to fall asleep using the Maintenance of Wakefulness Test (MWT) or the Multiple Sleep Latency Test (MSLT), respectively. The second edition also defines fatigue as ‘‘Lack of energy, listlessness, or weariness as from labor. Not necessarily associated with an increased tendency to fall asleep’’ [2]. While a variety of scales have been developed for assessing fatigue and sleepiness, a recent study by Bailes and colleagues [3] indicates that six items from the Epworth sleepiness scale may be more specific for sleepiness, while three items selected from two fatigue scales (Chalder fatigue scale [4] and Fatigue severity scale [5]) were more specific for weakness and tiredness arising from exertion. Their analysis indicated that the three most specific items for this type of fatigue are the following: ‘‘Exercise brings on my fatigue,’’ ‘‘I start things without difficulty but get weak as I go on,’’ and ‘‘I lack energy.’’

The Fatigue severity scale in its entirety has been validated and found to correlate well with ‘‘disabling fatigue’’ independent from depressive symptomatology in patients with disorders such as lupus, multiple sclerosis, and insomnia [3,5,6].

Psychiatric diagnosis The Diagnostic and Statistical Manual (DSM-IV-TR) [7], much like ICSD-2, outlines the diagnostic criteria, epidemiologic data, and associated features for each disorder summarized. Within the diagnostic criteria for each psychiatric disorder, the DSM stipulates that the symptoms in question are not better explained by a medical condition (eg, a sleep disorder). Although sleep clinicians may feel unqualified or not obligated to assess psychiatric disorders in the sleep clinic, some familiarity with the diagnostic criteria and how to use them is essential. Awareness of psychiatric disorders and their means of diagnosis is so critical that 10% of the ICSD-2 is dedicated to a review of the information found within DSMIV-TR (Appendix B, ICSD-2) [2]. This knowledge facilitates the recognition of possible erroneous psychiatric diagnoses in a patient suffering primarily from a sleep disorder, as well as for the diagnosis of comorbid sleep disorders in those with primary psychiatric conditions. These distinctions are more difficult after the burden of social consequence and adjustment to sleepiness or fatigue takes its toll. For example, a sleepy patient with undiagnosed sleep apnea may feel ‘‘depressed’’ because of difficulty maintaining his or her performance at work. When liberated from sleepiness this patient may perform better and subsequently feel relatively well; hence, a diagnosis of depression would be inappropriate. We briefly outline the diagnostic criteria for these disorders at the beginning of each section, but recommend Appendix B of the ICSD2, or the DSM-IV-TR, for sleep physicians wishing to review psychiatric diagnostic criteria in more detail.

Cognitive disorders Attention Deficit-Hyperactivity Disorder (ADHD) DSM-IV-TR characterizes attention deficit disorder/ inattentive type as a problem with attention and concentration that is accompanied by six symptoms of inattentiveness from a list of nine potential symptoms. These symptoms must arise in a variety of circumstances (eg, work, school, home), begin before age 7, and persist for greater than 6 months. An additional six symptoms of hyperactivity or impulsivity from a list of nine symptoms are required for the diagnosis of attention deficit

Sleepiness and Fatigue

disorder/hyperactive type. Given evolving diagnostic criteria and changes in identification of the disorder in clinical practice, estimates of prevalence have varied, but prevalence in schoolchildren is roughly estimated to be approximately 3% to 8%. Characterized as a cognitive disorder and treated for decades with stimulant medications [8], ADHD is essentially a disorder of cognitive function that has significant overlap with the deficits in attention, concentration, vigilance, and impulse regulation seen in conditions of sleep fragmentation and/or sleep deprivation. Until recent versions of the DSM, presence of a sleep disturbance was included in the diagnostic criteria. The DSM-IV-TR has excluded sleep disturbance from the diagnostic criteria for ADHD and instead qualifies the diagnosis stating that the symptoms of poor attention, concentration, or hyperactivity cannot be attributed to a general medical condition. Therefore, sleep deprivation or sleep fragmentation from a sleep disorder must be reasonably excluded before a patient receiving a diagnosis of, and treatment for ADHD. This process can be complicated in the patient who presents for a sleep evaluation while receiving treatment for ADHD. Sleepiness may be missed in these children if masked by stimulant medication, which can obscure the common symptoms of childhood sleepiness such as irritability; reduced frustration threshold; impulsivity; and decreased vigilance, alertness, and concentration. Cohen-Zion and Anconi-Israel distilled 47 ADHD-research studies, published between 1980 and 2004, including 13 involving stimulant intervention and another 34 using medication free subjects [9]. Their review clarifies that many studies to date are limited due to reliance on subjective reports of sleep; none-the-less, these reports documented a high rate of sleep disturbance, increased nocturnal activity, decreased REM sleep, and excessive daytime somnolence in stimulantfree children with ADHD when compared with controls. Another recent review by Cortese and colleagues [10] summarizes that apnea-hypopnea index (AHI, a measure of sleep-related breathing disturbance severity), EDS, and movements during sleep were all higher in children with ADHD compared with controls. Much research evidences that children, adolescents, and adults carrying a diagnosis of ADHD often have an associated sleep disorder that may better account for their symptoms of inattention, poor concentration, or hyperactivity [11–14]. Beyond the high rates of association for these syndromes, recent work has demonstrated successful management of ADHD with surgical or positive air-pressure treatments [15–20] in some patients with comorbid sleep-related breathing disorders. Stimulant use carries some risk including

dose-dependent increases in insomnia, systolic and diastolic blood pressure, and heart rate [21]. While a recent actigraphy study in patients without sleep disordered breathing (SDB), suggested methylphenidate reduces movement during nocturnal sleep [22], these other side effects may be particularly disadvantageous in a patient with an unrecognized sleep-related breathing disorder. Other groups have demonstrated high associations between periodic limb movements, restless leg symptoms, and ADHD symptoms in children [12,23] and suggest that the strength of these associations warrants increased investigation. Oosterloo and colleagues [24] compared symptoms of sleepiness and deficiencies in attention and concentration between patients with narcolepsy and those with ADHD. They found a high incidence of sleepiness in their ADHD patients, with 38% having an Epworth greater than or equal to 12. Nineteen percent of their narcoleptic patients met criteria for ADHD based on self-report scales. From this, they concluded that given the high degree of overlap between these two populations, the validity of self-report scales in these populations is unclear and there should be attentiveness to the possibility of misdiagnosis in sleep-disorder patients with psychiatric disorders. In view of the mounting evidence demonstrating ADHD-like symptoms are common among individuals with sleep disorders, patients with the diagnosis of ADHD, or in whom ADHD is suspected, should undergo a sleep evaluation that includes, when indicated, full polysomnography. While there are reports of circadian misalignment in children with ADHD, published studies thus far indicate that interventions such as sleep hygiene and melatonin use timed for phase-advancing ADHD children with delayed sleep phase or initiation insomnia is beneficial for decreasing sleep latency, but does not appear to have a significant impact on overall ADHD symptomatology [25,26]. However, adults with ADHD treated with phase-advancing light therapy during winter months had improvements in ADHD based on improved symptom scales and neuropsychological testing [27]. Given the similarities between ADHD symptoms and sleepiness and the associations between ADHD and sleep disorders in the literature, it is clearly important to detect and treat any comorbid sleep disorder [28].

Dementia Dementia arises from a variety of conditions including Alzheimer’s, Huntington’s, and Parkinson’s diseases, as well as from conditions such as cerebrovascular disease, human immunodeficiency virus

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infection, and head injury. Dementia is characterized by loss of memory and is often associated with a variety of other cognitive impairments. Prevalence increases with age, with an estimated 1% prevalence from age 60 to 64, but increases up to 30% to 50% in those older than 85. Patients with Alzheimer’s disease often struggle with excessive daytime sleepiness and circadian abnormalities. In contrast to the normal decline in sleep period for aging adults, dementia patients have been shown to have a longer sleep period, which is positively correlated with dementia severity [29] Objective measures of daytime sleepiness are also higher in patients with Alzheimer’s disease. Furthermore, the magnitude of sleepiness in this population, measured by MSLT, appears to be associated with the level of cognitive impairment on a variety of neuropsychologic measures [30]. Sundowning is a common phenomenon in demented patients, referring to increased disorientation and agitation that tends to occur in evening hours. There is evidence that sundowning is related to an inappropriate decrease in vigilance and alertness during the waking hours [31]. This may be in part related to a genetic predisposition for some people to phase advance into a circadian phase advanced or ‘‘morningness’’ pattern with age [32]. Reports of treatment with morning light, and evening melatonin have shown improvement in the consistency of nighttime sleep and consolidation of the sleepwake cycle [29,33–36]. Two studies have reported some degree of behavioral improvement with such treatment as well [31,37]. Overall, demented patients may show inappropriate sleepiness or inappropriately timed sleepiness, both of which will often benefit from good sleep hygiene, daytime light and activity, and maintaining a quiet and appropriately dark environment conducive to sleeping at night [34].

Mood disorders Depression Major depressive disorder can be a devastating illness causing significant social or occupational disruption. Death by suicide occurs at an alarming rate of up to 15% in patients with severe major depression [38]. The lifetime risk of depression varies from about 5% to 25% of the population, depending on the study, but occurs more commonly in women than men with an average age of onset in the mid 20s [38]. The disorder is characterized by one or more incidents of a major depressive episode. Diagnostically, these episodes must be longer than 2 weeks in duration, represent a change from baseline, and include at least five symptoms, at least one of which must be either depressed

mood or anhedonia (loss of interest or pleasure in activities). The remaining symptoms may include unintentional weight loss, weight gain, insomnia, hypersomnia, changes in activity level, fatigue or loss of energy, feelings of worthlessness or excessive guilt, poor concentration or indecisiveness, or recurrent thoughts of death or suicide. Like nearly all psychiatric diagnoses, the critical stipulation within the DSM-IV-TR is: ‘‘Do not include symptoms that are clearly due to a general medical condition’’ [38]. It is easy for sleep clinicians to recognize patients with five of these symptoms. However, it is difficult for us to tell whether the symptoms are due to a general medical condition or sleep disorder, such as restless legs syndrome or obstructive sleep apnea (OSA) (Boxes 1–3). Patients and their psychotropic prescribers should be informed about which of their previously attributed depressive symptoms, such as hypersomnia, fatigue, sleepiness, performance changes, changes in activity level, reductions in interest or pleasure in activities, sleep alterations, poor concentration, and weight gain might have a sleep disorder etiology. Indeed all of these symptoms are common complaints in patients with OSA. Some authors have suggested that, fatigue, uncontrolled sleep deprivation, and the inability to initiate or maintain sleep may carry increased risk for suicide. Polysomnographic findings consistent with both depression and sleepiness, such as decreased sleep latency, shortened rapid-eye movement (REM) latency, and increased REM percentages are seen in both sleep-deprived patients and suicidal patients [39,40]. Several studies have indicated that insomnia, but not sleepiness or fatigue, is correlated with thoughts of suicide, plans for suicide, or attempted suicide [41–43]. Patients with depression-related symptoms that present initially to the sleep disorders specialist should be screened in the sleep disorders clinic for depression and suicide and referred to appropriate mental health services. Box 1: DSM-IV diagnostic criteria for depression Symptoms associated with sleep disturbance Depressed mood Weight change Insomnia Decreased activity Fatigue/poor energy Poor concentration Symptoms specific to depression Anhedonia Worthlessness Suicidal thoughts

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Box 2: DSM-IV Diagnostic criteria for dysthymia Symptoms specific to dysthymia

Symptoms associated with sleep loss

Poor appetite Low self esteem Feelings of hopelessness

Overeating Insomnia Hypersomnia Low energy or fatigue Decreased energy Poor concentration

Research has been conducted in an effort to discriminate sources of fatigue and sleepiness in depressed patients with sleep disorders such as obstructive sleep apnea. Given the circular nature of this line of inquiry, the research is difficult and inherently confounded. Some findings from crosssectional data suggest that fatigue may be more substantively explained by self-reported depression scales than by severity of obstructive sleep apnea [44]. The authors of this study also make the critical point that management of depression in patients with comorbid OSA may yield better improvement in their fatigue than pursuing OSA treatment solely. Other authors have placed more emphasis on the need for optimization of treatment for OSA, and the necessity of adequately treating sleepiness and fatigue for successful treatment of the patient with comorbid depression [40,42,45–47]. Depression symptoms often improve or are resolved in patients successfully treated for obstructive sleep apnea [48]. Optimal treatment of the patient with depression who is newly diagnosed with a sleep disorder includes treatment continuation for depression while the sleep disorder is formally diagnosed and treated. Mood and fatigue have been shown to correlate with sleep fragmentation associated with sleep-related breathing disorders more than with the frequency of oxygen desaturations [6,42]. Therefore, optimizing the treatment of fatigue and sleepiness in these patients requires attention to

Box 3: DSM-IV Diagnostic criteria for atypical depression Symptoms specific to atypical depression

Symptoms associated with sleep loss

Long standing interpersonal rejection sensitivity

Mood reactivity Appetite and weight increase Decreased energy ‘‘leaden paralysis’’ (fatigue)

sensitive measures of airflow limitation, such as snoring, hypopneas, and flow signal alteration and not simply dependence on a slowly responding and insensitive indicator of disturbance such as oxygen desaturation. If depression treatment is enhanced by treatment for a sleep disorder, a cautious re-consideration of the psychiatric diagnosis by a psychiatrist (or appropriate professional) able to provide follow-up and observation of the patient over time should take place. Observation over time is critical given the relapsing-remitting cycle of mood disorders. In some cases, it may be appropriate for the psychiatrist to reconsider the dosage or need for medications depending on the patient’s history of response to antidepressants and sleep-related treatments. Although not Food and Drug Administration (FDA) indicated, several studies support the use of modafinil as an augmentation strategy in depressed patients presenting with a significant component of fatigue or sleepiness. Dysthymia is a condition similar to depression that presents with a more mild but chronic symptomatology characterized by depression occurring more days than not and persisting for more than 2 years. In some cases, dysthymia may occur with major depression. Dysthymia is typically associated with complaints such as fatigue and poor energy and can be difficult to discriminate from chronic fatigue syndrome [49] or the fatigue of a sleep disorder. Like depression, dysthymia patients benefit from diagnosis and appropriate treatment for any comorbid sleep disorder compounding their fatigue. Seasonal affective disorder (SAD) is not a term found in the DSM-IV-TR, rather the term ‘‘seasonal pattern’’ is used as a qualifier to describe a patient with a mood disorder that tends to occur with a seasonal association more often than not. The qualifier can be applied to major depressive disorder or Bipolar types I or II. SAD of the depressed type is considered a psychiatric disorder, but interestingly appears to arise from changes in sleepiness, fatigue, and cognition secondary to mismatch of life and social obligations with circadian phase, much like other circadian disorders such as jet lag, shift work, or delayed sleep phase syndrome. SAD is arguably the only psychiatric disorder with a biological marker correlating with depression severity and its response to treatment [50]. Degree of circadian phase misalignment has been correlated with severity of depression symptoms in this population throughout illness, treatment, and posttreatment [50]. Impressive associations with variants of biological clock genes (Per2, Arntl, Npas2) have been demonstrated in humans at higher risk for seasonal depression [51]. While antidepressant treatment and cognitive behavioral therapies may be

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beneficial, treatment with appropriately timed light (usually early morning light for patients with a delayed phase presentation) is currently the treatment of choice [50,52–54]. Appropriately timed lowdose melatonin (eg, 0.5 mg in the early evening for patients with a delayed phase presentation) has also demonstrated a robust effect [50].

Bipolar disorder Bipolar disorder may be one of the most fascinating human models of disordered sleep homeostasis, but research has lagged given the complexities of studying this population during active manic episodes. Bipolar disorder is divided into two major categories including Bipolar I and Bipolar II. The essential distinguishing feature between the two is that Bipolar I patients have experienced at least one manic episode (manic symptoms lasting 7 days or longer). Bipolar II patients have a similar presentation that tends to be slightly less severe with manic symptoms lasting less than 4 days per episode. Diagnostically, three manic symptoms are required in addition to an ‘‘abnormally and persistently elevated, expansive, or irritable mood’’ lasting the appropriate duration. The other three symptoms may include increased self-esteem or grandiosity that is nondelusional, decreased need for sleep, increased rate of speech or thoughts, and increased activity in risky or pleasurable activities with disregard for the consequences or associated risks. Regarding the nature of the sleep disturbance, ‘‘almost invariably, there is a decreased need for sleep. The person usually awakens several hours earlier than usual, feeling full of energy. When the sleep disturbance is severe, the person may go for days without sleep and yet not feel tired.’’ This fascinating clinical presentation has been neglected from a sleep and fatigue research standpoint and more work is certainly needed in this area given the limited efficacy of available treatment options, high morbidity of the bipolar population, and the opportunity for furthering our understanding of sleep-wake homeostasis and the generation and experience of sleepiness and fatigue. While it is rare to find an actively manic patient presenting to the sleep clinic, it is common to see bipolar spectrum patients on maintenance medications for their mood disorder. Essentially all of the common mood-stabilizing agents have a high incidence of fatigue or sedation as a side effect. These medications include typical and ‘‘atypical’’ antipsychotic medications, anticonvulsants, and lithium. An effort to clarify whether the fatigue or sleepiness changed with initiation or dosage adjustment in one of these medications is warranted.

Anxiety disorders Post traumatic stress disorder Posttraumatic stress disorder (PTSD) affects 8% of the general population and is characterized by the development of a variety of symptoms occurring after a traumatic or life-threatening event [38]. It can arise after a broad range of emotionally laden exposures, but occurs more commonly in a third to half of patients that have been exposed to rape, combat, war-related captivity, or genocide [38]. Traumatic exposures are disturbingly common in children, but only 0.5% of children will manifest the number and severity of symptoms required for the diagnosis of PTSD in an adult [55]. While DSM-IV PTSD criteria have been derived more from work in combat exposure, the next edition may tailor PTSD criteria more specifically to other populations such as rape, abuse, and childhood trauma. Difficulty initiating sleep (considered a symptom of hyperarousal) and nightmares (considered much like a reexperiencing of the traumatic event) are two sleep-specific symptoms that are included in the DSM-IV-TR diagnostic criteria for PTSD. Although not required for the diagnosis, recurring nightmares have been reported to occur in approximately 50% of combat veterans [56]. These miserable reliving experiences often compromise sleep quality, quantity, and daytime mood and function. Polysomnographic evaluation evidences increased sleep latency, decreased sleep efficiency, and the presence of dream recall and increased motor activity in both REM and non-REM (NREM) sleep in these subjects. Many patients have fatigue or frank sleepiness that they attribute to this obvious sleep disruption, but as of yet these symptoms have not been examined with more objective measures in the literature. Like many PTSD symptoms vivid, frightening, reexperiencing nightmares and sleep disruption have proved difficult to treat. A variety of pharmacologic strategies have been attempted and reported, including antidepressant medications, anticonvulsant medications, hypnotics, and anti-adrenergic medications [57]. The most effective and welldemonstrated treatment to date is the alpha-1 adrenergic antagonist prazosin titrated up to 2 to 10 mg as tolerated at bedtime [58–62]. Some patients report lethargy when dosed during waking hours and titration requires appropriate vigilance for orthostatic hypotension, but studies in a variety of populations have found prazosin to be well tolerated. Initially studied in a Vietnam-era combat-veteran population, benefits are now being reported in civilian and ethnically and culturally diverse PTSD populations that struggle with

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nightmares, difficulty maintaining sleep, and autonomic arousal [63–65]. Polysomnographic data, from a placebo-controlled study, has demonstrated that while decreasing nightmares and sleep complaints, prazosin increases total sleep time, REM sleep time, and average REM episode duration without changing sleep latency [64]. While there is evidence prazosin improves patient global level of functioning and sleep, there is currently no research available on the subsequent impact on fatigue or sleepiness in patients with PTSD and prazosin is not FDA indicated for use in PTSD.

Generalized anxiety disorder Generalized anxiety disorder (GAD) is characterized by excessive anxiety or worry about multiple concerns that is difficult to control and occurs more days than not for 6 months. To receive the diagnosis, three of the following six associated symptoms should be present: restlessness, fatigue, irritability, muscle tension, poor concentration, or sleep disturbance. The sleep disturbances can be either difficulty initiating or maintaining sleep or nonrestorative sleep. Interestingly, fatigue, irritability, poor concentration, and disturbed sleep often occur in the setting of a primary sleep disorder. Polysomnographic studies have indicated lower sleep efficiency, slow wave sleep, and sleep time [2]. Research findings demonstrate increased sleep complaints in GAD [66], but it is difficult to tell whether these subjects have an increased incidence of sleep disorders, or just the increased subjective report of sleep complaints. Disturbance of sleep worsens anxiety symptoms [67], and although anxiety can make the treatment of sleep disorders more complicated, these patients should be diagnosed and treated aggressively for any comorbid sleep conditions. Panic disorder is characterized by the sudden onset of intense anxiety that is unexpected and followed by at least 1 month of persistent worrying about recurrence of the attacks, significance of the symptoms, or a sustained change in behavior due to the attacks. Panic disorder can occur with or without agoraphobia. One third of patients with panic disorder have attacks that occur during sleep and it is important to differentiate these from sleepdisordered breathing given the often associated symptoms of sweating, racing heart, and shortness of breath. Excessive daytime sleepiness, fatigue, or consistent changes in polysomnographic measures have not been reported. First-line pharmacologic treatment for GAD, panic disorder, and PTSD often includes selective serotonergic reuptake inhibitors (SSRIs). Tricyclic antidepressants (TCAs) and serotonergic-noradrenergic reuptake inhibitors (SNRIs) may also be used,

although tricyclic antidepressants are not FDA approved for panic disorder, generalized anxiety disorder, or PTSD. SSRIs and SNRIs are generally well tolerated, but sedation from those with higher antihistaminic activity (ie, paroxetine, sertraline, mirtazapine, trazodone) can exacerbate sleepiness or fatigue. TCAs commonly cause sedation and are therefore typically administered at bedtime.

Emerging circadian findings The rapidly growing field of chronobiology sits at the intersection of the expanding frontiers of sleep disorders research and psychiatric research. Circadian abnormalities may be an occult problem causing inappropriately timed sleepiness in a wide range of patient presentations. In addition to findings mentioned previously in the respective sections on dementia, ADHD, and SAD, there are recently emerging associations between circadian abnormalities and other psychiatric disorders. A recent study demonstrated that Clock gene mutant mice demonstrate maniclike behavior (high-risk behavior, lowered anxiety and depression, hyperactivity, and decreased sleep), and that many of these symptoms returned to normal with lithium administration—a first-line treatment for bipolar disorder [68]. Furthermore, these abnormal behaviors were reversed via virally mediated gene transfer to reinstate functional Clock protein in the ventral tegmental area [54,68]. These animal findings are of note given recent reports of abnormal circadian rhythms in some bipolar and schizophrenic populations [52,54]. There has been some speculation of a possible circadian misalignment in some cases of nonseasonal depression but data are limited at this time. Sleep specialists are uniquely suited to help patients understand how inappropriately timed sleepiness may complicate the management of the patient’s psychiatric condition.

Psychiatric medications The impact of medications and nonprescription substances on daytime fatigue and sleepiness is important to consider in the evaluation of a patient complaining of EDS. Special consideration should be given to sedating antidepressants, antipsychotics, sedating anti-epileptics (often used in psychiatry for mood stabilization), hypnotic or sleep aids, and stimulant use. Many psychotropic medications involve antidopaminergic, anti-adrenergic, anticholinergic, or antihistaminic activity all of which may contribute to sleepiness –or fatigue (Tables 1–3). While side effects are typically worse at drug initiation or during dose escalations, patients on stable dosing may continue to have

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Table 3: Relative sedation of mood stabilizers (antimanic agents)a

Table 1: Relative sedation of antipsychotic medications

Carbamazepine (Tegretol) Lithium (Eskalith, lithobid) Valproic acid (Depakote) Topiramate (Topomax) Lamotrigene (Lamictal)

Typical antipsychotics Chlorpromazine (Thorazine) Thioridazine (Mellaril) Loxapine (Loxitane) Molindone (Moban) Perphenazine (Trilafon) Thiothixene (Navane) Droperidol (Inapsine) Haloperidol (Haldol) Atypical antipsychotics Clozapine (Clozaril) Olanzapine (Zyprexa) Quetiapine (Seroquel) Risperidone (Risperdal) Ziprasidone (Geodon) Fluoxetine (Prozac) Citalopram (Celexa) Escitalopram (Lexapro)

111 111 11 11 1 1 1 1 111 11 11 1 1 1 1 1

1, Low; 11, Moderate; 111, High.

sedation or fatigue related to their medication regimen. A study evaluating side effects of antidepressants found that 40% of 117 patients deemed to have a successful response to their antidepressant had symptoms of persistent fatigue or sleepiness [69]. It is difficult to determine the proportion of Table 2: Relative sedation of antidepressant medications Tricyclic antidepressants Amitriptyline (Elavil) 111 Clomipramine (Anafranil) 111 Doxepin (Sinequan) 111 Trimipramine (Surmontil) 111 Maprotiline (Ludiomil) 11 Amoxapine (Asendin) 1 Desipramine (Norpramin) 1 Nortriptyline (Pamelor) 1 Protriptyline (Vivactil) 1 Selective serotonin reuptake inhibitorsa Paroxetine (Paxil) 1 Sertraline (Zoloft) 1 Fluvoxamine (Luvox) 1 Mono amine oxidase inhibitors Phenelzine (Nardil) 1 Tranylcypromine (Parnate) 1 Other antidepressants Trazadone (Desyrel) 111 Nefazadone (Serzone) 11 Mirtazapine (Remeron) 11 Venlafaxine (Effexor) 1 Bupropion (Wellbutrin) 1 a Relative sedation to other medications in Table 1; SSRI sedation is most common with paroxetine. 1, Low; 11, Moderate; 111, High.

11 11 11 1 1

a

Relative sedation to other medications in Table 1; Sedation and fatigue can occur with all mood stabilizing agents. 1, Low; 11, Moderate; 111, High.

these symptoms that are due to the underlying disorder versus a medication side effect; however, reductions in fatigue or sleepiness on medication withdrawal suggest a significant component is directly attributable to medications for many patients. Stimulant medications for ADHD or antidepressant augmentation carry risks of insomnia. Additionally, a careful review of supplements, alcohol, tobacco, and illicit substances may yield insight into complaints of disrupted nocturnal sleep, sleepiness, and fatigue. When side effects of antidepressant medication contribute to a patient’s sleepiness or fatigue, sleep physicians play an important role in collaborating with the prescribing physician. General recommendations include the use of reduced medication dosage to the extent adequate efficacy is retained, use of antidepressant medications that are less likely to contribute to fatigue or sedation, use of antidepressants with more activating side effects (fluoxetine, duloxetine, venlafaxine), and/or adjunct stimulant medications, if appropriate [40,45,70,71]. While there are case reports of combating medication-related fatigue and sedation with modafinil, this is exceedingly rare and does not have an FDA indication. The management of medication-induced fatigue or sleepiness is more complicated in disorders such as bipolar disorder or schizophrenia. A sleep physician respectfully noting potential sedating side effects and suggesting the use of less-sedating alternatives, if clinically appropriate, may be helpful for physicians working with these populations. Communicating the observation of a sleep disorder that interacts with the patient’s psychiatric disorder, coordinating evaluation and treatment with the prescribing primary care physician or psychiatrist, and alerting him or her to the potential need for altered medication requirements over time are all critical roles for the sleep physician consulting on a patient with a psychiatric disorder. As frequently occurs in the management of various medical conditions, medication regimens may need to be changed in some patients after treatment for OSA, PLMD, and circadian or other sleep disorders.

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According to the DSM-IV diagnostic qualifier that psychiatric disorders or their symptoms are not better accounted for by a medical condition, in some cases psychiatrists must reconsider the original psychiatric diagnosis once a confounding diagnosis, such as a sleep disorder, is identified and treated. In summary, there is significant symptom overlap and uncertainty when fatigue and sleepiness are found at the intersection of sleep and psychiatric disorders. Recognition of comorbid sleep disorders in this population will only occur with appropriate vigilance and evaluation. Sleep disorder specialists are obligated to attend to sleepiness and fatigue in the psychiatric patient as thoroughly as they would in the medical or surgical patient. Detection of psychiatric symptoms and appropriate mental health referral is important in the management of the sleepy or fatigued patient, particularly when a risk of suicide exists. While it is difficult to determine the origin of sleepiness and fatigue in the patient with comorbid sleep and psychiatric disorders, careful evaluation and treatment for both provides themost comprehensive and appropriate care. Depressed and fatigued patients may require more sensitive techniques for detection of comorbid sleep disorders as mood and fatigue are correlated more with respiratory related arousal frequency than oxygen desaturation frequency in some studies. Clarifying the potential benefits and limitations of sleep disorder treatment with both the patient and the mental health provider is essential in the co-management of the sleepy or fatigued patient.

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[71]

with posttraumatic stress disorder: a report of 4 cases. J Clin Psychiatry 2000;61:129–33. Boehnlein JK, Kinzie JD. Pharmacologic reduction of CNS noradrenergic activity in PTSD: the case for clonidine and prazosin. J Psychiatr Pract 2007;13:72–8. Taylor FB, Martin P, Thompson C, et al. Prazosin effects on objective sleep measures and clinical symptoms in civilian trauma posttraumatic stress disorder: a placebo-controlled study. Biol Psychiatry 2008;63(6):629–32. Taylor F, Raskind MA. The alpha1-adrenergic antagonist prazosin improves sleep and nightmares in civilian trauma posttraumatic stress disorder. J Clin Psychopharmacol 2002;22:82–5. Alfano CA, Beidel DC, Turner SM, et al. Preliminary evidence for sleep complaints among children referred for anxiety. Sleep Med 2006;7: 467–73. Mellman TA. Sleep and anxiety disorders. Psychiatr Clin North Am 2006;29:1047–58. Roybal K, Theobold D, Graham A, et al. Manialike behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A 2007;104:6406–11. Fava M, Graves LM, Benazzi F, et al. A crosssectional study of the prevalence of cognitive and physical symptoms during long-term antidepressant treatment. J Clin Psychiatry 2006;67:1754–9. Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry 2005;66:85–93. Stahl SM, Zhang L, Damatarca C, et al. Brain circuits determine destiny in depression: a novel approach to the psychopharmacology of wakefulness, fatigue, and executive dysfunction in major depressive disorder. J Clin Psychiatry 2003; 64:6–17.

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Parasomnias: Psychiatric Considerations David T. Plante, -

-

-

-

a,b

MD

, John W. Winkelman,

Non–rapid eye movement parasomnias: disorders of arousal Confusional arousals Sleepwalking Sleep terrors Sleep-related sexual behavior and sleep-related violence Evaluation and treatment of non–rapid eye movement parasomnias Rapid eye movement–related parasomnias

Parasomnias are a group of sleep disorders broadly defined as undesirable physical or experiential events that occur within entry into sleep, during sleep, or during arousals from sleep [1]. In centuries past, parasomnias were often thought related to mystical or supernatural forces. In the early twentieth century, with the development of psychoanalytic theory, which introduced for the first time the notion that unconscious drives affect human behavior, psychoanalysts debated the nature of parasomnias, often under the assumption that such behavior represented the expression of latent desires [2]. As a result, parasomnias were believed for decades to be caused by underlying mental illness. With the more recent rise and development of sleep medicine as a discipline, most parasomnias

-

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c,d,

MD, PhD

*

Rapid eye movement behavior disorder Sleep paralysis Nightmare disorder Other parasomnias Sleep-related eating disorder Sleep-related hallucinations Sleep-related dissociative disorders Summary References

are not believed to be directly related to psychiatric illness [3]. However, since these disorders are behavioral in nature, often co-occur with psychiatric illness, may present as psychiatric complaints, and can be induced by psychotropic medications, parasomnias are best conceptualized from an interdisciplinary perspective, and their optimal management requires that psychiatric considerations be understood by all clinicians who treat them, regardless of discipline of origin. Within psychiatry, the standard of diagnostic categorization is the Diagnostic and Statistical Manual (DSM), which in its most current edition minimally delineates the parasomnias into one of four diagnoses (Table 1). Unfortunately, this diagnostic schema fails to capture the heterogeneity of the

a Department of Psychiatry, Massachusetts General Hospital and McLean Hospital, Harvard Medical School, Boston, MA, USA b McLean Hospital, Outpatient Clinic, 115 Mill Street, Belmont, MA 02478, USA c Divisions of Sleep Medicine and Psychiatry, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA d Sleep Health Center Affiliated with Brigham & Women’s Hospital, 1505 Commonwealth Avenue, Brighton, MA 02135, USA * Corresponding author. Sleep Health Centers, Affiliated with Brigham & Women’s Hospital, 1505 Commonwealth Avenue, Brighton, MA 02135. E-mail address: [email protected] (J.W. Winkelman).

1556-407X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

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Table 1:

Parasomnia classification of DSM-IV and ICSD-2 ICSD-2 Disorders of arousal (from NREM sleep)

DSM-IV-TR

Parasomnias usually associated with REM sleep

Other parasomnias

 Sleepwalking  Sleep terrors

 Nightmare disorder

 Parasomnia not otherwise specified/unspecifieda

 Confusional arousals

 REM sleep behavior disorder  Recurrent isolated sleep paralysis

 Sleep-related dissociative disorders  Sleep enuresis  Sleep-related groaning (catathrenia)  Exploding head syndrome  Sleep-related hallucinations  Sleep-related eating disorder

Abbreviations: DSM-IV, Diagnostic and Statistical Manual, 4th edition; ICSD, International classification of sleep disorders; NREM, non–rapid eye movement; REM, rapid eye movement. a ‘‘Parasomnia not otherwise specified’’ according to DSM-IV-TR includes those parasomnias not boxed; whereas ‘‘parasomnia unspecified’’ according to ICSD-2 includes parasomnias not listed. Of note, ICSD-2 notes that ‘‘parasomnia unspecified’’ is intended for parasomnias that cannot be classified elsewhere or for cases in which the physician has a clinical suspicion that an underlying psychiatric condition may cause the parasomnia. Omitted are ‘‘parasomnias due to medical condition’’ and ‘‘parasomnia due to drug or substance’’ (ICSD-2), which are classified as sleep disorder caused by a general medical condition, parasomnia type, and substance-induced sleep disorder, parasomnia type, respectively under DSM-IV-TR [1,72].

parasomnias, and is not based on current knowledge of the underlying pathology of these disorders. As the brain cycles through three primary states of being (wakefulness, non–rapid eye movement [non-REM] sleep, and rapid eye movement [REM] sleep) separation between the states may become blurred or oscillate rapidly, giving rise to parasomnias [3,4]. The International Classification of Sleep Disorders (ICSD), used primarily by sleep medicine clinicians, is structured around this pathologic paradigm, and is further differentiated than the DSM. Fortunately, most practicing psychiatrists realize the limitations of the DSM, and it is the authors’ hope that the upcoming fifth edition of the DSM (expected to be published in 2012) will reflect more current understanding of these disorders. This article focuses on parasomnias that are most frequently seen in psychiatric settings or have connections to neuropsychiatric illness including non-REM parasomnias of arousal, REM-related parasomnias, and other parasomnias including sleep-related eating disorder (SRED), sleep-related hallucinations, and sleep-related dissociative disorders (SRDD) (Table 2). It should be noted that there are no pharmacologic agents approved by the Food and Drug Administration for the treatment of parasomnias, and recommendations are based on the available scientific literature or the clinical experience of the authors.

Non–rapid eye movement parasomnias: disorders of arousal The non-REM parasomnias (sleepwalking, sleep terrors, and so forth) are a group of related disorders of arousal that share common features and likely underlying pathology. During a partial arousal from sleep, behaviors (eg, ambulation, eating, and so forth) or mood states (eg, anger, fear) are expressed that are not fully (or at all) under conscious control; nor do they occur with ordered judgment or full integration of environmental feedback [5]. Episodes tend to arise from slow wave sleep ([SWS] stages 3 and 4 of non-REM sleep); typically occur during the first 1 to 2 hours of the sleep period; and are seldom remembered by the individual on final awakening. Non-REM parasomnias are common in childhood, but usually diminish with increasing age. There is frequently a family history of disorders of arousal in individuals who present for evaluation, and these disorders are likely expressed when environmental factors affect a genetically predisposed individual [6]. In susceptible individuals, precipitating events can be either endogenous (eg, breathing or movement abnormalities, pain) or exogenous (eg, noise, light, sleep deprivation, medications) factors that disturb sleep [4]. As a result of similarities between these disorders, the categorization of non-REM parasomnias is

Table 2:

Characteristics of parasomnias Non-REM parasomnias

REM parasomnias

Other parasomnias

Sleepwalking

Sleep terrors

RBD

Sleep paralysis

Stage of arousal Typical time of night

II, III, IV Anytime

III, IV First 2 h

III, IV First 2 h

REM Anytime

EEG during event

NA

Mixed

Mixed

EMG activity during event Decreased responsiveness during event Autonomic hyperactivity Amnesia

[

[

[

REM pattern [

1

1

1

1

1

1



1

(dream recall)

(experience recall)

(dream recall)

Confusion postepisode Family history

1

1

1

1

1

1

1

1

1

Nightmare disorder

SRED

SRHa

SRDD

REM Anytime (first 2 h)

REM Anytime

II, III, IV Anytime

NREM or REM Anytime

Wake pattern Y

NA

Mixed

NA

[

REM Onset/ offset of sleep Wake pattern NA

1

1



Wake pattern [ 1





 (partial)

1

1

1

1



Unknown

Abbreviations: EEG, electroencephalogram; EMG, electromyogram; NREM, non–rapid eye movement; RBD, REM behavior disorder; REM, rapid eye movement; SRED, sleep-related eating disorder; SRH, sleep-related hallucinations; SRDD, sleep-related dissociative disorders. a SRH for this table includes hypnagogic/pompic hallucinations. The few EEG studies of complex nocturnal hallucinations suggest they can occur from NREM.

Parasomnias: Psychiatric Considerations

Confusional arousals

Parasomnia

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typically based on the types of behaviors and mood states exhibited. In the following sections, these disorders are presented along a continuum of behavioral and affective arousal, acknowledging that clinical overlap often exists among these disorders.

Confusional arousals Confusional arousals are typically brief, simple motor behaviors that occur with little emotional expression, lack of responsiveness to the environment, and are associated with mental confusion on arousal or awakening [7]. The motoric behaviors are simple and may be accompanied by indistinct vocalization. Episodes are brief, and because of dense amnesia for the episode, without collateral information from a bedpartner or parent, they often go unnoticed. Cross-sectional prevalence is estimated at 4.2%, with comparable rates among men and women, and prevalence that decreases with age [7]. A variant of confusional arousals has been described as ‘‘sleep drunkenness’’ or excessive sleep inertia [8,9]. Confusional arousals are distinguished from excessive sleep inertia because the latter phenomenon occurs from final awakening; however, both are similar in regards to their immediate development from sleep, impaired mentation, automatic behavior, and relative unresponsiveness to the environment. The duration during which excessive sleep inertia can affect an individual is typically minutes, but can be up to 4 hours [9]. Sleep inertia occurs from both naps and full sleep periods, and its severity and duration is likely related to the depth of prior sleep. Studies using self-report to examine the prevalence of confusional arousals may focus on sleep inertia, because patients are more apt to recall these episodes as they achieve full wakefulness. One such study found bipolar disorder, a major mood disorder characterized by episodes of depression and mania, was strongly associated with such self-reported confusional arousals, although the significance of this finding is unclear [7].

Sleepwalking Sleepwalking, or somnambulism, is distinguished by greater complexity of behavior than confusional arousals. Individuals who sleepwalk have limited conscious control during an episode, but may recall simple motivations (eg, desire to urinate) if awakened during an episode. Sleepwalkers typically have eyes open during an event; may be clumsy in their behavior; and if undisturbed, typically return to sleep, although they may do so in atypical places [10,11]. Although sleepwalking behaviors are not usually dangerous, individuals may injure

themselves (eg, climbing out a window) or others, and interruption may evoke a range of responses, including agitation or violence. Similar to other non-REM parasomnias, episodes typically arise from SWS during the first part of the sleep episode, and amnesia for the episode is usually present. Somnambulism is common in childhood, occurring in 10% to 20% of all children, with the greatest prevalence occurring between 3 and 10 years of age [12]. Because its prevalence decreases with increasing age, sleepwalking is considered in most cases to be a transiently disruptive, rather than pathologic, process that typically resolves by adolescence. Somnambulism occurs in 1% to 4% of adults, however, with roughly 80% of cases a continuation of childhood behavior [7]. Evaluation in adults is typically prompted when an individual’s bedpartner is concerned by the frequency or dangerousness of the behavior. Prevalence of sleepwalking does not seem to be associated with gender, race, or socioeconomic conditions [12]. Individuals with sleepwalking likely have a genetic predisposition, as evidenced by epidemiologic, twin, and HLA mapping studies [13,14]. The risk of somnambulism is roughly doubled if one parent, and tripled if both parents, have a history of sleepwalking. The relationship between mental illness and sleepwalking has been a long debated issue [15]. Although childhood sleepwalking does not seem to be directly related to psychiatric pathology, it has been suggested that psychopathology may be associated with sleepwalking in adolescence and adulthood [7,16]. There is insufficient evidence to suggest sleepwalking behaviors represent unconscious motivations acted out during sleep; however, there are no controlled studies of sleepwalkers simultaneously in psychotherapy during which unconscious desires might be explored in detail [17]. It is critical to realize, however, that psychotropic medications may raise the risk of adult somnambulism because of their effects on sleep and wakefulness [18]. Also, because nearly every major psychiatric illness (eg, depression, bipolar disorder, schizophrenia) is associated with disturbed sleep, this may increase the risk of sleepwalking in these individuals, particularly if they had sleepwalking behaviors as a child [19].

Sleep terrors Sleep terrors are similar to sleepwalking; however, they are distinguished by more intense motor, emotional, and autonomic activity. Rather than construing sleep terrors and somnambulism as distinct disorders, it is more useful to consider them related entities that can evolve from one another. Similar to somnambulism, sleep terrors usually occur in the first third of the sleep period and are believed to

Parasomnias: Psychiatric Considerations

be caused by a confluence of genetic susceptibility with precipitating factors [20]. Sleep terrors occur in roughly 5% of children and are typically dramatic: a piercing scream, followed by fear, crying, and inconsolability [7,21]. In adults, the prevalence of sleep terrors is 1% to 2%, and presentation is less stereotypical, usually involving agitation, often with injury to self, others, or property during an episode [7,21]. Similar to somnambulism, simple thoughts may be recalled (eg, ‘‘I am in danger’’), which can be difficult to dispel even once awakened, but patients typically do not report dreaming and are amnesic for the episode. Confrontation of an individual in the midst of an episode can be dangerous, because there is the real danger of being incorporated into the sleep terror leading to violence.

Sleep-related sexual behavior and sleep-related violence Sleep-related sexual behavior and sleep-related violence are non-REM parasomnias that consist of more complex behaviors and emotional states and are poorly understood compared with those previously discussed. Because these disorders cause significant harm and may have forensic implications, however, there is an urgency to develop a more comprehensive understanding of these disorders. Sleep-related sexual behavior, or ‘‘sexsomnia,’’ is a parasomnia in which sexual behavior occurs with limited awareness during the act, relative unresponsiveness to the external environment, and amnesia for the event [22]. The sexual behavior may range from sexual vocalizations to intercourse, and may be atypical for the patient in terms of partner or type of sexual act (eg, anal intercourse) [23]. It has been proposed that distinguishing features of sexsomnia that differentiate it from sleepwalking include more widespread autonomic activation, sexual arousal, and duration of behavior that can occasionally exceed 30 minutes [22]. Of note, parasomnias are not the only potential cause of sleep-related sexual behavior, and other disorders including nocturnal seizures and Kleine-Levin syndrome, a rare disorder typically presenting in adolescence with episodic hypersomnolence, hyperphagia, and hypersexuality, should be included in the differential diagnosis [24]. Sleep-related violence is best conceptualized as an overlap disorder of sleep terrors following sleepwalking [25]. Violent behavior occurs in a state consistent with night terrors, with anger or fear as the primary emotion, and agitation directed toward individuals who may be in close proximity or confront the individual [26]. Individuals slowly return to normal levels of alertness, or may go back to

sleep, and typically have amnesia for the episode. Like sexsomnia, the violent behavior is often atypical for the patient. Most cases have been young to middle-aged men with a previous history of sleepwalking [27]. The legal concept of mens rea, criminal intent, is of great import in the prosecution of individuals with sleep-related violence or sleep-related sexual behavior. Because the pathophysiology of disorders of arousal may involve relative deactivation of the frontal lobe, which is largely responsible for logic and reasoned judgment, and the inappropriate activation of limbic areas, regions in the brain responsible for the expression of emotion, it may be argued that criminal intent does not exist in these cases [26]. Often defendants may argue that alcohol induced the violent or sexual act; however, there is currently no direct experimental evidence that alcohol triggers sleepwalking or related disorders [28]. Typically, these cases are quite complex and conviction or acquittal by a jury in cases where a non-REM parasomnia is used as a defense is relatively unpredictable.

Evaluation and treatment of non–rapid eye movement parasomnias Polysomnography (PSG) is often not necessary for the evaluation of non-REM parasomnias, and attempts to document somnambulism and sleep terrors by PSG are often unsuccessful [29]. Polysomnographic markers of susceptibility have been studied, however, for both their diagnostic use and potential insight into pathogenesis. Most polysomnographic studies of sleepwalkers demonstrate increased brief arousals from SWS with a preserved sleeping electroencephalogram, and autonomic activation following the arousal [30,31]. Similarly, multiple brief arousals with autonomic hyperactivity may be observed as a marker of sleep terrors [32]. PSG may be indicated when there is a new onset of parasomnias without a prior history of childhood parasomnias, because there may be a treatable cause of arousal from SWS present, such as sleep-related breathing disorder, periodic limb movements of sleep, or nocturnal seizures. The differential diagnosis of unwanted nocturnal behaviors also includes nocturnal panic attacks, frontal lobe seizures, delirium associated with medical or neurologic disorders, and nocturnal dissociative disorders and REM sleep behavior disorder (discussed later). Of note, nocturnal panic attacks refer to episodes where individuals awaken from sleep, typically without dream recall, and experience panic attacks with full awareness that may include tachycardia, diaphoresis, shaking, shortness of breath, chest discomfort, nausea, paresthesias,

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or intense fear. These episodes are common among individuals with panic disorder, and a daytime history of similar events should be elicited, although nocturnal panic attacks may occasionally occur in isolation [33]. The frequency of the parasomnia event, the risk of injury to self or others, and the distress the behavior is causing the patient or family members, should all be carefully considered when managing non-REM parasomnias [5]. For most children, parasomnias do not require pharmacologic treatment because the behavior may be intermittent, self-limited, poses little risk of harm to the child, and does not negatively affect daytime functioning. Keeping regular sleep-wake times, avoidance of sleep deprivation, voiding before bed, and treatment of underlying sleep disorders (eg, sleep apnea, restless legs syndrome) may decrease the frequency of episodes. Also, improving the safety of the sleeping environment (eg, locking doors and windows, keeping hallways and stairs well lit) is important in reducing potential harm from such episodes. When treatment of non-REM parasomnias in adults is indicated, it is done following a threestep model: (1) modifying predisposing and precipitating factors, (2) improving the safety of the sleeping environment, and (3) pharmacotherapy if necessary. In the decision to pursue pharmacologic therapy, patients and physicians should collaboratively decide whether continuous treatment for behaviors that are usually episodic in nature is warranted. The agents most frequently used to treat non-REM parasomnias are benzodiazepines; however, there are no controlled trials of these agents, and their use is generally guided by clinical experience. Clonazepam (0.5–2 mg at bedtime), a long-acting benzodiazepine, has been used successfully for extended periods without the development of tolerance in most cases [34]. The long half-life of clonazepam increases the likelihood of daytime side effects, however, and in such instances a shorter-acting benzodiazepine (eg, lorazepam, triazolam) may be efficacious. Although clinically useful, it is unclear whether these medications work by suppressing arousals during sleep or decreasing SWS.

Rapid eye movement–related parasomnias Specific physiologic and experiential changes that occur during REM sleep include atonia of the voluntary muscles (except extraocular); elevated autonomic activity; and dreaming. REM-related parasomnias involve either the incoordination of these processes or the inappropriate admixture of REM sleep and wakefulness.

Rapid eye movement behavior disorder REM behavior disorder (RBD) is characterized by the loss of coordination of dreaming and paralysis of the skeletal muscles during sleep, causing individuals with this disorder to act out their dreams, with a mixture of simple and complex motor behaviors, which can include screaming, punching, kicking, and so forth. Behavior is enacted with eyes closed and unresponsiveness to the surrounding environment. When awakened while acting out a dream, the individual rapidly achieves full alertness and often reports a dream that corresponds to their behavior. Agitated or violent behavior leading to self-injury or injury of a bedpartner is often the impetus that leads to evaluation by a physician. RBD may also present coincidentally with primarily psychiatric symptoms (eg, as part of a depressive episode), with symptoms of RBD symptoms unearthed when taking a sleep history [35]. Similarly, given the propensity of serotonergic antidepressants to provoke RBD, psychiatrists may be the first physicians consulted for this problem. The prevalence of RBD is estimated to be between 0.04% and 0.5% of the population [36]. RBD is typically separated into acute versus chronic forms, which are thought to have different underlying causes. Acute RBD is often associated with medications; drugs of abuse; or withdrawal (particularly alcohol) [37]. Chronic RBD is most commonly seen in men over 50 years of age, and is further subdivided into two types: idiopathic and secondary to a neurologic process. The diseases most commonly associated with RBD are the a-synucleinopathies including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, all of which are characterized by pathologic accumulation of the protein a-synuclein [38]. Although the three largest cohorts of chronic RBD suggest that roughly 60% of chronic RBD is idiopathic, ongoing followup studies suggest that idiopathic RBD may be a prodromal symptom of an underlying neurologic illness that may or may not manifest during the lifespan of patients with the disorder [36,39]. Although the pathophysiology of RBD is not entirely elucidated, the extrapyramidal and REM sleep systems in the brainstem share specific neuronal connections, which may be central to RBD pathogenesis. Animal models of RBD in which brainstem lesions near the locus coeruleus produced REM sleep without atonia existed well in advance of clinical description of the disorder, and more recent research suggests neurons may be reduced in similar regions in RBD [40,41]. Furthermore, reduced dopamine transporters and reduced dopaminergic innervation in the striatum have been demonstrated in RBD [42,43]. One intriguing hypothesis is that

Parasomnias: Psychiatric Considerations

the pedunculopontine nucleus may play a role in the REM-atonia circuitry and its disruption in RBD, connecting clinical observations regarding the a-synucleinopathies and extrapyramidal system and RBD with observations in pontine-lesioned animal models [44]. PSG along with clinical history is necessary to confirm the diagnosis of RBD. PSG demonstrates elevated muscle tone or increased phasic muscle activity in the chin (submental) or limb (anterior tibialis) electromyogram during REM sleep [1]. Periodic limb movements of sleep are common in RBD, although otherwise the PSG is typically normal. Further nonspecific findings in RBD may include general slowing of the waking EEG, subtle neuropsychologic dysfunction, autonomic dysfunction, subtle abnormalities of motor and gait speed, impairment in color discrimination, and olfactory dysfunction [45–48]. The management of RBD, like other parasomnias, is typically behavioral and pharmacologic. Ensuring safety of the bedpartner is important, and it may be recommended that the bedpartner sleep in another room until symptoms are controlled, particularly if there is a history of injurious behavior. Patients may devise their own home remedies, such as tying themselves to the bed, but these may be dangerous as evidenced by the fact that restraint of agitated psychiatric patients in inpatient settings is a significant cause of morbidity and mortality [37,49]. Prudent behavioral management includes locking doors and windows; limiting objects (eg, furniture) on which a patient may injure themselves in the bedroom; sleeping on a mattress on the floor; and sleeping on the ground floor if possible. Before starting a medication to treat RBD, it is important to limit any medications that may be contributing to or causing the disorder. Serotonergic antidepressants, monamine oxidase inhibitors, and tricyclic antidepressants have been associated with subclinical RBD (the disinhibition of motor tone during REM sleep without obvious clinical symptoms), and may lead to or exacerbate RBD and should be discontinued if clinically feasible [50,51]. Any discontinuation of antidepressant medication should be discussed with the prescribing physician (eg, psychiatrist) before discontinuation, however, because 15% of those with depressive disorders commit suicide, necessitating coordination of care after antidepressant discontinuation [52]. Benzodiazepines are typically the first-line pharmacologic agents in the treatment of RBD. Clonazepam (0.5–2 mg) is most commonly used and has been shown to decrease the frequency and extent of problematic dream-enacting behavior [51]. In general, clonzaepam is well-tolerated; however,

cognitive impairment, motor disturbance, and daytime sedation may limit its use, particularly in older individuals. Alternative treatment strategies include using a benzodiazepine with a shorter half-life (eg, lorazepam, 1–2 mg), or using a different class of medications. There are small case series suggesting efficacy of melatonin (3–15 mg qhs) and pramipexole (0.5–1 mg qhs) in RBD, which may be useful in patients who cannot tolerate a benzodiazepine or who may have a history of substance abuse or dependence [53,54].

Sleep paralysis Sleep paralysis (SP) refers to paralysis of the voluntary musculature associated with a conscious state at the onset or offset of sleep. Episodes may last seconds to minutes, and often resolve spontaneously on reentry into sleep or when touched. SP is thought to result from inappropriate REM intrusion into wakefulness, or conversely the failure to maintain sleep during REM periods [55]. SP can occur at any time of night, but tends to be clustered in the first 2 hours of the sleep period or at the final awakening, and may be worsened by sleep deprivation and supine positioning [55–57]. Estimates of the lifetime prevalence of SP vary widely between 2.3% and 40%, with multiple episodes occurring in 1% to 10% of the population [55]. Although most patients with SP likely do not have associated psychiatric illness, SP occurs at higher rates among individuals with bipolar disorder, depression, anxiety disorders, and posttraumatic stress disorder (PTSD) compared with the general population [58,59]. Cultural factors may influence a patient’s subjective experience and report of symptoms, with many cultures relating the phenomenon to beliefs about spirits or supernatural forces [60]. Although many patients may have symptoms in isolation, SP with or without hypnogogic-popmic hallucinations (discussed later) should prompt inquiry about other symptoms of narcolepsy, because SP is a classic, although nonspecific, symptom of this disorder [61]. Unless narcolepsy is suspected by history, PSG is typically not indicated for SP. Treatment of underlying psychiatric illness (eg, depression) may be helpful in the management of SP; however, in the absence of comorbid illness, reassurance and education is most useful in isolated cases. If the frequency of SP is bothersome to patients, there is a suggestion that antidepressants may be of benefit, likely because of their REMsuppressing properties [62].

Nightmare disorder The study of dreams has long been of interest in psychiatry, likely stemming from early psychoanalytic theory. Freud, who himself developed myriad

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revolutionary theories on the workings of the mind (although many have been criticized in modern times), considered his theory on the meaning of dreams to have been his greatest accomplishment [63]. Although the complexities of his theory are beyond the scope of this discussion, Freud believed dreams to be ‘‘the royal road to a knowledge of the unconscious,’’ because they were disguised fulfillments of wishes and desires that could not be expressed consciously [64]. With advances in sleep medicine, it is known from a physiologic perspective that dreams occur predominantly (although not exclusively) during REM sleep. Nightmare disorder is characterized by recurrent, affect-laden dreams, followed by awakening, typically with detailed recall of the dream. Fear is the most common emotion; however, anger, embarrassment, and sorrow might also be experienced. Nightmares typically occur in the latter third of the night, which coincides with the increased proportion of REM sleep within that portion of the sleep period [65]. Unlike RBD, nightmares are not typically associated with motoric dream enactment. After awakening, nightmare recall and heightened autonomic activity may make it difficult for an individual to return to sleep. In addition, fear of nightmares may lead some individuals to be afraid to initiate sleep at the beginning of the night. Nightmares can lead to either sleep onset or sleep maintenance insomnia. Estimates of the prevalence of nightmares and their association with psychiatric illness are hindered by inconsistent definitions among researchers. Still, roughly 5% to 8% of adults in the general population experience current nightmares, and nightmares are more common in women than men [66,67]. Most studies have found nightmares to be associated with many psychiatric diagnoses including depression, substance abuse disorders, and personality disorders [68]. Interestingly, there is growing evidence of a connection between nightmares and suicidality, although a causal relationship cannot be inferred at present [69,70]. There is some evidence suggesting distress from nightmares, rather than frequency of occurrence, may be more closely tied to mental illness [71]. The psychiatric illness most commonly associated with nightmares is PTSD. PTSD is currently classified as an anxiety disorder in the DSM-IV, and its technical diagnostic criteria are somewhat complex [72]. In brief, diagnosis of the disorder requires that an individual has been exposed to a traumatic event and experiences symptoms from three clusters: (1) re-experiencing of the trauma (eg, nightmares about the event); (2) avoidance of stimuli associated with the trauma; and (3) persistent symptoms of arousal [72]. Within current

DSM-based nosology, nightmare disorder should not technically be diagnosed if the nightmares are thought secondary to PTSD. Conversely, the ICSD-2 considers PTSD a predisposing factor for nightmare disorder [1]. In clinical practice, many psychiatrists treat nightmares as a separate, treatable component of PTSD, directing specific interventions toward this symptom. Nightmares associated with PTSD tend to be recurrent, and have similar thematic content to the experienced trauma history [73]. The prevalence of nightmares in those with PTSD varies depending on the study population and nature of the trauma. Surveys of the general population reveal individuals with PTSD report nightmares at rates five times that of the general population [74]. Interestingly, a tendency to experience ‘‘bad dreams’’ and disrupted sleep preceding Hurricane Andrew was found to be a risk factor for developing PTSD after the event, suggesting premorbid sleep disruption may be a susceptibility marker for those who develop PTSD [75]. PSG is not routinely indicated for evaluation of nightmares unless necessary to rule out another sleep disorder. Numerous small studies have suggested effectiveness of prazosin, topiramate, and atypical antipsychotics in the treatment of PTSDrelated nightmares, although no uniform consensus strategy exists and choice of medication is best made on a case-by-case basis [76–78]. Psychotherapeutic strategies including imagery rehearsal therapy and guided hypnosis, in which alternative versions of nightmares with better outcomes are rehearsed while awake or in a state of deep relaxation, have also shown potential benefit for the treatment of nightmares, both trauma and nontrauma related [79,80].

Other parasomnias The following section details three parasomnias characterized in the ICSD-2 as ‘‘other’’ parasomnias: SRED, sleep-related hallucinations, and SRDD [1]. Although in some instances they may be more closely related to non-REM parasomnias (eg, SRED) or REM parasomnias (eg, sleep-related hallucinations), their categorization as ‘‘other’’ reflects divergence in presentation and management from more classic non-REM and REM parasomnias already discussed.

Sleep-related eating disorder SRED is a parasomnia that has only recently been described in the medical literature, but has become a popular topic in the media [81]. SRED is best conceptualized as a combination of the binge eating behaviors of bulimia nervosa or binge eating disorder (eating disorders in which patients eat excessive

Parasomnias: Psychiatric Considerations

quantities with or without purging) with the disordered arousal, confusional behavior, and amnesia of a non-REM parasomnia [82,83]. Episodes typically occur with repetitive partial arousals within the first 2 to 3 hours of sleep, and ingestion of food occurs in a hurried or ‘‘out of control’’ manner, despite frequent lack of hunger at the time of the episode. Foods consumed are often high-carbohydrate, but may also be unusually combined foods, frozen foods, or nonnutritive substances. Patients often feel ashamed of their behaviors, gain weight because of the binges, and may forcibly attempt to control their overall caloric intake by daytime anorexia. Awareness during episodes can be variable, with patients often reporting that they were mostly asleep or half-awake, half-asleep. In some instances, patients report complete amnesia for the episodes, and specifics may be elucidated by witnesses to the episodes, or reconstructed from evidence on awakening (eg, food missing, messy eating place, food in bed). Unlike other classic non-REM parasomnias, the level of awareness may vary between episodes within the same night, and from night to night over the longitudinal course of the disorder. Level of awareness during the eating episode is what distinguishes SRED from night eating syndrome (NES), a disorder characterized by eating excessive amounts of food either before bed or during nocturnal awakenings, while maintaining full consciousness [84]. It is likely most useful to consider NES and SRED as related disorders that exist at opposite ends of a continuum of awareness during nocturnal eating [85]. The prevalence of SRED is estimated to be 1% to 5% in the general population, two to four times more common in females, and tends to have onset in late adolescence or early adulthood, although patients often do not present until many years after they first develop symptoms [86]. Patients with SRED may have a history of sleepwalking; however, once eating behaviors become established, they tend to replace any other distinct sleepwalking behaviors. The pathophysiology of SRED and NES is unclear; however, it has been hypothesized that nocturnal eating may be caused by abnormal coordination of hormones regulating appetite and the sleep-wake cycle [87,88]. SRED seems to be more common in patients with a daytime eating disorder (eg, anorexia nervosa, bulimia nervosa); however, most patients with SRED do not have an eating disorder that manifests while awake [86,89]. It is noteworthy, however, that the prevalence estimates of NES are as high as 12.3% in psychiatric outpatients [90]. Approximately one third of patients with SRED have a first-degree family member with nocturnal eating, similar to familial patterns observed in sleepwalking and

certain eating disorders [91,92]. Polysomnographic studies have demonstrated frequent arousals from SWS, similar to other non-REM parasomnias, but eating episodes can emerge at any time of night and from all states of non-REM sleep [82,83]. Occasionally, SRED may be secondary to conditions that cause arousal from sleep (eg, obstructive sleep apnea, periodic limb movements of sleep), in which case PSG may be helpful to rule out such disorders [93]. Restless legs syndrome is often comorbid with SRED, and treatment of RLS with dopamine agonists may diminish the nocturnal eating behaviors [89]. Also, many psychotropic medications may induce the disorder in susceptible individuals, including benzodiazepine-receptor agonists (eg, zolpidem) and atypical antipsychotics (eg, risperidone, olanzapine) [94–97]. Treatment of SRED is similar to other non-REM parasomnias, with some notable exceptions. Besides avoidance of sleep deprivation and maintaining the safety of the sleeping environment, normalization of a daytime eating schedule is important. Pharmacotherapy is typically tailored to the individual patient. Those with a history of sleepwalking can be given short- to intermediate-acting benzodiazepines or other non–appetite-stimulating sedatives (eg, trazodone); however, this may have the paradoxical effect of worsening eating behaviors and amnesia. Antidepressants including selective serotonin reuptake inhibitors and buproprion may also be of benefit in some patients [98,99]. There is growing evidence that topiramate, an antiepileptic medication, may be the treatment of choice in SRED because numerous open-label case series have shown it to be efficacious in decreasing frequency of nocturnal eating, often with decrease in weight [100–102].

Sleep-related hallucinations Sleep-related hallucinations include hypnagogic and hypnopompic hallucinations, and complex nocturnal visual hallucinations [1]. The latter is a less common syndrome in which the individual experiences visual hallucinations, often of a person or animal, after full awakening from sleep, which may remain present for several minutes, but usually disappears if illumination is increased. Although these may be related to neuropsychiatric disease (eg, dementia with Lewy bodies), there are individuals who experience complex nocturnal visual hallucinations in whom anxiety is the only associated feature [103]. Hypnagogic and hypnopompic hallucinations are classically visual, but may include auditory, tactile, or kinetic hallucinations that occur at the onset of sleep or on awakening. Although the precise pathophysiology is unknown, it is thought that

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they may represent REM dreaming intruding into wakefulness. This may account for the observation that these hallucinations often co-occur with SP, the combination of which can be quite distressing to patients. Hypnagogic and hypnopompic hallucinations are common in the general population, with prevalence estimates of 37% and 12.5%, respectively [104]. Individuals with mood, anxiety, and psychotic disorders experience hypnagogicpompic hallucinations at greater rates than the general population, but they are neither sensitive nor specific for mental illness [104]. Because hypnagogic-pompic hallucinations are more frequently seen in psychotic disorders (eg, schizophrenia) than other psychiatric disorders, when encountered in a clinical setting, practitioners should inquire about other signs of psychosis (eg, daytime hallucinations, delusions, and so forth) and refer to psychiatrists when appropriate.

but may be indicated to rule out frontal lobe seizures, RBD, or more clearly delineate a nocturnal dissociative episode from a non-REM parasomnia.

Summary Parasomnias represent undesirable experiences or behavior that arise from sleep but are not fully under voluntary control. As a group of disorders, they challenge the arbitrary separation between disciplines, and reflect the interdisciplinary nature of sleep medicine. Appreciation of the psychiatric aspects of parasomnias is necessary by those who manage these disorders because they are often comorbid with mental illness, may present with psychiatric complaints, may be induced by psychotropic medications, and are often effectively managed with psychopharmocologic and/or psychotherapeutic interventions.

Sleep-related dissociative disorders

References

SRDDs have been included as a parasomnia in the ICSD-2, reflecting a shift from previous nosology, and merit discussion [1]. SRDD occurs when an individual with a dissociative disorder (eg, dissociative amnesia, dissociative fugue, dissociative identity disorder [formerly multiple personality disorder], and depersonalization disorder) has nocturnal episodes of dissociation. Although the pathophysiology of dissociative disorders is not known, they are thought to arise when normally integrated functions of consciousness, memory, identity, or perception are separated (ie, dissociated) from one another [72]. Dissociative disorders are more predominant in women, and often (although not always) there is a history of past trauma. Nocturnal dissociative episodes occur during electroencephalogram established wakefulness, and can occur at varied intervals from sleep, ranging from the transition from sleep to wakefulness to several minutes after achieving wakefulness. Myriad behaviors may manifest during these episodes that may be complex, violent, self-mutilating, abuse re-enactments, or fugue [105]. Prevalence is not known; however, 7 out of 100 consecutive patients referred to a sleep disorders center for sleep-related injury were found to have SRDD [106]. Nocturnal episodes of dissociation may occur in roughly one quarter of patients with dissociative disorders [107]. Although nocturnal dissociative episodes tend to arise from more clearly established wakefulness than other disorders previously discussed, their undesirable behavior and relatedness to sleep challenge the understanding of parasomnias as a group of disorders [108]. Treatment of nocturnal dissociation is typically directed at the underlying dissociative illness. PSG is not routinely indicated,

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Sleep in Mood Disorders Michael J. Peterson, -

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a

MD, PhD

, Ruth M. Benca,

Epidemiology Classification and diagnosis of mood disorders Prevalence and types of sleep problems in mood disorders Epidemiology of sleep disturbance and mood disorders Predictive value and specificity of sleep disturbance for mood disorders Interepisodic persistence of subjective sleep disruption Psychiatric comorbidities associated with sleep and mood disorders Comorbidity of primary sleep disorders and mood disorders Sleep findings in mood disorders Subjective sleep complaints Polysomnographic and architectural sleep changes

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Sleep disturbances are among the most common symptoms in patients with acute episodes of mood disorders, and patients with mood disorders exhibit higher rates of sleep disturbances than the general population, even during periods of remission. Insomnia and hypersomnia are associated with an increased risk for the development or recurrence of mood disorders, and increased severity of psychiatric symptoms. Similarly, primary

a,b,

MD, PhD

*

Advanced sleep electroencephalogram analysis Power spectral analysis Automated slow wave analysis Coherence of sleep electroencephalogram rhythms Topography of sleep electroencephalogram activity Biologic mechanisms of sleep changes in mood disorders Neurotransmitters Neuroimaging Endocrine changes Genetic polymorphisms Treatment of sleep disturbance and mood disorders Sleep-deprivation therapy Sleep loss and bipolar disorder Clinical use of polysomnography Summary References

sleep disorders, such as obstructive sleep apnea (OSA) and restless legs syndrome (RLS), are also associated with an increased incidence of depression. Sleep electroencephalogram (EEG) recordings have identified objective abnormalities associated with mood disorders, providing insight into the neurobiologic relationships between mood and sleep. Future studies will continue to investigate this association, and potentially

This work was supported by NIH Roadmap Interdisciplinary Award T32 MH75880 (MJP), and a NARSAD Young Investigator Award (MJP). a Department of Psychiatry, University of Wisconsin-Madison, 6001 Research Park Boulevard, Madison, WI 53719, USA b University of Wisconsin Sleep Program, 6001 Research Park Boulevard, Madison, WI, USA * Corresponding author. Department of Psychiatry, University of Wisconsin-Madison, 6001 Research Park Boulevard, Madison, WI 53719. E-mail address: [email protected] (R.M. Benca). 1556-407X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

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improve the treatment of both sleep and mood disorders.

Epidemiology Classification and diagnosis of mood disorders Sleep complaints are one of the most consistent symptoms associated with mood disorders. Disruptions of typical sleep patterns are a core diagnostic criterion of mood episodes in the Diagnostic and statistical manual of mental disorders-IV-TR (Tables 1 and 2) [1], reflecting their importance and prevalence in the presentation of these disorders. Mood disorders are among the most common categories of psychiatric diagnoses, second only to anxiety disorders. They are responsible for tremendous Table 1:

socioeconomic costs worldwide, including eventual suicide in 15% of persons with major depression, increased morbidity and mortality from other illnesses, and economic impacts from associated disability (http://www.who.int/topics/depression/en/). Mood disorders are diagnosed based on the pattern of depressive and/or manic episodes (see Table 1). Major depressive disorder is characterized by the occurrence of one or more episodes of major depression. Patients with a bipolar disorder diagnosis must have at least one manic, hypomanic, or mixed episode, and frequently have episodes of major depression. Major depressive or manic episodes are categorized as psychotic or nonpsychotic, based on the presence or absence of delusions and hallucinations. Depressive episodes, in both major depression and bipolar disorder, can have

Diagnostic and Statistical Manual of Mental Disorders-IV-TR mood disorders and subtypesa

Mood disorder

Clinical features

Major depression Bipolar I

Either single or recurrent MDEs. No periods of mania or hypomania. At least one manic episode. Recurrent MDEs are typical, but not formally required for DSM diagnosis. Persistent depressed mood and symptoms that are not severe enough for diagnosing an MDE. Symptoms must be present most of the time for at least 2 years. At least one hypomanic episode and one MDE. Typical course consists of recurrent MDEs and some hypomanias. Recurrent hypomanic episodes and recurrent or chronic depressive symptoms. Depressive symptoms not severe enough to meet MDE criteria.

Dysthymia

Bipolar II Cyclothymia Subtype

Clinical features

Atypical

Clinical picture of depression characterized by mood reactivity (mood brightens in response to positive events), and at least two of the following features: Significant weight gain or increase in appetite Hypersomnia Heavy, leaden feeling in arms or legs Long-standing pattern of interpersonal rejection sensitivity (not limited to depressive episodes) that results in significant social or occupational impairment Clinical picture of depression characterized by a lack of pleasure in almost all activities or does not feel better, even temporarily, when something good happens. Also includes at least three of the following: Depression distinct from feeling after significant loss (eg, death of a loved one) Depression usually worse in the morning (diurnal pattern of symptoms) Early morning awakening (at least 2 h before usual time of awakening) Marked psychomotor retardation or agitation Significant anorexia or weight loss Excessive or inappropriate guilt Periods of depression consistently recur at the same time of year (most often fall and winter), unrelated to nonseasonal factors (eg, being unemployed each winter). Full remissions of depression (or switch to (mania or hypomania) also occur at a characteristic time of year (eg, spring). This pattern must be consistently present for at least the last 2 years.

Melancholic

Seasonal

Abbreviations: DSM, Diagnostic and Statistical Manual of Mental Disorders; MDE, major depressive episodes. a Sleep-related criteria are in bold.

Sleep in Mood Disorders

Table 2: Diagnostic and Statistical Manual of Mental Disorders-IV-TR diagnostic criteria for mood episodesa Type

Criteria

Major depressive episode

Depressed mood for most of the day or decreased interest or pleasure in almost all activities, present nearly every day for at least 2 weeks. Must include at least three or more of the following symptoms: 1. Significant weight loss (without dieting) or weight gain (>5% in a month), or decrease or increase in appetite 2. Insomnia or hypersomnia 3. Psychomotor agitation or retardation 4. Fatigue or loss of energy 5. Feelings of worthlessness or excessive or inappropriate guilt 6. Diminished ability to think or concentrate, or indecisiveness 7. Recurrent thoughts of death (not just fear of dying), suicidal thoughts (with or without a plan), or a suicide attempt A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or shorter if hospitalization necessary). Must include at least three or more of the following symptoms: 1. Inflated self-esteem or grandiosity 2. Decreased need for sleep (eg, feels rested after only 3 h sleep) 3. More talkative than usual or pressure to keep talking 4. Flight of ideas or subjective experience that thoughts are racing 5. Distractibility 6. Increased activity (either socially, at work or school, or sexually) or psychomotor agitation 7. Excessive involvement in pleasurable activities without considering risks (eg, unrestrained buying sprees, sexual indiscretions, driving too fast, and so forth)

Manic episode

a

Sleep-related criteria are in bold.

a seasonal pattern, with a typical onset in the fall or winter and remission (or even hypomania) in the spring, suggesting a correlation with diurnal patterns of light exposure (see Table 1). Major depression has been further subcategorized based on common symptom clusters (see Table 1). Current diagnostic subtypes include melancholic and atypical depression, and both involve distinct features related to sleep patterns. Interestingly, patients with melancholic depression are more likely to have an improvement of depression with total sleep deprivation, further suggesting that sleep patterns may define biologic subtypes of depression.

amounts of sleep. During manic periods, patients usually report reductions in total sleep, often with a sense of decreased sleep need. Similar to major depression, patients with bipolar disorder may also report insomnia during a depressed episode [4]. Hypersomnia, generally defined as daily sleep in excess of 9 to 10 hours and reported in 3% to 8% of the general population [5,6], is also commonly reported in major depression with atypical features, a seasonal pattern, or in bipolar disorders. A subset of patients may have complaints of both insomnia and hypersomnia, perhaps suggesting a more severe pathophysiology [2,6].

Prevalence and types of sleep problems in mood disorders

Epidemiology of sleep disturbance and mood disorders

Complaints of sleep disruptions are common both preceding and during major depressive or manic episodes, and may even persist during remission. From 65% to 75% of both adults and children and adolescents with depression reported insomnia, hypersomnia, or both compared with healthy controls [2,3]. Other common complaints include more frequent nocturnal awakenings, nonrestorative sleep, disturbing dreams, or decreased total

The relationship between sleep and mood is bidirectional: sleep complaints are more common in people with mood disorders than in the general population, and mood disorders are more common in those with sleep complaints. Population surveys indicated that adults with insomnia were up to nine times more likely to have major depression at the time of the interview than those without insomnia [7,8]. Additionally, the degree and duration of

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insomnia were positively correlated with more severe or recurrent major depression [7]. In a survey of the general population, those with insomnia at baseline and at a 1-year follow-up had a relative risk of 39.8 for major depression compared with those without insomnia [5]. The correlation between sleep and mood seems to be even higher in medical populations. In outpatients at general medical clinics, sleep and fatigue symptoms had the highest positive predictive value for major depression (61% and 69%, respectively [9]). Over three quarters of patients with insomnia evaluated in a multicenter study also met criteria for psychiatric disorders, including mood disorders [10]. The prevalence of major depression in patients with insomnia in general medical (31%) [11] or sleep center clinics (32.3%) [12] is much higher than patients without insomnia (4%).

Predictive value and specificity of sleep disturbance for mood disorders Remarkably, sleep problems even without concurrent psychiatric diagnoses are predictive of future mood disorders. Young adults with a history of insomnia, hypersomnia, or both showed a 10- to 20-fold increase in the lifetime prevalence of major depression compared with those with no sleep problems [6]. In a survey of adolescents (13– 16 years old) with both insomnia and a psychiatric diagnosis, onset of insomnia more commonly preceded depression, whereas anxiety disorders more often preceded insomnia, suggesting distinct, directional associations [13]. Insomnia or hypersomnia are also associated with an increased risk of a new onset of major depressive or manic episodes [2,14]. Subjects reporting insomnia at an initial assessment were 2 to 5.4 times more likely than those without insomnia to develop major depression during follow-up periods of 3.5 to 34 years [6,15]. Similarly, hypersomnia was associated with a relative risk of 2.9 for developing major depression [6]. Notably, two of these studies were longitudinal studies of young adults [6,15], demonstrating that insomnia at a young age conferred a lifetime risk for developing mood disorders. The presence of disruptive or stressful life events in the preceding 4 months was also predictive of increased time awake after sleep onset, but only for subjects with a previous history of depression and not healthy controls [16]. Women with more disrupted sleep also had more depression both antepartum and postpartum, and their newborns perhaps also had more disrupted sleep and less deep sleep [17,18]. The presence of initial insomnia (delayed sleep-onset latency) seemed to be the most relevant screening question for identifying

women at risk for postpartum depression [18], which corresponds to findings in the aforementioned studies. Insomnia and fatigue were the most frequently reported symptoms preceding a recurrent depressive episode [2,19]. In about half of new-onset or recurrent depressive episodes, and in about three quarters of manic episodes, insomnia preceded the appearance of mood changes [14]. More ominously, an increase or decrease of 3 hours or more of sleep suggested imminent onset of a recurrent mood episode in patients diagnosed with bipolar disorder [20].

Interepisodic persistence of subjective sleep disruption Subjective reports of insomnia may improve, but not necessarily normalize, with remission from major depression. Insomnia is the most commonly reported residual symptom during remission of mood episodes in patients with major depression [21] or bipolar disorder [22]. Persistence of sleep disturbances has been shown to be predictive of increased severity and recurrence of major depression [23].

Psychiatric comorbidities associated with sleep and mood disorders Suicide and thoughts about suicide (suicidal ideation) are common symptoms of depression with serious implications. Independent of the severity of depression, decreased sleep time, insomnia, and particularly nightmares were predictive of suicide attempts and suicidal ideation. Among patients with a recent suicide attempt, almost 90% reported some sleep disturbance, further suggesting a link between insomnia and suicidality in depression [24]. Although suicide and suicidal ideation are closely linked to major depression, individuals who had suicide attempts were more likely than depressed nonattempters to report insomnia or nightmares. Moreover, major depression combined with insomnia confers an increased risk of suicide in both adolescents [25] and adults [24]. This association again emphasizes the importance of monitoring insomnia (and nightmares) in patients with or without depression at the time.

Comorbidity of primary sleep disorders and mood disorders Such conditions as OSA and RLS, generally considered primary sleep disorders, also seem to be more prevalent in patients with mood disorders than the general population [26–28]. This relationship is bidirectional for OSA, because approximately one in five patients with OSA also were diagnosed with major depression, and nearly one in five patients

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with major depression were diagnosed with OSA [26]. In a recent longitudinal study, individuals with sleep-related breathing disorders showed a severity-related risk of developing depression: odds ratios of 1.6 (minimal sleep-related breathing disorders); 2 (mild sleep-related breathing disorders); to 2.6 (moderate or worse sleep-related breathing disorders) [29]. Depression is also a modifier of clinical course: in patients with OSA and depression, depression is directly associated with daytime fatigue severity, independent of OSA severity [30]. Furthermore, recent studies have shown that treating OSA results in a sustained improvement in depression [31], and the degree of improvement in OSA with continuous positive airway pressure also correlated with the improvement in depression [32]. The relationship between major depression and RLS is less well defined. Several studies have, but other studies have not, shown a correlation between the two disorders [28,33,34]. This relationship is complicated by the fact that serotonergic antidepressant medications can exacerbate RLS. At least some studies have accounted for this, however, such as a recent population survey that indicated RLS is associated with depressed mood, but antidepressant medication use was not higher in the RLS group than the general population [33].

Sleep findings in mood disorders Subjective sleep complaints Some reports suggest that there is a discrepancy between subjective and objective sleep measurements in patients with mood disorders. For example, in many of the depressed patients who reported sleep complaints, no abnormalities were identified by polysomnographic recordings [35]. Similarly, a recent study of adolescents with major depression found subjective, but not objective, sleep disturbances [36]. A number of studies have investigated the underestimation or overestimation of sleep parameters, including sleep-onset latency, number of awakenings, sleep depth, and total sleep time [37–39]. The study designs and results have varied, however, and there is no clear consensus on the topic. Depressed subjects did not differ from controls in their self-report accuracy in some studies, but substantially overestimated or underestimated sleep parameters compared to controls in others studies. Similarly, although less studied, objective measures of hypersomnia and daytime sleepiness often correlate poorly with subjective reports [38]. It is important to keep in mind that insomnia, like major depression, is a clinical diagnosis based on the patient’s reported symptoms. Nevertheless,

general trends suggest that in patients with major depression, increased stage 1 sleep correlates with subjective reports of poor sleep quality, and with treatment, increased amounts of slow wave sleep ([SWS] stage 3–4) correlate with reports of ‘‘deeper’’ or more satisfying sleep [37,40]. This subjective decrement in sleep quality is consistent with the objective decreases in SWS seen in the polysomnography of patients with major depression [41]. Correspondingly, in an 8-week treatment response study of patients with major depression, increases in SWS correlated with subjective scores of sleep depth and satisfaction [37]. Objective measures from polysomnographic recordings may be better biologic markers, but based on epidemiologic studies described previously, subjective measures do seem to have a value in the clinical assessment and treatment of major depression, and may be a better indicator of treatment onset and measure of response. This is particularly relevant because reports of insomnia improve, but do not normalize, with remission of depression. Ideally, however, both subjective and objective measures are used because they relate to different clinical aspects of sleep and mood.

Polysomnographic and architectural sleep changes Since the late 1960s, sleep EEG changes have been studied extensively as biologic markers of major depression. Most patients with major depression have some objective findings of sleep disturbance [41], but these findings are not always specific for depression and can vary with age and other factors. Sleep architecture abnormalities in major depression can be grouped into three general categories (Table 3) [42]. 1. Sleep continuity disturbances. Patients with major depression often show prolonged sleep-onset latency (time from lights out to first appearance of sleep); increased number and duration of waking periods during sleep; and early morning awakening. These disturbances are reflected by increased sleep fragmentation and decreased sleep efficiency. 2. SWS deficits. Stages 3–4 of non–rapid eye movement sleep are considered SWS, colloquially referred to as ‘‘deep’’ sleep, because the arousal threshold is high in this state. Depressed patients often have a reduction of SWS, both as the percent of total sleep and as actual minutes of SWS. Furthermore, an abnormal temporal distribution of sleep has been identified in some studies of this population. Healthy subjects have a peak in SWS time during the first sleep cycle, with a gradual decline through subsequent

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Table 3:

Sleep abnormalities in depression (and mania)

Subjective complaints

Polysomnographic findings

Insomnia Difficulty falling asleep (initial insomnia) Increased awakening at night/restless sleep (middle insomnia) Early morning awakening (terminal insomnia) Decreased amounts of sleep Sleep less deep or less refreshing

Sleep continuity disturbances Prolonged sleep-onset latency Increased wake time during sleep

Disturbing dreams

Increased early morning wake time Decreased total sleep time SWS deficits Decreased SWS amount Decreased SWS percentage of total sleep REM sleep abnormalities Reduced REM sleep latency Prolonged first REM sleep period Increased REM activity (total number of eye movements during the night) Increased REM density (REM activity/total REM sleep time) Increased REM sleep percentage of total sleep

Abbreviations: REM, rapid eye movement; SWS, slow wave sleep.

cycles. Depressed subjects often have less SWS during the first cycle, and a relative peak during the second cycle [43]. Recently, computerized analysis has led to further descriptions of these patterns (discussed in the next section). 3. Rapid eye movement sleep abnormalities. Changes in rapid eye movement sleep parameters have long been thought to be the most consistent and relatively specific sleep abnormalities in major depression [41,42]. Decreased time to the onset of rapid eye movement sleep (reduced rapid eye movement sleep latency) is the most commonly reported and studied sleep finding in major depression. Other abnormalities include a prolonged first rapid eye movement sleep period; increased rapid eye movements during rapid eye movement sleep periods (increased rapid eye movement density); and increased percentage of rapid eye movement sleep. Similar findings have also been documented in patients with bipolar disorder with depression or mania, although these populations have been less well studied. During manic episodes, disrupted sleep continuity, shortened rapid eye movement (REM) sleep latency, and increased REM density have been reported in polysomnographic studies [44]. Interestingly, patients with bipolar depression and hypersomnia did not consistently have decreased REM sleep latency, and also did not show decreased sleep latency despite complaints of daytime sleepiness; however, these results are from a single study [45]. As with bipolar disorder, relatively few studies have investigated sleep patterns in dysthymia

(chronic low-grade depressive symptoms [see Table 1]), and the results have been variable. Some studies lacked control or comparison groups with major depression, limiting the comparability of this small pool of studies. In general, it seems that patients with dysthymia may have some of the sleep findings characteristic of major depression, but not to the same extent [46]. Although the EEG changes described previously occur frequently in depression, they are not specific to depression. Some studies have found similar changes in REM sleep or SWS in other psychiatric disorders, such as schizophrenia and anxiety disorders [41]. Attempts have been made to correlate polysomnographic findings in major depression with specific symptoms, symptom severity, or course of illness. Giles and colleagues [47] showed that features of melancholic depression (see Table 1) were more strongly associated with reduced REM sleep latency. Another multivariate analysis identified 15 core depressive symptoms that correlated with nine sleep variables, suggesting a biologic relationship between core mood and sleep findings [2]. Some sleep changes, including increased REM density and reduced sleep efficiency, seem more correlated with illness severity and seem to normalize with remission from depression [48]. Reduced REM sleep latency and decreased SWS can persist for long periods of time, even while patients are asymptomatic [48,49]. These results lend support to the hypothesis that sleep findings may reflect both the ‘‘state’’ (current level of symptoms) and ‘‘trait’’ (biologic disposition) of major depression. The severity of these persistent findings may reflect a more pronounced biologic subtype of illness and

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an increased risk of recurrence [50]. The hypothesis that REM sleep latency is a trait marker for major depression is also supported by evidence from family studies; first-degree relatives of patients with major depression tend to have shortened REM sleep latency, whether or not they have a personal history of depression [51]. EEG sleep variables in depression are also affected by gender and age. Studies have shown that loss of SWS in major depression was more prominent in men than women, for both adults [52] and adolescents [53]. This may suggest differing biologic effects of depression between women and men, perhaps in part related to endocrine or developmental differences. Age effects may also increase the depressionrelated changes in sleep. Some studies have shown clear differences between older adults (up to the seventh decade of life) with major depression and age-matched controls [54]. In contrast to adults, younger patients with major depression are often indistinguishable from age-matched controls [55,56]. Another study suggested that no differences in SWS were identified between depressed and control subjects until the middle of the fourth decade of life, and these differences remained until the seventh decade [57]. Amount of SWS is greatest in children and adolescents, and it decreases to adult amounts by the end of puberty. This shift is likely related to synaptic pruning and maturation of the prefrontal cortex. The maturation of endocrine systems (including the hypothalamic-pituitary-adrenal axis) is involved in this process and is also dynamically changing during this time [42,55,56]. Overall, sleep changes associated with mood disorders are best characterized and most easily identified in adult subjects, particularly compared with children and adolescents. The relationships between gender, age, major depression, and sleep, however, are not yet fully elucidated.

Advanced sleep electroencephalogram analysis Recent advances in EEG recording, including digital recording and increased availability of powerful computational analyses, have provided new tools to study sleep in relation to mood disorders. Techniques include quantitative analysis of EEG activity across a broad range of frequencies (power spectral analysis); the automated detection and investigation of specific EEG waveforms, such as slow waves, spindles, and REMs; and measures of EEG synchronization across brain regions (synchrony and coherence). The use of high-density EEG, with the application of 60 to 256 recording electrodes to the scalp, now allows topographic analysis of

sleep-related waveforms, allowing localization of EEG activity over specific cortical regions, and the possibility of accurate source localization to specific brain regions involved in their generation.

Power spectral analysis Analysis of the EEG power spectra (also known as ‘‘power density’’) allows quantification of EEG activity changes during sleep in different frequency ranges. Power spectra for individual subjects are extremely consistent between nights [58], and also show characteristic changes when comparing patient and control groups. An advantage of power spectral analysis over traditional sleep scoring is that activity can be quantified over sleep cycles or whole nights independent of staging. Because sleep EEG waveforms, such as slow waves, are not restricted to single stages (eg, slow waves are present in stage 2 and in SWS [stages 3 and 4]), power spectral analysis within this frequency band (the ‘‘delta’’ frequency band, 0.5–4.5 Hz) allows a more complete assessment of slow-wave activity ([SWA] delta band EEG power). Total minutes of SWS for the night are decreased in most studies of depressed patients [41]. Borbely and colleagues [59] used power spectral analysis to characterize SWA in control and depressed subjects, both confirming that SWS reductions in major depression were correlated with decrements in SWA and validating the use of EEG power spectra to quantify SWS. A similar study of bipolar depression did not identify SWA differences, however, and speculated that this result could be caused by differences between the biologic basis of unipolar and bipolar depression [60]. Additionally, subjects with major depression who had an acute increase of SWA over the whole night following antidepressant administration were more likely to respond to subsequent treatment [61,62]. Kupfer and colleagues [63] extended their findings to demonstrate that delta band power was a stable finding between acute depression and remission, and more likely is a trait marker of major depression. Buysse and colleagues [64] did not identify significant differences in SWA between women in remission from depression who responded to psychotherapy alone and either psychotherapy nonremitters or psychotherapy and medication (a serotonin reuptake inhibitor). They speculated that the severity of depression, gender, and response to psychotherapy in their subjects could account for the differences. Also, these differences across studies highlight a difficulty inherent in psychiatric research: illnesses based on patient and clinician descriptions may reflect a diverse spectrum of biologic illness. In contrast, they also reflect the importance of objective measures, such as sleep EEG findings, that might identify biologic subtypes

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of illness, and could be important in selecting study populations. Most research on sleep and major depression using power spectral analysis has focused on differences in the delta frequency range, because of its relationship to slow waves. A few studies have identified differences in other frequency ranges, however, including an increase in 12 to 20 Hz power [63] for subjects in remission as compared with those same subjects when acutely depressed; and increases from 20 to 35 Hz (beta2) and 35 to 45 Hz (gamma) ranges in depressed subjects compared with controls [59,61,65]. The significance of these findings is not as clear, because they do not correlate with predominant sleep waveforms; however, these investigators have speculated that higherfrequency EEG activity could reflect changes in overall levels of arousal or integrative processing associated with a depressive state.

Automated slow wave analysis The technique of computerized slow wave counts using automated algorithms has also advanced slow wave analysis. This technology has allowed for more sensitive detection of slow waves, and a more quantifiable measure of slow waves than from sleep staging alone [42]. In addition to a reduction of total minutes of SWS, an altered distribution of SWS during the night has been shown in subjects with major depression. Minutes of SWS generally are greatest in the first non-REM (NREM) sleep period, and decrease linearly through subsequent periods. Many depressed subjects show increased or equal minutes of SWS in the second compared with the first period. This difference has been more clearly defined by automated slow wave counts. Kupfer and coworkers [66] defined the delta sleep ratio as the ratio of the average slow (delta) wave counts per minute in the first NREM sleep period to the average counts per minute in the second NREM sleep period. In control subjects, this ratio (typically >1.6) reflects the higher density of slow waves in the first NREM sleep period. Depressed subjects typically have a lower ratio (%1.10) reflecting this abnormal distribution. The delta sleep ratio has been thought to reflect an abnormal homeostatic regulation of sleep in depression (deficient process ‘‘S’’ [67]). With prolonged wakefulness, there is an increase in SWS at the beginning of the night and delay in REM sleep onset, reflecting a homeostatic increase in SWS during the first NREM sleep period. In major depression, REM sleep onset is earlier, and there is less SWS during the first NREM sleep period, the opposite of the normal homeostatic pattern. It has been suggested that a higher ratio of SWA in the first

to second NREM sleep periods (delta sleep EEG power, not slow wave counts) predicted a more robust antidepressant response effect of sleep deprivation [68]. The delta sleep ratio, as with other SWA markers, has been shown to predict treatment response and likelihood of recurrence [48,49,66]. Although reduced SWA in the first NREM sleep period has also been found in subjects with schizophrenia, only subjects with depression showed a reduced delta sleep ratio, suggesting this measure may be more specific for major depression [69,70].

Coherence of sleep electroencephalogram rhythms Coherence is a measure of the similarity of EEG rhythms at different cortical locations. Measures of EEG coherence are thought to reflect the functional relationships between different cortical regions. Functional cortical connections may be impaired in psychiatric disorders including major depression. Both intrahemispheric and interhemispheric coherence have been shown to be lower in major depression compared with controls [71]. Decreased coherence has been identified primarily in the delta (0.5–4 Hz) and beta (16–32 Hz) frequency ranges in both adolescents and adults with major depression [71–73]. Reduced coherence also seems to be present in offspring at risk of developing major depression [74,75], and correlates with risk of recurrence in children and adolescents with major depression [71], suggesting it may be a biologic marker of depression. Most reports suggest that coherence changes are more prominent in girls and women with major depression, in contrast with reduced numbers of slow waves that tend to be more prominent in men [76]. Fewer studies have investigated coherence changes in adults with major depression, and the relationship of coherence to age and other sleep measures, such as SWA, should be further delineated.

Topography of sleep electroencephalogram activity Sleep EEG patterns have classically been recorded from one or two central electrodes. EEG recordings from different scalp locations can vary significantly, however, and analyses of EEG patterns across the scalp can yield substantial additional information. The use of high-density EEG (generally >20–256 electrodes) has facilitated the description of normal sleep EEG topography and how it varies over the course of the night. Topographic patterns seem to be stable between nights, despite differences in sleep architecture [77–79]. Additionally, different frequency ranges have characteristic distributions of activity, likely related to different cortical sources of rhythm generation [78,79]. In particular, SWA

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shows a characteristic frontal distribution, with an increased power density but stable topography after sleep deprivation, which is consistent with the homeostatic increase in SWS [67,77,79,80]. Despite the potential advantages of high-density EEG, few studies have applied this technology to psychiatric populations. Given the convergence of imaging data demonstrating regional differences in brain activity (see previous and following sections summarizing this research) and the clear associations of altered SWS-SWA during depression, high-density EEG studies of sleep are likely to yield important information that furthers the understanding of the common biologic bases of sleep and mood disorders.

Biologic mechanisms of sleep changes in mood disorders The high coincidence and overlapping symptoms of major depression and insomnia suggest common neurobiology. Reflecting their common clinical presentations, many of the criteria in the recently published American Academy of Sleep Medicine research diagnostic criteria for insomnia [81] are shared with the Diagnostic and Statistical Manual of Mental Disorders-IV-TR criteria for major depressive episodes. This raises the question as to which is the primary or secondary disorder, or if they are manifestations of the same underlying process representing a spectrum disorder. Despite the prevalence and impact of mood disorders, the exact etiologies are still not fully understood. Similarly, there have been many speculations about the mechanisms for sleep changes in mood disorders and correlations with other biologic abnormalities identified in depression. At an even more fundamental level, the regulation of and biologic need for sleep are still incompletely defined (see the article by K. Doghramji elsewhere in this issue) [80]. The close association of mood and sleep suggest that the neurobiology is closely intertwined; it is likely that advances in the understanding of either component will lead to a more complete explanation of the other. The following sections discuss some of the hypotheses explaining this association.

Neurotransmitters The classic neurotransmitter hypothesis of mood regulation was based on the discovery that increases or decreases in monoaminergic neurotransmitters (eg, serotonin, norepinephrine, and dopamine) correlated with improved or worsened depression, respectively. Most pharmaceutical agents (including tricyclics, monoamine oxidase inhibitors, and serotonin-reuptake inhibitors) used to treat depression primarily increase synaptic levels of these

neurotransmitters. Conversely, the same medications can trigger manic episodes in susceptible individuals, suggesting that the other pole of the mood spectrum relates to excessive monoamine transmission. Recent evidence continues to support this hypothesis, and has identified alterations in neurotransmitter levels, activity of brain areas primarily associated with monoaminergic activity, and of candidate genes associated with serotonin levels and function [82]. Normal regulation of sleep is closely tied to these systems; the onset of REM sleep requires a decrease in monoaminergic tone (including serotonin and norepinephrine) and increased cholinergic tone [83]. Most antidepressant medications increase serotonin, and correspondingly increase REM sleep latency, decrease REM sleep amount, and increase SWS, reversing the typical architectural abnormalities of sleep in depression [84,85]. Although this has been proposed to be the primary mechanism for antidepressant effect, some antidepressants do not alter either REM sleep or serotonin levels [85]. More recently, investigations have suggested roles for additional neurotransmitter systems in mood disorders. Amino acid neurotransmitters, such as glutamate acting by a-amino-3-hydroxy-5- methyl4-isoxazolepropionic acid (AMPA) receptors signaling pathways, have increasingly been found to play a role in depression [86]. Particularly relevant are the associations of glutamate signaling with plasticity (by increased brain-derived neurotrophic factor levels) and learning [87–89]. A decrease in neurotrophic factors, such as brain-derived neurotrophic factor, related to depression could result in decreased neurogenesis, or even neural cell loss, in brain regions critical to mood regulation and responsiveness. The glutamate system is also intimately tied to both REM and NREM sleep regulation. Glutamate interacts with cholinergic neurons to increase activity of the reticular system associated with REM sleep onset. During NREM sleep, excitatory glutamate neurotransmission has a prominent role in the thalamocortical generation of sleep EEG oscillations [83]. Additionally, sleep has increasingly been shown to be necessary for plastic processes, such as learning and memory, and it affects the expression of plasticity-related genes [90]. The intertwined processes of mood, sleep, and plasticity, and their modulation through such factors as glutamate and brain-derived neurotrophic factor, make them appealing targets for future therapies [89]. Evidence indicates that conventional serotonergic antidepressants may indirectly potentiate AMPA receptors, possibly relating to their efficacy [86]. The evidence for involvement of neuroplasticity and other signaling cascades perhaps explains

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the therapeutic lag between drug initiation and clinical effect. Similarly, overlapping signaling pathways that regulate cell death and survival may be long-term targets for both mood stabilizers and antidepressants [89]. As one of such pathways, the glutamate system and downstream signaling cascades may also provide a therapeutic target for future generations of antidepressants [86,89].

Neuroimaging A growing body of literature has started to identify the brain regions involved in regulation of sleep and how their activity is altered in mood disorders with sleep disturbances. Imaging studies are identifying brain areas involved in the sleep disturbances exhibited by depressed patients, such as reduced SWS and increased REM sleep. During normal NREM sleep, metabolic activity is broadly decreased in the frontal, temporal, and parietal cortexes compared with waking levels. Nofzinger and colleagues [91] demonstrated that subjects with current major depression have a smaller decrease in these cortical regions from waking to sleep, and a relative hypoactivity in waking. It is possible that the waking hypofrontality could reflect a deficit in a sleepwake–related process present in major depression, such as decreased synaptic potentiation (during waking) or decreased downscaling (during sleep) [80]. Other brain areas involved in emotional regulation (anterior cingulate cortex, amygdala, parahippocampal cortex, thalamus [92]) also had a smaller decline in metabolic level from waking to NREM sleep. Relative to control subjects, however, these areas have elevated metabolic levels during sleep. Altered function in these regions could relate to a failure of arousal mechanisms to decline from waking to sleep, and changes in cognition, attention, and emotional regulation in depression [93]. Similarly, investigations of increased REM sleep (which correlates with depression severity and clinical outcomes) in subjects with major depression demonstrated increased metabolic activity during REM sleep compared with controls in diffuse cortical and subcortical structures [94]. Because there is a shift from predominantly monoaminergic activity during waking to cholinergic activity during REM sleep, these alterations could also reflect an imbalance of monoaminergic-cholinergic systems in altered mood states. A state of relative arousal with lower monoaminergic activity in depression could explain the increased REM sleep, decreased REM sleep latency, and decreased SWS. Other imaging studies have focused on changes in brain activity in depressed patients after total or partial sleep deprivation, which results in an antidepressant response in about 50% of patients with major depression [95]. These studies suggest that

there is a biologic subtype of depression with deficits that can be corrected by sleep deprivation, lending further support to the hypothesis that sleep and mood regulation are controlled by overlapping brain regions. Several studies show consistency with this hypothesis: patients who responded to sleep deprivation initially had increased metabolic activity in the amygdala, orbital prefrontal cortex, inferior temporal, and anterior cingulate, which normalized after sleep deprivation [96–99]. Volk and colleagues [96] demonstrated predeprivation perfusion levels correlating with the reduction of depressive symptoms. Functional imaging studies with single-photon emission CT suggest that sleep deprivation responders may have a particular deficit in monoaminergic systems involved with attention, arousal, and mood, particularly in dopaminergic and serotonergic systems [97,100].

Endocrine changes Neuroendocrine dysregulation, particularly overactivation of the hypothalamic-pituitary-adrenal axis, has also been long recognized as playing a key role in the genesis of mood disorders, and could potentially lead to sleep disturbance [101]. Elevations of both corticotrophin-releasing hormone and cortisol have been associated with major depression and could contribute to atrophy of hippocampal neurons, in turn reducing their inhibition of adrenocorticotropic hormone secretion, further exacerbating the elevation of hypothalamic-pituitary-adrenal axis activity. Abnormalities of the hypothalamic-pituitaryadrenal axis are found in almost half of patients with major depression. The most common abnormality is hypercortisolemia, which has classically been assessed by the dexamethasone suppression test. Elevated levels of cortisol are also associated with stress and can lead to more fragmented sleep and hippocampal damage. Coincident with cortisol elevations, corticotrophin-releasing hormone is also secreted based on circadian rhythms and is elevated in depressed patients. Increased nocturnal corticotrophin-releasing hormone may actually be responsible for increased awakenings with hypothalamic-pituitary-adrenal axis hyperactivity [102]. Supporting this hypothesis, administration of a corticotrophin-releasing hormone receptor antagonist was reported to improve sleep EEG patterns of depressed patients [103]. Growth hormone–releasing hormone has a reciprocal relationship with corticotrophin-releasing hormone, and promotes sleep. Growth hormone–releasing hormone and growth hormone may also be decreased in some patients with depression, further contributing to SWS decrements [101].

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Genetic polymorphisms Genetic factors likely account for at least 33% of the risk for major depression, and over 85% of the risk for bipolar disorder [104,105]. Both of these disorders are likely polygenic and heterogeneous, and the result of a combined genetic and environmental factors. Based on the understanding of the neurobiology of these disorders, there are a number of candidate genes and possible associations of polymorphisms that could at least partially account for some cases of mood disorders. A handful of genes have been implicated in both mood disorders and sleep regulation. Genes that regulate monoamine levels (particularly serotonin and norepinephrine) have been particularly intriguing candidates, given the importance of these neurotransmitters in the response to most antidepressant medications. Both the gene for monoamine oxidase–A and the serotonin transporter gene promoter (‘‘linked polymorphic region’’ 5-HTTLPR) have been implicated in depression, and may correlate with insomnia scores (monoamine oxidase–A) or treatment response to sleep deprivation (5-HTTLPR) [106]. There have recently been reports that the angiotensin I-converting enzyme gene and mineralocorticoid receptor gene expression are altered in major depression and bipolar disorder, respectively [107,108]. Both genes are candidates to explain, at least partially, abnormalities of the hypothalamicpituitary-adrenal axis in both mood and sleep disturbances. Recent years have seen rapid advances in identifying ‘‘clock’’ genes involved in regulating circadian rhythms. No specific circadian genes have been clearly linked to depression or bipolar disorder, but a number of them have been implicated and may help explain treatment responses and some aspects of these disorders. A weak association has been found between susceptibility for major depression with a seasonal pattern (see Table 1) and an NPAS2 gene polymorphism [109]. Similarly, some reports suggest that the period-3 (per3) gene variants may be associated with certain features of mood disorders [110]. Multiple reports have now linked a CLOCK gene polymorphism to the presence of insomnia and decreased sleep time in depressed and bipolar patients [111], and the genotype may interact with lithium treatment [111]. Lithium, the prototypic pharmacologic mood stabilizer, has been shown to inhibit glycogen synthase kinase 3 (gsk3), which is also a circadian regulator. The gsk3 gene has been under intense scrutiny as a possible candidate gene for bipolar disorder, but several studies have revealed only a moderate linkage in relatively small populations [112]. More

importantly, the polymorphism in question has not been shown to have an effect on gene expression or activity. Yin and colleagues [113] recently demonstrated that lithium also affects stability of the Rev-erb a protein, which in turn regulates the activation of other clock genes. This is an intriguing possible link between bipolar disorder and circadian genes, but an involvement in patients has not yet been demonstrated. Plasticity-related cascades are a developing area of investigation for identifying both candidate genes and novel molecular targets for therapeutics [89]. These include genes involved in regulation of DNA replication, such as histone deacetylase, and others that are members of signal transduction cascades. Glutamate-AMPA receptor cascades are particularly interesting targets, and a number of experimental therapeutic agents affect this system [89]. Plasticity is closely linked to learning, sleep, and hormonal (cortisol) regulation. Supporting this connection, molecular investigations of the genes regulated by sleep and sleep deprivation identified a number of plasticity-related gene targets [90,114]; genes related to plasticity and synaptic potentiation tend to be expressed during wakefulness, and genes related to synaptic downscaling tend to be expressed during sleep [80]. It is feasible that sleep is required for the downscaling of synapses on a daily basis, and that alteration in sleep or mood disorders could affect this normal process. Conversely, sleep deprivation could strengthen synapses in brain regions involved in affect regulation, potentially explaining some of the acute effects of sleep deprivation therapy. Although anatomic, neurochemical, neuroendocrine, and genetic evidence seems to be converging, it remains unknown which abnormalities are responsible for initiating mood disorders and sleep disturbance. Nevertheless, approaches to identify both gene linkages and molecular targets potentially involved in illness continue to be critical for nderstanding and treating the overlapping disturbances of mood and sleep.

Treatment of sleep disturbance and mood disorders Because of the high comorbidity of mood disorders and insomnia (or hypersomnia), patients presenting with complaints of one must be assessed for the other. Both pharmacologic and nonpharmacologic treatment modalities for insomnia have already been discussed in this issue; however, a few specific topics regarding mood disorders deserve attention. Although pharmacologic treatments for depression are more commonly prescribed, empirically validated psychotherapies (eg, cognitive

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behavioral therapy and interpersonal therapy) are also efficacious treatments. Similarly, increasing evidence supports the efficacy of cognitive behavioral therapy for insomnia for improvement of sleep disturbances associated with mood disorders [115]. Psychotherapy may be a valuable treatment option that can address both mood and sleep symptoms of depression, particularly for patients who do not tolerate the sleep-related side effects of antidepressant medications. Of note, almost all of the available antidepressant medications, including tricyclic antidepressants, monoamine oxidase inhibitors, trazodone and nefazodone serotonin reuptake inhibitors (fluoxetine, citalopram, escitalopram, sertraline, paroxetine), or serotonin-norepinephrine reuptake inhibitors (venlafaxine or duloxetine), bupropion, and mirtazapine can have effects on sleep (Table 4) [116]. Despite their typical profiles, any of them can exacerbate insomnia or hypersomnia, impair or improve sleep quality, and affect EEG measures of sleep architecture. Unfortunately, it is not always possible to predict specific medication effects in particular patients. This can have significant clinical consequences, because exacerbation of insomnia could contribute to medication noncompliance. Daytime sedation, similarly, could further impair the ability of patients to carry out daily activities. Although not approved by the Food and Drug Administration (FDA) specifically for this purpose, sedating antidepressants, such as tricyclic antidepressants, trazodone, and mirtazapine, are sometimes used to treat insomnia associated with depression, with varying levels of empiric data [116]. The use of the antidepressant trazodone deserves particular mention, because it is one of the most prescribed agents to improve sleep, even in those without depression. Trazodone is not FDAapproved for treating insomnia, but it is used far more frequently as a sleep aid than as an antidepressant. Despite its prevalent use, relatively little objective data on its effects on sleep are available, although some studies have suggested it may improve insomnia in depression [117]. It is important to remember that in general, doses of antidepressant medications used specifically for insomnia are far below the therapeutic dose for depression and likely provide little benefit for depressed mood. It is critical to monitor both insomnia and hypersomnia when treating depression. Even in ‘‘adequately treated’’ patients in remission from mood symptoms, sleep disturbance is the most common residual symptom [118]. Insomnia is a strong predictor for recurrent episodes of depression. Whether treatment of residual insomnia prevents recurrence is not clear. Just as the standard of care for treating a mood disorder with psychotic features

requires specific interventions for mood and psychosis, treatment of mood disorder with sleep disturbance should address both aspects of illness. A few recent studies have addressed this issue by coadministering antidepressants (serotonin reuptake inhibitors or tricyclic antidepressants) with hypnotic agents, such as eszolpiclone [119,120], zolpidem, or lorazapam. Although the number of studies and number of subjects within the studies is limited, the results suggested that addition of a hypnotic was generally well tolerated and improved insomnia. The addition of zolpidem [121] or lorazepam [122] to antidepressant therapy in depressives did not slow antidepressant response or cause clinically significant adverse drug interactions, and decreased symptoms of insomnia [121,122]. One more recent study suggested that coadministration of fluoxetine with eszolpiclone led to greater decreases in depression ratings (measured at 4 and 8 weeks) and improved sleep measures compared with fluoxetine with placebo alone [119]; after an 8-week course, discontinuation did not result in significant withdrawal or rebound insomnia, and sleep and depression improvements persisted [120]. Hypnotics alone are unlikely to have a direct antidepressant response, however, and are not a substitute for approved antidepressant treatments. Second-generation antipsychotics, including risperidone, olanzapine, quetiapine, and clozapine, have also been used as primary or adjunctive treatments for mood disorders. Atypical antipsychotics are approved treatments for psychotic mood episodes, and for mania and mood stabilization in bipolar disorder, but are not FDA-approved for treatment of nonpsychotic depression. Additionally, they have also been used off-label to treat mood-related sleep disruption. Despite their increasingly common use for sleep, there are few studies investigating sleep changes related to the use of these medications in depression. Most studies report only limited subjective reports of sleep changes, whereas the few studies including polysomnography data were not blinded and were performed with only small numbers (N 5 8–15) of subjects [123–125]. Although the newer antipsychotics could be useful adjunctive treatments to serotonin reuptake inhibitors in treatment-resistant depression, the limited data regarding their efficacy on sleep and their significant potential side effects (eg, weight gain and metabolic syndrome) do not warrant more widespread use. At the other end of the spectrum, stimulants (including both amphetamine derivatives and modafinil) are sometimes used as an adjunctive, but not FDA-approved, treatment for (unipolar or bipolar) depression. Although these medications certainly

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Table 4:

Antidepressant medications and sleep

Medication class examples Tricyclic antidepressants Amitryptiline

Nortriptyline Doxepin Clomipramine

Dosage: depression Pharmacologic (insomniaa) mechanism 75–150 mg (25–50 mg) 50–150 mg (25–50 mg) 75–300 mg (6–50 mg) 100–250 mg

Effects on sleep

Inhibit serotonin and Sedation norepinephrine reuptake; REM sleep suppression anticholinergic and Increased stage 2 sleep antihistaminergic effects

Monoamine oxidase inhibitors Phenelzine Tranylcypromine

45–90 mg 30–60 mg

Inhibit monoamine Insomnia oxidase, thus increasing Potent REM suppression norepinephrine, serotonin, and dopamine

Serotonin reuptake inhibitors Fluoxetine Sertraline Paroxetine Citalopam Escitalopram

20–80 mg 50–200 mg 15–60 mg 20–60 mg 10–30 mg

Inhibit serotonin reuptake Insomnia REM suppression Increased eye movements in NREM sleep

Serotonin-norepinephrine reuptake inhibitors Venlafaxine 150–450 mg Duloxetine 20–60 mg

Other antidepressants Trazodone

150–600 mg (25–75 mg)

Bupropion

100–450 mg

Mirtazapine

15–45 mg (7.5–15 mg)

Inhibit serotonin and norepinephrine reuptake

Insomnia REM suppression Increased eye movements in NREM sleep

Inhibit serotonin reuptake; blocks a1 adrenoreceptors; serotonin-2A receptor antagonist Inhibits norepinephrine and dopamine reuptake a2 receptor antagonist; serotonin-2 and -3 receptor antagonist; antihistaminergic

Sedation

Insomnia/activation Sedation; REM sleep suppression

Abbreviation: REM, rapid eye movement. a Use of these medications for treatment of insomnia is an off-label usage, not approved by the Food and Drug Administration.

have an effect on sleepiness, there are no data that they directly affect mood. Modafinil has received increasing attention, given its novel but not well-characterized mechanism, and apparently low abuse potential, in contrast to amphetamine derivatives. Fatigue or hypersomnia associated with (seasonal or atypical) depression were reportedly improved with the addition of modafinil, but the effect on

mood was not clear [126–128]. Two of these studies were not placebo controlled, however [126,128], and in the controlled study, differences in mood and sleepiness ratings did not reach statistical significance between the modafinil and placebo groups [127]. Recently, a trial of adjunctive modafinil combined with a mood stabilizer was shown to improve both response and remission

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rates in bipolar depression resistant to treatment with mood stabilizer alone [129]. Although this study did not observe an increased incidence of treatment-emergent mania or hypomania with modafinil, this is an off-label use, and evidence is too limited to suggest that modafinil is safe in bipolar disorder; it should be considered to be associated with a potential risk of inducing mania, similar to other stimulants. Furthermore, in all patients treated with modafinil, as with all stimulants, clinicians need to be vigilant for treatment-emergent insomnia and decreased sleep time.

Sleep-deprivation therapy One of the most rapid, but perhaps least frequently used, treatments for depression is sleep deprivation. Total sleep deprivation (preventing any sleep during the night) can reduce depressive symptoms (a 50% reduction of Hamilton Depression Rating Scale scores) within hours in 30% to 60% of patients with major depression [130]. Partial sleep deprivation (particularly during the latter part of the night) has been shown in some studies to provide a similar improvement and is easier to implement. The effect of total sleep deprivation or partial sleep deprivation is often short-lived, however, and a relapse of symptoms may occur after even short periods of sleep in at least 50% to 80% of responders. Sleep deprivation has been combined with other treatment modalities (including medications, sleep phase advance, light therapy, and transcranial magnetic stimulation) to combine the rapid response with sustained improvements from other modalities. The response to sleep deprivation provides another clear link between the neurobiology of mood disorders and sleep regulation. Although neither total sleep deprivation nor partial sleep deprivation has become a widely used therapy, both provide opportunities simultaneously to investigate rapidly occurring changes in mood and other biologic variables [95,131,132]. The antidepressant response to sleep deprivation has been correlated with other biologic markers in sleep EEG [68], imaging [96,97,99,100], and genetic [133] studies. Additionally, response to sleep deprivation may serve as a biologic marker of a major depression subtype, and the basis for designing novel antidepressants.

Sleep loss and bipolar disorder Sleep loss has long been recognized as a trigger for manic episodes in patients with bipolar disorder [20,134,135]. Although it can be difficult to isolate insomnia’s possible role as a prodromal symptom of mania, studies have used various designs to demonstrate that sleep loss may be a risk factor for mania, independent of prodromal mood symptoms.

Additionally, laboratory-based experiments suggest that sleep loss induced by forced wakefulness, medication, or other factors can trigger mania in the absence of other changes [135]. Interestingly, sleep loss has also been associated, although not as strongly, with bipolar depression [19,20,134]. Sleep loss in bipolar patients is often followed by the onset of mood episodes in the following 24-hour period, and the magnitude of sleep change seems to correlate with the likelihood of a subsequent mood change [20,134]. These findings stress the importance of closely monitoring sleep patterns in patients with bipolar disorder, and aggressively treating the first signs of sleep loss and insomnia.

Clinical use of polysomnography Despite the numerous EEG abnormalities of sleep associated with mood disorders, none is currently considered specific or sensitive enough to warrant the use of routine polysomnography in the diagnosis of mood disorders. As EEG technologies and analysis tools become more advanced, and routine evaluation of sleep recordings moves beyond sleep architecture, use of sleep EEG will be an invaluable tool in evaluating insomnia, fatigue, and psychiatric disorders. A careful sleep history and evaluation is valuable and necessary in all patients with mood disorders. A polysomnogram may be indicated when a primary sleep disorder is suspected (eg, OSA, sleep-related movement disorders, or narcolepsy), given their high comorbidity. For example, recent reports suggest that the incidence of OSA is higher in a cohort of subjects with major depression, and mood disorders are more common in patients with OSA than in controls [26,27]. Furthermore, increasing evidence shows that appropriate treatment of the sleep disorder can positively affect mood [31,32]. Combined with the increasing prevalence of obesity and other risk factors in the general population, assessing and treating OSA is becoming increasingly important in the psychiatric setting. Additionally, psychiatrists and other physicians need to be vigilant for iatrogenic sleep disorders caused or exacerbated by psychopharmacologic agents. Weight gain associated with antipsychotics, mood stabilizers, and antidepressants can contribute to OSA. Additionally, serotonergic antidepressants can induce or worsen several primary sleep disorders, such as RLS, periodic leg movements, and REM sleep behavior disorder [136,137].

Summary Because of the close association between mood and sleep disorders, it is critical to assess all patients

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with sleep complaints for mood disorders and vice versa. The presence of sleep disturbance alone is also strongly predictive of onset of mood problems in the future. Simultaneous treatment of both insomnia and major depression is often helpful, because insomnia is the most frequent residual symptom, and its persistence is an important predictor of future illness. Ongoing studies of the relationship between sleep disturbances and mood disorders should provide a better understanding of their neurobiologic underpinnings, and more importantly for those suffering from these conditions, safer and more effective treatments. Just as understanding other medical disorders can help clinicians understand normal biologic processes, it is hoped that an understanding of the sleep disorders will lead to an understanding of normal sleep and mood.

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[89] Zarate CA Jr, Singh J, Manji HK. Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry 2006;59(11):1006–20. [90] Cirelli C. A molecular window on sleep: changes in gene expression between sleep and wakefulness. Neuroscientist 2005;11(1): 63–74. [91] Nofzinger EA, Buysse DJ, Germain A, et al. Alterations in regional cerebral glucose metabolism across waking and non-rapid eye movement sleep in depression. Arch Gen Psychiatry 2005;62(4):387–96. [92] Davidson RJ, Pizzagalli D, Nitschke JB, et al. Depression: perspectives from affective neuroscience. Annu Rev Psychol 2002;53(1):545–74. [93] Nofzinger EA, Buysse DJ, Germain A, et al. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004; 161(11):2126–8. [94] Nofzinger EA, Buysse DJ, Germain A, et al. Increased activation of anterior paralimbic and executive cortex from waking to rapid eye movement sleep in depression. Arch Gen Psychiatry 2004;61(7):695–702. [95] Berger M, van Calker D, Riemann D. Sleep and manipulations of the sleep-wake rhythm in depression. Acta Psychiatr Scand Suppl 2003; 108(s418):83–91. [96] Volk SA, Kaendler SH, Hertel A, et al. Can response to partial sleep deprivation in depressed patients be predicted by regional changes of cerebral blood flow? Psychiatry Res 1997;75(2): 67–74. [97] Wu JC, Buchsbaum M, Bunney WE Jr. Clinical neurochemical implications of sleep deprivation’s effects on the anterior cingulate of depressed responders. Neuropsychopharmacology 2001;25(5 Suppl):S74–8. [98] Clark CP, Brown GG, Archibald SL, et al. Does amygdalar perfusion correlate with antidepressant response to partial sleep deprivation in major depression? Psychiatry Res 2006;146(1): 43–51. [99] Clark CP, Brown GG, Frank L, et al. Improved anatomic delineation of the antidepressant response to partial sleep deprivation in medial frontal cortex using perfusion-weighted functional MRI. Psychiatry Res 2006;146(1): 43–51. [100] Ebert D, Berger M. Neurobiological similarities in antidepressant sleep deprivation and psychostimulant use: a psychostimulant theory of antidepressant sleep deprivation. Psychopharmacology (Berl) 1998;140(1):1–10. [101] Steiger A. Neurochemical regulation of sleep. J Psychiatr Res 2007;41(7):537–52. [102] Buckley TM, Schatzberg AF. On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders. J Clin Endocrinol Metab 2005;90(5):3106–14.

[103] Held K, Kunzel H, Ising M, et al. Treatment with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with depression. J Psychiatr Res 2004;38(2):129–36. [104] Fava M, Kendler KS. Major depressive disorder. Neuron 2000;28(2):335–41. [105] McGuffin P, Rijsdijk F, Andrew M, et al. The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry 2003;60(5):497–502. [106] Benedetti F, Colombo C, Serretti A, et al. Antidepressant effects of light therapy combined with sleep deprivation are influenced by a functional polymorphism within the promoter of the serotonin transporter gene. Biol Psychiatry 2003;54(7):687–92. [107] Baghai TC, Schule C, Zwanzger P, et al. Influence of a functional polymorphism within the angiotensin I-converting enzyme gene on partial sleep deprivation in patients with major depression. Neurosci Lett 2003;339(3):223–6. [108] Xing GQ, Russell S, Webster MJ, et al. Decreased expression of mineralocorticoid receptor mRNA in the prefrontal cortex in schizophrenia and bipolar disorder. Int J Neuropsychopharmacol 2004;7(2):143–53. [109] Johansson C, Willeit M, Smedh C, et al. Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference. Neuropsychopharmacology 2003; 28(4):734–9. [110] Artioli P, Lorenzi C, Pirovano A, et al. How do genes exert their role? Period 3 gene variants and possible influences on mood disorder phenotypes. Eur Neuropsychopharmacol 2007; 17(9):587–94. [111] Benedetti F, Dallaspezia S, Fulgosi MC, et al. Actimetric evidence that CLOCK 3111 T/C SNP influences sleep and activity patterns in patients affected by bipolar depression. Am J Med Genet B Neuropsychiatr Genet 2007;144(5):631–5. [112] Benedetti F, Serretti A, Pontiggia A, et al. Longterm response to lithium salts in bipolar illness is influenced by the glycogen synthase kinase 3-beta -50 T/C SNP. Neurosci Lett 2005;376(1): 51–5. [113] Yin L, Wang J, Klein PS, et al. Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock. Science 2006; 311(5763):1002–5. [114] Cirelli C, Gutierrez CM, Tononi G. Extensive and divergent effects of sleep and wakefulness on brain gene expression. Neuron 2004;41(1): 35–43. [115] Smith MT, Huang MI, Manber R. Cognitive behavior therapy for chronic insomnia occurring within the context of medical and psychiatric disorders. Clin Psychol Rev 2005;25(5):559–92. [116] DeMartinis NA, Winokur A. Effects of psychiatric medications on sleep and sleep disorders. CNS Neurol Disord Drug Targets 2007;6(1): 17–29.

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[117] Mendelson WB. A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psychiatry 2005;66(4):469–76. [118] Nierenberg AA, Keefe BR, Leslie VC, et al. Residual symptoms in depressed patients who respond acutely to fluoxetine. J Clin Psychiatry 1999;60(4):221–5. [119] Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry 2006;59(11):1052–60. [120] Krystal A, Fava M, Rubens R, et al. Evaluation of eszopiclone discontinuation after cotherapy with fluoxetine for insomnia with coexisting depression. J Clin Sleep Med 2007;3(1):48–55. [121] Asnis GM, Chakraburtty A, DuBoff EA, et al. Zolpidem for persistent insomnia in SSRItreated depressed patients. J Clin Psychiatry 1999;60(10):668–76. [122] Buysse DJ, Reynolds CF III, Houck PR, et al. Does lorazepam impair the antidepressant response to nortriptyline and psychotherapy? J Clin Psychiatry 1997;58(10):426–32. [123] Sharpley AL, Bhagwagar Z, Hafizi S, et al. Risperidone augmentation decreases rapid eye movement sleep and decreases wake in treatment-resistant depressed patients. J Clin Psychiatry 2003;64(2):192–6. [124] Sharpley AL, Attenburrow ME, Hafizi S, et al. Olanzapine increases slow wave sleep and sleep continuity in SSRI-resistant depressed patients. J Clin Psychiatry 2005;66(4):450–4. [125] Armitage R, Cole D, Suppes T, et al. Effects of clozapine on sleep in bipolar and schizoaffective disorders. Prog Neuropsychopharmacol Biol Psychiatry 2004;28(7):1065–70. [126] Ninan PT, Hassman HA, Glass SJ, et al. Adjunctive modafinil at initiation of treatment with a selective serotonin reuptake inhibitor enhances the degree and onset of therapeutic effects in patients with major depressive disorder and fatigue. J Clin Psychiatry 2004;65(3): 414–20.

[127] Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry 2005;66(1):85–93. [128] Lundt L. Modafinil treatment in patients with seasonal affective disorder/winter depression: an open-label pilot study. J Affect Disord 2004;81(2):173–8. [129] Frye MA, Grunze H, Suppes T, et al. A placebocontrolled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry 2007;164(8):1242–9. [130] Wu JC, Bunney WE. The biological basis of an antidepressant response to sleep deprivation and relapse: review and hypothesis. Am J Psychiatry 1990;147(1):14–21. [131] Gillin JC, Buchsbaum M, Wu J, et al. Sleep deprivation as a model experimental antidepressant treatment: findings from functional brain imaging. Depress Anxiety 2001;14(1):37–49. [132] Wirz-Justice A, Van den Hoofdakker RH. Sleep deprivation in depression: what do we know, where do we go? Biol Psychiatry 1999;46(4): 445–53. [133] Benedetti F, Serretti A, Colombo C, et al. Dopamine receptor D2 and D3 gene variants are not associated with the antidepressant effect of total sleep deprivation in bipolar depression. Psychiatry Res 2003;118(3):241–7. [134] Leibenluft E, Albert PS, Rosenthal NE, et al. Relationship between sleep and mood in patients with rapid-cycling bipolar disorder. Psychiatry Res 1996;63(2–3):161–8. [135] Wehr TA, Sack DA, Rosenthal NE. Sleep reduction as a final common pathway in the genesis of mania. Am J Psychiatry 1987;144(2):201–4. [136] Yang C, White DP, Winkelman JW. Antidepressants and periodic leg movements of sleep. Biol Psychiatry 2005;58(6):510–4. [137] Schenck CH, Mahowald MW. Rapid eye movement sleep parasomnias. Neurol Clin 2005; 23(4):1107–26.

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Sleep in Schizophrenia Kathleen L. Benson, -

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Schizophrenia: a brief overview The abnormalities of sleep in schizophrenia Subjective assessment Objective assessment Clinical and biologic correlations Clinical correlates Biologic correlates Treatment issues

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Aserinsky and Kleitman’s [1] historic discovery of rapid eye movement (REM) sleep and its association with dream reports suggested to many that one of the defining features of the schizophrenic psychosis (ie, hallucinations) might constitute an intrusion of the dream state into waking. Although the ensuing years witnessed many attempts to validate this hypothesis, polysomnographic (PSG) studies of patients with schizophrenia failed to identify any consistent REM sleep abnormalities or any intrusions of REM sleep into wakefulness [2–4]. In contrast, many of these studies revealed other sleep abnormalities or dyssomnias that are more consistently characteristic of patients with schizophrenia. This article describes many of these dyssomnias and discusses their significance. It also discusses the relationship of these dyssomnias to some of the clinical and neuropathologic features of schizophrenia. Finally, it presents an overview of antipsychotic (AP) treatments; their effects on sleep; and their potential to facilitate or augment clinical sleep disorders, such as sleep disordered breathing (SDB) and restless legs syndrome (RLS). A brief overview of the clinical features and neuropathology of schizophrenia is first presented.

First- and second-generation antipsychotics: an overview Antipsychotic medications: their effects on sleep patterns Antipsychotics: side effects of insomnia and somnolence Adjunct medications Antipsychotics: associated sleep disorders Summary References

Schizophrenia: a brief overview Schizophrenia has been variously described as psychoticism, a gross impairment of reality testing, or a fundamental cognitive dysfunction known as ‘‘formal thought disorder.’’ Currently, the defining features and diagnostic criteria are best defined in the American Psychiatric Association’s [5] Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The defining features include a mixture of both positive and negative symptoms. Positive symptoms reflect ‘‘an excess or distortion of normal functions’’ and include delusions, hallucinations, disorganized speech, and disorganized or catatonic behavior. Negative symptoms reflect a ‘‘diminution or loss of normal functions’’ and include ‘‘restrictions in the range and intensity of emotional expression (affective flattening), in the fluency and productivity of thought and speech (alogia), and in the initiation of goal-directed behavior (avolition).’’ The diagnostic criteria also include significant social or occupational impairment. Estimates of the prevalence rate of schizophrenia range from 0.5% to 1%. The age of onset typically occurs in the late teenage years upward to the

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early 30s. Although there is not a significant lifetime preponderance of males over females, males typically express an earlier age of onset. An early age of onset is also associated with poorer clinical outcome, greater negative symptoms, and increased cognitive impairment. For some, the onset of the disease may be abrupt; for others, a constellation of symptoms is expressed gradually over time. The course of illness is also a variable feature. Some schizophrenics remain chronically impaired and some are permanently institutionalized. For others, the illness is punctuated by episodic flare-ups of positive symptoms. Negative symptoms may persist during intervening periods of partial remission. These episodic flare-ups are often preceded by a prodromal phase, a gradual development of signs and symptoms. Schizophrenic patients also experience a higher mortality rate from suicide and poor health. Finally, it is not uncommon for a patient with schizophrenia to be diagnosed with a concomitant substance-related disorder. There is no disease-specific laboratory abnormality diagnostic of schizophrenia; rather, the diagnosis is based entirely on a comprehensive clinical assessment. Although the etiology and pathophysiology of the illness continue to be the focus of vigorous study, there is neither a cure nor definitive preventive measures. The consensus view is that schizophrenia is a neurodevelopmental disorder involving the interaction of multiple susceptibility genes with one another and with environmental factors, some of which may be prenatal. The broad array of presenting signs and symptoms of schizophrenia is consistent not only with the clinical heterogeneity of schizophrenia but also with the diversity of potential etiologic factors. The early age of onset of schizophrenia, coupled with its poor prognosis, is consonant with the devastating human costs associated with this illness. One of these human costs is the marked dyssomnia subjectively reported by patients with schizophrenia and objectively validated by overnight sleep studies.

The abnormalities of sleep in schizophrenia Subjective assessment Although it is a common clinical experience that major depression and primary insomnia are associated with disturbed sleep, patients with schizophrenia describe the subjective quality of their sleep in very similar terms [6]. Their subjective assessment of poor sleep quality is predictive of self-assessed poor quality of life and impaired coping skills [7,8]. Self-assessed poor sleep quality includes subjective reports bearing on measures of sleep maintenance (ie, loss of total sleep time [TST], degraded sleep efficiency [SE]) defined as the percent of TST

relative to time in bed, early insomnia as measured by sleep onset latency [SL], middle insomnia, and early morning awakenings). Early and middle insomnia are among the most common complaints [9,10]. Patients may also report a degraded quality of sleep including restlessness and agitation. Episodic flare-ups of psychotic symptoms may be accompanied by nights of significant insomnia or total sleeplessness. There is also a greater likelihood of sleep-wake reversals (ie, sleeping during the day and wakefulness at night). This sleep-wake reversal is also correlated with subjective complaints of poor sleep quality [11]. Finally, it is important for clinicians to take note of two observations. First, severe insomnia is one of the prodromal signs associated with impending psychotic exacerbation or with relapse following the discontinuation of AP treatment [12–16]. Second, these studies of subjective sleep quality have, for the most part, sampled schizophrenics on standard doses of APs; this suggests that some APs may have limited efficacy in treating schizophrenia-associated dyssomnias.

Objective assessment The impetus for many of the earliest studies of sleep patterns in schizophrenics rested with the potential role of REM sleep intrusions in the pathogenesis of schizophrenia. Subsequent to their failure to identify any consistent REM sleep abnormality, investigations turned to an examination of other aspects of sleep architecture: measures of sleep maintenance (SL, TST, SE); measures of non-REM sleep, in particular sleep stages 3 and 4; REM latency (ie, the interval between sleep onset and the first REM period); REM sleep eye movement activity; and the quantification of sleep-related brain wave patterns, such as electroencephalogram (EEG) delta (0–3 Hz) activity, EEG beta and gamma (20–45 Hz) activity, and sleep spindles (12–15 Hz events). Many of these investigations hoped to find a unique sleep pattern or abnormality that might serve as a biologic marker to identify those with schizophrenia. Others hoped that sleep abnormalities in schizophrenia might be predictive of prognosis or treatment outcome or, better yet, might provide some insight into the underlying pathophysiology of schizophrenia. Although many of these goals went unmet, these studies did provide a comprehensive description of the range of sleep abnormalities seen in patients with schizophrenia. In the 50 plus years subsequent to the discovery of REM sleep, scores of published studies have added to this description. These studies have differed in many ways including sample size; protocol design; control groups; algorithms quantifying sleep parameters; the age of the subjects; their medication status and history; and their clinical features

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(eg, hallucinating versus nonhallucinating) and clinical history (eg, early onset versus late onset). In recent years, two meta-analyses [17,18] and two reviews [19,20] have brought some coherence to the diversity of these studies. The next section summarizes their observations regarding the more salient dyssomnias associated with schizophrenia. Measures of sleep maintenance Subjective complaints of insomnia have been extensively validated by objective PSG study. Broadly speaking, unmedicated schizophrenics who are actively symptomatic evidence poor SE; reductions in TST; and early, middle, and late insomnia. Schizophrenic patients typically take a protracted amount of time to reach a state of persistent sleep. This early insomnia (or long SL) is the most consistently reported abnormality shown in empiric studies of sleep patterns in schizophrenia. In healthy controls, SL rarely exceeds 30 minutes, but in empiric studies of symptomatic schizophrenics SL frequently exceeds 30 minutes, and often exceeds 1 hour. This characteristic insomnia may be associated with the pathophysiology of schizophrenia or may reflect hyperarousal secondary to ongoing emotional and psychotic turmoil. Measures of non–rapid eye movement sleep Attention now turns to those components of sleep that have been extensively studied and scrutinized: notable non-REM stages 3 and 4, known collectively as slow wave sleep (SWS); and REM latency (REML). The reader is again referred the meta-analyses and reviews previously cited [17–20] for a more detailed enumeration and exposition of the many investigative efforts. In contrast to the consistent demonstration of sleep maintenance failures, SWS deficits and abnormally short REMLs have been found in some studies and not in others. Because of this variability, abnormalities of SWS and REML have not been confirmed by the metaanalytic approach. The lack of consistent findings is frequently attributed to between-study differences in medication status or clinical features, such as concomitant depression; however, it may also reflect the heterogeneity of the disease itself. Although SWS deficits and short REMLs are not disease specific, these dyssomnias have been observed in most studies including first episode, AP-naive patients with schizophrenia [21]. The motivation to document SWS deficits and short REMLs in patients with schizophrenia reflected not only an interest in identifying, within the framework of those sleep abnormalities, biologic markers for the disease, but also the hope that SWS deficits and short REMLs might shed some light on underlying pathophysiologic

mechanisms. The homeostatic model of SWS was first advanced in 1974 [22]. According to this model, the homeostatic drive builds up during waking hours and dissipates in SWS across successive non-REM sleep cycles. The strength of the drive reflects both the amount of prior waking and the intensity of prior waking brain activity. In healthy subjects, this homeostatic drive is clearly demonstrated by an augmentation of SWS following a period of sleep deprivation. This dynamic overshoot suggests that SWS serves a restorative role in brain function. By implication, SWS restoration in patients with schizophrenia may be an important contributor to their clinical and neurocognitive outcome. SWS deficits are potentially related to another non-REM sleep abnormality, short REML. There is lack of agreement regarding the mechanism(s) underlying short REMLs in patients with schizophrenia. First, SWS deficits, particularly in the first non-REM cycle, might permit the passive advance or early onset of the first REM period. Alternatively, short REML might represent a primary abnormality of REM sleep (ie, an augmented drive for REM sleep). Measures of rapid eye movement time and rapid eye movement sleep eye movement activity The meta-analyses and reviews previously cited [17–20] revealed no systematic augmentations or reductions in the amount of REM sleep time when comparing schizophrenics with healthy or psychiatric controls. In addition to empiric studies of the tonic amounts of REM sleep time, other research has quantified one of the phasic events of REM sleep, notably REM sleep eye movements. These studies have demonstrated no consistent increase or decrease in REM sleep eye movements activity in schizophrenic patients (both AP-naive or currently unmedicated) relative to nonpsychiatric and psychiatric controls [23–26]. Measures of sleep-related brain wave activity In contrast to visual scoring of SWS, computer algorithms have been developed to quantify the incidence and amplitude of underlying EEG delta (0–3 Hz) frequencies of non-REM sleep. Studies using computer quantifications have confirmed the loss of power in the delta range in schizophrenics relative to nonpsychiatric controls [24,27,28]. This loss of non-REM delta power can occur despite comparable amounts of visually scored SWS [25]. In 1983, Feinberg [29] proposed a neurodevelopmental model of schizophrenia that accounts for both SWS deficits and the loss of underlying delta EEG. According to this model, schizophrenia

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develops during the second decade of life because of a fault in the normal maturational process of synaptic elimination scheduled for this stage of development. Less synchronous slow or delta EEG activity (and associated SWS deficits) would reflect excess synaptic pruning. In addition to sleep-related abnormalities in the slow or delta range of EEG activity, it has been reported that unmedicated schizophrenics exhibit greater power in the high-frequency beta (20–35 Hz) and gamma (35–45 Hz) EEG ranges than healthy controls during all stages of sleep [30]. Finally, a reduction in both the number and amplitude of non-REM sleep spindles (12–15 Hz) has been observed in medicated schizophrenics; this finding hints at some abnormality in thalamic-reticular and thalamocortical function in schizophrenia [31].

Clinical and biologic correlations Clinical correlates The relationship of the dyssomnias of schizophrenia to clinical symptoms, neurocognitive impairment, and prognosis has been extensively studied. Although some studies investigated global assessments of symptom severity, others examined the components of symptom severity, such as positive or negative symptoms and cognitive dysfunction. Studies have documented a positive correlation between global symptom severity and increased waking, reduced REM sleep time, SWS deficits, and short REML [32–34]. Positive symptoms, such as hallucinations and delusions, have been directly associated with long SLs [35], impaired SE [36], short REML [21,23,33,37], increased REM sleep eye movements density [26,38], and high-frequency EEG brain wave activity [30]. Negative symptoms have also been directly associated with short REML [33,39], SWS deficits [27,40–44], and underlying high-amplitude delta wave activity [45]. Formal thought disorder, or cognitive dysfunction, also correlates with SWS deficits, which is perhaps indicative of frontal lobe dysfunction [46]. In addition, poor clinical and psychosocial outcome have been associated with SWS deficits [47] and short REMLs [39,48]. Finally, in comparisons of schizophrenics with healthy controls, a small collection of studies demonstrated sleeprelated impairments in neuropsychologic performance tasks: procedural memory [49], reaction time in a selective attention task [50], visuospatial memory [51], and tasks of attention and cognitive flexibility [52]. These correlational studies of sleep abnormalities reflect a diversity of clinical assessment instruments, different algorithms to quantify sleep parameters,

small sample sizes, major differences in medication status and history, and clinical heterogeneity of the subjects. Consequently, an overarching synthesis is premature. Finally, most of these studies were cross-sectional in design; a longitudinal, within-patient, assessment of sleep patterns across changing clinical states may prove to be a more productive methodology.

Biologic correlates Research has also documented significant associations between brain structures and the dyssomnias of schizophrenia. The four studies reporting these linkages used CT brain imaging technology. Two studies reported that SWS deficits or reductions in its stage 4 component were associated with enlarged ventricular system volume [40,53]. This finding was not confirmed in a later study of AP-naive schizophrenics [23]. Poor sleep maintenance has also been associated with brain dysmorphologies. Longer sleep latencies [40] and the number of awakenings [23] have been linked to size increases in the proportion of ventricular system volume to whole brain volume, known as the ‘‘ventricular brain ratio’’ [40]. A positive correlation has also been reported between the number of awakenings and both global and prefrontal cortical atrophy [40]. Finally, negative correlations have been reported between TST and third ventricle width [40] and between sleep maintenance and third ventricle/brain ratio, caudate/brain ratio, and anterior horn/brain ratio [54]. Interpretation of these diverse findings requires a note of caution. The four studies summarized here represent a mere snapshot in time. All were cross-sectional designs. Only longitudinal studies could justify the use of such terms as ‘‘enlargement’’ and ‘‘atrophy,’’ with the former suggesting illness-related growth and the latter suggesting shrinkage. Changes in the volumes of these brain structures before the point of study are speculative. A second note of caution concerns the interpretation of brain structure correlates. Neuroanatomic correlates of sleep abnormalities might suggest a stable or traitlike impairment. As is seen in subsequent sections, however, patterns of sleep maintenance and staging can and do undergo change, particularly in response to AP treatment. Furthermore, anatomic structures in the human brain are subject to adult neurogenesis [55], and longitudinal brain imaging studies of schizophrenics have demonstrated brain structure changes associated with AP treatment [56–58]. The observation that adult neurogenesis can be inhibited by sleep loss [59] suggests that the chronic dyssomnias of schizophrenia might themselves contribute to brain structure abnormalities.

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In addition to neuroanatomic correlates, neurochemical associations have also been explored, but these investigations have been few and not systematically related. There are no studies of the dyssomnias of schizophrenia in relationship to dopamine (DA), the neurotransmitter long thought to be a major factor in the pathophysiology of schizophrenia. Four other neurotransmitter systems (ie, acetylcholine, serotonin [5-HT], norepinephrine, and hypocretin), however, have been examined. With regard to acetylcholine, short REMLs have been associated with cholinergic supersensitivity [60]. SWS deficits have been linked to a serotonergic (5-HT) dysfunction in a study finding a positive correlation between SWS time and cerebrospinal fluid levels of the principal 5-HT metabolite [61]. Increased cerebrospinal fluid levels of norepinephrine and its primary metabolite, 3-methoxy–4-hydroxyphenylglycol (MHPG), have accompanied psychotic decompensation and relapse-related insomnia [14]. Finally, a positive correlation has been reported between sleep latency and levels of cerebrospinal fluid hypocretin, a wakepromoting neurotransmitter; the authors suggest a possible relationship between the neurotransmitter hypocretin and hyperarousal in schizophrenia [62].

Treatment issues First- and second-generation antipsychotics: an overview Most patients diagnosed with schizophrenia are exposed to AP medications. APs have signature effects on neurotransmitter receptors (eg, DA, 5-HT, a-adrenergic, cholinergic, and histaminic receptors) and their numerous subtypes; these unique receptorbinding profiles are associated with their therapeutic efficacy and a wide range of potentially adverse effects. The first-generation AP medications are known as ‘‘traditional’’ or ‘‘typical’’ APs. Generally speaking, the typical APs have a strong affinity for the DA D2 postsynaptic receptor. Although this affinity has been credited with their therapeutic efficacy, this same affinity, particularly to D2 receptors in the nigrostriatal pathways, has been linked to an array of extrapyramidal side effects, such as akathisia, dystonia, and parkinsonism. Furthermore, D2 receptor-binding is associated with a more adverse effect, namely tardive dyskinesia. The adverse effects of extrapyramidal side effects and tardive dyskinesia have contributed to the poor compliance associated with first-generation APs. The second-generation AP medications are known collectively as ‘‘novel’’ or ‘‘atypical’’ APs. In current clinical practice, atypical APs are first-line

therapy for schizophrenia. The atypical APs include clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and paliperidone. Although each has a unique receptor-binding profile, all have high 5-HT to DA binding ratios [63]. As a consequence, the incidence of extrapyramidal side effects and tardive dyskinesia is lower in second-generation APs. Among the atypicals, risperidone, olanzapine, and paliperidone show some dose-related increase in extrapyramidal side effects [63]. Second-generation APs have also been linked to other morbidities, such as weight gain, glucose dysregulation, type 2 diabetes, and hyperlipidemia [63]. The amount of weight gain associated with the atypical APs is greatest for those taking clozapine and olanzapine; moderate for those taking risperidone and quetiapine; and lower for patients on ziprasidone, aripiprazole, and paliperidone [63]. Weight gain is a risk factor for metabolic disturbances, such as glucose dysregulation, but it is also a risk factor for sleep-disordered breathing, a dyssomnia further taxing sleep-related restorative processes.

Antipsychotic medications: their effects on sleep patterns Several studies have evaluated the effect of first-generation APs on the sleep of patients with schizophrenia using PSG methodology. Haloperidol was most commonly studied, but other studies have included such agents as chlorpromazine, thiothixene, and fluphenazine. Traditional APs have been shown to improve measures of sleep maintenance, increasing both TST and SE and reducing both SL and wake after sleep onset; their effects on REML, stage REM minutes, and REM sleep eye movements density were less consistent [64–69]. Chlorpromazine was found to increase SWS minutes and REML [64]. Empiric studies of the sleep of schizophrenic patients treated with second-generation APs have examined the effects of clozapine, risperidone, olanzapine, and paliperidone. Clozapine, being the first of the atypical APs, has been the most extensively studied [69–71]. These three studies have been in broad agreement in finding clozapine-related increases in TST, SE, and stage 2 minutes; they have also reported clozapine-related decreases in SL, waking, and SWS. PSG studies of schizophrenic patients treated with olanzapine have reported increased SE and SWS [72,73]. One of these two studies also noted significantly increased TST, stage 2 minutes, REM sleep eye movements, density, and significantly decreased amounts of waking and stage 1 minutes [72]. The second olanzapine study also reported significantly increased stage REM minutes [73]. An enhancement of SWS

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has also been observed in risperidone-treated schizophrenics [74]. The effect of paliperidone on sleep patterns in patients with schizophrenia reported the following: increased SE, TST, stage 2 minutes, and stage REM minutes; decreased SL, waking, and stage 1 minutes [75]. There are no empiric PSG studies of schizophrenics treated with quetiapine, ziprasidone, and aripiprazole; however, in a PSG study of healthy controls, quetiapine was associated with significant improvements in sleep induction and sleep continuity [76]. Broadly speaking, these acute and short-term dosing studies of the effects of APs on the sleep of patients with schizophrenia demonstrate a positive improvement in sleep maintenance and architecture. Given that clinical improvement typically lags behind the initiation of AP treatment, improvements in sleep maintenance and architecture are not mere by-products of clinical improvement. Rather, the restoration or normalization of sleep processes may contribute to a positive clinical outcome.

Antipsychotics: side effects of insomnia and somnolence The National Institute of Mental Health–sponsored Clinical Antipsychotic Trials of Intervention Effectiveness study documents the prevalence of adverse effects in AP-treated schizophrenics [77]. These adverse events include reported rates of daytime sedation and somnolence, and rates of residual insomnia. AP-treated schizophrenics reported somnolence rates ranging from 24% to 31%. Rates of residual insomnia ranged from 16% to 30%. Although improvements in sleep maintenance and architecture have been amply documented, these figures suggest that a large number of AP-treated schizophrenics suffer from daytime somnolence or from residual insomnia. These sleep-related adverse effects may contribute to noncompliance and potentially to a poorer outcome.

Adjunct medications Benzodiazepine tranquilizers and hypnotics may be prescribed to address complaints of residual insomnia; however, they should be prescribed cautiously, particularly for those schizophrenics with a sleeprelated breathing disorder or a history of alcohol or drug abuse. Mood stabilizers and antidepressants also have positive effects on insomnia; these agents are frequently prescribed for patients diagnosed with concomitant affect disorders or impulse control problems. Melatonin Melatonin, the chief hormonal product of the pineal gland, has been used to treat insomnias

associated with disturbed patterns of melatonin secretion. Studies have shown that the nighttime peak in melatonin secretion is blunted in medicationfree schizophrenics and is not normalized even after clinical improvement with AP treatment [78,79]. Two studies have tested the effect of exogenous melatonin on residual insomnia in AP-treated schizophrenics. First, melatonin replacement (2 mg controlled release) significantly improved SE as measured by actigraphy [80]. Second, exogenous melatonin (3–12 mg/night, modal dose of 3 mg) increased self-reported TST and reduced selfreported nighttime awakenings [81]. Modafinil Modafinil is a wakefulness-promoting agent currently approved by the Food and Drug Administration for the treatment of excessive daytime sleepiness associated with narcolepsy. Modafinil has been considered an adjunct medication to offset the somnolence associated with many AP agents. Case studies [82] and an open-label pilot study [83] show that modafinil, as an adjunct to AP treatment, can increase wake time, reduce fatigue and TST, and improve quality of life. Because stimulant drugs that promote wakefulness may increase the risk of relapse or exacerbation of psychosis in patients with schizophrenia [84], offlabel use of modafinil to control AP-related sedation in schizophrenia requires more extensive investigation.

Antipsychotics: associated sleep disorders It is not uncommon for patients with schizophrenia to present with symptoms of other sleep disorders regularly seen in sleep disorders clinics. These may include inadequate sleep hygiene, irregular sleepwake patterns, parasomnias, sleep-related movement disorders, and sleep-related breathing disorders. Because there are no large-scale prevalence studies of sleep disorders in AP-naive schizophrenics, their baseline rates for comorbid sleep disorders are unknown. Clearly, some of these dyssomnias, such as irregular sleep-wake patterns, may be associated with their illness. Unfortunately, others may be enhanced by, or induced by, AP treatment. Somnambulism and sleep-related eating disorder: two parasomnias Somnambulism or ‘‘sleep-walking’’ is typically initiated during an arousal from SWS. It has been described as a potential side effect of treatment with first-generation APs, particularly in combination with lithium [85]. Sleepwalking also has been observed in patients treated with the atypical AP olanzapine [86]. Both lithium and olanzapine have

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been credited with enhancing SWS, and thus may be associated with an increased risk of impaired arousal. Clonazepam, a treatment option in primary arousal disorders, might be considered for the treatment of AP-induced somnambulism [87]. Sleep-related eating disorder is another parasomnia that can be induced by AP medication. This syndrome has been associated with haloperidol [88], olanzapine [89], and risperidone treatment [90]. Sleep-disordered breathing High prevalence rates for SDB in schizophrenic patients are suggested by research protocols. These studies reported the following estimates of SDB: 17% with a respiratory disturbance index greater than five events per hour of sleep [91], 48% with a respiratory disturbance index greater than 10 events per hour of sleep [92], and 19% with a desaturation index greater than five events per hour [93]. In contrast, a study of schizophrenic patients referred to a sleep clinic for a suspected sleep disorder determined that more than 46% had a respiratory disturbance index greater than 10 events per hour; the mean respiratory disturbance index was 64.8 events per hour; the best predictor of SDB was obesity [94]. Weight gain secondary to AP treatment, particularly second-generation APs, carries a serious morbidity risk including the development of moderate to severe SDB [95]. Clinicians must consider the differential diagnosis of comorbid SDB for schizophrenics who present with daytime somnolence and who are obese by history or who have undergone weight gain secondary to AP treatment. These patients may be poor historians and frequently have no bed partner to provide information regarding snoring and breathing pauses. Importantly, daytime somnolence in patients with schizophrenia may signal more than AP-related sedation. Patients who are comorbid for schizophrenia and SDB can be treated effectively with nasal continuous positive airway pressure; they also can demonstrate relatively good compliance and significant clinical improvement [96,97]. Sleep-related movement disorders DA deficiency has been linked to the pathophysiology of sleep-related movement disorders, such as RLS and periodic limb movement disorder (PLMD); consequently, RLS and PLMD may be more prevalent in schizophrenics because of antagonism of the DA receptor by APs. The diagnosis of RLS is based on the self-report of symptoms evaluated by a trained clinician using well-defined diagnostic criteria. In the case of schizophrenics, RLS must be distinguished from the restlessness of akathisia. In contrast, overnight PSG is the objective methodology used to make the diagnosis of

PLMD. Most patients diagnosed with RLS are often comorbid for PLMD. In a study of the prevalence of RLS in AP-treated schizophrenics, 21.4% of the schizophrenics met diagnostic criteria for RLS in contrast to 9.3% of healthy controls [98]. This group also found that the severity of psychiatric symptoms (as measured by the Brief Psychiatric Rating Scale) was greater in those schizophrenic with RLS than in the schizophrenics without RLS. The prevalence of PLMD in patients with schizophrenia has been less rigorously examined. Prevalence rates for patients treated with first-generation APs are in the 13% to 14% range [91,92]. Two case reports link second-generation APs to the development of RLS and a clinically significant PLMD index in patients with schizophrenia; the first case was associated with olanzapine treatment [99], the second case with risperidone treatment [100]. Both cases resolved on switching to a different atypical AP. Although DA agonists are first-line therapeutic options to treat RLS or PLMD, they are not treatment options for patients diagnosed with schizophrenia. Rather, a reduction in AP dose or a change in medication must be considered whenever RLS or PLMD develop secondary to AP treatment.

Summary Patients diagnosed with schizophrenia may be comorbid for dyssomnias either induced by or exacerbated by their treatment with AP agents. These dyssomnias include somnambulism, sleep-related eating disorders, sleep-related breathing disorders, and sleep-related movement disorders. Every effort should be made to treat comorbid sleep disorders vigorously in patients with schizophrenia. A favorable prognosis or positive clinical outcome may require some normalization of sleep and its restorative processes.

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[55] Gross CG. Neurogenesis in the adult brain: death of a dogma. Nat Rev Neurosci 2000;1: 67–73. [56] Corson PW, Nopoulos P, Miller DD, et al. Change in basal ganglia volume over 2 years in patients with schizophrenia: typical versus atypical neuroleptics. Am J Psychiatry 1999; 156:1200–4. [57] Dazzan P, Morgan KD, Orr K, et al. Different effects of typical and atypical antipsychotics on grey matter in first episode psychosis: the ´ SOP Æ study. Neuropsychopharmacology 2005;30:765–74. [58] Newton SS, Duman RS. Neurogenic actions of atypical antipsychotic drugs and therapeutic implications. CNS Drugs 2007;21(9):715–25. [59] Guzman-Marin R, Suntsova N, Methippara M, et al. Sleep deprivation suppresses neurogenesis in the adult hippocampus of rats. Eur J Neurosci 2005;22:2111–6. [60] Riemann D, Hohagen F, Krieger S, et al. Cholinergic REM induction test: muscarinic supersensitivity underlies polysomnographic findings in both depression and schizophrenia. J Psychiatr Res 1994;28(3):195–210. [61] Benson KL, Faull KF, Zarcone VP. Evidence for the role of serotonin in the regulation of slow wave sleep in schizophrenia. Sleep 1991;14:133–9. [62] Nishino S, Ripley B, Mignot E, et al. CSF hypocretin-1 levels in schizophrenia and controls: relationship to sleep architecture. Psychiatry Res 2002;110:1–7. [63] Conley RR, Kelly DL. Clinical pharmacology and medication-associated side effects: a review of second-generation antipsychotic for schizophrenia. Clinical Schizophrenia and Related Psychoses 2007;1(2):135–46. [64] Kaplan J, Dawson S, Vaughan T, et al. Effect of prolonged chlorpromazine administration on the sleep of chronic schizophrenics. Arch Gen Psychiatry 1974;31:62–6. [65] Taylor SF, Tandon R, Shipley JE, et al. Effect of neuroleptic treatment on polysomnographic measures in schizophrenia. Biol Psychiatry 1991;30:904–12. [66] Nofzinger EA, van Kammen DP, Gilbertson MW, et al. Electroencephalographic sleep in clinically stable schizophrenic patients: two-weeks versus six-weeks neuroleptic free. Biol Psychiatry 1993;33:829–35. [67] Keshavan MS, Reynolds CF III, Miewald JM, et al. A longitudinal study of EEG sleep in schizophrenia. Psychiatry Res 1996;59:203–11. [68] Maixner S, Tandon R, Eiser A, et al. Effects of antipsychotic treatment on polysomnographic measures in schizophrenia: a replication and extension. Am J Psychiatry 1998;155(11):1600–2. [69] Wetter TC, Lauer CJ, Gillich G, et al. The electroencephalographic sleep pattern in schizophrenic patients treated with clozapine or classical antipsychotic drugs. J Psychiatr Res 1996;30(6):411–9.

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[84] Narendran R, Young CM, Valenti AM, et al. Is psychosis exacerbated by modafinil? Arch Gen Psychiatry 2002;59(3):292–3. [85] Charney DS, Kales A, Soldatos CR, et al. Somnambulistic-like episodes secondary to combined lithium-neuroloeptic treatment. Br J Psychiatry 1979;135:418–24. [86] Kolivakis TT, Margolese HC, Beauclair L, et al. Olanzapine-induced somnambulism [letter]. Am J Psychiatry 2001;158(7):1158. [87] Goldbloom D, Chouinard G. Clonazepam in the treatment of neuroleptic-induced somnambulism [letter]. Am J Psychiatry 1984;141:1486. [88] Horiguchi J, Yamashita H, Mizuno S, et al. Nocturnal eating/drinking syndrome and neuroleptic-induced restless legs syndrome. Int Clin Psychopharmacol 1999;14(1):33–6. [89] Paquet V, Strul J, Servais L, et al. Sleep-related eating disorder induced by olanzapine [letter]. J Clin Psychiatry 2002;63(7):597. [90] Lu ML, Shen WW. Sleep-related eating disorder induced by risperidone [letter]. J Clin Psychiatry 2004;65(2):273. [91] Benson KL, Zarcone VP. Sleep abnormalities in schizophrenia and other psychotic disorders. Review of Psychiatry 1994;13:677–705. [92] Ancoli-Israel S, Martin J, Jones DW, et al. Sleep-disordered breathing and periodic limb movements in sleep in older patients with schizophrenia. Biol Psychiatry 1999;45(11):1426–32. [93] Takahashi KI, Shimizu T, Sugita T, et al. Prevalence of sleep-related respiratory disorders in 101 schizophrenic patients. Psychiatry Clin Neurosci 1998;52:229–31. [94] Winkelman JW. Schizophrenia, obesity, and obstructive sleep apnea. J Clin Psychiatry 2001;62(1):8–11. [95] Wirshing DA, Pierre JM, Wirshing WC. Sleep apnea associated with antipsychotic-induced obesity. J Clin Psychiatry 2002;63:369–70. [96] Boufidis S, Kosmidis MH, Bozikas VP, et al. Treatment outcome of obstructive sleep apnea syndrome in a patient with schizophrenia: case report. Int J Psychiatry Med 2003;33(3): 305–10. [97] Karanti A, Lande´n M. Treatment refractory psychosis remitted upon treatment with continuous positive airway pressure: a case report. Psychopharmacol Bull 2007;40(1):113–7. [98] Kang SG, Lee HJ, Jung SW, et al. Characteristics and clinical correlated of restless legs syndrome in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:1078–83. [99] Kraus T, Schuld A, Pollma¨cher T. Periodic leg movements in sleep and restless legs syndrome probably caused by olanzapine. J Clin Psychopharmacol 1999;19:478–9. [100] Wetter TC, Brunner J, Bronisch T. Restless legs syndrome probably induced by risperidone treatment. Pharmacopsychiatry 2002;35(3): 109–11.

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Sleep and Anxiety Disorders Thomas A. Mellman, -

MD

Sleep in specific and social phobias Sleep in obsessive-compulsive disorder Sleep in generalized anxiety disorder Sleep in panic disorder Sleep panic attacks

Sleep disturbances and anxiety symptoms are inextricably intertwined. With insomnia, anxious arousal interferes with sleep onset. Insufficient sleep sustains and predisposes to persisting anxiety states. Anxiety disorders are psychiatric conditions whose primary features are anxiety that is persistent, maladaptively triggered, and of sufficient intensity to disrupt function. The anxiety disorders in the Diagnostic and Statistical Manual, 4th Edition (DSM-IV) are generalized anxiety, panic, posttraumatic stress, obsessive-compulsive, and phobic disorders. Sleep disturbances are frequently associated with, and can comprise core features of, anxiety disorders. Posttraumatic stress disorder (PTSD) and generalized anxiety disorder (GAD) feature sleep disturbances among their DSM-IV diagnostic criteria. PTSD develops in some individuals after exposure to severely threatening stress and manifests with symptoms of re-experiencing the trauma, emotional numbing and avoidance behaviors, and heightened arousal. Specific criteria for the disorder related to sleep include nightmares with traumarelated content and difficulty initiating and maintaining sleep, which is the common definition of insomnia. The principal feature of GAD is chronic worry and tension. Impaired sleep initiation and maintenance is also a symptom criterion for GAD. Panic disorder features recurring severe and

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Sleep in posttraumatic stress disorder Sleep anxiety symptoms and sleep apnea Treatment and prevention Acknowledgments References

unpredictable episodes of anxiety with crescendolike onsets called ‘‘panic attacks,’’ which are often complicated by anticipatory anxiety and phobic avoidance. Although not among the specific diagnostic criteria, panic disorder has also been associated with complaints of difficulty initiating and maintaining sleep in many studies. In addition, panic attacks can arise from sleep in many patients diagnosed with the disorder. Sleep disturbances can occur with, but seem to be less salient features of, obsessive-compulsive disorder (OCD) and specific and social phobic disorders. In addition frequently to being a part of their presenting symptoms, insomnia is a risk factor for the subsequent onset of anxiety disorders [1–3]. There is overlap between interventions that target insomnia and other sleep disturbances and those that are used in treating anxiety disorders. Overlapping approaches include medications, and cognitive behavioral strategies that target worry, tension, and maladaptive cognitions. Optimal sequencing or integration of treatments targeting insomnia and sleep disturbance, however, are not well investigated. Much of the emphasis regarding overlap of anxiety and sleep disturbance is appropriately focused on insomnia. There can be overlapping features of the sleep manifestations of anxiety disorders with other primary sleep disorders. For example,

Department of Psychiatry, Howard University Hospital, 2041 Georgia Avenue, NW, Washington, DC 20060, USA E-mail address: [email protected] 1556-407X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

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symptomatic episodes in panic disorder sometimes need to be differentiated from clinical manifestations of sleep apnea, and GAD from restless legs syndrome. In the following sections clinical issues and laboratory information where available regarding sleep aspects of specific anxiety disorders are reviewed. This review is followed by discussion of interfaces of anxiety and sleep apnea and treatment issues that overlap sleep and anxiety disorders.

Sleep in specific and social phobias Fear and avoidance of situations are the key features of phobic disorders. Because these situations occur during interactions with the environment during wakefulness, sleep disturbances are not typically regarded as central to or commonly associated with these conditions. Nonetheless, persons with phobic disorders may experience anticipatory anxiety that affects their sleep and dreams. Investigations relating sleep to phobias are limited. In one study, persons with social phobia subjectively reported had poorer sleep quality, longer sleep latency, more frequent sleep disturbance, and increased daytime dysfunction compared with controls [4]. The one pilot study of social phobia identified that used polysomnography (PSG), however, reported normal findings [5]. Clark and colleagues [6] noted that sleep architecture was similar in depressed persons with and without simple phobias (the term that predated the DSM-IV). A study on parasomnias, including sleep terrors and sleepwalking, among adolescents found increased comorbidity with simple phobias and other anxiety disorders [7].

Sleep in obsessive-compulsive disorder Sleep disturbances are also not included among the symptom criteria, and are not commonly associated with OCD. PSG has been applied to OCD and other disorders to evaluate overlap with depression where reduced latency to rapid eye movement (REM) sleep is a well-established biologic marker. An early polysomnographic study noted impaired sleep maintenance and a reduced latency to REM sleep in a group with persons with OCD, which is consistent with a linkage between OCD and affective illness [8]. Two more recent polysomnographic studies of persons with OCD failed to replicate these results, however, reporting instead that the sleep patterns of persons with OCD were essentially normal [9,10].

Sleep in generalized anxiety disorder There is a high degree of overlap between GAD and insomnia. DSM-IV criteria for GAD are chronic

worry and three of six additional criteria that include difficulty initiating or maintaining sleep, or restless and unsatisfying sleep. Two of the other symptom criteria, fatigue and irritability, can be consequences of sleep loss. In addition, the principal attribute of GAD, excessive worry or apprehensive expectation, is commonly implicated in the genesis and maintenance of insomnia problems. Ohayon and colleagues [3] found that the comorbidity of GAD and insomnia was greater than for all of the other psychiatric disorders surveyed. Studies using objective sleep recordings corroborate the reported associations of GAD and insomnia by demonstrating impaired sleep initiation and maintenance in persons with GAD [11–13]. High comorbidity with major depression has generated interest in comparing biologic markers of the disorders. Latency to REM sleep was normal in these studies, in contrast to findings from major depression where REM sleep latency is reduced [11–13]. Consistent with their high degree of overlap and comorbidity, there is also substantial overlap of treatment approaches for GAD and insomnia. Overlapping approaches include the use of medications that target benzodiazepine receptors and psychotherapeutic interventions that target excessive worry. Application of these approaches in treating co-occurring generalized anxiety and sleep disturbances is discussed later.

Sleep in panic disorder Panic attacks are distinguished from other anxiety episodes by their sudden, crescendo-like onset, intensity and number of symptoms, and at times unpredictable pattern of occurrence. Panic attacks can emerge from sleep. Panic disorder also typically features chronic anxiety related to anticipating subsequent attacks and phobic avoidance (agoraphobia). Panic attacks arising from sleep (sleep panic attacks) have been suggested to condition fear and apprehension of sleep resulting in secondary insomnia [14]. Surveys document that insomnia is more frequent in patients with panic disorder than in control populations [15,16]. Most [17–20] but not all [21,22] published studies of panic disorder that used objective methods of sleep recording (PSG) have found evidence of impaired sleep initiation and maintenance. Survey data have noted associations between sleep complaints and comorbid depression in persons with panic disorder [21]. There are several possible explanations for the relationship between sleep disturbance and the presence of depression in persons with panic disorder. First, much of the associated sleep disturbance may be caused by depressive illness that commonly coexists with panic

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disorder. The two studies that failed to identify any impairment in sleep duration and maintenance specifically excluded depression. One of the studies documenting sleep disturbance in panic disorder excluded depressive illness, however, and it is uncertain whether depression accounted for the entire sleep disturbance documented in the remaining positive studies. A second consideration is that comorbid depression may be more common with a more severe variant of panic disorder that also features sleep disturbance. Because insomnia is a risk factor for the subsequent onset of depression [1,2], a third possibility is that depression is more likely to evolve as a comorbid condition when panic disorder features disturbed sleep.

Sleep panic attacks Sleep panic attacks are not uncommon among persons with panic disorder. In a study that prospectively monitored panic attacks, 18% occurred during sleep hours [23]. In surveys and clinical evaluations 33% to 71% of panic disorder patients reported having experienced sleep panic attacks [15,24–26]. As many as a third of panic disorder patients experience sleep panic as often as or more frequently than wake panic attacks [14,15]. It is not known how common it is for patients only to have sleep panic; however, in this author’s experience patients who exclusively panic from sleep are rare. Sleep panic attacks have been described as being awakened with a jolt. They also feature apprehension and somatic symptoms, similar to panic attacks that are triggered during wake states. Studies that have captured sleep panic attacks during polysomnographic recordings find that the episodes were preceded by either stage 2 or 3 of non-REM sleep [17,27]. Mellman and Uhde [17] more specifically noted that the sleep panic attacks originated during the transition from stage 2 into early slow wave sleep, which is a period of diminishing arousal. Slow wave sleep is also a state where cognitive activity is at a relative nadir [28]. Panic being triggered during sleep might seem counterintuitive in view of the more intuitive circumstance of panic attacks evolving from states of heightening arousal where apprehension is building. The phenomenon of sleep panic indicates that panic attacks can also be precipitated during states of diminishing arousal. This phenomenon adds to evidence from pharmacologic challenge and treatment studies and twin and familial genetic data that endogenous neurobiologic mechanisms can underlie anxiety. Specific mechanisms postulated to underlie sleep panic include increased sensitivity to increased carbon dioxide blood levels [29], irregular breathing during slow wave sleep [30], and rebound noradrenergic surges [17,18]. A cognitive

mechanism of sensitivity to and catastrophic interpretation of interoceptive stimuli has also been suggested to underlie sleep panic [25]. The greater sensitivity of panic disorder patients to pharmacologic challenges that induce panic has provided an important research paradigm for investigating the psychobiology of panic attacks. Sodium lactate and pentagastrin challenges, which trigger panic attacks from wake states, have been demonstrated also to trigger panic attacks from sleep [31,32]. Greater cardiac and respiratory responses to lactate infusion during sleep absent panic awakenings have also been noted [18,33]. Findings that panicogenic triggers can elicit attacks from sleep states indicate that elevated basal arousal is not required for experimentally inducing panic. Several investigations have explored the significance of sleep panic by comparing patients who experience sleep panic attacks with patients who only experience panic attacks from wake states. These studies have indicated that patients with sleep panic have early illness onset, higher symptom load, depression, and suicidal ideation. Sleep panic may be associated with a more severe variant of the illness [24,34]. Patients with sleep panic have also been noted to experience anxiety from relaxation and hypnosis, and to have less agoraphobic avoidance and fewer catastrophic cognitions compared with panic patients who do not experience sleep panic [15,25,35,36]. Having sleep panic seems also to mark a propensity to have panic triggered by reductions in arousal and for attacks to occur relatively independently of situational and cognitive stimuli that are associated with nonsleep panic.

Sleep in posttraumatic stress disorder The trauma-related nightmares and difficulty initiating and maintaining sleep denoted in the DSMIV criteria for PTSD are often prominent among the symptom complaints of patients with the disorder [37,38]. Nightmares and insomnia are also common in the early aftermath of trauma, especially among those who are developing PTSD [39–42]. Furthermore, sleep disruption leads to fatigue and irritability, which are daytime symptoms of PTSD. Sleep disruption may also interfere with healthy emotional adaptation and regulation and thereby contribute to the development of PTSD. Findings from sleep laboratory studies have not yielded a consensus regarding the fundamental nature of sleep disturbances in PTSD. All but a few of the studies are focused on the chronic phase of the disorder and many include only male war veterans. These studies have been mixed in terms of finding objective indices of impaired sleep initiation and maintenance [43,44].

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Evidence for abnormalities related to REM sleep in PTSD has been more consistent. Increased phasic motor activity and eye movement density during REM sleep have been reported in combat veterans with PTSD [45–47]. Nightmares and other symptomatic awakenings disproportionately arise from REM sleep [48,49]. Breslau and colleagues [50] recently reported more frequent transitions from REM sleep to stage 1 or wake in a community sample with either lifetime only (ie, remitted) or current PTSD compared with trauma-exposed and trauma-unexposed controls. There is converging evidence for disruptions of REM sleep continuity (symptomatic awakenings, increased awakening and arousals, and motor activity) and increased REM activation (eye movement density) with chronic PTSD. The limited number of studies that used objective recordings of sleep following trauma also suggest the relevance of REM sleep disruption. An early report of three cases with ‘‘acute combat fatigue’’ described ‘‘markedly disrupted sleep’’ and ‘‘rare or absent REM episodes’’ [51]. Mellman and colleagues [52] reported PSG findings from PSG recordings conducted within a month of trauma in 21 recently injured patients and 10 healthy controls. REM density was elevated in the recently traumaexposed, injured patients compared with healthy controls but was similar among those who did and did not develop PTSD. The patients who were developing PTSD, however, had shorter continuous periods of REM sleep before stage shifts or arousals. Findings suggesting a relationship between fragmented patterns of REM sleep and PTSD were also provided by a recent study of PTSD patients with limited chronicity and comorbidity [53]. Studies have demonstrated that insomnia is very common among people who have been recently exposed to trauma. Green [39] found insomnia to be the most frequent symptom endorsed by survivors in the aftermath of a natural disaster. Koren and colleagues [41] found that complaints of insomnia and excessive daytime sleepiness 1 month after motor vehicle accidents predicted being diagnosed with PTSD at 3 months. In contrast, although Koren and colleagues [41] found an association of early subjective reports of sleep disturbance with the development of PTSD, these investigators did not find differences in early actigraphic measurements of sleep initiation or maintenance in their prospective study of traffic accident victims, nor in PSG measures in a subgroup recorded 1 year later [54]. Trauma-related nightmares are among the DSM-IV criteria for PTSD. Mellman and colleagues [42] evaluated relationships of recalled dream content elicited within a month of traumatic injuries with the development of PTSD. Reports of dreams rated as ‘‘highly similar’’ to the traumatic experience

and distressing were associated with concurrent and subsequent PTSD severity. The trauma-exposed group who did not subsequently develop PTSD either did not recall dreaming or reported dreams that did not depict actual memories, although some represented threatening scenarios. The authors theorized that dreams with highly replicative content represent a failure of adaptive emotional memory processing that is a normal function of REM sleep and dreaming. A role for noradrenergic functioning in sleep disturbances during the early development of PTSD is suggested by previously established relationships of noradrenergic activity with PTSD [55] and PTSD sleep disturbances [56], and the noradrenergic signal terminating REM sleep [57]. Mellman and colleagues [58] also evaluated heart rate variability during sleep following trauma, which indexes autonomic regulation of heart rate including sympathetic nervous system activity, which is a peripheral manifestation of noradrenergic function. The index of sympathetic nervous system activity, the low-frequency/high-frequency ratio, was greater in the subgroup that developed PTSD during their initial REM sleep periods. Subjective sleep complaints are common in the aftermath of trauma and with PTSD. Nightmares that are similar to trauma memories seem to be relatively specific to the disorder. Overall, studies do not indicate that sleep initiation and maintenance is markedly more impaired among those developing or who have been diagnosed with PTSD. Several studies now converge in suggesting that disruptions of REM sleep may have a role in PTSD and its development.

Sleep anxiety symptoms and sleep apnea When a patient reports waking up in the middle of the night with his or her heart pounding and feeling short of breath, can this be confidently attributed to anxiety, or should the physician first evaluate cardiac and respiratory parameters before even considering psychiatric disorders as the likely primary diagnosis? Clinical experience and review of relevant literature indicate that clinical acumen and common sense can often guide the direction of the evaluation and that there is a place for physiologic monitoring and treatment of comorbid medical and psychiatric symptoms. With sleep apnea, arousals are usually below the threshold of awareness and memory, although awakenings with gasps, snorts, or symptoms of gastroesophageal reflux are sometimes reported. Excessive daytime sleepiness and reports of loud snoring are reliable signs of the diagnosis [59]. Sleep anxietyrelated episodes have characteristic features that

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have been previously described. The differential diagnosis between primary sleep disorders and sleep-related features of anxiety disorders, which characteristically manifest with abrupt awakenings to high levels of arousal, can often be made with reasonable confidence on clinical grounds based on their features and associated clinical findings. It is also the case that anxiety disorders with sleep manifestations not infrequently co-occur with primary sleep disorders. Some co-occurrence is inevitable because anxiety disorders and primary sleep disorders are both common. To the best of this author’s knowledge there is not currently evidence available from large community samples that indicate whether the relationship between sleep apnea and anxiety disorders is greater than expected by random association. An analysis from the large Veteran’s Administration Healthcare database, however, did indicate an increased association of diagnoses of ‘‘anxiety’’ and PTSD (and other psychiatric disorders) with sleep apnea [60]. There is some evidence that detection and treatment of anxiety disorder, sleep breathing disorder comorbidity is relevant to patient outcomes. One study reported very high rates of sleep breathing disorders (apnea and upper airway resistance syndrome) in a group of female research participants seeking treatment for PTSD related to sexual assault [61]. A study that recruited PTSD cases from a community sample, however, did not find elevated rates of sleep apnea or other primary sleep disorders [50]. Krakow and colleagues [62] have described clinically significant improvement of PTSD symptoms with treatment of sleep breathing disorders. Edlund and colleagues [63] have similarly reported frequent associations of sleep panic attacks and sleep apnea and response of nocturnal anxiety symptoms to continuous positive airway pressure treatment. That panic attacks are exacerbated by interruptions of respiration is consistent with observations of increased sensitivity to anxiogenic effects of carbon dioxide in panic disorder [29] and the ‘‘suffocation alarm’’ hypothesis of the etiology of the disorder [29]. Indirect support for the hypothesis that increased carbon dioxide receptor sensitivity underlies forms of pathologic anxiety includes the observation that children with congenital central hypoventilation syndrome (Ondine’s curse) have lower rates of anxiety symptoms than age-matched children [64].

Treatment and prevention Sleep disturbances are commonly associated with anxiety disorders, particularly GAD, panic, and PTSD. In contrast to melancholic subtypes of depression where mood can paradoxically improve,

anxiety disorders do not benefit, and can worsen from sleep deprivation [65–67]. Insomnia has also been found to be a prospective risk factor for psychiatric disorders including anxiety disorders [1,2]. In addition to alleviating distress from insomnia, amelioration of sleep disturbances could possibly have therapeutic impact on other symptoms and serve to prevent relapse and exacerbation. Therapies for anxiety disorders and sleep disturbances overlap. Cognitive behavioral treatments that were developed for insomnia have well-established efficacy [68]. In addition to recommendations for maintaining consistent bedtimes and wake times, avoidance of maladaptive use of substances, and not spending excessive time awake in bed, effective cognitive behavioral interventions for insomnia often include components that are also used in the treatment of anxiety [69]. These include relaxation techniques and identifying and challenging dysfunctional beliefs that perpetuate symptoms. Given the overlapping use of anxiety management, exposure, and cognitive restructuring it seems that behavioral interventions designed for insomnia and anxiety disorders can be synergistically applied. One study documents improvement in insomnia symptoms in association with cognitive behavioral treatment of GAD [70]. In contrast, DeViva and colleagues [71] identified a group of patients with significant residual insomnia who had otherwise benefited from cognitive behavioral treatment for PTSD. They further describe a series of these cases where the residual insomnia was reduced by a subsequently administered cognitive behavioral intervention focused specifically on the insomnia. A technique where recurrent distressing dream content is the target of exposure and cognitive restructuring (nightmare imagery rehearsal) has been found to ameliorate nightmares and sleep disruption with PTSD [72]. These observations notwithstanding, development and evaluation of sequential or integrated treatments for insomnia and anxiety disorders has been limited. Various benzodiazepine receptor agonist medications are approved and marketed for hypnotic indications or treatment of anxiety disorders, particularly for GAD. One study found agents that are marketed and approved as hypnotics had benefits toward daytime anxiety in treating insomnia associated with GAD (zopiclone and triazolam are not approved by the Food and Drug Administration [FDA] for GAD and zopiclone is not marketed in the United States) [73]. There is preliminary evidence that the novel agents pregabalin and tiagebine, which also target benzodiazepine receptors or related GABAergic neurotransmission, benefit insomnia symptoms associated with GAD, although

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neither have FDA approval for GAD or insomnia [74,75]. The newer antidepressant medications, particularly those in the selective serotonin reuptake inhibitor and selective serotonin and norepinephrine inhibitor categories, have become established as effective for a range of anxiety disorders. They also have advantages with respect to tolerance and dependence concerns relative to benzodiazepines and are now considered to be first-line treatments for panic disorder, social phobia, GAD, OCD, and PTSD. The effects on sleep of these agents vary between agents and to a greater degree between individuals and some have been noted to stimulate insomnia [76]. Among the novel antidepressants mirtazipine, which is neither a selective serotonin reuptake inhibitor nor a selective serotonin and norepinephrine inhibitor, tends to have sedating and sleep effects. Mirtazapine was recently reported to have been beneficial to GAD patients in a preliminary open label trial [77], although it is not FDA approved for GAD or insomnia. A study using the selective serotonin reuptake inhibitor citalopram for late-life anxiety disorders indicated improvement in subjective sleep quality with treatment in this subpopulation [78]. Presently, selective serotonin reuptake inhibitors, specifically sertraline and paroxetine, are the only agents approved by the FDA for the treatment of PTSD. Benefits of these treatments tend to be modest and do not typically include reductions in sleep disturbance. Adjunctive interventions are often used, often with the intent of targeting nightmare and insomnia symptoms [79]. Among these, there is support from controlled trials for adjunctive prescription of olanzapine [80] and prazosin [81], which are not FDA approved for PTSD. The emerging use of prazosin for this indication is consistent with the role of noradrenergic stimulation in disrupting REM sleep suggested by previously reviewed research.

Acknowledgments The author acknowledges Denver Brown for her assistance in preparing this article.

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SLEEP MEDICINE CLINICS Sleep Med Clin 3 (2008) 269–279

Behavioral Sleep Disorders in Children and Adolescents Lisa J. Meltzer, -

-

a,

PhD

*, Jodi A. Mindell,

Assessment of sleep disorders Sleep history Further assessment Behavioral sleep disorders Behavioral insomnia of childhood Insufficient sleep and inadequate sleep hygiene Insomnia Circadian rhythm disorder, delayed sleep phase type

Sleep is essential, accounting for approximately 40% of a child’s typical day. When children and adolescents do not get enough sleep, aspects of their physical, emotional, cognitive, and social development are negatively affected. Furthermore, the clinical symptoms of medical and psychiatric disorders are likely to be worsened if a child has a sleep problem. Sleep problems in children and adolescents are quite common (estimated prevalence of 25%– 40% [1]) and can be chronic; however; sleep problems are also highly treatable. This article reviews the assessment, features, prevalence, and treatment of behavioral sleep disorders in children and adolescents. In addition, behavioral sleep issues that are frequently experienced by children and adolescents with common psychiatric disorders are discussed.

-

-

b,c

PhD

Nighttime fears Sleep and psychiatric disorders in children and adolescents Attention-Deficit–Hyperactivity Disorder Autism Depression Anxiety Summary References

Assessment of sleep disorders In children and adolescents, not all sleep problems meet criteria for a disorder based on diagnostic criteria of the International Classification of Sleep Disorders, 2nd Edition (ICSD-2) [2] or the Diagnostic and Statistical Manual, 4th Edition [3]; however, they are of significance and should always be considered as part of any medical or psychiatric evaluation. It is important for all health care specialists who regularly interact with children and adolescents (eg, pediatricians, psychiatrists, psychologists, nurses) to assess for sleep concerns. Most often, information about sleep problems is provided by the parent or caregiver, rather than the child or adolescent; however, older children and adolescents can provide important additional information.

a Division of Pulmonary Medicine, The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, 3535 Market Street, 14th Floor, Philadelphia, PA 19104, USA b Department of Psychology, Saint Joseph’s University, Philadelphia, PA 19131, USA c The Sleep Center at The Children’s Hospital of Philadelphia, 34th & Civic Center Boulevard, Wood Building, 5th Floor, Philadelphia, PA 19104, USA * Corresponding author. E-mail address: [email protected] (L.J. Meltzer).

1556-407X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

sleep.theclinics.com

doi:10.1016/j.jsmc.2008.01.004

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Furthermore, given that a child’s day-to-day experience is dependent on the systems around him or her (parents, teachers, peers), input from all involved is important to provide a complete assessment of the sleep issues. Such an assessment that integrates information from multiple sources also supports treatment success, given the need for open communication with all family members. Thus a comprehensive assessment allows practitioners to understand better the nature of the child’s sleep problems, the impact of the sleep problems on daytime functioning, and to set feasible treatment goals.

Sleep history A thorough sleep history covers all aspects of a child’s sleep patterns and behaviors related to sleep. Questions should focus on (1) the child’s or adolescent’s sleep schedule, including bedtime, sleep-onset latency, wake time, and variations in the sleep schedule on nonschool nights (eg, weekends, summer, holidays); (2) the sleep routine and sleep environment, including the consistency of the bedtime routine, if the bedroom is shared, the presence of cosleeping, and any technology (eg, television, computer) in the bedroom; (3) bedtime behaviors, including bedtime stalling or refusal, inability to fall asleep independently, and anxiety or fears at bedtime; (4) nocturnal behaviors, such as snoring, pauses in breathing, the frequency and duration of night wakings, nightmares, sleep terrors, and enuresis; and (5) daytime behaviors, including daytime functioning, naps, caffeine intake, and medications. For this last factor, it is important to recognize that daytime sleepiness often presents differently across developmental age groups. For example, young children may seem more energetic when sleepy, whereas older children and adolescents may be more likely to be moody, fatigued, and withdrawn. Along with sleep and daytime behaviors, a psychosocial history provides information about potential aspects of the child’s social, academic, and family life that may affect sleep. For example, changes or stressors in a child’s life can have a significant impact on both their sleep quality and quantity. For young children, common disruptive events are the birth of a new sibling or a sudden change to their environment or routine (eg, a parent returning to work). School-age children and adolescents may experience sleep problems related to a death in the family, concerns about being bullied or getting poor grades, or marital discord between the child’s parents. Finally, for children of all ages who ‘‘worry’’ more than their peers, sleep onset and maintenance may be affected by thoughts of peers, school, family relations, or current events (eg, September 11th, Iraq war).

Further assessment Although parents and often children or adolescents provide a significant amount of information about sleep difficulties, further information can be gathered with the use of sleep diaries, actigraphy, or polysomnography (PSG). Sleep diaries track bedtime, wake times, sleep-onset latency, night wakings, and daytime naps over a period of 1 to 2 weeks. One advantage of a sleep diary over the sleep history is that parents or patients complete them daily, allowing for an assessment of night-to-night variability and other inconsistencies in sleep patterns over an extended period of time. This variability can be a significant contributor to some behavioral sleep disorders, such as insufficient sleep, insomnia, and delayed sleep phase syndrome. Actigraphy also provides an objective assessment of sleep patterns over an extended period (typically 1–2 weeks) that can be used to obtain additional information about sleep patterns, especially nighttime awakenings, or it can be used as an alternative for families who are poor historians. This small device is the size of a wristwatch, and is worn on the child’s nondominant wrist (or ankle in very young children). Using an internal motion detector, actigraphy has been shown reliably to distinguish between sleep and wake in children and adolescents [4–6]. The sleep-wake patterns data gathered by actigraphy can assist with differential diagnoses for behavioral sleep disorders, guide treatment decisions, and measure treatment effectiveness. Drawbacks of actigraphy include the cost of the units, and the requirement of a valid daily sleep diary to assist with the interpretation of the results. PSG is considered the gold standard for the assessment of sleep stages and physiologic sleep disorders (eg, obstructive sleep apnea [OSA], periodic limb movement disorder [PLMD]). PSG is less effective, however, in the diagnosis of behavioral sleep disorders. PSG most commonly involves a single night assessment in a sleep laboratory, which may or may not represent the typical patterns or problems for children or adolescents with behavioral sleep concerns. Other limitations of PSG include the cost and limited availability of sleep laboratories, especially those that are pediatricbased. However, since behavioral sleep disorders often have comorbid presentations with other sleep disorders (eg, OSA, PLMD), PSG can be an important adjunct to rule out underlying sleep disruptors that manifest as daytime sleepiness or irritability.

Behavioral sleep disorders In general, behavioral sleep disorders present with at least one of the following complaints: (1) bedtime problems, including bedtime stalling or

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resistance; (2) difficulties falling asleep; (3) frequent or prolonged night wakings; (4) early morning wakings; or (5) excessive daytime sleepiness. Despite these common symptoms, the causes, diagnoses, and treatments for behavioral sleep disorders vary depending on the nature of the disorder and the child’s age. The next section reviews the prevalence, causes, and recommended treatment approaches for behavioral sleep disorders in children and adolescents.

Behavioral insomnia of childhood Behavioral insomnia of childhood (BIC) presents with complaints of bedtime problems or night wakings [2]. Across cultures, the prevalence of these sleep problems is 20% to 30% [7–10]. There are three subtypes of BIC, with the sleep difficulties linked to an identified behavior in the parent or child. Sleep-onset association type A sleep-onset association is an environmental condition required for the child to fall asleep at bedtime and return to sleep following normal nighttime arousals. Without the sleep-onset association, the child may have a prolonged sleep-onset latency and frequent night wakings. There are two types of sleep associations: positive and negative. A positive sleep association is a condition that the child can create independently (eg, thumb sucking, cuddle object). A negative sleep association is a condition that can require another individual (eg, the parent who nurses or rocks an infant to sleep or lays next to a toddler until the child is asleep) or external stimuli (eg, riding in the car, television on). Because all children typically arouse two to six times per night [11], any condition present at bedtime is required again following a naturally occurring arousal. When the association is present, the child returns to sleep quickly during the night. Because negative sleep associations involve parental assistance, these associations result in frequent night wakings and sometimes prolonged periods of wakefulness. Self-soothing without the need for parental assistance to fall asleep is a developmental skill that typically occurs between 3 and 6 months [9]; therefore it is not appropriate to diagnose BIC sleep-onset association type before 6 months of age. BIC sleeponset association type is seen most commonly in infants and toddlers (6 months–3 years). Some negative associations naturally cease with time as conditions that facilitate sleep are faded out (eg, weaning from nursing). If negative associations continue (eg, rocking instead of nursing), however, frequent and persistent night wakings also continue. Behavioral treatments (described in the next

section), including extinction, graduated extinction, and positive routines with faded bedtime, have been found to be highly efficacious in the treatment of BIC sleep-onset association type [12]. Limit-setting type Bedtime refusal or bedtime stalling (at an age-appropriate bedtime) is the defining feature of BIC limit-setting type [2]. Bedtime refusal is when a child refuses to get ready for bed, go to bed, or stay in bed, often involving temper tantrums and resulting in a delayed bedtime. Bedtime stalling is an attempt to delay bedtime, and manifests as repeated requests for additional activities (eg, another television show, one more book or trip to the bathroom) or attention (eg, another hug). Once the child falls asleep, he or she has normal sleep quality, although the delayed sleep onset often results in decreased sleep quantity. Bedtime problems have been reported in 10% to 30% of toddlers, and up to 15% of school-aged children (4–10 years) [1]. Just as sleeping through the night is a developmental skill, the behaviors associated with BIC limit-setting type are also related to normal child development. Toddlers and preschoolers (the most common populations diagnosed with BIC limit-setting type) are learning to navigate the world by testing limits and exerting their newfound independence during the day and at bedtime. As long as parents set no limits (eg, allow child to chose the bedtime or fall asleep in front of the television) or inconsistent limits (eg, some nights the child is allowed to fall asleep in own bed, other nights allowed to fall asleep in parents’ bed), bedtime problems persist. If limits are consistently set, the child usually falls asleep quickly and easily. As children get older, parental involvement with the bedtime routine decreases, limiting the opportunity for problematic behaviors at bedtime. Behavioral interventions have been shown to be highly efficacious for the treatment of bedtime problems in young children, as discussed later [12]. Combined type Some children may experience both BIC sleep-onset association type and BIC limit-setting type, thus a separate diagnosis of BIC-combined type is included in the revised ICSD [2]. A typical example of BIC-combined type is a child who stalls, makes multiple requests, and has tantrums at bedtime resulting in a prolonged sleep-onset latency (limitsetting type), with a parent finally lying with the child in his or her bed at which time the child falls asleep quickly (sleep-onset association type). During the night, the child has frequent night wakings when he or she needs the parent to lay with him or

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her until the child returns to sleep (sleep-onset association type).

Treatment of behavioral insomnia of childhood There are a number of efficacious treatments for BIC [12], yet basic sleep hygiene is required for all children with this sleep disorder. First, children should have an age-appropriate bedtime (typically 7:00–8:30 PM). If the child’s bedtime is too late, they often become overtired, resulting in hyperactivity and emotion disregulation [13]. Naps are also an essential aspect of sleep for young children, with most children napping until age 3, and 26% until age 5 [14]. Skipping or withholding naps in a younger child does not facilitate an easier sleep onset at bedtime, but rather can result in the child becoming overtired and having more difficulty falling asleep. Second, children should have a consistent bedtime routine that is short (20–30 minutes) and involves the same three to four activities every night [15]. Third, parents must be consistent every night in terms of their management of the child’s bedtime behavior. Recently, the American Academy of Sleep Medicine published standards of practice documents on behavioral treatments of bedtime problems and night wakings in young children [16]. The cornerstone of these empirically supported behavioral interventions is having children fall asleep independently [12]. Infants should be placed in the crib drowsy but awake, and children should fall asleep in their own crib or bed at bedtime without a parent present. To achieve this, the most common approach is an intervention based on extinction (a behavioral technique based on operant conditioning). Although standard extinction (or ‘‘cry it out’’) is the fastest treatment approach, it is not tolerated well by most parents [17,18]. Modified versions of this approach (graduated extinction, faded parental presence) have been developed and are found to be effective [19–21]. Graduated extinction is the approach most commonly recommended in popular parenting publications [22,23]. Other treatment approaches for BIC include (1) scheduled awakenings, where the child is woken approximately 15 minutes before a typical nighttime waking for approximately 10 days; (2) parent preventive education, through written materials or classes that can prevent the onset of sleep problems in infants; and (3) positive routines with faded bedtime and response cost, where the child’s bedtime is delayed to coincide with their regular sleep-onset time. Bedtime is preceded by an enjoyable routine that ends immediately if the child begins to tantrum. The bedtime is then advanced gradually in

15-minute increments over a period of several weeks.

Insufficient sleep and inadequate sleep hygiene Insufficient sleep, or getting inadequate sleep relative to the child’s sleep need, is a significant problem for youth of all ages. A national survey of sleep in children ages 0 to 10 years found that 45% to 59% of children are sleeping less than what is typically recommended for their age [14]. Preadolescents and adolescents reported averaging 7.6 hours of sleep on school nights, with less than 20% of respondents obtaining the recommended 9 hours per night in this age group [24]. Over time, insufficient sleep results in chronic partial sleep deprivation, which leads to a number of negative daytime consequences, including excessive daytime sleepiness, mood disturbances, behavior problems, cognitive impairment, and increased risk-taking behaviors [13,25,26]. In adolescents, insufficient sleep can result in drowsy driving, which can be fatal to these new drivers if they fall asleep at the wheel. Over 60% of juniors and seniors have reported driving drowsy at least once in the previous year, with 15% reporting drowsy driving at least once in the prior week. Further, 3% of juniors and 9% of seniors reported nodding off or falling asleep behind the wheel in the past year [24]. Multiple factors contribute to insufficient sleep. For children and adolescents, the most common are academic and extracurricular demands, social activities, part-time employment; electronics (eg, television, computer, video games), and early school start times. For youth of all ages, inadequate sleep hygiene can also contribute to insufficient sleep. There are two types of behaviors that contribute to inadequate sleep hygiene: practices that increase arousal (eg, caffeine, rough play, or watching television at bedtime), and inconsistent sleep organization (eg, naps late in the day, irregular sleep-wake schedule, excessive time in bed relative to actual time asleep). Prolonged inadequate sleep hygiene may result in insomnia (see next section on insomnia). Causes of inadequate sleep hygiene include inadequate parental supervision of bedtime and sleep behaviors, and insufficient education about sleep needs and appropriate sleep behaviors. Interventions for insufficient sleep and inadequate sleep hygiene involve changes to a child’s daily routine and sleep-related behaviors. To increase sleep time, parents may need to weigh the benefits of multiple extracurricular activities with the costs of insufficient sleep. In addition, a number of schools have begun to change school start times,

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resulting in increased sleep time for junior high students [27] and high school students [28]. Children of all ages should have a consistent and age-appropriate sleep-wake schedule. This schedule includes no more than 1- to 2-hour differences between weekday and weekend bedtimes and wake times. Bedrooms should be sleep conducive, including being comfortable, cool, dark, and quiet. In addition, all technology should be removed from the bedroom. Youth of all ages should avoid eating or drinking products with caffeine (eg, soda, iced tea, coffee, energy drinks, chocolate), especially in the late afternoon and evening. Finally, naps should be encouraged as appropriate for age and developmental stage. Regular naps are important for infants and toddlers, whereas children and adolescents who are unable to obtain sufficient sleep at night may benefit from a 30- to 45-minute nap in the early afternoon.

Insomnia The hallmark features of insomnia are difficulties initiating and maintaining sleep [2]. Because of developmental considerations, the ICSD-2 definition of pediatric insomnia is the ‘‘repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite age-appropriate time and opportunity for sleep and results in functional impairment for the child and/or family.’’ This differs from insomnia in adults in that the complaints of insomnia may not come from the child, but can be reported by the parent. Further, the age-appropriate bedtime takes into consideration factors for BIC, and circadian factors seen in adolescents (see next section on delayed-sleep phase). Estimates of insomnia in children and adolescents range from 6% to 39% depending on the definition used [29–32]. Insomnia is more prevalent in girls than boys postpuberty, but few racial differences have been found [30,32]. Insomnia is a symptom of many psychiatric disorders and is associated with a number of medical conditions. A thorough history is needed to determine the cause of the insomnia before deciding on a treatment approach. When insomnia is not related to a psychiatric or medical disorder, the two primary factors that contribute to the insomnia are maladaptive sleep behaviors and negative cognitions (beliefs and attitudes) about sleep. Insomnia typically results from a combination of predisposing factors (eg, genetic vulnerability, underlying medical or psychiatric conditions) and perpetuating factors (poor sleep habits, caffeine use, maladaptive cognitions) [33]. Treatment focuses on changing the maladaptive sleep behaviors and negative sleep cognitions. Cognitive-behavioral

treatment for insomnia typically includes a combination of the following interventions [34]:  Sleep hygiene: Good sleep hygiene includes having a consistent and appropriate bedtime, avoiding caffeine, maintaining an appropriate sleep environment, and having a consistent wake time regardless of the amount of sleep achieved the previous night.  Stimulus control: Individuals are instructed that if they are unable to fall asleep at bedtime or return to sleep following night wakings within 20 to 30 minutes, they should get out of bed and engage in a quiet activity (eg, reading), only returning to bed when they feel sleepy. This may need to be repeated multiple times before sleep occurs.  Sleep restriction: After determining an individual’s current sleep quantity, he or she is instructed to limit the amount of time in bed to the number of hours they are currently sleeping. The goal of both stimulus control and sleep hygiene is to improve sleep efficiency, consolidate sleep, and disrupt the negative association between not sleeping and being in bed.  Cognitive restructuring: Through challenging and reframing negative cognitions that interfere with sleep, this intervention strives to shorten sleep-onset latency and wake after sleep onset. The three steps of cognitive restructuring are (1) identifying inappropriate sleep cognitions (eg, I’ll never fall asleep); (2) challenging the validity of the cognitions (eg, I did fall asleep last night eventually, and there has never been a night where I haven’t fallen asleep at all); and (3) replacing the thoughts with more realistic and productive cognitions (eg, I may not fall asleep right away, but eventually I will).  Relaxation techniques: As with standard behavior therapy, these include progressive muscle relaxation, visual imagery, medication, and diaphragmatic breathing.

Circadian rhythm disorder, delayed sleep phase type Circadian rhythm disorder, delayed sleep phase type (also known as ‘‘delayed sleep phase syndrome’’ [DSPS]) is most commonly seen in adolescents, although occasionally is experienced by children. The defining feature of DSPS is a sleepwake schedule that is significantly and persistently delayed by 2 or more hours beyond the desired bedtime, and conflicts with an individual’s activities of daily living (eg, school, work, scheduled activities). Once asleep, there are no problems with sleep

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quality [2]. The feature that distinguishes DSPS from insomnia is that if sleep is attempted at the time the adolescent typically falls asleep (eg, 3:00 AM), he or she falls asleep quickly. Individuals with insomnia continue to have difficulties initiating sleep regardless of bedtime. It has been estimated that approximately 5% to 10% of adolescents have DSPS [35,36]. DSPS is a multicomponent disorder, caused by genetic, biologic, and psychosocial factors [37–39]. The most common clinical presentation of DSPS is a complaint of the adolescent being awake until the early morning hours (eg, 3:00 or 4:00 AM), and then being extremely difficult to wake in the morning. Treatment for DSPS involves shifting an individual’s sleep timing, and requires strict maintenance of a consistent sleep-wake schedule. Adolescents need to be highly motivated for treatment to be successful. There are two approaches that can be used. In phase advancement, adolescents do not go to bed until their usual sleep-onset time (eg, 3:00 AM), and once they are falling asleep quickly each night, the bedtime is advanced by 15 minutes every few nights. For phase delay (or chronotherapy), both bedtime and wake time are delayed for 2 to 3 hours each day until the desired sleep-wake scheduled is reached (eg, starting with a 3:00 AM bedtime, day 1:3:00 AM–11:00 AM, day 2:6:00 AM–2:00 PM, day 3:9:00 AM–5:00 PM, and so forth) [40]. For both approaches, once the desired sleep-wake schedule is reached, it must be adhered to every night of the week, including weekends. Melatonin has also been recommended for the treatment of DSPS [41–43]. Although dose recommendations have ranged from 0.3 to 5 mg, there are a number of shortcomings with melatonin. First, the studies on the effectiveness and potential side effects for children and adolescents are sparse and inconclusive. Second, melatonin is only sold as an over-the-counter supplement, with no regulation for the actual concentration of melatonin in each dose. Third, there is no clear consensus on the timing and dosing of melatonin, with recommendations ranging from 30 minutes to 4 hours before the desired bedtime.

of a more severe anxiety disorder. In these cases, symptoms are also seen during the day. If nighttime fears persist or cause significant distress for the child or family, a further evaluation of psychiatric issues is recommended. If not addressed, nighttime fears may interfere with a child’s sleep by delaying sleep onset or prolonging nighttime wakings. The presence of a parent may alleviate these fears at bedtime, but may also create a negative sleep association. A recent literature review found that cognitive-behavioral interventions, such as positive self-talk, positive imagery, relaxation, and desensitization, have been successfully used to address nighttime fears [46]. A key component to treatment may be behavioral reinforcement [47], with children being rewarded for making steps toward confronting their fears and sleeping independently.

Sleep and psychiatric disorders in children and adolescents There is a complex and bidirectional relationship between sleep disturbances and psychiatric disorders in children and adolescents. For example, insomnia and hypersomnia can be signs of depression, and sleep disturbances can be a sign of anxiety [3]. Conversely, sleep disturbances can cause or exacerbate negative mood and psychiatric problems. Studies of patients referred to pediatric sleep clinics have found that 31% to 50% of children and adolescents have a diagnosed psychiatric disorder [48,49]. In one of these centers, 40% of children and adolescents without a psychiatric diagnosis had significant psychiatric symptoms based on both a validated questionnaire and clinical interview [48]. Furthermore, children and adolescents seen in a mental health clinic have significantly more sleep complaints (25%–68%) compared with nonpsychiatric controls (1%–24%) [50]. Sleep problems are most common in children and adolescents with ADHD, autism, and mood-anxiety disorders. The following sections review the prevalence of sleep problems in these populations, and identify potential causes and interventions for these sleep disturbances.

Nighttime fears Nighttime fears are a normal feature of development, with 73% of children ages 4 to 12 experiencing fears at some point [44,45]. The development of nighttime fears parallels cognitive development in young children, with imagination, creativity, and an awareness of ‘‘bad things’’ contributing to these fears. Nightmares may also contribute to nighttime fears [45,46]. Along with normal developmental fears, nighttime fears and nightmares may occur following a traumatic event or be a symptom

Attention-Deficit–Hyperactivity Disorder Sleep problems have been reported in 25% to 82% of children and adolescents with ADHD [51,52]. Prevalence estimates have been found to vary, however, based on the type of assessment. For example, significant differences have been found in bedtime resistance, sleep-onset latency, night wakings, and total sleep time when comparing parent reports of children with and without ADHD [51]. Actigraphy data, however, have shown that when averaged,

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sleep continuity variables may not significantly differ between children and adolescents with and without ADHD. Rather, there is significantly more night-to-night variability in children with ADHD [53]. This variability may contribute to the increased parental reports of sleep problems. Similarly, there are discrepancies in findings across studies that have examined sleep in children with ADHD using PSG with some studies noting differences, and other studies not reporting differences in sleep between children with and without ADHD. Overall, the conflicting results of studies that use different assessment methodologies suggest the need for a comprehensive, multimodal approach to the assessment of sleep problems in children and adolescents with ADHD. There are a number of factors that can contribute to sleep problems in children and adolescents with ADHD, including intrinsic sleep disorders, behavior problems at bedtime, medications, and comorbid psychiatric disorders [51]. First, children and adolescents with ADHD have been found to have more intrinsic sleep disorders (ie, OSA, PLMD) than children and adolescents without ADHD [54–57]. Both OSA and PLMD disrupt sleep quality and total sleep time, resulting in exacerbation of the daytime behavior problems seen in children and adolescents with ADHD. When sleep-disordered breathing is treated, studies have found that symptoms of ADHD (eg, hyperactivity, inattention, poor emotion regulation) improve [58,59]. When PLMD is treated by dopamine agonists, one study found both sleep quantity and quality improved [60]. Further, signs of ADHD that had previously been resistant to psychostimulants also improved. In terms of behavioral problems, children and adolescents with ADHD have more bedtime struggles than children without ADHD [50]. It is unclear, however, if sleep-onset latency differs between these groups of children [55,61]. Psychostimulants and other medications that are used to treat ADHD can also contribute to prolonged sleep-onset latency and poor sleep quality. The timing and dosage of these medications need to be considered when determining if a child’s sleep problems are intrinsic, behavioral, a result of medications, or a combination of these factors. Furthermore, some medications for ADHD have been found to have less impact on sleep than others [62]. Children and adolescents with ADHD commonly have comorbid psychiatric diagnoses that need to be evaluated carefully before the diagnosis and treatment of a sleep problem. For example, children with ADHD and comorbid anxiety may benefit from relaxation strategies, whereas a child with ADHD and oppositional defiant disorder may benefit from a specific reinforcement of desired

behaviors (eg, positive reinforcement for desired behaviors, ignoring negative behaviors). Finally, if a behaviorally based sleep problem is diagnosed (eg, BIC, DSPS), behavioral interventions should be tailored to the child’s individual needs. For example, consistent bedtime routines and limit-setting may be required for a child with ADHD and bedtime resistance.

Autism It is clear that children with autism have a significant number of sleep problems. Prevalence estimates range from 44% to 83%, again with differences caused by assessment method. Compared with both typically developing children and children with intellectual disabilities, children with autism have a significant number of sleep problems by parent report (difficulty falling asleep, frequent or prolonged night wakings, or early morning wakings) [63–70]. When sleep patterns in children with autism have been assessed with actigraphy, differences in sleep have not been as pronounced as with parent report [65,71]. Sleep problems in children with autism have been found to be related to more energetic, excited, and problematic daytime behaviors [69], and stereotypic behaviors [72]. The etiology of sleep problems in children with autism remains to be determined. A number of potential causes, however, can help guide treatment decisions for behavioral sleep problems in this population. For example, it has been suggested that the timing of melatonin secretion is altered in children with autism; thus, exogenous melatonin may help facilitate sleep onset [73]. More research is needed, however, to determine the efficacy and safety of melatonin use in children with autism. An alternative to melatonin for treatment of circadian-related sleep problems is light therapy, with bright light therapy in the morning advancing the secretion of melatonin, and light therapy late in the day delaying melatonin onset. Other potential etiologies that may benefit from some type of physiologic or pharmacologic intervention are abnormal electroencephalograms or brain pathology. Children with autism also experience behavioral sleep problems including bedtime struggles and the inability to self-soothe at bedtime, all of which can prolong sleep onset. As with typically developing children, bedtime problems and night wakings that are associated with inconsistent limits or negative sleep-onset association can be treated with behavioral interventions, including a consistent sleep schedule, consistent bedtime routines, and graduated extinction. Behavioral interventions need to be tailored to the specific needs of the child, and take into consideration the age and intellectual functioning of the child [73]. More research is

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needed on the efficacy of behavioral interventions for children with autism and sleep problems, especially in light of findings suggesting that parents find behavioral interventions more helpful than medications, even though medication is a far more common treatment approach [74].

Depression The prevalence of sleep problems in children and adolescents with depression ranges from 66% to 90% [75–77]. Sleep disturbances (ie, insomnia, hypersomnia) can be a symptom of depression for children and adolescents [3]. Furthermore, disrupted or insufficient sleep can contribute to, or exacerbate, signs of depression [76,78]. A study of sleep in depressed youth that used actigraphy found poor sleep quality and abnormal circadian rhythms [79]. There have been mixed results when sleep in depressed youth has been measured by PSG [80,81]. Because sleep problems and depression are so highly related, a multimodal approach to treatment is often necessary [77]. Treatment may need to include pharmacology in combination with behavioral techniques described previously for other sleep disorders, especially insomnia (eg, consistent sleep routine and schedule, relaxation, cognitive restructuring). For pharmacologic treatments, the impact of the medication on sleep should be considered, because some antidepressants can exacerbate sleep problems.

Anxiety As with the other psychiatric disorders previously discussed, there is a strong relationship between sleep and anxiety. In particular, children who are anxious during the day may have difficulties initiating sleep because of worries or fears, resulting in shortened sleep that can heighten signs of anxiety. Other underlying causes of anxiety can also contribute to sleep problems. For example, children who have experienced a traumatic event may experience excessive arousal, hypervigilance, and fears when expected to fall asleep alone in a dark room [82]. The treatment of sleep problems in children and adolescents with anxiety should also be multimodal, not only addressing the underlying cause of the anxiety, but having good sleep hygiene, positive reinforcement for desired behaviors, and graduated extinction to help children learn to fall asleep independently. In addition, at bedtime, children should be made to feel safe and secure.

Summary Behavioral sleep disorders are common, and if left untreated can have a significant impact on the

cognitive, social, and emotional functioning of children and adolescents. A complete assessment of sleep patterns, sleep disruptions, psychosocial factors, and psychiatric disorders is essential to disentangle the complex and often comorbid presentation of behavioral sleep disorders. In addition, age and developmental stage need to be considered when weighing different diagnoses, and when selecting an appropriate intervention. Nonpharmacologic treatments for behavioral sleep disorders have been found to be efficacious and often preferred, especially by parents of children with psychiatric disorders. It is suggested that all pediatric health care practitioners consider sleep issues as part of their comprehensive assessment of all children.

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SLEEP MEDICINE CLINICS Sleep Med Clin 3 (2008) 281–293

Sleep and Its Disorders in Seniors Carl J. Stepnowsky, Jr., -

-

a

PhD

, Sonia Ancoli-Israel,

Sleep and aging Circadian rhythm disturbances Insomnia Depression Sleep and medical illness Sleep and medications Insomnia treatment Primary sleep disorders

-

Over the past decade, knowledge about age-related changes in sleep has significantly increased. It is now known that there are both normal, agerelated changes in sleep architecture and sleep patterns, and a variety of sleep complaints and sleep disorders that increase with age. This article reviews both normal and abnormal sleep in the elderly.

Sleep and aging Survey data show that half of elderly individuals report some form of sleep difficulty, including longer sleep-onset times, lower rates of sleep efficiency, more time in bed, more awakenings during the night, earlier wake-up times, and more daytime naps. Elderly individuals complain primarily about insomnia, which is often comorbid with other disorders. The symptoms in the elderly are more likely to be comorbid with an underlying physiologic problem, rather than with stress as seen in younger adults.

b,

PhD

*

Sleep-related breathing disorder Periodic limb movements in sleep and restless legs syndrome Rapid eye movement sleep behavior disorder Sleep in dementia Sleep in institutionalized elderly Summary References

A number of subjective changes in sleep are experienced in the elderly: Increase in time to fall asleep Spend less time asleep Increase in number of awakenings Spend too much time in bed Less satisfied with nighttime sleep Significant increase in daytime sleepiness Napping more often and longer Objective evidence of these subjective changes in sleep is corroborated by polysomnography. With age, sleep becomes more fragmented and lighter with an increase in the number of arousals and awakenings. There is a reduction in the amount of slow wave sleep (stages 3 and 4), beginning in middle age, with some evidence suggesting that slow wave sleep is completely absent after the age of 90 [1,2]. There is a compensatory increase in stages 1 and 2, and there is a decrease in rapid eye movement (REM) sleep, which is proportional to the

This work was supported by NIA AG08415, NIA AG15301, NCI CA112035, NIH M01 RR00827, VA IIR 02-275, and the Research Service of the Veterans Affairs San Diego Healthcare System, and HS17246-01 (CS). a Department of Medicine, University of California, San Diego, 3350 La Jolla Village Drive, San Diego, CA 92161, USA b Department of Psychiatry (116A), University of California, 9500 Gilman Drive, La Jolla, CA 92093, USA * Corresponding author. E-mail address: [email protected] (S. Ancoli-Israel). 1556-407X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

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decrease in total sleep time. Sleep efficiency and total sleep time are reduced with age and there are an increased number of sleep stage shifts. Van Cauter and colleagues [3] found that total sleep time decreased on average by 27 minutes per decade from mid-life until the eighth decade in a sample of men aged 16 to 83. Older adults spend more time in bed but have deterioration in both the quality and quantity of sleep. All of these sleep changes can lead to excessive daytime sleepiness, which in turn can lead to napping (both intentional and unintentional). Objective tests (eg, the Multiple Sleep Latency Test) of daytime sleepiness in the elderly show that they are sleepier than younger adults [4], suggesting that the elderly may not be able to obtain an adequate amount of nighttime sleep [5]. It is still not clear whether older adults need less sleep; however, it is clear that there is a reduced ability to obtain adequate sleep in this population [1,6]. This reduced ability can be linked to several potential causes: Circadian rhythm changes Primary sleep disturbances (eg, sleep-related breathing disorder, periodic limb movements in sleep, REM sleep-behavior disorder) Medical illness (eg, hyperthyroidism, arthritis) Psychiatric illness (eg, depression, anxiety disorders) Multiple medications Dementia Poor sleep hygiene habits Effective treatments exist for many of these sleep difficulties. Given the high prevalence of sleep complaints and sleep disorders in this population and the link between insufficient sleep and heightened levels of morbidity and mortality, there is a clear need for increased awareness, assessment, and treatment of sleep disturbances in the elderly.

Circadian rhythm disturbances Circadian (24-hour) rhythms are biologic rhythms or changes that control many physiologic functions, including core body temperature, endogenous hormone secretions, and the sleep-wake cycle. These rhythms originate in the suprachiasmatic nucleus in the anterior hypothalamus, which houses the internal circadian pacemaker. The rhythms are also under the control of external cues, such as light, time of day, social activities, and meals. Circadian rhythm sleep disturbances typically develop when there is a dysynchrony between the internal circadian pacemaker and external environment demands.

Several factors likely contribute to circadian rhythm desynchronization in the elderly. First, the suprachiasmatic nucleus deteriorates with age, which may result in weaker or more disrupted rhythms [7]. Second, other circadian rhythm disturbances known to be involved in the entrainment of the circadian rhythm of sleep may develop, such as the gradual reduction of nocturnal secretion of melatonin with age [8]. The decline in melatonin secretion may result in reduced sleep efficiency and an increased incidence of circadian rhythm sleep disturbances. Third, elderly patients may have exogenous cues that are too weak to entrain the circadian rhythm of sleep-wake. For example, light is one of the most powerful zeitgebers (literally ‘‘time-giver’’ or cues), yet studies have shown that elderly patients, especially those who are institutionalized, spend too little time in daylight. Exposure to daily bright light averages about 1 hour for healthy elderly, 30 minutes for Alzheimer’s disease patients living at home, and less than 10 minutes for nursing home patients [9–12]. This reduced level of bright light is associated with nighttime sleep fragmentation and circadian rhythm sleep disorders [12]. Another common circadian rhythm change in older age is a shift in the timing of the sleep-wake cycle. Many older patients experience a phase advance in their sleep-wake cycle, causing them to feel sleepy early in the evening. Individuals with advanced sleep phase syndrome typically fall asleep between 7 PM and 9 PM and wake up between 3 AM and 5 AM. Not uncommonly, many older individuals may stay up late in spite of their sleepiness, yet still awaken early in the morning because of their advanced sleep-wake cycle. This cycle can cause sleep deprivation, excessive daytime sleepiness, and subsequent daytime napping. Finally, the amplitude (ie, the difference in the level between the peak and trough values) of the circadian rhythm may also decrease with age, which can increase the frequency of nighttime awakenings and the severity of excessive daytime sleepiness [13]. Circadian rhythm changes are considered to be common with age, and presenting symptoms may mimic those of primary insomnia (discussed later). Making a distinction between the two disturbances is important, however, because each warrants different treatment approaches. In addition to a careful and detailed sleep history, sleep diaries and activity monitoring with wrist actigraphy can be useful in distinguishing between the two conditions. The most appropriate therapies for shifts in the circadian rhythm are those known to strengthen and entrain the sleep-wake cycle. Because light is the strongest cue for circadian entrainment, one of the most effective and common treatments for

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circadian rhythm shifts is bright light therapy. Evening light exposure has been found to delay circadian rhythms and strengthen the sleep-wake cycle in both healthy community living older subjects and in nursing home patients [14,15]. Patients with advanced rhythms should spend more time outdoors during the late afternoon or early evening and avoid bright light in the morning hours. If patients are unable to spend enough time outdoors, studies have shown that exposure to artificial light by a bright light box in the early evening can improve sleep continuity in both healthy and institutionalized elderly patients [14,16]. In addition, a regular sleep schedule helps to promote a stronger sleep-wake cycle. Endogenous secretion of melatonin is known to promote sleep and is reduced in older adults. Some studies suggest that melatonin-replacement therapy may improve sleep efficiency in this population [17,18]. There is little consensus, however, on the recommended dose or timing of administration. In addition, melatonin is not regulated by the Food and Drug Administration (FDA), and there is no control over the purity and exact drug composition of the various brands currently available. Little is known about the possible drug interactions or side effects related to the longterm administration of melatonin. Clinicians should exercise caution when considering a trial of melatonin-replacement therapy in elderly patients. The National Institutes of Health (NIH) State-of-the-Science Insomnia Conference concluded that although melatonin seems to be effective for the treatment of circadian rhythm disorders, there is little evidence for efficacy in the treatment of insomnia [19]. It was also concluded that there is no definition of an effective dose. Although melatonin is thought to be safe in the short term, there is no information about the safety of long-term use [19]. It should be noted, however, that the FDA recently approved the first melatonin agonist, ramelteon, for the treatment of sleep-onset insomnia [20].

Insomnia Insomnia is defined as the inability to initiate or maintain sleep that results in daytime consequences. Studies have found insomnia to be the most common sleep disturbance in older adults, with up to 40% to 50% of those over the age of 60 reporting difficulty sleeping [21] and an annual incidence rate of 5% in those over the age of 65 [22]. Insomnia complaints include difficulty falling asleep, difficulty staying asleep, and early morning awakenings. Women tend to have higher rates of insomnia than men [23].

There are a variety of factors associated with or comorbid with insomnia in the elderly including depression and other psychiatric conditions, medical conditions, medications, and circadian rhythm disturbances [24]. Foley and colleagues [22] reported that only 7% of the incident cases of insomnia in the elderly occur in the absence of one of these risk factors.

Depression Patients with insomnia often have comorbid psychiatric conditions. In the classic study by Ford and Kamerow [25], 40% of insomnia patients had a psychiatric diagnosis, with anxiety being the most common, followed closely by depression. The same study also showed that persistent insomnia was associated with an increased risk of a future psychiatric disorder. Studies have suggested, however, that insomnia also puts an individual at greater risk for a new, future episode of depression [26–30]. In a study by Weissman and colleagues [31], over 7000 adults with insomnia were followed for 1 year. The results confirmed that the odds ratio of a new-onset psychiatric disorder in the baseline insomnia group was 5.4 for major depression, 20.3 for panic disorder, and 2.3 for alcohol abuse. The Breslau and colleagues [32] and Chang and colleagues [33] studies showed similar results; however, these studies have primarily been conducted in younger adults. The only study to include older adults was a study by Roberts and colleagues [34] of 2370 community residents with a mean age of 64.9 years. Survey data were collected at baseline and again 1 year later. The prevalence of insomnia at baseline was 23%. At follow-up, for those who either had insomnia 1 year previously, or still had insomnia, there was an 8.08 odds ratio for new-onset major depression. More data examining the comorbid relationship between psychiatric disorders and insomnia in the elderly are needed. The overall conclusions from research studies are that about 20% of patients with insomnia have depression, and about 90% of patients with depression report a sleep disturbance. Insomnia can be a symptom of depression, can contribute to the onset of depression or depressive episodes, can predict a prognosis and response to antidepressant therapy, can be linked to recurrence or relapse of depression, and can be linked to anxiety and other psychiatric disorders [35]. Because insomnia and depression are considered comorbid conditions [19], the treatment implications are that the two conditions should be treated concurrently. In a study by Fava and colleagues [36], depressed patients were randomized to either a fluoxetine-placebo arm or a fluoxetine-eszopiclone arm. For those on both an antidepressant

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and a sedative hypnotic, sleep was significantly longer and less disrupted than for those on fluoxetine and placebo. Of even greater interest, however, is that the response to depression was also greater in the group treated concurrently. Although these data were in younger adults, the results suggest that treating the psychiatric condition at the same time as treating the insomnia might result in a better overall response. It is important to remember, however, that hypnotic agents are not FDA indicated for the treatment of depression.

Sleep and medical illness Older individuals often suffer from medical comorbidity. In a National Sleep Foundation survey of adults aged 65 years and over, those with more medical conditions, including cardiac and pulmonary disease and depression, reported significantly more sleep complaints [37]. Osteoarthritic pain, shortness of breath caused by chronic obstructive pulmonary disease or congestive heart failure, nocturia caused by enlarged prostate, and neurologic deficits related to cerebrovascular accidents or Parkinson’s disease all can lead to difficulty with sleep initiation and maintenance. Studies examining the prevalence of sleep disturbances in patients with chronic medical diseases have reported that 31% of arthritis and 66% of chronic pain patients report difficulty falling asleep, whereas 81% of arthritis, 85% of chronic pain, and 33% of diabetes patients report difficulty staying asleep [38,39].

Sleep and medications The issue of polypharmacy is of significant concern in the elderly. The medications used to treat the underlying geriatric medical problems can also cause disruptions in sleep. Bronchodilators, b-blockers, corticosteroids, decongestants, and diuretics are all well-known to cause sleep disturbances, as are other cardiovascular, neurologic, psychiatric, and gastrointestinal medications. Whenever feasible, the offending medications should be stopped, or at minimum the dose and timing adjusted. Sedating medications should be administered before bedtime, whereas stimulating medications and diuretics should be taken during the day.

Insomnia treatment Treatments for insomnia are comprised of behavioral, pharmacologic, and combined treatment approaches. Nonpharmacologic interventions Nonpharmacologic interventions are effective in the treatment of insomnia [19,40]. Good sleep hygiene, or the practice of appropriate sleep behaviors, provides the basis for the behavioral approach

to insomnia. Sleep hygiene rule for older adults include the following: Check effect of medication on sleep and wakefulness Keep a regular bedtime-waketime schedule Avoid naps or limit to one nap a day, no longer than 30 minutes Restrict naps to late morning or early afternoon Avoid caffeine, alcohol, and tobacco after lunch Increase overall daytime light exposure (eg, spend more time outside, especially late in the day) Exercise regularly Eat a light snack (ie, milk, bread) before bed Limit liquids in the evening Do not spend too much time in bed Get out of bed if unable to fall asleep Poor sleep hygiene practices can be associated with behavioral patterns that contribute to sleep disturbances. Patients should be educated on how to identify specific factors that affect their own sleep. The use of alcohol, which is widely used as a sleep aid because of its ability to shorten sleep latency, should be discouraged, because it has been shown to contribute to sleep fragmentation and early morning awakenings [41]. Two commonly prescribed behavioral therapies are stimulus control therapy and sleep-restriction therapy. Stimulus control is based on the belief that insomnia may be the result of maladaptive classical conditioning [42]. Patients are instructed to eliminate all in-bed activities other than sleep, such as reading and television watching. If they are not able to fall asleep within 20 minutes, they are instructed to get out of bed until they feel sufficiently sleepy, when they can return to bed and again attempt to fall asleep. If they are not able to fall asleep within 20 minutes, the pattern of getting out of bed until sleepy repeats itself. This therapy tries to break the association between the bed and wakefulness. Sleep-restriction therapy limits the time spent in bed to about 15 minutes beyond the duration of time spent asleep at night [43]. As sleep efficiency improves (ie, the amount of sleep relative to the amount of time in bed), the time in bed gradually increases. Cognitive behavioral therapy Cognitive behavioral therapy (CBT) for insomnia involves educational, behavioral, and cognitive components. The educational component involves encouraging the patient to determine which factors might be predisposing, precipitating, or perpetuating the insomnia. The therapist explains that CBT is effective by eliminating the perpetuating factors

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with behavioral and cognitive strategies. The behavioral component involves the behavioral techniques (ie, stimulus control, sleep-restriction therapy) described previously. The cognitive component deals with the maladaptive thoughts or dysfunctional beliefs that the patient has about the insomnia. CBT has been shown to be as effective as medications in the short run and to have better long-term outcomes in the treatment of insomnia, in both younger and older adults [44]. In an 8-week double-blind treatment longitudinal outcome study, CBT, an intermediate-acting benzodiazepine (temazepam), a combined CBT-temazepam condition, and a placebo condition were compared in a sample of older adults [45]. Compared with baseline, all three active treatments reduced night wakings at posttreatment; however, only CBT alone and CBT-temazepam were associated with continued improvement at 3-, 12-, and 24-month follow-up interviews. In addition, one study found even two 25-miunte CBT sessions for insomnia are effective in reductive nocturnal awakenings, which may be a more practical approach in the primary care setting. The NIH 2005 State-of-the-Science conference on insomnia concluded that CBT is the most effective treatment for insomnia; that CBT has demonstrated efficacy; that CBT is as effective as prescription medications for brief treatment of chronic insomnia; that the beneficial effects of CBT (in contrast to those produced by medications) may last well beyond the termination of treatment; and that there is no evidence that CBT produces adverse effects [19]. Although pharmacologic treatments may be of more immediate help in the acute treatment phase, nonpharmacologic or combined approaches may be more effective for long-term clinical gains. Pharmacologic interventions Historically, a number of different classes of medications have been used to treat insomnia in the elderly including sedative-hypnotics, antihistamines, antidepressants, antipsychotics, and anticonvulsants. The 2005 NIH State-of-the-Science Conference on Insomnia concluded with several recommendations regarding medications for insomnia [19]. All antidepressants have potentially significant adverse effects, raising concerns about their risk-benefit ratio. Barbiturates and antipsychotic medications have significant risks, and their use in the treatment of chronic insomnia cannot be recommended at this time. There is particular concern with the use of antihistamines for insomnia in the elderly, although these drugs are easy to obtain and are cheap. In a study of 426 older hospitalized medical patients,

all 70 years and older, 27% received 25 to 50 mg diphenhydramine during hospitalization. Compared with patients who were not given diphenhydramine, these patients were shown to be at increased risk for any delirium symptoms, inattention, disorganized speech, altered consciousness, urinary catheter placement, and longer median length of stay. A dose-response relationship was demonstrated for most adverse outcomes [46]. The NIH concluded that there is no systematic evidence for the efficacy of antihistamines, yet there are significant concerns about the widespread use and risks with these agents, particularly in the older patient. Sedative-hypnotic medications are at times appropriate for the management of insomnia, and choosing the sedative-hypnotic that best fits the specific complaint related to insomnia is the key to using this class of medications successfully. Potentially harmful effects must be taken into account when prescribing sedative-hypnotics, particularly benzodiazepines, in the elderly. The administration of long-acting hypnotics can cause adverse daytime effects, such as excessive daytime sleepiness and poor motor coordination, which can lead to injuries [47]. In the elderly, the risk of falls, cognitive impairment, and respiratory depression are of particular concern, although some recent studies have suggested that insomnia is a risk for falls and hypnotic use is not [48]. Chronic use of long-acting benzodiazepines can lead to tolerance and withdrawal symptoms if abruptly discontinued, and the benefits of these agents for long-term use have not been studied with randomized clinical trials. Additionally, the potential for exacerbating coexisting medical conditions, such as hepatic or renal disorders, exists when these medications are used. The newer selective short-acting type-1 g-aminobutyric acid benzodiazepines receptor agonists (ie, zolpidem [49,50], zolpidem [51], zaleplon [52,53], eszopiclone [54,55]) have been shown to be effective in older adults, with a low propensity for causing withdrawal, dependence, tolerance, or clinical residual effects. All were shown either to decrease the time it takes to fall asleep or to increase total sleep time. In younger adults, eszopiclone has been found to be safe and effective in the long-term treatment of chronic insomnia [56]. These long-term studies have not yet been published, however, in older adults. Ramelteon, a melatonin agonist, has also been shown to be safe and effective in the treatment of insomnia in older adults [57]. The NIH concluded that although the older benzodiazepines are safe in the short-term treatment of insomnia, the frequency and severity of adverse effects are much lower in the newer nonbenzodiazepines [19]. The NIH panel also expressed significant concerns, however, about the

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risks associated with the use of these medications in older adults.

Primary sleep disorders Three primary sleep disorders are commonly found in the elderly: (1) sleep-related breathing disorder (SRDB), (2) restless legs syndrome–periodic limb movements in sleep (RLS-PLMS), and (3) REM sleep-behavior disorder (RBD).

Sleep-related breathing disorder SRBD has been shown to be quite common in the elderly. In the largest series of randomly selected community-dwelling elderly (65–95 years of age), Ancoli-Israel and colleagues [58] reported that 81% of the study subjects had an apnea-hypopnea index (AHI) greater than or equal to 5, with prevalence rates of 62% for an AHI greater than or equal to 10, 44% for an AHI greater than or equal to 20, and 24% for an AHI greater than or equal to 40. The Sleep Heart Health Study studied a large cohort of 6400 patients with a mean age of 63.5 (range: 40–98 years) and reported on prevalence rates of SRBD by 10-year age groups: for those aged 60 to 69, 32% had an AHI 5 to 14 and 19% had an AHI greater than or equal to 15; for those aged 70 to 79, 33% had an AHI 5 to 14 and 21% had an AHI greater than or equal to 15; for those aged 80 to 98, 36% had an AHI 5 to 14 and 20% had an AHI greater than or equal to 15 [59]. In contrast, middle-aged adults 30 to 60 years of age have an estimated prevalence of 4% in men and 2% in women (with SRBD defined as AHI R5 and the presence of excessive daytime somnolence [60]). Longitudinal and cross-sectional studies have shown that the prevalence of SRBD increases or stabilizes with increasing age [58,59]. The Sleep Heart Health Study found a small increase in SRBD prevalence with increasing 10-year age groups for those subjects with an AHI greater than or equal to 15 [59]. In a longitudinal study where older adults were followed for 18 years, Ancoli-Israel and colleagues [61] found that AHI remained stable and only changed with associated changes in body mass index. Elderly nursing home patients, in particular those with dementia, have been shown to have higher prevalence rates of SRBD than those who live independently, with prevalence rates ranging from 33% to 70% [62,63]. Several studies have also found that the severity of the dementia was positively correlated with the severity of the SRBD [62,64]. Despite these findings, several other studies have failed to show a significant difference in the amount of SRBD in demented elderly compared with agematched controls [65,66].

SRBD risk factors in the elderly include increasing age, gender, obesity, and symptomatic status [67]. Other factors that increase the risk of developing SRBD include the use of sedating medications, alcohol consumption, family history, race, smoking, and upper airway configuration [67]. Snoring and excessive daytime sleepiness are two principal symptoms of SRBD in the elderly. Other less common presentations in the elderly include insomnia, nocturnal confusion, and daytime cognitive impairment including difficulties with concentration and attention, and short-term memory loss. It is also not uncommon for the symptoms and clinical presentations of SRBD to be similar to that of younger adults. Approximately 50% of patients with habitual snoring have some degree of SRBD, and snoring has been identified as an early predictor of SRBD [68]. In subjects 65 years and older, Enright and colleagues [69] found that loud snoring was independently associated with BMI, diabetes, and arthritis in elderly women and alcohol use in elderly men, but that self-reported snoring decreased with age. It should be noted, however, that not all patients who snore have SRBD and not all patients with SRBD snore. Because many elderly live alone, this symptom may be difficult to identify. Excessive daytime sleepiness results from recurrent nighttime arousals and sleep fragmentation and is a major feature of SRBD in the elderly. The presence of excessive daytime sleepiness may be manifested as unintentional napping because individuals may fall asleep at inappropriate times during the day, such as while watching television or movies, while reading, during conversations, while working, and while driving. Excessive daytime sleepiness can cause reduced vigilance and is associated with cognitive deficits, which may be particularly serious in older adults who may already have some cognitive impairment [70]. There is a rapidly evolving body of literature on cardiovascular consequences related to SRBD, including hypertension, cardiac arrhythmias, congestive heart failure, myocardial infarction, and stroke. Most of the research to date has focused on younger or middle-aged adults, however, and the exact relationship between SRBD and these comorbidities in the elderly remains unknown. Earlier studies have reported a positive association between SRBD and hypertension in the elderly [71]. The Sleep Heart Health Study found no association between SRBD and systolic-diastolic hypertension in those aged greater than or equal to 60 years [72]. The study did find a positive association between the SRBD severity and the risk of developing cardiovascular disease, however, including coronary artery disease and stroke and the

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development of congestive heart failure [73]. Importantly, even mild to moderate SRBD was associated with its development. The negative effect of severe SRBD (AHI R30) on cognitive dysfunction in the healthy elderly is well established, with consistent reports of impairment on attentional tasks, immediate and delayed recall of verbal and visual material, executive tasks, planning and sequential thinking, and manual dexterity [74]. Studies examining the relationship between milder SRBD and cognition are less clear-cut, because some studies have found that milder SRBD (AHI 10–20) does not cause cognitive dysfunction in the absence of sleepiness [75]. In addition to the cognitive deficits that may occur as a result of SRBD, there is evidence that many of the progressive dementias including Alzheimer’s disease and Parkinson’s disease involve degeneration in areas of the brainstem that are responsible for regulating respiration and other autonomic functions relevant to sleep maintenance. This degeneration may place the patient at an increased risk of developing SRBD. For example, Ancoli-Israel and colleagues [62] found that those institutionalized elderly with severe dementia had more severe SRBD compared with those with mild-moderate or no dementia. Furthermore, those with more severe SRBD performed worse on the dementia rating scales, suggesting that more severe SRBD was associated with more severe dementia. Higher rates of mortality are seen with SRBD. In general, rates from all causes increase 30% during the night, and for those aged 65 and over, the excess deaths typically occur between the hours of 2 AM and 8 AM [76]. The presence of unrecognized or untreated SRBD may partially account for these findings because several studies have found an association between SRBD in the elderly and increased mortality rates [77,78], although some studies of community-dwelling, nondemented elderly subjects have not found AHI to be an independent predictor of mortality [79,80]. Rather than directly causing an increased mortality, these studies have found that SRBD may be one of several predisposing factors for cardiopulmonary disease, which in combination leads to increased mortality. This hypothesis is strengthened by a study by Ancoli-Israel and colleagues [81], which reported that elderly men with congestive heart failure had more severe SRBD than those with no heart disease, and men with both conditions (congestive heart failure and SRBD) had shortened life spans compared with those with just congestive heart failure, just SRBD, or neither. More studies need to be undertaken to understand better the exact nature of the relationship of SRBD and mortality in the elderly, including studies specific to older women because most of the

studies completed in this age category have involved predominantly men. To assess accurately the SRBD in the elderly, a multiple step process should be used. A complete sleep history should be obtained, focusing on symptoms of SRBD including excessive daytime sleepiness, unintentional napping, snoring, symptoms of other sleep disorders (ie, RLS), and sleep-related habits and routines, if possible in the presence of a bed partner, roommate, or caregiver. The patient’s medical history, including psychiatric and medical records, should be thoroughly reviewed, paying particular attention to associated medical conditions and medications, the use of alcohol, and evidence of cognitive impairment. Lastly, when there is a suggestion of SRBD, an overnight sleep recording should be obtained. Treatment of SRBD in the elderly should be guided by the significance of the patient’s symptoms and the severity of the SRBD [82]. Patients with more severe SRBD (AHI >20) deserve a trial of treatment. For those with milder SRBD (AHI <20), treatment should be considered if comorbid conditions are present, such as hypertension, cognitive dysfunction, or excessive daytime sleepiness. Age alone should never be a reason to withhold treatment, nor should assumed noncompliance [83]. There are a number of effective treatments for SRBD. Continuous positive airway pressure (CPAP) is the gold standard treatment for SRBD and provides positive pressure by the nasal passages or oral airway, creating a pneumatic splint to keep the airway open during inspiration. When used appropriately, CPAP has been shown safely and effectively to manage SRBD at night with minimal side effects. Three months of compliant CPAP use in older adults has been reported to improve cognition, particularly in the areas of attention, psychomotor speed, executive functioning, and nonverbal delayed recall [74]. CPAP compliance can be an issue for any adult with SRBD, and clinicians should not assume that elderly patients would be noncompliant simply because of age. The authors’ laboratory has determined that patients with mild-moderate Alzheimer’s disease and SRBD can tolerate treatment with CPAP devices [84], and the only factor associated with poor CPAP compliance was the presence of depression; age, severity of dementia, or severity of SRBD were not associated with poor compliance [84]. Alternatives to CPAP include oral appliances and surgery; however, neither has been shown to be as effective as CPAP. All patients should be counseled on weight loss and smoking cessation, if indicated. Longer-acting benzodiazepines should generally be

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avoided in the elderly with SRBD because most of these medications are respiratory depressants and may actually increase the number and duration of apneas. Elderly patients with SRBD should be encouraged to abstain completely from alcohol consumption, because even small amounts can make SRBD worse. Although there is a growing body of literature exploring SRBD in the elderly, there is also an ongoing debate in the field as to what the presence of SRBD in the elderly means. Some propose that a distinction should be made between age-dependent conditions, in which aging causes the pathology, and age-related conditions, in which the disease only occurs during a particular age period [85]. Whether SRBD is an age-dependent or an age-related condition remains unknown. Ancoli-Israel and colleagues [58] and others [86–88] have found that the prevalence of SRBD increases with age, and SRBD may be thought of as an age-dependent condition. If this is the case and SRBD in older adults is the same condition with the same outcomes, then the presence of SRBD in the elderly warrants the same aggressive treatment. Although the prevalence of SRBD in the elderly may be age-dependent, the severity of the SRBD and its clinical significance in the elderly may be age-related. Ancoli-Israel and colleagues [61] showed in an 18-year follow-up study of elderly patients with SRBD that AHI did not continue to increase with age, and that if the patient’s body mass index remained stable, so did the AHI. Bixler and colleagues [88] reported in a sample of older men that the prevalence of SRBD increased but that after controlling for body mass index, the severity based on number of events and oxygen saturation actually decreased with age. Studies aimed at answering these questions and those related to mortality and SRBD in the elderly are ongoing [83]. In terms of treatment, it does not matter if sleep apnea in older adults is the same as sleep apnea in younger adults. The driving force behind the decision whether to treat or not to treat should be the clinical presentation of the patient and consequences of sleep apnea that patient is experiencing. The bottom line is that if the sleep apnea is associated with clinical symptoms, then it should be treated regardless of the age of the patient [83].

Periodic limb movements in sleep and restless legs syndrome Insomnia complaints may be associated with RLS or with PLMS. Although the prevalence of RLS is about 10% in younger adults, several studies have shown that the prevalence almost doubles with age [89,90]. The prevalence of a related disorder, PLMS, also increases with age [91].

Pharmacologic intervention is required to manage RLS-PLMS. Dopamine agonists are effective in both reducing the number of kicks and associated arousals and are the FDA-approved treatments for RLS, specifically ropinirole and pramipexole. Therapeutic studies, however, have only been conducted in younger adults.

Rapid eye movement sleep behavior disorder RBD is characterized by the intermittent absence of normal skeletal muscle atonia during REM sleep, associated with excessive motor activity while dreaming and typically occurring during the second half of the night when REM is more common. Patients may walk, talk, eat, or seem to be acting out their dreams, which can result in violent movements that are potentially harmful to themselves and their bed partner. Vivid dreams, consistent with the patient’s aggressive or violent behavior, may be recalled on waking. The exact prevalence of RBD is unknown but studies have found it to be most common in elderly men [92,93]. Although the etiology of RBD remains unknown, there seems to be a strong association between idiopathic RBD and degenerative neurologic diseases, including Parkinson’s disease, multiple system atrophy, and Lewy body dementia [92,94,95]. In addition, in many cases of neurodegenerative disease, RBD may precede other symptoms of the neurodegenerative disorder by years [92,95,96]. Olson and colleagues [92] reported that 50% of patients diagnosed with idiopathic RBD developed Parkinson’s disease or multiple system atrophy within 3 to 4 years. Schenck and colleagues [96] found that Parkinsonism developed in 38% of men a mean of 3.7 years after an initial diagnosis of idiopathic RBD. Withdrawal of REMsuppressing agents, such as alcohol, tricyclic antidepressants, amphetamines, and cocaine, has been strongly linked to the onset of acute RBD [92,97]. Other medications and conditions reported to induce acute RBD include monoamine oxidase inhibitors, fluoxetine, and stress disorders [92,97]. As with other primary sleep disorders, the diagnosis of RBD requires a thorough sleep history along with bed partner report, if possible. The RBD diagnosis requires a simultaneous overnight polysomnogram and video recording of the nighttime behavior, to confirm a relationship between REM sleep and the complex motor behaviors exhibited by the patient. On reading the polysomnography, clinicians should pay close attention to intermittent elevations in muscle tone or limb movements during REM sleep, which should be relatively rare. The treatment of choice for RBD, although used offlabel, is clonazepam, a long-acting benzodiazepine.

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Although not in randomized clinical trials, clonazepam has been shown to result in partial or complete cessation of abnormal nocturnal motor movements in 90% of patients [98]. Patients may complain of residual sleepiness, however, because of its long half-life, and it is contraindicated in patients with coexisting SRBD. Several alternative medications have shown some positive effects in RBD including carbamazepine [99], melatonin [100], and dopaminergics agents [101], although none has been shown to be as effective as clonazepam. In addition to pharmacologic treatment, sleep hygiene education of the patient and the bed partner are important aspects of RBD treatment, including (1) efforts to make the bedroom safer (eg, removing heavy or breakable or potentially injurious objects from the bed’s vicinity); (2) placing heavy curtains on bedroom windows and locking doors and windows at night; and (3) having patients sleep on a mattress on the floor to avoid falling out of bed.

Sleep in dementia There is considerable evidence that dementia affects sleep differently from the normal aging process [1]. This is not surprising considering that dementing illnesses, such as Alzheimer’s disease, Parkinson’s disease, multi-infarct dementia, or Lewy body dementia, may involve irreversible damage to the brain in areas responsible for regulating sleep. In general, patients with dementia have disturbed sleep at night, and laboratory sleep studies of demented patients have found increased sleep fragmentation and sleep-onset latency, and decreased sleep efficiency, total sleep time, and slow wave sleep [13]. Furthermore, the severity of dementia seems to be associated with the severity of the sleep disruption [102]. Because of these changes in sleep architecture, patients with dementia may have excessive daytime sleepiness; nighttime wandering; confusion; and agitation (sundowning). Such nighttime behavior and disruptions may eventually lead to institutionalization [103]. Addressing the issues related to sleep disturbances in the community-dwelling demented elderly is especially important, because it may potentially enable caregivers to postpone institutionalization. It may be difficult to determine the exact nature of the sleep disturbance in patients with dementia, although caregivers can be a valuable source of information. The same causes of sleep disruption in the nondemented older adult are also found in the patient with dementia. Pain from medical illnesses, medications, circadian rhythm changes, and depression are all potential causes of sleep

disturbances in this population. It is also important to inquire about treatable primary sleep disorders, such as SRBD, RLS, or PLMS. Depending on the severity of the dementia, overnight sleep studies may not be an option and actigraphy may serve as a useful method to assess sleep and circadian rhythms in these patients [104]. Treatment of specific sleep disturbances in the elderly with dementia should be guided by that specific sleep disorder. SRBD should be treated with continuous CPAP, RLS-PLMS should be treated with a dopamine agonist, and circadian rhythm disturbances should be treated with bright light therapy. Maintenance of regular physical activity and social interaction can also promote a more robust sleep-wake cycle. Sedative-hypnotics including benzodiazepines, tricyclic antidepressants, antihistamines, anticonvulsants, and antipsychotics, are frequently prescribed in an off-label fashion for the nighttime restlessness associated with dementia. Attempting to enhance sleep continuity with these medications, however, may paradoxically result in increased sleep disturbance and daytime sleepiness. Because of the many side effects associated with these medications, including drug interactions and residual daytime sleepiness (hangover effect) resulting in impaired motor and cognitive function, nonpharmacologic interventions are preferred. In addition, the FDA recently put a black-box warning on the use of the atypical antipsychotics agents in patients with dementia.

Sleep in institutionalized elderly Institutionalized elderly experience extremely fragmented sleep [105]. Middelkoop and colleagues [106] reported that patients living in nursing homes had poorer sleep quality, more disturbed sleep onset, more phase-advanced sleep periods, and higher use of sedative-hypnotics when compared with those elderly living in the community or in assisted living environments. Studies have found that for older adults living in nursing homes, not a single hour in a 24-hour day was spent fully awake or fully asleep [102,105,107]. There are a variety of environmental factors that contribute to the reduction in sleep quality. Noise and light exposure occur intermittently throughout the 24-hour day. Schnelle and colleagues [108] demonstrated that both ambient light and nighttime noise contributed significantly to sleep disruption in nursing home patients. This study also found that those patients living in nursing homes where nighttime noise and light were kept to a minimum had better sleep. Ancoli-Israel and Kripke [105] reported that the nursing home patients were exposed to less than 10 minutes of bright light

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per day and those with more light exposure had fewer sleep disruptions [12]. Chronic bed rest is known to disrupt circadian rhythms, yet institutionalized patients typically spend large amounts of the 24-hour day in bed [105]. Changes in sleep hygiene and the sleep environment may greatly improve the sleep quality of nursing home inhabitants. Strategies to reduce nighttime disturbances and to promote stronger sleep-wake cycles are consistent with those listed previously.

Summary Significant changes in sleep accompany aging for most adults. There are a variety of potential causes including medical illnesses; medications; circadian rhythm disturbances; depression and other psychiatric disorders; and primary sleep disorders (SRBD, RLS-PLMS, and RBD). The diagnosis requires a good sleep history and, when indicated, a sleep study. Treatment should address the primary problem rather than the complaint itself and can result in significant improvement in quality of life and daytime functioning in the elderly.

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Sleep Disturbances in Women: Psychiatric Considerations Claudio N. Soares, MD, PhD, FRCPCa,b,*, Brian J. Murray, MD, FRCPC, D, ABSMc -

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Insomnia in women: prevalence, risk factors, and clinical characteristics Reproductive-related mood and sleep problems in women Perimenstrual changes, premenstrual syndrome, and premenstrual dysphoric disorder

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Insomnia has been more frequently described in women than in men [1–3]. The risk for developing insomnia among women is 1.3- to 1.8-fold greater than that observed in men [4]. Moreover, insomnia and other sleep disturbances have been reported in association with female reproductive cycle events, such as premenstrual periods [5], pregnancy [6,7], and menopause [8]. The association between changes and fluctuations in female sex hormones and the occurrence of sleep disturbances has become a subject of increasing research and some controversy [4]. Reports suggest, for example, that women are more likely to experience insomnia during perimenopausal and early postmenopausal years [9]. Insomnia is a common complaint during the menopausal transition, affecting up to 60% of women [10–12]. Putative causes of insomnia

Perinatal changes Menopausal transition, mood symptoms, and sleep disorders Diagnosis and management of sleep disturbances in women: clinical considerations Summary References

associated with the menopausal transition and postmenopausal years include the occurrence and severity of nocturnal hot flashes, mood disorders, and sleep-disordered breathing [8,13–15]. This article reviews what is currently known about sleep problems in women, with emphasis on the association between common sleep disturbances and the presence and co-occurrence of psychiatric conditions across the female lifespan. Existing evidence on the clinical characteristics, risk factors, and treatment options for insomnia in women and the potential implications of concomitant psychiatric problems for diagnosis and treatment are reviewed. Lastly, some of the hormonal and nonhormonal strategies for the clinical management of sleep disturbances in women are discussed.

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Department of Psychiatry and Behavioural Neurosciences, McMaster University, Ontario, Canada Women’s Health Concerns Clinic, St. Joseph’s Healthcare Hamilton, 301 James Street South, FB #638, Hamilton, Ontario L8P 3B6, Canada c Sunnybrook Health Sciences Centre, 76 Grenville Street, Burton Hall 418, Toronto, Ontario M5S 1B2, Canada * Corresponding author. Women’s Health Concerns Clinic, McMaster University, St. Joseph’s Healthcare Hamilton, 301 James Street South, FB #638, Hamilton, Ontario L8P 3B6, Canada. E-mail address: [email protected] (C.N. Soares). b

1556-407X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

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Insomnia in women: prevalence, risk factors, and clinical characteristics The National Sleep Foundation’s Women and Sleep Poll, involving 1012 women aged 30 to 60 years, found that 53% of women experienced one or more symptoms of insomnia during the month before the assessment; the most common symptom reported, more associated with sleep quality, was ‘‘feeling tired upon awakening’’ (35% of the women). Other characteristics included difficulty falling asleep; several awakenings during the night followed by difficulties in getting back to sleep; and waking too early in the morning (reported by approximately 20% of the women surveyed) [16]. Female gender has been consistently identified as a risk factor for insomnia, particularly in community-based studies [3,17–20]. When compared with men, women 65 years of age or older have more trouble falling asleep (36% versus 29%); wake up too early (31% versus 21%); or are unable to fall asleep again (25% versus 20%) [18]. Gender differences also exist in younger populations; in a survey of 529 participants aged 20 to 45 years, there were a significantly higher percentage of women reporting difficulties maintaining sleep (20% versus 10%, female versus male) [21]. The gender difference remained significant after adjustments for age, smoking, and psychologic status. These findings are consistent with other reports of difficulty initiating or maintaining sleep in a significant percentage of women, particularly among certain subgroups, such as the elderly [22]; subjects with depression [23]; or those that are medically ill [24,25], with pain or dyspnea [26,27]. Various factors contribute to a heightened risk for insomnia in women compared with men [28]. The presence of a psychiatric disorder is a strong risk factor for insomnia in both men and women [29]; however, women are at higher risk (lifetime) for the development of depression and anxiety disorders [30,31], which may ultimately contribute to their heightened prevalence of insomnia. Lindberg and colleagues [21] examined the presence of psychologic symptoms as a possible explanation for gender differences in sleep disturbances in 529 young adults (aged 20–45 years). There was a higher percentage of women suffering from anxiety symptoms (33% versus 19%, females compared with males, respectively); in addition, women with anxiety showed an increased prevalence of difficulty initiating sleep (9% versus 3%), difficulty maintaining sleep (32% versus 15%), and early morning awakening (10% versus 3%), compared with those without anxiety. In contrast, men with or without anxiety did not show significant differences respect to sleep disturbances.

These findings suggest that women might be more susceptible to develop sleep disturbances concomitant to depression or anxiety. It is important to note, however, that the possible relationships between sleep difficulties and psychiatric disorders are numerous. Insomnia and other sleep disturbances can be precursors to the onset of major depressive disorder, so they may act as risk factors for or predictors of depression [20,32–34]. Conversely, persistent altered sleep is one of the perpetuating factors for difficult-to-treat depressive episodes; recent studies even suggest that treatment of depression with concomitant insomnia could be optimized with the use of sleep-inducing agents in association with antidepressants [35]. Other female-specific risk factors have been identified in studies involving subpopulations of different ethnic or racial backgrounds. In a study of gender differences in insomnia in a Chinese population (N 5 9851, aged 18–65 years), women who were divorced or widowed were more susceptible to insomnia than men; exposure to environmental noise at night and frequent alcohol intake also contributed more significantly to the occurrence of insomnia in women compared with men [1]. In Finland, in a community survey of 1600 individuals, the presence of worries, human relationship problems, and regrets were the top-ranked risk factors affecting sleep, more significantly among women (19%) than men (13%) [36]. The relative contribution of sex steroids and reproductive-related events for the occurrence of gender differences in insomnia is complex and still understudied. Existing data on this topic are examined in more detail in the next few sections.

Reproductive-related mood and sleep problems in women Perimenstrual changes, premenstrual syndrome, and premenstrual dysphoric disorder For some women, sleep problems may emerge secondary to menstrual symptoms (eg, cramping, bloating, headaches, and tender breasts) or dysmenorrhea [37,38]. Polysomnographic (PSG) data indicate that women with dysmenorrhea experience less efficient sleep and more wakefulness than women without painful menstrual cycles [39]. Polycystic ovarian syndrome also increases the occurrence of sleep-disordered breathing, which can contribute to sleep fragmentation and daytime sleepiness [40]. There have been reports of hypersomnia [41] and insomnia [42] temporally linked to the premenstrual phase of the menstrual cycle. Despite frequent subjective reports of sleep being disrupted

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during this period of time, consistent evidences of changes in sleep architecture (eg, PSG measures) associated with symptomatic premenstrual periods are lacking. The inconsistency in the literature is likely related to small sample sizes studied, and significant heterogeneity of underlying sleep or endocrine characteristics assessed [9]. Although clinically intuitive, some [42] but not all [43] studies corroborated the existence of significant sleep disruption associated with premenstrual complaints, premenstrual syndrome, or with the diagnosis of premenstrual dysphoric disorder [44– 46]. Premenstrual dysphoric disorder constitutes a more severe form of premenstrual syndrome and affects 3% to 9% of women during reproductive years; women with premenstrual dysphoric disorder report significant dysphoria (irritability, mood swings, and aggressive behavior) and functional impairment during the late luteal phase of the menstrual cycle (3–10 symptomatic days) with full remission of symptoms on onset of menses [47]. More definitive data on altered sleep in patients with premenstrual dysphoric disorder are lacking; in addition, most studies that explored the efficacy of hormonal and nonhormonal treatments for premenstrual dysphoric disorder have focused primarily on mood and anxiety symptoms rather than insomnia [48,49]. Selective serotonin reuptake inhibitors are the treatment of choice for premenstrual dysphoric disorder and it is reasonable to expect that sleep disturbances secondary to mood swings and increased anxiety would respond to such treatment [48]. The intermittent use of benzodiazepines may also constitute an interesting option for women with perimenstrual, circumscribed symptoms of anxiety and altered sleep and low risk for potential abuse [50].

Perinatal changes Sleep is substantially disrupted during pregnancy and the postpartum period; prevalence rates for altered sleep during pregnancy range from 15% to 80%, depending on the population studied and the time of assessment (eg, higher rates during the third trimester of pregnancy compared with first trimester) [51]. Sleep in the postpartum period is markedly disrupted by care of the infant [52]. Nonetheless, even in the absence of infant care, the sleep that follows pregnancy is disrupted and quite often does not return to the prepregnancy state [53]. This may reflect the outcome of some of the physiologic changes that had occurred over the course of pregnancy or even the emergence of anxiety and hypervigilance behaviors that some mothers develop toward the newborn. Survey studies indicate that women attribute many different reasons to justify their altered sleep

during pregnancy; during the first trimester, nausea and vomiting are frequently associated with sleep problems [54]; psychosocial stressors are also reported particularly in cases involving first-time pregnancies, unplanned pregnancies, or in the absence of a solid psychosocial support or network [55]. As pregnancy progresses into the second and third trimesters, there are more reports of increased number of awakenings, fatigue, leg cramps, and shortness of breath. Overall, women are more likely to go to bed earlier and frequently nap during the day as they try to compensate for the disruption of the nighttime sleep pattern [56]. Objective assessments of sleep during pregnancy have produced inconsistent results, again likely because of limited sample sizes and differing research methodology. One study revealed changes in sleep during the first trimester, with a significant increase in total sleep time and decrease in slow wave sleep (restorative sleep) compared with prepregnancy assessments [7]. In this study, total sleep time tended to return to normal levels at the end of the third trimester, as women reported more frequent awakenings and a decline in sleep efficiency. Pregnant women who report sleep disturbances during pregnancy should also be screened for depressive symptoms. Pregnancy does not confer any protective effect against depression and the presence of disrupted sleep in this population may be indicative of mood changes. In a recent prospective study of 201 nondepressed pregnant women (all taking antidepressants because of prior history of depression but asymptomatic for at least 3 months before the conception) the decision of discontinuing treatment early in pregnancy resulted in a fivefold greater risk for relapse over time compared with treatment maintenance. These results reinforce the importance of carefully assessing mood symptoms in women at risk during pregnancy [57]. Hormonal changes in pregnant women may contribute to the occurrence of sleep-disordered breathing and altered sleep. Snoring, for example, tends to increase during pregnancy, possibly caused by changes in upper airway resistance, which is sensitive to hormonal factors, particularly progesterone levels [58]. In addition, pregnant women, particularly during the final trimester, seem to have a heightened risk for developing sleep apnea and restless legs syndrome [59]. Studies suggest that a restless legs syndrome might be more associated with lower ferritin and folate levels. Nutritional supplements should be considered for symptomatic individuals or subpopulations at risk [60]. Depletion of iron can be noted in basal ganglia structures in the brain of patients with restless legs syndrome [61], which is even more interesting, given the roles of these structures for mood

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regulation [62]. Furthermore, iron is the rate-limiting step in the synthesis of dopamine in the brain. The relationship between iron loss, restless legs syndrome, and peripartum mood disorders warrants further investigation, because iron deficiency remains common in women of childbearing age [63]. Other factors contribute to sleep-disordered breathing over the course of pregnancy including weight gain, mucosal edema, and changes in respiratory mechanics [64]. More commonly, upper airway resistance increases throughout pregnancy [65], and may contribute to frequent arousals and sleep maintenance insomnia with subsequent daytime sleepiness. Interestingly, disrupted sleep during pregnancy has been associated with poor obstetric outcomes, particularly length of labor and type of delivery. In a prospective, longitudinal follow-up of 131 pregnant women, Lee and Gay [66] demonstrated that women who slept less than 6 hours at night had longer labors and were 4.5 times more likely to have cesarean deliveries. The researchers highlighted the importance of monitoring sleep quantity and quality during prenatal assessments as potential predictors of labor duration and delivery type. The assessment of changes in sleep architecture and sleep efficiency during the postpartum period constitutes a challenging task given the hormonal changes inherent to the postpartum period, sleep deprivation caused by frequent awakenings associated with breastfeeding, and the presence and severity of postnatal mood and behavior changes. Objective assessments (PSG) of women immediately following delivery indicate an increase in wake time after sleep onset, and awakenings even in the absence of nocturnal activities involving the infant’s care and nursing [53]. Women in the postpartum period develop lower sleep efficiency, with shorter latency to rapid eye movement sleep (characteristic of depression) and reduction in total sleep time. Although most studies suggest that most awakenings and changes in sleep/wake ratios are directly related to the newborn’s direct nursing care, it has been hypothesized that other factors could contribute to disrupted sleep patterns; these include an abrupt decline in progesterone immediately after delivery, a hormone with known sedative properties, and changes in melatonin levels, the latter possibly affecting the normal circadian rhythm [9]. Moreover, the occurrence of increased irritability and mood swings postpartum (postnatal blues) could lead to a disruption of new mothers’ sleep efficiency and increase the risk for subsequent development of postpartum depression [67]. Another possibility is that the sleep disruption itself directly contributes to many of these mood changes.

Preliminary, but intriguing, evidence suggests that some strategies to promote protected sleep time immediately following delivery (eg, prolonged hospital stay, ‘‘rooming out’’ infants under the partner or nurse’s care, and use of sedatives as needed) may reduce the risk of clinically significant depression or anxiety in the first few months of the postpartum period (Steiner, personal communication, 2006).

Menopausal transition, mood symptoms, and sleep disorders For some women, the menopausal transition is characterized by the occurrence of vasomotor symptoms (eg, hot flashes, night sweats), sleep disturbances, and changes in sexual function that can adversely affect quality of life [68]. More recently, several studies revealed that women entering perimenopause are at higher risk for developing depression, even in the absence of prior episodes of depression [69–71]. About 45% to 75% of women in the menopausal transition experience hot flashes [72]. Hot flashes are transient sensations of heat dissipation, and may be accompanied by palpitations, nausea, dizziness, headache, and ultimately insomnia [73]. The presence of nocturnal hot flashes is commonly associated with sleep disturbances [9]. The pathophysiology of hot flashes is not fully understood, but it is thought to be mediated through the anterior hypothalamus, an area that regulates temperature and sleep [13,74]. The existence of a more direct association between hot flashes and insomnia has been considered controversial, because most studies using objective sleep measures (ie, PSG) or subjective measures (ie, sleep questionnaires) have shown inconsistent findings. Early PSG studies in menopausal women suggested a significant correlation between hot flashes and sleep disturbances [75], with estrogen therapy resulting in a significant reduction of sleep latency, frequency of awakenings, and improvement of rapid eye movement sleep [76]. More recent studies, however, failed to show positive effects of hormone therapy on sleep architecture in menopausal women [77]. Many women who develop depressive symptoms during the menopausal years also experience hot flashes and insomnia [71], suggesting a potential association between sleep disruption and the occurrence or severity of vasomotor symptoms, leading to an adverse impact on mood and well-being [78]. Depression has been found in some menopausal women, however, even in the absence of clinically significant hot flashes [79]. It is possible that fluctuating estrogen (E2) levels during the perimenopause exacerbate the hypothalamic-pituitary-adrenal axis activity in response

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to stressful events, resulting in mood and sleep disorders [80]. Estrogen modulates the synthesis, release, and metabolism of monoamines that affect mood, behavior, and sleep [81]. More specifically, estrogen exerts an agonist effect on serotonergic activity by increasing the number of serotonin receptors, increasing transport and uptake of the neurotransmitter, increasing synthesis of serotonin, up-regulating 5-HT1 receptors, down-regulating 5-HT2 receptors, and decreasing monoamine oxidase activity [82]. It is intuitive that intense estrogen fluctuations and depletion could affect different monoaminergic systems leading to disrupted sleep, mood changes, and the emergence of vasomotor symptoms [83]. Fluctuations in estrogen and progesterone may also alter g-aminobutyric acid (GABA) function and play a role in menopause-related insomnia [84]. GABA acid plays a central role in sleep initiation and maintenance. Preclinical studies have shown that gonadal hormones have a barbituratelike action on the GABA receptor complex. Estrogen reduces the number of GABA-A receptors, but progesterone has been shown to counter that effect [85]. Several factors may contribute to the occurrence of obstructive sleep apnea syndrome in menopausal women; diminishing progesterone levels may be a factor, because progesterone is a known respiratory stimulant and upper airway dilator [86]. Increased body weight associated with menopause may also be an important factor, although an increased risk of obstructive sleep apnea syndrome has been observed independently of body weight [87].

Diagnosis and management of sleep disturbances in women: clinical considerations The first step in management is to establish a clear diagnosis. A careful interview of the patient (and more importantly the bed partner, who is an objective observer for behaviors of which the patient may be unaware) is essential. To address women’s sleep problems fully, a routine history and physical examination is required. When necessary, hormonal status (ie, serum follicle-stimulating hormone, E2, progesterone concentrations) to confirm menopausal staging should be obtained. A typical day’s sleep behavior can be obtained chronologically and should include details of sleep onset, sleep maintenance, and daytime alertness. Often, a sleep problem has both medical and behavioral components. Both factors need to be addressed to ensure clinical improvement. To that end, it is important to ensure that medical causes

of insomnia (restless legs syndrome in particular for sleep initiation difficulties, and sleep-disordered breathing for sleep maintenance problems) have been adequately treated before embarking on behavioral management. Some intrinsic sleep disorders, such as poor sleep hygiene or restless legs syndrome, can be established purely based on history, whereas others, such as obstructive sleep apnea, require formal PSG assessment. Studies on nonpharmacologic and pharmacologic therapies for female-specific sleep disorders are scarce. In pregnancy and breast-feeding scenarios, special attention must be made to the safety of medications that may be considered for treatment. Unfortunately, many medications are not formally tested in these populations, leaving significant knowledge gaps. Nonpharmacologic therapies become critically important for these patients. In addition, some patients are reluctant to use medications for insomnia, particularly because of the possibility of habituation, withdrawal, and rebound insomnia with the use of pharmacologic therapies [88]. A greater acceptability of the use of nonpharmacologic interventions, however, has other obstacles including limited number of controlled studies for specific interventions (particularly for herbal preparations); cost and lack of insurance reimbursement; and slower speed of onset [89,90]. Behavioral approaches provide similar shortterm clinical benefits for the management of insomnia compared with pharmacologic therapies, but have better long-term benefits, especially in older adults [90]. Overall, stimulus control and sleep-restriction therapies are the most effective behavioral approaches [91]. Other behavioral techniques include meditation, biofeedback, and hypnotherapy. Hypnotherapy has shown some efficacy in small trials [92]. In one of these studies, hypnotherapy was used in women treated for breast cancer, and had a positive impact on hot flashes and improved quality of sleep [93]. Data on the efficacy of behavioral therapies for the treatment of insomnia in menopausal women are limited. Given many unique factors contributing to insomnia in this population (ie, the higher incidence of hot flashes and sleep-disordered breathing) it is difficult to predict the extent to which these treatments would be efficacious when used alone. For symptomatic menopausal women, hormone therapy has been the treatment of choice for most menopausal complaints, including hot flashes and insomnia [77,94]. There is also evidence for its efficacy for the treatment of depression during the menopausal transition and, to a lesser extent, for obstructive sleep apnea syndrome [95–98]. The long-term safety of hormone therapy has been

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Table 1: Clinical scenarios and treatment strategies for the management of sleep and mood disorders in women across the reproductive life cycle Clinical scenario

Treatment strategies and points to consider

1. A young woman (mid-20s) reports disrupted sleep associated with premenstrual discomfort (back pain, menstrual migraines, bloating, increased irritability) and menstrual irregularity. Symptoms seem to remit with the onset of menses. No significant history of sleep disorders or mood symptoms are experienced except for the ones noted during the premenstrual periods.

1. Rule out an underlying mood or sleep disorder and confirm possible diagnosis of severe PMS or PMDD through careful history and prospective tracking of symptoms. 2. Oral contraceptives may help to regulate cycles and promote alleviation of PMS symptoms; additional benefits for sleep symptoms are unknown. 3. Antidepressant use, particularly SSRIs, is the treatment of choice for the management of both depressive and somatic symptoms. Its use may have a positive impact on disrupted sleep. 4. Sleep hygiene measures and CBT for depression and for sleep symptoms may be helpful; efficacy data focused on these specific subpopulations are scarce. 1. Possible recurrence of major depressive disorder, with concomitant symptoms of anxiety and disrupted sleep. Careful psychiatric assessment (including the evaluation of potential risk for suicidal thoughts and behaviors) is recommended. 2. Risks/benefits of reintroducing treatment with SSRIs should be reviewed with the patient and her partner or family members. 3. Benzodiazepines could be a viable treatment strategy for the alleviation of these symptoms with careful monitoring of use throughout the remaining time of pregnancy. 4. Sleep-breathing disorder should be ruled out by history and partner’s information. 5. Sleep hygiene measures and CBT for depression and for sleep symptoms may be helpful; efficacy data focused on these specific subpopulations are scarce.

2. A woman in her mid-30s is pregnant (second trimester) and reports increasing sleep difficulties (sleep onset and sleep maintenance) associated with low motivation, increasing marital conflicts caused by her irritability, and ruminative thoughts about her baby’s health and her financial conditions. Prior history of depression (several depressive episodes), but stable for many years while using antidepressants (SSRIs); recent treatment discontinuation (at 6 weeks of gestation) because of pregnancy.

3. A patient (early-50s) reports amenorrhea for 2 years, accompanied by the occurrence of moderate vasomotor symptoms (4–6 hot flashes per day, night sweats). Significant sexual dysfunction, mainly low libido and dryness. Decreased energy, cognitive decline (difficulty concentrating), and lack of motivation have become more evident over the past year along with sleep problems (constant awakenings, poor sleep efficiency).

1. Possible occurrence of menopause-related symptoms (vasomotor symptoms, sexual dysfunction). 2. Further assessment is needed to characterize the severity of mood and sleep problems and whether these symptoms constitute a new complaint (in the context of the menopause) or a re-emergence of prior mood and sleep disorders. 3. If there are no contraindications to hormone therapies, consider a trial with estrogens, preferably transdermal E2 (50–100 mg/day). If efficacious, response (mood, sleep, sexual function, and vasomotor symptoms) should be observed with 4–8 weeks of treatment. 4. The use of progestins is fundamental in patients with intact uterus; patient might benefit from using micronized progesterone (100–200 mg/day, either continuously or cyclically) because of sedating effects. 5. Patients with partial response may benefit from the use of antidepressants in combination with hormone therapy. Consider the use of antidepressants with a more favorable profile with respect to sexual adverse events. 6. Consider sleep hygiene measures and behavioral techniques to address sleep problems. 7. Consider the use of nonbenzodiazepines (eg, zolpidem, eszopiclone) to improve sleep problems. 8. CBT for depression may be helpful, despite scarce efficacy data available for these specific subpopulations.

Abbreviations: CBT, cognitive-behavioral therapy; PMDD, premenstrual dysphoric disorder; PMS, premenstrual syndrome; SSRIs, selective serotonin reuptake inhibitors.

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questioned, however, particularly in light of the results from the Women’s Health Initiative study [99]. Consequently, many physicians and patients are seeking nonhormonal therapies for the relief of menopausal symptoms; as a result, herbal preparations have gained considerable attention. Most herbal preparations have showed inconsistent results in well-controlled trials. Valerian (Valerian officinalis) has sedative and muscle-relaxant effects and its use has become increasingly popular among women [100]. The evidence for its efficacy as a treatment for insomnia is inconclusive, based on a systematic review of nine clinical trials [101]. In addition, sleep benefit may be delayed for 2 weeks and some patients experience residual daytime effects [102]. Cimicifuga racemosa (black cohosh) has shown some positive results for the treatment of menopause-related physical and psychologic complaints in some [103–105] but not all [106] studies. No specific studies with black cohosh for the treatment of menopause-related insomnia have been published to date. The use of antidepressants in perimenopausal and postmenopausal women (eg, paroxetine, citalopram, mirtazapine) may have an indirect effect on sleep and quality of life by improving other menopause-related symptoms (eg, vasomotor symptoms, pain, and mood swings); these agents might constitute a treatment option for symptomatic women who are unable or unwilling to receive hormone therapies [107–109]. Other potential pharmacologic therapies include the use of benzodiazepines and non–benzodiazepine receptor agonists. Benzodiazepines primarily modulate GABA-A receptors and exert their effect on the benzodiazepine site of the receptors, thereby potentiating the inhibitory effect of GABA on neurotransmission [110]. Non–benzodiazepine receptor agonists, also known as ‘‘Z-compounds’’ (eg, zolpidem, zaleplon, and eszopiclone), are recommended for short-term treatment of insomnia; some have demonstrated sustained efficacy and safety without the development of tolerance or rebound insomnia over 6 months to 1 year [111,112]. A 4-week, placebo-controlled trial (N 5 141) with zolpidem showed statistically significant improvement in some parameters of insomnia (increased total sleep time, decreased wake time after sleep onset, and number of awakenings) in perimenopausal and postmenopausal women; however, the study did not assess whether zolpidem affected positively or negatively other menopauserelated complaints [113]. In a larger study (N 5 410), eszopiclone showed superior efficacy compared with placebo for the treatment of insomnia in perimenopause and early menopause subjects who had developed insomnia

in the context of transitioning to menopause, and reported other menopause-related symptoms (eg, hot flashes, night sweats) without comorbid depression or anxiety [114]. Subjects receiving eszopiclone reported significantly greater improvement in sleep induction; sleep maintenance (total awakenings, awakenings caused by hot flashes, and time awake after sleep onset); sleep duration; sleep quality; and next-day functioning. The use of eszopiclone resulted in improvement of quality of life and other menopause-specific symptoms, assessed by the Greene Climacteric Scale, the Menopause-Specific Quality of Life questionnaire, and by changes in the family life and home disability domains of the Sheehan Disability Scale.

Summary Women commonly report sleep disorders that may predispose or contribute to the occurrence of other psychiatric problems, particularly mood and anxiety disorders. In addition, many reproductive life events in women are associated with unique features of sleep disruption that are at least partially modulated by hormonal factors. Pregnancy, peripartum, and perimenopausal states are particularly associated with sleep disruption, and have the clearest published evidence base. Many factors contribute to a heightened incidence of insomnia in women, including the occurrence and severity of somatic symptoms (eg, hot flashes, dysmenorrhea); psychiatric symptoms, such as depression or anxiety; and intrinsic sleep disorders. The presence of insomnia has been associated with poorer quality of life and impaired daytime functioning; its management is imperative. Table 1 explores some of the common clinical scenarios in which sleep disorders may occur in women associated with reproductive life events. Given the strong possibility that sleep disorders are contributing to mood changes during pregnancy and postpartum, careful attention must be taken for the development of treatment strategies that address both medical and psychologic factors to assist fully this vulnerable population. Hormone therapy is still the treatment of choice for shortterm management of menopause-related symptoms, particularly hot flashes; however, its safety as a long-term treatment option has been questioned and many physicians and their patients are seeking nonhormonal alternatives. An accurate diagnosis must be made in this population, and treatment of underlying mood disorders is crucial. Most nonpharmacologic symptomatic treatments for insomnia (eg, stimulus control, sleep restriction) have not been systematically studied in menopausal patients, despite their proved efficacy for

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insomnia in general. The use of antidepressants seems to be more helpful when sleep complaints result from the emergence of menopause-related depression or anxiety. Women who suffer insomnia during the menopausal transition or postmenopause may benefit from the therapeutic effects of newer agents, such as the non–benzodiazepine receptor agonists (zolpidem, eszopiclone), and melatonin receptor antagonists; more studies are needed to determine the extent to which these agents can offer a safe and efficacious long-term management of insomnia, with a positive impact on quality of life and overall functioning.

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Seasonal Affective Disorder and Light Therapy Brenda Byrne, -

PhD*,

George C. Brainard,

Definition SAD symptoms Epidemiology of SAD Pathogenesis of SAD Physiologic aspects of SAD Light therapy

The syndrome of fall and winter depression known as Seasonal Affective Disorder (SAD) has had a relatively short history—less than 30 years— in psychiatric research and practice. Observations of the effects of environment on human health were made over 2000 years ago by Hippocrates [1], and reports of seasonal depression and of the benefits of sunlight are found through accounts of Greek and Roman medicine and in occasional case studies during the past two centuries [2]. In 1980, Lewy and colleagues [3] reported that bright artificial light, but not ordinary room light, suppressed melatonin secretion in humans. This finding established that the response of humans to light is comparable to that of other mammals and was followed by a case report of the effective light treatment of seasonal manic-depressive disorder [4]. Light also was found to phase shift circadian rhythms [5,6], and SAD was early suspected of being a circadian rhythm disorder. In 1984, Rosenthal and colleagues [7] offered both diagnostic criteria for SAD and the first clinical trial of the effectiveness of bright light therapy for major depression marked

-

PhD

Risks and side effects Assessment of SAD Other strategies of SAD treatment Summary Acknowledgments References

by fall/winter onset and spring/summer remission. In the intervening years, numerous controlled studies, case reports, review papers, and meta-analyses have contributed to a widening base of science and medical practice regarding the phenomenon of SAD.

Definition SAD is a blend of physiologic and mood disturbances with a clear seasonal pattern. Diagnostic criteria in DSM-IV-TR [8] permit a Seasonal Pattern Specifier to be applied to a pattern of major depressive episodes in bipolar disorders (Bipolar I or Bipolar II) or in recurrent major depressions. In the case of winter depressions, a seasonal pattern of onset in the fall and winter and full remissions (or a switch to mania or hypomania) in the spring must be established for the 2 years preceding clinical assessment. Over a patient’s lifetime, seasonal depressions must outnumber nonseasonal episodes, and there must be no obvious seasonally recurring stressors (eg, unemployment or

Both authors are supported by the National Space Biomedical Research Institute under NASA Cooperative Agreement NCC 9-58. Department of Neurology, Thomas Jefferson University, 1025 Walnut Street, Suite 507, Philadelphia, PA 19107, USA * Corresponding author. Margolis Berman Byrne Health Psychology, 1015 Chestnut Street, Suite 901, Philadelphia, PA 19107. E-mail address: [email protected] (B. Byrne). 1556-407X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.

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anniversaries of a loved one’s death) that might account for recurrent depression. SAD criteria from Rosenthal and colleagues [7] are similar, adding the requirement than no other major psychiatric disorder is present. Seasonality refers to changes in mood and behavior that alter with changes of season. Some forms of seasonality are mild and common; some, as in SAD, are more severe.

SAD symptoms SAD sufferers typically describe a cluster of complaints and symptoms including decreased activity, sadness, anxiety, social withdrawal, increased appetite (especially for carbohydrates), weight gain, decreased libido, and hypersomnia. Depressed SAD sufferers sometimes report instead the more typical vegetative symptoms of decreased appetite, weight loss, and insomnia. SAD sufferers seem to frequently report cold intolerance and to complain of never feeling warm enough in winter. Women with SAD often report intensified premenstrual mood difficulties in the fall and winter. The most common spontaneous complaints of SAD sufferers are an overwhelming lack of motivation or energy and a disinclination to ‘‘be bothered’’ by anyone. SAD sufferers generally have to push themselves through the fall and winter after the onset of symptoms, and—despite presumably suffering from light deprivation—prefer being indoors, eating and sleeping. Cold intolerance, when present, naturally increases the tendency to stay indoors; notions of ‘‘hibernating’’ through the winter may have strong appeal. Sleep may be longer and daytime sleepiness greater, but sleep itself is likely to be of poorer quality [7]. Persons predisposed to SAD commonly become symptomatic in response to prolonged dark or cloudy weather in any season. They may report increased symptoms when exposed for prolonged periods to dark indoor settings. Relief frequently comes from periods spent in warm bright environments, with mood and energy lifting within a few days. In cases of classic SAD, complete remission of symptoms occurs in the longer daylight and warmer weather of the springtime. Seasonal depressive symptoms may be combined with mood disorders other than major depression, for instance in a milder subsyndromal form (termed by researchers ‘‘S-SAD’’). Compared with symptoms of the full SAD syndrome, symptoms of S-SAD affect more people but are less disruptive of mood, activity, or productivity. Light therapy, which is effective in reversing SAD symptoms, has been reported to be beneficial as well in treating S-SAD [2].

In early reports, SAD was presented as a form of manic-depressive, or bipolar, disorder. Of the first group of 29 SAD patients treated with bright light [7], 22 (76%) had been diagnosed with bipolar II affective disorder; that is, a history of recurrent major depressive episodes and of recurrent hypomanic episodes (elevated mood not meeting criteria for mania). As evidence from multiple studies has accumulated, however, the reported proportion of SAD sufferers with diagnosed bipolar disorders is between 11% and 50% [9]. Most SAD sufferers alternate between a winter symptom cluster and normal good mood and energy.

Epidemiology of SAD Most studies of the prevalence of seasonal symptoms have been completed in North America and have varied widely in method. The Seasonal Pattern Assessment Questionnaire (SPAQ) [10], the mostused assessment instrument in such studies, obtains self-report of how a variety of experiences and behaviors change with seasons and with environmental conditions. A total score, the Global Seasonality Score (GSS), is derived from indications of seasonal changes. Specifically, item 12 of the SPAQ asks to what degree seasonal changes are experienced in sleep length, social activity, mood (overall feeling of well-being), weight, appetite, and energy level. Each is rated on a 5-point scale from ‘‘no change’’ to ‘‘extremely marked change’’ and the item responses yield a GSS score from 0 to 24. Designed as a screening tool for use with clinical samples, the SPAQ does not reliably detect major depression and so does not differentiate SAD from subsyndromal SAD conditions or clarify how completely winter seasonal symptoms remit in the spring/summer. Community-based surveys using the SPAQ have produced estimates of prevalence in North America as high as 9.7% in northern latitudes. Studies using more stringent DSM diagnostic criteria have reported lower estimates of prevalence, between 0.8% and 2.2% in North America and between 1.7% and 2.2% in Canada. Prevalence in Europe has been reported at between 1% and 3% and in Asia as less than 1% [2]. A positive correlation between SAD/S-SAD prevalence and latitude has been reported more for North America than for Europe. Overall, latitude may be less important than are other factors such as genetic vulnerability, climate, and cultural factors [11]. Although a summer version of seasonal depression has been reported [12], winter SAD appears much more common and has been almost exclusively the focus of seasonal mood studies [13]. SAD symptoms are reported in children but are more common following puberty. Women are

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more affected than men of the same age group, especially during childbearing years, with typical age of onset in the early to mid-twenties. Rates of SAD decline among elderly populations, and men and women are more equally affected. Overall, community studies have reported the female-to-male ratio to be about 1.6 to 1 [2]. Although by definition a recurrent disorder, SAD is not necessarily a life-long disorder. Follow-up studies of SAD subjects reveal variable courses, with a core group of SAD patients continuing in a winter depression, summer remission pattern. A follow-up study of the first 59 patients of the National Institutes of Health (NIH) Seasonal Studies Program was performed after a mean of 8.8 years following their treatment. Results showed that 42% of this sample continued to experience symptoms of SAD, and 41% of the sample continued to use light treatment. Other patients, 14% of the sample, had fully remitted, and 44% were experiencing forms of nonseasonal depression [14]. In two other studies, 18% to 20% of patients followed up after several years had recovered and others had milder symptoms or recurrent but nonseasonal major depressions or some other altered forms of mood disorder [15,16].

Pathogenesis of SAD Early in the study of SAD diagnosis and treatment, Rosenthal and colleagues [7] suggested that potential causal factors deserving study were photoperiod (number of hours between sunrise and sunset), hours of daily sunshine, and mean daily temperature. Light treatment initially was applied in the morning and evening, based on the ‘‘photoperiod hypothesis’’ that extending the duration of daylight would be corrective. Animal models of seasonal rhythms such as hibernation identify length of the dark period as the potent cue for behavioral shifts [17,18], Indeed, careful studies done at the National Institute of Mental Health showed that healthy humans retain photoperiodic responses to light [19,20]. Because daily hours of sunshine, daily temperature, and other weather factors are variable and highly correlated, these have not been promising explanatory variables for predicting SAD onset or duration. Photoperiod, however, is predictable, varying with latitude and day of the year, and is highly correlated with other environmental factors [21]. In two studies of SAD symptom onset in the Chicago area, Young and colleagues [22] found that photoperiod correlated 0.97 with SAD onset risk and accounted for 26% of the total variance in the weekly risk of SAD symptom onset in the fall, with no other environmental variables accounting for much additional variance.

Alternative hypotheses to the photoperiod hypothesis have been proposed, however: a photoncounting hypothesis based on the total amount of light received within a day regardless of day length, a phase-shift hypothesis based on the assumption of a mismatch between the sleep-wake cycle and other circadian rhythms, and a melatonin-based hypothesis based on presumed differences in melatonin levels in affected versus normal subjects. Melatonin has been of great interest based on the finding that bright light presented within nighttime darkness suppresses melatonin secretion by the pineal gland in humans [3,23,24] and that morning light advances the onset of melatonin secretion in the evening [6]. Periods of elevated melatonin secretion are extended during the longer nights of winter and have been produced in laboratory studies of the effects of ‘‘summer’’ versus ‘‘winter’’ schedules of environment lighting [19]. Both bright light and melatonin can be administered in schedules that will advance or delay circadian rhythms and have been used for circadian disorders such as jet lag, shift-work disorders, and advanced or delayed sleep-wake patterns [25]. Since SAD patients are more typically phase delayed in their circadian and sleep-wake patterns, the effects of light in advancing circadian rhythms is of interest. Of the alternative explanations offered for SAD, the phase-shift hypothesis has received the most support, based on findings in multiple studies that morning light therapy is superior to evening light therapy for most subjects [26–29]. Although some studies have failed to support the superiority of morning to evening light, no study has found evening light to be superior. Further, a grouped analysis of studies failed to find that morning plus evening light was superior to morning light alone [30]. The conclusion of a rigorous meta-analysis of 14 studies of light-box therapy for SAD concluded that bright light was superior to dimmer light and that morning treatment was superior to treatment at any other time of day [31]. Morning light treatment has been proposed as effective because it produces phase advances of the internal circadian clock, revealed in measurements of the DLMO, or dim light melatonin onset; that is, the onset of melatonin production measured in the evening during a dim-light condition [29,32]. Terman and colleagues [33] report that circadian rhythm phase advances in melatonin onset often accompany antidepressant responses and that the magnitude of the phase advance correlates with degree of clinical improvement. In other SAD studies, the degree of phase advance has not been found to reliably correlate with clinical improvement [32–35]. Further, since some SAD patients improve on evening-light treatment, the best

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outcomes may result from matching a phaseshifting treatment to the phase-delayed or advanced state of the individual patient [25,36]. Despite support for the phase-shift hypothesis, several studies have reported contrary evidence; eg, that timing of light treatment may not be crucial [34,37] (this finding would support the photoncounting hypothesis) and that circadian profiles of plasma hormones (cortisol, prolactin, and thyrotropin) did not distinguish SAD patients from healthy controls [38]. Numbers of SAD patients may not show altered circadian phases and may respond to light for other reasons or may respond to alternate treatment approaches. Exogenous administration of melatonin, which, when properly timed, can advance or delay circadian rhythms, showed promise in reversing SAD symptoms in one pilot study [39]. A larger study found no overall improvement of SAD subjects treated with melatonin, but did identify improvement in the subjects who were most phase-delayed and responded to the phase-advancing effect of melatonin [40]. One effort to account for the variability in types and degrees of SAD symptoms has been offered in the ‘‘dual-vulnerability hypothesis’’ [41,42]. This hypothesis assumes that separate factors of seasonality and depression may occur separately or together. When only the seasonality factor is expressed, the diagnosis of S-SAD would apply (energy, sleep, or appetite/weight changes, for instance). When depression but not seasonality is expressed, a nonseasonal depression would be diagnosed. When seasonality and depression occur together, SAD is a likely diagnosis, although some milder forms of SAD occur in which depression is present but not severe enough to meet criteria for major depression. In one study, 552 patients with seasonal complaints were sorted into SAD, S-SAD, and incomplete summer remission (ISR) groups and then treated with light for 2 weeks. Rates of improvement were highest in the S-SAD group (78%), intermediate in the SAD group (66%), and lowest in the ISR group (51%) [36]. This study provides support for the provision of light treatment to S-SAD sufferers, since improvement with light does not depend on severity of depressive symptoms [43].

Physiologic aspects of SAD Numerous investigations of neurotransmitter function in SAD have focused on serotonin (5-HT) and on the catecholamines dopamine (DA) and noradrenaline (NA), given the importance of these in studies of major depression. Levels of 5-HT were found to be lower in winter than in summer in healthy men, with production of 5-HT increasing

with increased bright sunlight [44], lending support to a role for 5-HT in the development of the seasonal symptoms of SAD. A technique of reducing 5-HT by depleting tryptophan, a dietary precursor of 5-HT, has been used in studies of nonseasonal depression and of antidepressants; this technique applied to SAD patients in remission after light therapy led to their relapse [45]. A similar relapsing effect on SAD patients following successful light treatment was found in one study both with tryptophan depletion and catecholamine depletion [46]. A variety of studies have converged toward the conclusion that 5-HT plays a role in the pathophysiology of SAD, and light therapy may contribute to correcting this underlying factor [47]. Evidence has been less conclusive for the roles of DA and NA in SAD [2]. Family studies have found that first-degree relatives of SAD patients are more vulnerable to seasonal and nonseasonal depression than would be expected in the general population. Thirteen percent to 17% of these relatives have been reported to be affected by SAD and 25% to 67% by nonseasonal affective disorders [48,49]. Lifetime expectancy of developing a unipolar depression in the general population is estimated to be from 10% in men to 20% in women [50]. A twin study of seasonality (seasonal changes in functioning, not necessarily meeting criteria for SAD) in Australia assessed sleep, social activity, weight, appetite, and energy level among a cohort of 4639 adult twins. Genetic effects were estimated to account for 29% of the variance in seasonality [51]. A higher degree of heritability of SAD was found in a twin study in Canada, in which genetics accounted for 45% to 69% of the total variance [52]. Genetics may play a role in the association between SAD and alcoholism. In one family study, 41% of SAD patients reported alcoholism among their first-degree relatives, with similar elevated rates found by other researchers [53]. Studies of molecular genetics of SAD and seasonality have expanded in recent years, with special interest in the 5-HT transporter promoter repeat length polymorphism (5-HTTLPR) and 5-HT-related genes [32,49,53].

Light therapy Bright white light was the original treatment tested for SAD [4] and numerous studies have shown it to be effective as a therapeutic intervention for this condition [2,31]. Three studies published in 1998 provided strong evidence of its superiority to placebo [26–28]. Light therapy was originally administered via large light boxes holding fluorescent light

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tubes behind a diffusing screen; these emitted white light at 2500 lux, a measure of illuminance, and have generally filtered out ultraviolet light to reduce health risks to the skin and retina [54,55]. In early studies, patients were exposed to such lighting for 2 to 6 hours per day, usually in morning and evening doses. Since light must enter the eye to reverse symptoms [32,56], patients were advised to look directly at the light for a few seconds every minute or so. Compliance in study protocols was improved when it was demonstrated that comparable results could be obtained with 30-minute exposures to light measured at 10,000 lux, and by the development of units that produced sufficient intensity of light to be effective when reflected from a desk or table surface. Clinical response to light therapy is often reported within 1 week, but full response may take up to 3 to 4 weeks to develop. Fluorescent light sources have typically produced polychromatic white light, with great variability in the balance of wavelengths [57]. From early years of SAD study, interest in the potential effects of varying wavelengths of light across the visible spectrum has been the focus of a series of studies [58–60]. To date, the ideal blend of wavelengths for reversing SAD symptoms is not known, and broadband white light remains the standard therapy. Recent interest, however, has focused on the shorter wavelengths in the blue portion of the spectrum. Studies of melatonin suppression by light in healthy humans identified 446 to 477 nm as the region of the visible spectrum providing the most potent input for regulating melatonin [23,61]. Indeed, a series of eight published action spectra with rodents, monkeys, and humans have confirmed that the blue part of the spectrum is most potent for circadian, neuroendocrine, and neurobehavioral responses to light [62]. Further, equal photon densities of monochromatic blue light at a peak of 460 nm compared with green light with a peak of 555 nm induced a twofold greater circadian phase delay and was twice as potent in suppressing melatonin [24]. The development of light-emitting diodes (LEDs), which can restrict wavelengths emissions to narrow bandwidths, makes possible more precise studies of the effects of wavelength in SAD. In one study, narrow-band blue light at 468 nm significantly reduced SAD symptoms compared with a placebo condition of dimmer red light [63]. Conclusions about the relative efficacy of various wavelengths in SAD compared with broadband white light await further clinical trials. Light units for use in SAD therapy are now produced in a variety of sizes and configurations [57]. Fluorescent light boxes have been the most studied and are still the most widely used clinically, although much smaller units have been produced,

including head-mounted visors. LED light sources are now available in addition to fluorescent tubes. Light therapy has been presented in the form of ‘‘dawn simulation,’’ or light that turns on in one’s bedroom during morning sleep and gradually increases until wake-up time [64]. A recently completed 6-year study found that dawn simulation compared favorably to standard bright-light treatment (30 minutes at 10,000 lux) [29]. Many SAD sufferers obtain information and order treatment devices from the Internet. Web sites such as those offered by the Society of Light Treatment and Biological Rhythms [65] and the Center for Environmental Therapeutics [66] provide reliable information about the disorder and forms of treatment. As most treatment studies have shown morning light to be more effective than light at other times of day [31], a starting regimen of 30 minutes at 10,000 lux upon awakening is a common recommendation. The authors of one study [33] argue for individualizing the timing of morning light treatment to begin no later than 8.5 hours after evening melatonin onset, or 2.5 hours from the midpoint of sleep, and they offer the Morningness-Eveningness Questionnaire as a tool to estimate the ideal starting time for light treatment [67,68].

Risks and side effects A number of photobiological hazards have been identified in the biomedical literature relative to overexposure of the skin and eyes to the ultraviolet, visible, and infrared portions of the electromagnetic spectrum. Different parts of the spectrum can induce problems such as infrared cataract, photokeratitis, photoretinitis, retinal thermal injury, ultraviolet cataract, and ultraviolet erythema [see Refs. 69–71 for reviews]. If light therapy equipment blocks the transmission of ultraviolet radiation to the eyes, this hazard is not a problem for patients using the equipment. Most commercial light units for treatment of SAD or of circadian disorders generally filter out ultraviolet radiation, which subtracts from risk potential but not from therapeutic effect [54]. The Blue Light Hazard Function is potentially relevant to the light exposures from equipment that emits broad-spectrum white light, broad-spectrum blue light, or narrow bandwidth blue light. This function relates to photochemically induced retinal injury resulting from optical radiation exposure at wavelengths primarily between 400 nm and 500 nm. The action spectrum for this adverse effect has a peak activity in the 435 to 440 nm wavelength range with short and long wavelength limbs that drop rapidly with increasing and decreasing wavelengths [70–74]. Problems

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related to the blue light hazard can be avoided if the manufacturer verifies the safety of their product by having an independent hazard analysis performed on the equipment according to national and international safety guidelines [72–74]. Requesting ultraviolet radiation and blue light safety information from the manufacturer is reasonable when one purchases or recommends specific lighttherapy equipment. Side effects to light therapy are infrequent and generally mild, especially when compared with the side effects of pharmacologic agents. They generally subside within the first few days of light treatment or after light exposure is shortened or intensity of light reduced. The most common complaints reported have been headache, eyestrain, nausea, irritation, anxiety, or overactivity [1,2,75]. Patients with a history of bipolar disorder are at increased risk for manic or hypomanic episodes in response to light therapy, especially if not taking mood-stabilizing medication.

Assessment of SAD Basic assessment of seasonality relies on the patient’s retrospective account of symptoms and their timing. Although a diagnosis of major depression combined with a seasonal pattern is required by the formal DSM criteria for SAD, inquiry should cover seasonal changes that may be milder or less definitive. As stated above, subsyndromal SAD (SSAD) has been shown to improve with light treatment, sometimes more fully than will classic SAD [43,76]. Further, light may also reduce the severity of winter symptoms in patients who report combined seasonal and nonseasonal mood disturbances. In most but not all cases of SAD, the atypical depressive symptoms of hyperphagia, weight gain, and hypersomnia will be present, and light therapy has been predicted to be most effective for patients reporting these atypical depressive symptoms [77]. Among the standard elements of clinical assessment, inquiry of possible SAD sufferers should include seasonal patterns over previous years, seasonality and mood symptoms, whether unipolar or bipolar, anticipatory anxiety about the fall and winter, evidence of ‘‘skipped’’ winters or year-round depression, effect of travel to warm sunny locales, cold tolerance, ophthalmologic history, current medications and photosensitizing medications, and family history of affective disorders and of alcoholism. Severity of depression must be assessed, as depression whether seasonal or nonseasonal can present risks of suicide. The SPAQ is a brief and useful screening tool for SAD, which can be supplemented

with the Beck Depression Inventory II and other self-report measures. Research studies have commonly used as an outcome measure responses on the Structured Interview Guide for the Hamilton Depression Scale—Seasonal Affective Disorder Version (SIGH-SAD) [78]. The SIGH-SAD is useful clinically as well and is available in a self-report form [79]. Several other assessment instruments have been developed and are commercially available [66].

Other strategies of SAD treatment Most studies of medication management of SAD have focused on selective serotonin reuptake inhibitors (SSRIs), several of which have been shown to be superior to placebo. Effective doses are similar to those applied to nonseasonal depression [2,9]. The few comparisons of light treatment to medications in treating SAD have not resulted in clear differences in efficacy [9]. For some patients, a combination of light therapy and medication management may have additive benefits. Cognitive behavioral therapy (CBT) has been tested in SAD treatment alone and in combination with light treatment. In a randomized controlled trial, CBT was administered to groups of SAD subjects in twice-weekly 1.5-hour sessions over 6 weeks. Three other randomly assigned groups received 6 weeks of light treatment, combined CBT and light, or delayed treatment with minimal contact [80]. Results of this trial were similar to an earlier feasibility study showing that combination CBT and light treatment resulted in a remission rate of 73%, significantly higher than control group remission (20%). The light-treatment condition resulted in a 50% remission rate, similar to results of many other studies of light treatment for SAD. A promising treatment direction for SAD sufferers was discovered when negative ion generators were used as putative placebos in light-therapy studies. The degree of response noted to negative ions led to studies of the treatment potential of negative ions for SAD. Treatment with high-density negative ions has been superior to treatment with low-density negative ions, and high-density negative ion treatment has resulted in improvement in 50% of cases [28]. A study of high-density negative air ionization presented to subjects while asleep resulted in therapeutic benefits that were not significantly different from those of standard postawakening bright-light treatment provided to subjects in the same study. Low-density negative ions provided little benefit [29]. No side effects to treatment with air ionization for SAD have been identified, which may recommend it as an alternative treatment or a companion treatment to light.

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It remains unknown how air ions improve SAD symptoms.

Summary Light is universally acknowledged as a basic element of life as we know it, from the ‘‘dawn of creation,’’ and the field of contemporary research is shedding light on light’s healing power. As applied to SAD, a proliferation of studies of this disorder, of its response to light, and of its psychologic and psychophysiological correlates leads to a view of SAD as multidimensional, manifested in individual patterns that have both common elements and also highly divergent aspects. The importance of light as a corrective treatment with results superior to placebo has been established, and standards for the safe and effective practice of light therapy have been propounded [2,29,70,72–74]. Meanwhile, research continues on strategies for optimizing the effectiveness of light timing, intensity and spectrum for SAD and related circadian disorders.

Acknowledgments The authors gratefully acknowledge John Hanifin, Claudia Penrose, and Mike Jablonski for their excellent assistance with referencing and seeking copyright permissions. In addition, we appreciate Kat West for her thorough editorial comments on the final draft.

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