Psychiatry Bullets

Psychiatry Bullets

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Psychiatry Bullets

Mimi W.Thein, M.D.

Instructor, Harvard Medical School Assistant Medical Director, Berkshire On-Call Associates Staff Psychiatrist, Children’s Hospital Boston Boston, Massachusetts

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Acquisitions Editor: Charley Mitchell Product Manager: Tom Gibbons Vendor Manager: Bridgett Dougherty Senior Manufacturing Manager: Benjamin Rivera Marketing Manager: Brian Freiland Design Coordinator: Doug Smock Production Service: SPi Global © 2011 by LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER business Two Commerce Square 2001 Market Street Philadelphia, PA 19103 USA LWW.com All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. Printed in China Library of Congress Cataloging-in-Publication Data Thein, Mimi W. Psychiatry bullets / Mimi W. Thein. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-1-60913-450-1 ISBN-10: 1-60913-450-8 1. Psychiatry—Outlines, syllabi, etc. 2. Psychiatry—Examinations, questions, etc. I. Title. [DNLM: 1. Mental Disorders—Outlines. WM 18.2] RC457.2.T44 2011 616.89—dc22 2010028404 Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices. However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication. Application of the information in a particular situation remains the professional responsibility of the practitioner. The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new or infrequently employed drug. Some drugs and medical devices presented in the publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings. It is the responsibility of the health care provider to ascertain the FDA status of each drug or device planned for use in their clinical practice. To purchase additional copies of this book, call our customer service department at (800) 638-3030 or fax orders to (301) 223-2320. International customers should call (301) 223-2300. Visit Lippincott Williams & Wilkins on the Internet: at LWW.com. Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to 6 pm, EST. 10 9 8 7 6 5 4 3 2 1

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For my parents, San andWendy Thein Thank you for teaching me Love,Wisdom, Humor, and The Main Point



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Preface

This manuscript represents a synopsis of countless conferences and publications presented by some of the world’s thought leaders in the field of psychiatry. The purpose of this manuscript is to provide a succinct yet comprehensive overview of psychiatry. The ideal reader would be one preparing for board certification or simply wishing to reference the most current information. My intent is to provide a thorough, detailed presentation of the vast compendium of the most up-to-date, cutting-edge thinking in psychiatry in the most efficient, succinct form possible. This manuscript is not intended to replace the details found in the current comprehensive literature.

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Acknowledgements

Thank you to Richard Lampert of Lampert Consulting Agency for his invaluable advice and counsel in the preparation of this manuscript. Thank you to the many superb colleagues with whom I have worked over the past years and my mentors through residency, fellowship, and in my clinical practice. Special thanks are due to those clinicians and scientists whose tireless research in psychiatry has provided the foundation for this work. Thank you to my siblings, May-Win and Minn, for their patience and support. For the memory of my older brother, Moe, who always inspires me to laugh through absurd and intolerant moments. Thank you to my husband, Marc, for his unbelievable love and strength.

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Contents

Unit I: Brain 1 2

Anatomy Related to Psychiatric Conditions Physiology

1 5

Unit II: Specific Diseases 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Schizophrenia Depression Bipolar Disorder Anxiety Substance Use Disorders Personality Disorders Somatoform Disorders Dissociative Disorders Factitious Disorders and Malingering Eating Disorders Sleep Gender Identity Disorders and Sexual Disorders PMDD, Pregnancy, Postpartum State, and Breast Feeding Impulse Control Disorders Pain Geriatric Psychiatry Mental Disorders Due to a General Medical Condition Child and Adolescent Psychiatry

9 31 51 65 87 125 129 131 133 135 143 159 163 171 175 183 205 215

Unit III: General Diagnostic Approaches 21 Laboratory and Diagnostic Testing 22 Psychological Assessments 23 Biometrics

259 263 267

Unit IV: Therapeutic Methods 24 25 26 27 28 29 30

Hypnosis Cognitive Behavioral Therapy Family Therapy Adult Psychodynamic Therapy Group Therapy Milieu Therapy Couples Therapy

271 273 275 281 285 287 289

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xii

Contents

Unit V: Law and Ethics and Economics 31 32

Law and Ethics Economic Issues

291 297

References

299

Index

309

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Unit

I Brain Chapter

1

Anatomy Related to Psychiatric Conditions Arousal and attention CNS areas Prefrontal cortex Limbic regions Reticular activating system (RAS) Memory Types Immediate seconds Recent minutes Remote months-years (working memory incorporates immediate and recent memory) Categories Episodic Recollection of events and details of events Located in medial temporal lobe anterior thalamic nuclei mammillary body fornix prefrontal cortex Semantic Knowledge of specific facts Located in inferolateral temporal lobes Procedural Knowing how to perform tasks Located in basal ganglia cerebellum supplementary motor area Motor and motoric behaviors CNS areas Frontal lobe Spinal tracts Rubrospinal tracts Vestibulospinal tracts Basal Ganglia Globus pallidus Caudate nucleus Putamen Substantia nigra Cerebellum 1

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Psychiatry Bullets

Autonomic motor system Sympathetic Parasympathetic Emotion (depression and anxiety) CNS areas Frontal lobe Orbital frontal cortex (OFC) Prefrontal cortex (PFC) Ventromedial (VMPFC) Lateral orbital (LOPFC) Dorsal lateral (DLPFC) Limbic system Hippocampus Fornix Cingulate gyrus Amygdala Septal nuclei Thalamus Nucleus accumbens Neuroendocrine HPA axis Perception Somatosensory Functions Light touch Pressure Pain Temperature Vibration Proprioception CNS areas Afferents/efferents to/from parasympathetic nervous system (PNS) Thalamus Homunculus (Brodmann areas 1, 2, and 3) Visual Functions Contextualizes visual stimuli CNS areas Afferents/efferents to/from PNS Occipital lobe Thalamus Temporal lobe Inferior temporal cortex Function—“the what” Shape Form Color Left sided (complex shapes) Posterior parietal cortex Function—“the where” Location Motion Destination Development of association fibers occurs early (postnatally)

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Chapter 1 Anatomy Related to Psychiatric Conditions

3

Auditory CNS areas Afferent/efferent to/from PNS Thalamus Temporal lobes Gustatory Function Taste CNS areas Afferent/efferent to/from PNS Brainstem (nucleus solitarius) Thalamus Olfactory Function Smell CNS areas Afferent/efferent to/from PNS Autonomic nervous system “unconscious” Addiction CNS areas Frontal lobe Nucleus accumbens Ventral tegmental area Obsessions and compulsions CNS areas Cingulate cortex Basal ganglia Thalamus

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Chapter

2

Physiology

BASIC INFORMATION 1011 neuronal cells 1012 glial cells, which comprise Astrocytes Actions Nutrition Deactivates neurotransmitters Integrates with the blood-brain barrier Types Oligodendrocytes found in the central nervous system Schwann cells found in the peripheral nervous system Microglia/macrophages—remove neurons after death Neural formations Neural tube results in the formation of the central nervous system Ectoderm gives rise to the neural crest, which results in the formation of the peripheral nervous system Peak of proliferation of cells occurs during the middle of the second trimester (250,000 born/ minute) Neurotransmitters Types Biogenic amines Serotonin (5-HT) Histamine Dopamine (DA) Acetylcholine (ACh) Amino acids Peptides Nucleotides Neurotrophic factors Brain-derived neurotrophic factor (BDNF) Neuronal growth factor (nGF) Neurotrophin 3, 4 Glial-derived neurotrophic factor Insulin Cytokines Eicosanoids Metabolite of arachidonic acid Prostaglandins Prostacyclins Thromboxane Leukotrienes

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Psychiatry Bullets

Anandamides Endogenous cannabinoid CB1 receptor found in the central nervous system CB2 receptor found in the peripheral nervous system Sigma receptors Membrane proteins distributed throughout the brain Role in binding to antipsychotic agents such as haloperidol Biogenic neurotransmitters DA Tracts Nigrostriatal Substantia nigra → striatum (movement) (associated disease: Parkinson’s) Mesolimbic Ventral tegmental area (VTA) → nucleus accumbens Tuberoinfundibular Mesocortical Hypothalumus → pituitary → release of prolactin Critical formations (NB: DA refers to dopamine NE refers to norepinephrine E refers to epinephrine DOPA refers to dihydroxyphenylalanine) Tyrosine → DOPA (the rate-limiting step) via tyrosine hydroxylase DOPA → DA → NE → E DA metabolism Reuptake via DAT (Dopamine transporter) in the striatum and basal ganglia then via monoamine oxidase A and B (MOA A, MOA B) → 3,4 dihydroxyphenylacetic acid (3,4 DPA) → via catechol-O-methyltransferase (COMT) → homovanillic acid (HVA) Reuptake via NET (Norepinephrine transporter) in the PFC (prefrontal cortex) Then via COMT → 3 methoxy tyramine → via MOA → HVA Receptors D1 involves stimulatory G-proteins which increases cAMP D2 found in the striatum involves inhibitory G-proteins which decreases cAMP (associated with attachment) D3 found in the nucleus accumbens (NA) involves inhibitory G-proteins which decreases cAMP D4 found in the frontal lobe involves inhibitory G-proteins which decreases cAMP D5 involves stimulatory G-proteins which increases cAMP Norepinephrine (NE) and Epinephrine (E) Formation DA → (via B-hydroxylase) → NE → (via PNMT) → E PNMT refers to phenylethanolamine N-methyltransferase Receptors Alpha-adrenergic Alpha 1A Alpha 1B Alpha 1D Blockade leads to sedation, lowered blood pressure Agonist leads to lowered blood pressure (via presynaptic down-regulation and release of NE––mechanism of action of clonidine) Alpha-2 antagonist (an area responsible for sexual dysfunction)

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Chapter 2 Physiology

7

Beta-adrenergic B1 B2 B3 Blockade postsynaptically involving Gi decreases cAMP 5-HT Rate-limiting step is availability of tryptophan (dietary source) Receptors (site of action of LSD) 5-HT1 agonist examples: buspirone, trazodone, nefazodone 5-HT1A activity involved in treatment of depression 5-HT2 5-HT3 Histamine Receptors H1 Antagonists at this site increase IP3 (inositol triphosphate) and DAG (diacylglycerol), both second messenger molecules used in signal transduction Postsynaptic receptor Antagonists block allergic response Via decreased vascular permeability Reduction of pruritus Relaxation of the smooth muscle Respiratory Gastrointestinal tract Common side effects of antagonism Nausea Vomiting Weight increase Sedation H2 Antagonists at this site increase cAMP Postsynaptic receptor Found primarily on gastric mucosa H3 Vasculature Presynaptic receptor Possible roles in Wakefulness Hunger Cognition H4 Recent identification Hematopoietic lines

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Unit

II Specific Diseases Chapter

3

Schizophrenia

EPIDEMIOLOGY Prevalence 0.3% to 0.4% or 15 to 20 per 100,000 per year 0.6% to 1% lifetime risk Pockets of low and high prevalence do exist Low socioeconomic status in United States Urban dwellers (1.5 to 2 times in the urban areas) Possibly due to migration to the city Population density and schizophrenia—possible connection Morbidity WHO—eighth leading cause of world medical disability Morbidity is greater in developed countries Less than 15% are employed 10% die of suicide High comorbidity (diabetes mellitus or cardiovascular disease) Higher homeless and incarceration rates Mortality Average lifespan decreased by 25% Average lifespan decreased by 15 to 20 years Age-standardized mortality doubled in schizophrenia Causes Suicide

10× greater risk than general population

Diabetes mellitus

2×

Cardiovascular disease

2× (general population’s no. 1 killer)

No increased risk with cancer, rheumatoid arthritis Metabolic syndrome present in 30% to 40% of individuals with nonmedicated schizophrenia Cancers females (breast, ovarian, endometrial, cervical) males (colorectal, prostate) Respiratory 3.2× Infectious disease 2.1×

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Psychiatry Bullets

Age of onset Very rarely presents prior to age 9 Childhood prevalence is rare—50 times less than adult (1/50,000 vs. 1/1,000) Sex ratio—over time, the ratio equalizes, but males may manifest earlier Type of onset—insidious rather than acute onset associated with poorer prognosis Deterioration in functioning Often severe at presentation and with significant deterioration Poor prognosis Early age of onset Family history Poor premorbid functioning Poor long-term functioning Disorganized type of schizophrenia

ETIOLOGY Historical Perspectives Kraepelin

“Dementia praecox” (cognitive changes over time)

Bleuler

“Four A’s”––Autism, Associations, Ambivalence, Affect and coined schizophrenia

Kretschmer

“Body type”—asthenia

Schneider

“First rank symptoms” Audible thought commenting, voices commenting, Thought withdrawal, insertion, and broadcasting “Second rank symptoms” Delusions, perplexity, emotional impoverishment

Jaspers

Psychotic meaning to delusions and auditory hallucinations

Meyer

Schizophrenia secondary to stress

DSMII schizophrenia in childhood intended for a wide spectrum of patients DSMIII resembled that of adult schizophrenia Historical Theories Frontal cortex—Bleuler, 1978 Frontal function abnormalities (hypofrontality)—Ingvar and Franzen, 1974 Frontal function affecting dopaminergic dynamics in the striatum—Meyer-Lindenberg, 2002 Symptomatic Cellular Neurochemical Dendritic Expression differences Hippocampus—Benes, 1991; Gao, 2001; Heckers, 1998 Thalamus—Andreasen, 1994 Cerebellum—Andreasen, 1994 Abnormal dopamine transmission—Laruell, 1996 Excitatory function abnormalities—Gao, 2000 GABA-mediated inhibition abnormality—Benes, 1996 Brain Regions Neurodevelopmental abnormality Premorbid evidence of “deviant” childhood development Characteristics of brain abnormalities Nonprogression of certain MRI findings over time possibility Aberrant neurodevelopment

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Chapter 3 Schizophrenia

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Obstetric complications Trimester II insults Rubella Flu Complications during pregnancy Abnormal fetal growth and development Complications during delivery Anoxia Neurologic soft signs Minor physical abnormalities Neurodegenerative disorder Diagnose and treat aggressively immediately—due to the toxicity of psychosis itself Progression of symptoms and deficits early in the illness Decline in cognitive function early in the illness Rapid decline in social functioning early in the illness Progression of some brain abnormalities Increased ventricular size Decreased dominant superior temporal lobe The longer the untreated illness progresses, the more severe the negative symptoms and dysfunction Suggested neuroanatomic abnormalities Brain structure Volume 3% reduction Gray matter reduction Ventricular size increase (lateral and third) Ventricle/brain ratio increased (most consistent neuroanatomic finding) Smaller hippocampus Limbic cortex—major part of the “psychosis circuit” Size Axial orientation Neuronal and nonneuronal cells Transmission and development changes Structural changes Hippocampus Pyramidal cell apical dendrite orientation (anterior/middle CA2 border) Reduced volume Regional abnormalities (particularly the head region) Entorhinal cortex Cytoarchitectural abnormality of entorhinal cortex (Nicotinamide adenosine dinucleotide phosphate neurons) Reduction in volume Reversal of normal cerebral asymmetry Reduced prefrontal cortex (PFC) structure volumes (the orbitofrontal cortex is the most inferior aspect of the prefrontal cortical area and is thought to be involved in emotional expressivity hypofrontality) and enlarged basal ganglia (BG) Various imaging studies examining neuroanatomical factors CT Enlarged lateral/third ventricles (most consistent) MRI Asymmetry of basal ganglia Reduced sizes of frontal and temporal lobes Greater ventricular volumes Cerebellum Smaller areas Smaller hemispheric sizes

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Psychiatry Bullets Temporal lobes Larger superior temporal gyrus Right smaller than left Associated with negative symptoms Thalamus—smaller midsagittal; subnuclei Corpus callosum—conflicting studies Cavum septum pellucidum enlarged in adolescence SPECT—MRI Abnormal frontal lobes with lower N-acetylamide (NAA)/creatine activity PET—decreased right parietal metabolism Brain Microstructure Disarray of pyramidal cells (hippocampal and entorhinal) Decreased density of small interneurons in anterior cingulate cortex, which are GABAergic Decreased neuropil in neocortex Absence of gliosis (thus, no inflammation seen in schizophrenia) Abnormal levels of phospholipids Abnormal G proteins Brain Physiology Blood flow and metabolism: hypofrontality Smooth pursuit eye tracking abnormalities Prepulse inhibition deficiencies (thus, unable to filter out unnecessary information) Reduced auditory P-300 amplitude of event-related potentials during visual recognition tasks Sleep physiology Abnormal sleep continuity and maintenance Decreased total sleep time Increased sleep latency Increased awakening after sleep onset Reduced slow-wave sleep Shortening REM latency Cognition Impaired verbal memory Impaired attention Impaired general intellectual ability Impaired working memory SPECT and PET findings Decreased prefrontal blood flow during Wisconsin card sorting task Electrophysiology Increased sensitivity to activation (as seen in sleep deprivation) Decreased alpha activity Increased theta and delta activity Epileptiform activity Greater left-sided abnormalities Evoked potentials Increased early component Decreased late component Spikes found in limbic areas Increased frontal slow-wave activity Increased parietal fast-wave activity Neurotransmitters Dopamine Pathways Mesolimbic pathway Responsible for positive symptoms Mesocortical pathway Responsible for negative symptoms

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Nigrostriatal pathway Responsible for tardive dyskinesia and other extrapyramidal symptoms Tuberoinfundibular pathway Pathway involving prolactin Neural connectivity abnormality “Too much dopamine”—overly simplistic? Limbic dopamine hyperfunctioning (MESOLIMBIC) Positive symptoms Cortical dopamine hypofunctioning (MESOCORTICAL) Negative symptoms Tonic dopamine hypofunctioning and phasic dopamine hyperfunctioning Decreased D1 receptors in the prefrontal cortex (cognitive symptoms) Medication principals Blocking DA-mediated transmission—Antipsychotic activity Partial DA agonist action—antipsychotic activity DA synthesis blockade—antipsychotic activity Hyperactive DA system—propsychotic activity Receptors—there are no consistent abnormalities Glutamate (metabotropic and NMDA ionotropic receptors) NMDA-sensitive glutamate antagonism can be propsychotic (ketamine effects) Areas of limbic cortex changes Anterior cingulate Hippocampus Ventral striatum Glutamate is found in Frontal cortex Hippocampus Limbic system Striatum Thalamus Cholinergic deficiency (muscarinic and nicotinic) Serotonin 5-HT6 and 7 receptors 5-HT2A involved in cognition GABAergic deficiency? Changes in GABA density, release—particularly in the hippocampus. Others are pending Peptides Neurotensin Somatostatin Dynorphin Substance P Neuropeptides Y Studies of the CSF metabolites––(nothing consistent)

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Dopamine overactivity

+ Symptoms

Serotonin

Atypical antipsychotic medications effectiveness for positive and negative symptoms

Norepinephrine

Responsible for anhedonia?

GABA

Regulates dopamine “the brakes”

Glutamate

PCP usage leads to psychosis

Neuropeptides

Substance P; neurotensin

Acetylcholine

Cognition

Nicotine

Cognition

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Psychiatry Bullets

Other Etiologies Genetic General population lifetime risk of 0.6% to 1% Gene and risk Monozygotic twins

100% genes shared

50% chance of transmission

Dizygotic twins

50% genes shared

10% chance of transmission

First-degree relatives

50% genes shared

10% chance of transmission

Second-degree relatives

25% genes shared

2% to 4% chance of transmission

Related genes (there is no major gene—all have <2% chance of transmission) COMT, DA, Glutamate, Nicotinic receptor COMT val/met polymorphism COMT val allele associated with increased DA breakdown Individuals with schizophrenia with greater COMT val allele occurrences Cytogenetic abnormalities Familial patterns Family history twin studies Paternal age greater than 60 years Genomics Suggested genetic testing via standard microarray 22q11 (and its association with VCFS) 1q21.1 15q13.3 15q11.2 DrD2 promoter region variation first episode DrD2-141C insertion/deletion response to atypical antipsychotics DrD2 A-241G response to atypical antipsychotics (agranulocytosis to clozapine) Neuropsychological factors Fine motor skills, attention, or short-term memory IQ functioning may be affected in childhood (possible baseline verbal and visual learning deficits) Neurolinguistic factors Pragmatics, prosody, auditory processing, abstract language Psychological and social factors—none found Risk factors Obstetric complications inconclusive Born January to April (July to September in southern hemispheres) Maternal flu during the second trimester Gender

Equal below the age of 15 years

Pubertal development

No clear findings

Medical conditions

Complex partial seizures like temporal lobe epilepsy

Neurological signs

Movement disorders Poor sensory integration

Infectious disease and immunological factors Infectious disease Prenatal rubella Prenatal influenza (as noted above) Elevated IgG and IgM to HSV2 Autoimmune

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Neurophysiological factors Event-related potential studies—dysfunction in the frontal lobes P300 Eye tracking studies—impairments of smooth pursuit eye movements Autonomic function studies—high levels of resting activity impaired response to new stimuli failure to stop responding to familiar stimuli

DIAGNOSIS Signs and Symptoms Characteristic symptoms Current DSM-IV TR diagnostic criteria for schizophrenia At least two symptoms for at least 1 month Delusions Hallucinations Disorganized speech Grossly disorganized or catatonic behavior Negative symptoms (affect, alogia, avolition) Deterioration in functioning (social, occupational, or appropriate functioning) Duration greater than 6 months (ICD 10 is actually 1 month) Not Mood with psychotic symptoms Substance intoxication/metabolic/neurologic Pervasive developmental disorder Typical clinical symptoms Hallucinations Mostly all had auditory or visual hallucinations (1/3 of patients), rarely tactile hallucinations Delusions Frequency varies, but persecutory/somatic much more frequent than thought disorders Cenesthetic hallucinations “brain is burning” Simulation of one sensory path leads to sensation of another sensory path Relatives of those with full condition Affective disturbances Thought disorder

Flattened affects, negative symptoms Illogical thinking and loose associations (poverty of speech) Symptoms of ADHD (inattention)

Cognitive functioning Subaverage IQ (average IQ is 80 to 84) Distractibility Memory deficits Short term (typically verbal—possible hippocampal role) Nonverbal Abstract thinking impairment Language, communication, and information processing frequently affected Neurobiological deficits Progressive increase in ventricular size Decrease in cortical gray matter in adolescents (frontal and temporal lobes) Smaller volumes with negative symptoms Comorbidity—obesity, diabetes mellitus, cardiovascular, HIV, COPD

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Psychiatry Bullets

Subtypes Paranoid Disorganized Catatonic Undifferentiated Other Bouffee delirante Latent Oneiroid Paraphrenia Pseudoneurotic Simple deteriorative disorder

lasting <3 months

Dreamlike Increased paranoia in presence of a known delusion Anxiety worsening to psychosis “Simple schizophrenia” Gradual decrease in ambition Postpsychotic depressive disorder of schizophrenia Early (< 18 years of age) versus late (> 45 years of age) Deficit Enduring idiopathic negative symptoms

Scales PANSS 30-item scale

(Positive and Negative Symptom Scale)

16 general psychopathology symptom questions 7 positive symptom questions 7 negative symptom questions 7-point severity scale Potential score of 30 to 210 Most commonly used Scores 60

Minimally ill

100

Moderately ill

Improvement is considered with 20% reduction of scores (Critics believe an improvement in symptoms should be a 50% reduction of scores) BPRS (Brief Psychiatric Rating Scale) Positive symptoms, general psychopathology, and affective symptoms 18-item scale 7-point severity scale Differential Diagnosis Mood disorder: Bipolar (consider proportion and duration of mood) Substance use/abuse/dependence (look for temporal relation between use and symptoms) Psychotic disorders Delusional, schizophreniform disorder (consider duration and extent of psychotic symptoms) Physiological causes Other psychiatric disorders Brief reactive psychosis Schizophreniform Schizoaffective disorder Delusional disorder Brief psychotic disorder Shared psychotic disorder Psychotic disorder due to a general medical condition Psychotic disorder NOS Autism Personality disorders Anxiety disorders

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<1 month <6 months Mood symptoms

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COURSE Premorbid personality Abnormal in 1/3 of patients Characteristics Shy Poor grades/academic functioning Difficulties in language acquisition especially speech development Poor peer relationships Bizarre preoccupations Dysphoria Polysubstance abuse Steeper decline leading to a first psychotic break Late adolescence or early adulthood (especially males) Females approximately 25 years (but after menopause, course is just as severe) suggesting estrogen as an attenuating factor Insidious onset is more common Earlier onset if substance abuse, head injuries are present If considering a neurodevelopmental etiology An earlier onset would be more prevalent But the condition often manifests during adolescence coinciding with pruning and myelinization Importance of early diagnosis and effective treatment Most deterioration occurs early—“toxicity of psychosis” There is an average of 1 to 1½ years delay between onset of the illness and treatment Lifelong prognosis Adolescent/early adult onset 90% lifelong 33% with mild impairment 33% with moderate impairment 33% with significant impairment High rates of medication nonadherence High rates of medical comorbidities Working with collateral systems is imperative Primary care providers School/employment systems Avocation Family

AFFECTIVE IMPAIRMENT ASSOCIATED WITH SCHIZOPHRENIA Depression Lifetime risk of general population is 7% to 25% and with schizophrenia is 50% to 80% 50% of individuals with schizophrenia have co-occurring depression Risk factor for poor prognosis of schizophrenia Important to treat both conditions to optimize patient outcome Suicide 10× higher risk for patients with schizophrenia than the general public 50% of patients with schizophrenia attempt suicide Lifetime suicide risk 10% Major risk factor: Substance abuse and depression Substance abuse 80% of individuals with schizophrenia utilize tobacco

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Consequences of substance abuse comorbidity Worsens mental illness Increased risk Suicide Violence Risky behavior Poorer health Increase in health service utilization Decreased service capacity and coordination Individual outcome optimization Treatment Treatment Medications Cognitive behavioral therapy Rehabilitation Enhance vocational skills Enhance social skills Supports Housing Supportive Costs and unintended side effects Side effects Costs Discrimination Related health risks Reduce disease burden and treatment burden Vocational or educational functioning Independent living Physical health Adherence Social integration Quality of life

TREATMENT Considerations of medication choices Choice of drug First episode Maintenance Multiple episodes Poor or partial responder History of nonadherence Comorbidities Dosage Minimum effective dose Maximum tolerated Increase dose if inadequate response noted (as tolerated) Potential helpfulness of blood levels Duration How long Wait 2 to 5 weeks for the initial response 2-week response predicts 3-month response What is most appropriate response measure?—PANSS Possible early predictors of response Therapeutic effects Adverse effects

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Alternative strategies Dose increase Augmentation Switching Clozapine Important factors in applying evidenced-based trial conclusions Physician skill (therapeutic alliance) Patient/family requests Existing systems of care Reimbursement Clinical decisions How much improvement is enough? When to change treatments? When to change again? When do side effects determine changes in treatment? Can locus of care be changed? First-generation antipsychotics (FGA) Based upon DA receptor antagonism (ranging from high to low potency) Second-generation antipsychotics (SGA) Based upon DA and 5-HT receptor activity Specific agent’s side effects Clozapine Myocarditis Interstitial nephritis Agranulocytosis More commonly associated during initial usage Check CBC weekly for first 6 months, then biweekly Seizures associated with doses >500 mg/d Olanzapine Pancreatitis Somnambulism Periodic leg movements and restless legs Weight gain Risperidone—Hyperprolactinemia Serum prolactin >30 ng/mL Mechanism of action Dopamine 2 receptor blockade increases prolactin and Risperidone’s 9-OH metabolite has a high affinity for D2 (Marketed as Invega) Greater risk when combined with clozapine Sex differences Males Ejaculatory dysfunction Gynecomastia Decreased libido Doses 4 to 10 mg correlates to side effects Females Amenorrhea Galactorrhea Decreased libido Osteoporosis Doses not correlated to side effects General categories of side effects QTc prolongation

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Psychiatry Bullets Specific agents Thioridizine associated with the longest (Black box warning) Ziprasidone 20.6 ms Quetiapine 14.5 ms Risperidone 10.0 ms Olanzapine 6.4 ms Haloperidol 4.7 ms Factors Advancing age Drug and alcohol abuse Polypharmacy Recommended interventions Screen Individual intervention If tachycardia, light-headedness, dizziness, or palpitations are reported, collaborate with primary care provider to determine course of action Avoid excessive alcohol intake Notify medication provider if over-the-counter agents or dietary supplements are used Holter monitoring Metabolic syndrome Defined by Waist circumference Males >40″ Females >35″ Triglyceride levels >150 mg/dL HDL—C levels Males <40 mg/dL Females <50 mg/dL Blood pressure >130/85 mm Hg Fasting glucose ≥110 mg/dL Time of occurrence Most often during the first 12 weeks Weight stabilizes after 6 to 12 months Consider that individuals may have preexisting symptoms prior to medication initiation CATIE: 4/10 pts already had metabolic syndrome Consideration of cardiovascular disease risk factors Modifiable and nonmodifiable risk factors Modifiable risk factors Obesity Dyslipidemia Glucose intolerance Hypertension Smoking Nonmodifiable risk factors Gender Family history Personal history Age The lipid profile “The Framingham Heart Study” Classic 1980 study examining the risk factors for coronary artery disease Although both HDL and LDL are important, low HDL more critical (<45 mg/dL)

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All statin agents show robust reduction of mortality Niacin may be helpful in raising HDL levels Triglyceride levels >200 mg/dL and HDL levels <45 mg/dL are poor prognostic signs Exercise decreases LDL levels Lowering high LDL levels is easier than increasing HDL levels Treatment of dyslipidemia Medications Statins Function—inhibits cholesterol synthesis All lowers LDL-C Rosuvastatin (Crestor) lowers LDL and triglycerides more robustly Mechanism of action Inhibition of HMG CoA reductase (rate limiting step of cholesterol synthesis) Clinical advisory—Hepatotoxicity is rare Fatal rhabdomyolysis is rare Nonstatins Types Niacin-immediate release (Nicotinic acid, vitamin B3) Side effects Flushing (long-acting forms cause less flushing but are more associated with hepatic side effects) Increased serum glucose (check HgA1c) Hyperuricemia (check uric acid—especially if gout is present) Fibrates Fenofibrate Careful if given along with stain Like niacin, increases HDL and lowers LDL and triglyceride levels Gemfibrozil (Lopid) Metformin Ezetimibe (Zetia) prevents absorption of cholesterol in the intestines (Vytorin) Diabetes mellitus Associations Body mass index (BMI) Especially if >30 Risk for Diabetic ketoacidosis (DKA) Nonketotic hyperosmolar coma Prevalence Ethnic Asians>Blacks>Latin>Caucasian Overall rates are increasing (10% of entire US predicted in 2010) Monitor regularly for worsening glucose control Check fasting plasma glucose prior to initiation Monitor regularly during treatment Screening questions Increased thirst Urinary frequency Unexpected lethargy Free fatty acids exit from adipose into plasma which then Decrease glucose utilization Decrease lipolysis Increase glucose output Plasma glucose ideally always should be <126 mg/dL Especially problematic in Asian individuals Individuals with type II diabetes and prior myocardial infarctions are at risk for fatal future myocardial infarction

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Psychiatry Bullets Possible mechanisms of action Weight gain D2 receptor antagonism (bromocriptine as an antidiabetic agent) 5-HT2c receptor is involved in food intake/appetite H1 receptor Muscarinic acetylcholine receptors Inhibition of glucose transport Insulin resistance Leptin resistance Insulin resistance Risk factors Hypertension Increased C-reactive protein levels High triglyceride levels Low HDL levels High plasma insulin levels Albuminema High plasma glucose Presence of insulin resistance seen 7 years prior to the diagnosis of diabetes Treatment Consultation on diet and exercise Specific agents Consider cessation of the SGA Consider switching to a different SGA Suggestion that risperidone is less diabetogenic Bromocriptine Dopamine agonist FDA-approved for diabetic treatment Metformin Weight neutral Side effects (diarrhea nausea) DPP-4 inhibitors Examples Sitagliptin (Januvia) Saxagliptin (Origlyza) Weight neutral Side effects—well tolerated hypoglycemia Sulfonyureas Examples Glipizide Glyburide Glimepiride Not weight neutral (weight gain) Side effects—hypoglycemia Thiazolidinediones Examples Rosiglitazone (Avandia) Pioglitazone (Actos) Not weight neutral (weight gain) Side effects edema contraindicated in CHF GLP-1 receptor agonists Examples Exenatide (Byetta) Liraglutide (Victoza) Weight loss Side effects, nausea, pancreatitis Insulin therapy

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Chapter 3 Schizophrenia

Role of blood pressure Systolic blood pressure appears to be more critical (>160) than diastolic However, if the person is younger than 50 years, diastolic levels (>95) are more critical With every 20/10 mm Hg increase, the risk for cardiovascular disease doubles 115/75 relative risk multiplied by 1 135/85 relative risk multiplied by 2 155/95 relative risk multiplied by 3 175/105 relative risk multiplied by 4 African Americans are at much greater risk for hypertension—thus, aim for blood pressure <120/80 mm Hg Treatment of hypertension algorithm PreHTN No medication Lifestyle modification Stage I Hydrochlorothiazide Beta-blockers Angiotensin, ACE inhibitors* Alpha blockade, Calcium channel blockers *6% risk for cough (50% risk in Asians) Stage II two medication combination (like HCTZ + ACE inhibitor) Early and aggressive treatment with a goal of 120/70 mm Hg Monitor for risk factors: Diabetes mellitus >2 other risk factors for heart disease African American ethnicity History of heart disease (especially past myocardial infarction) Chronic renal insufficiency or failure Classification of blood pressure readings Normal <120 mm Hg Prehypertension 120 to 139 mm Hg HTN Stage I 140 to 159 mm Hg Stage II >160 mm Hg

Encompassing Major Side Effects

Lithium Valproate Carbemazepine ± Lamotrigine Clozapine Olanzapine Risperidone Ziprasidone Quetiapine Aripiprazole

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Wt gain

CNS

EPS

Derm

GI

++ ++ +++ ± ++++ +++ ++ ± ++ ±

+++ ++ 0 − +++ ++ + + ++ +

0 0 +++ 0 0 + ++ + 0 +

++ + + +++ + + + + + +

++ ++ + + + + + + ++

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Psychiatry Bullets

Goal

Lower cardiovascular disease

Cholesterol

10% drop results in 30% drop in cardiovascular disease

Hypertension

4 to 6 mm Hg drop results in 16% to 42% drop in CVD/stroke

Smoking

Stopping drops 50% to 70% drop in cardiovascular disease

BMI < 25

Drops 35% to 55% chance of cardiovascular disease

Exercise

Drops 35% to 55% chance of cardiovascular disease (20 minutes daily)

STUDIES EXAMINING SGA’S CATIE: Schizophrenia trial design Phase I 1,460 patients randomized to Olanzapine Quetiapine Risperidone Ziprasidone Perphenazine Dosing of agents is controversial Olanzapine

High

Quetiapine

Low

Risperidone

Low

Ziprasidone

low (and without the emphasis of better absorption with food)

Patients with tardive dyskinesia were not randomized to take perphenazine Phase II Those who failed Phase I due to inefficacy were randomized to clozapine or other SGAs (as noted) or if they failed Phase I due to intolerability, were randomized to other SGAs (not clozapine) Phase III Those who failed Phase I and II were given options of above antipsychotics plus fluphenazine decanoate or any combination of two Phase I Double blinded and randomized Demographics and clinical characteristics (BROAD but no first break patients) Conclusions Discontinuation All agents were associated with discontinuation 75% discontinued before 18 months Causes of discontinuation Weight gain/metabolic symptoms Extrapyramidal side effects Overall, olanzapine associated with the least discontinuation (but caused the most weight gain) Overall, risperidone was the most tolerated Olanzapine Most effective Associated with greatest risk for metabolic syndrome Risperidone Lower efficacy than olanzapine, but comparable to others Highest prolactin serum levels Lowest discontinuation due to side effects

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Chapter 3 Schizophrenia Quetiapine Lower efficacy than olanzapine, but comparable to others Good extrapyramidal and prolactin profiles Ziprasidone Lower efficacy than olanzapine, but comparable to others Excellent safety profile Perphenazine Lower efficacy than olanzapine, but comparable to others Well tolerated Higher discontinuation due to extrapyramidal side effects Metabolic findings Mean plasma glucose and HgA1C levels Olanzapine>Quetiapine>Risperidone>Perphenazine>Ziprasidone Total cholesterol and triglycerides As above but ziprasidone may have reversed raised cholesterol levels

ADA Consensus on Antipsychotic Drugs and Obesity and Diabetes Drug

Weight Gain

Diabetes Mellitus Risk

Dyslipidemia

Clozapine

+++

+

+

Olanzapine

+++

+

+

Risperidone

++

discrepant

Quetiapine

++

discrepant

Ariprazole

±

−

−

Ziprasidone

±

−

−

Some other interesting findings Switching antipsychotics lowers weight Stronger H1 receptor affinity associated with stronger weight gain Clozapine>Olanzapine>Quetiapine>Risperidone >>Aripiprazole>Ziprasidone equal to Perphenazine The SGAs are independent risk factors for diabetes Clozapine>Olanzapine>Quetiapine=Risperidone Clozapine‘s effectiveness in schizophrenia—a meta-analysis Clozapine is underutilized Helpful for Poor or partial responders to other antipsychotic agents Suicidal individuals Aggressive individuals Individuals with substance use/abuse/dependence Comparing relapse rates between FGA and SGA Risperidone has smaller relapse rate compared to Haloperidol Olanzapine has smaller relapse rate compared to Haloperidol FGAs have relapse rate of 58%, whereas the SGAs have a relapse rate of 23% Adding SGA to FGA reduces relapse rate by 35% Possible explanations for above observations Adherence Mechanism of action not limited to dopamine Incidence of tardive dyskinesia with SGA Meta-analysis 2004 suggests substantially less incidence with SGA Monitoring for extrapyramidal side effects even with SGA critical Adding valproate—meta-analysis reveals a negative impact

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CUtLASS (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study [2006]) Design 14 clinics Randomized controlled trials FGA and SGA (except clozapine) Evaluation at week 12, 26, and 56 227 individuals aged 18 to 65 years Measure Quality of Life Scale Conclusions FGA and SGA are equally therapeutic Davis, J Arch Gen Psych, 2003—Effect sizes Clozapine

0.6

Risperidone

0.5

Olanzapine

0.5

Others “didn’t do as well” Kane, J Clin Psych, 2007: Perphenazine equivalent to aripiprazole Lindemeyer, 2007: Olanzapine superior to Haloperidol for negative symptoms SGAs more effective with negative symptoms Neither FGAs nor SGAs effective for neurocognitive Find improvement in quality of life Emphasis that neurocognitive improvement is critical for Social rehabilitation Cognitive rehabilitation Jones, Arch Gen Psych, 2006: FGA>SGA for quality of life Geddes MJG 2000: lower discontinuation rate for SGA (unless you look at comparable haloperidol doses) Multiple studies point out to similar therapeutic effects amongst SGAs, but clozapine had greater efficacy Differences in response—genetic polymorphisms? Cytochrome P-450 variants 2D6 7% of the Caucasian population are poor metabolizers leading to higher serum plasma levels due to slower metabolism 1% other ethnic groups 2D6 poor metabolizers Safe for Clozapine Olanzapine Quetiapine Ziprasidone Care required for FGA (especially thioridazine) SGA (possibly for aripiprazole)

PRACTICE RECOMMENDATIONS (FDA ISSUED A WARNING IN 2003 REGARDING SGA AND METABOLIC PROFILE; AND, IN 2008, ADDED FGA) Before initiating treatment History and physical exam

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Document personal/family history Diabetes Obesity Hyperlipidemia Cardiovascular disease Weight and height (to determine BMI) Waist circumference Blood pressure Laboratory tests Fasting glucose Fasting lipids Prolactin levels TSH Monitoring Weight At month 1, 2, 3 If >5% (especially in first month), consider switch/cessation Monitor Glucose Consultation if glucose > 300 mg/dL Lipids Blood pressure Others as applicable

PHARMACOLOGICAL STRATEGIES FOR TREATMENT-RESISTANT SCHIZOPHRENIA Rapid treatment for extreme agitation Haloperidol and lorazepam Fast acting per oral forms Quetiapine 200 to 800 over 4 days Olanzapine 40 mg over 4 days Intramuscular atypical antipsychotic agents Ziprasidone 10 to 20 mg/d; max 40 mg daily Olanzapine 10 mg/d Aripiprazole 9.75 mg Clozapine for antihostility Mood stabilizers—modest results Beta-blockers/SSRIs—modest results Benzodiazepines—watch for exacerbation or disinhibition Combination Polypharmacy strategy Benefits Symptom targeted treatment Address unremitted symptoms Lower the dose of a more toxic agent Risks Cumulative toxicity/adverse events Adherence issues Enables suboptimal monotherapy Lack of evidenced-based strategies Compensates for Weak D2 blockade Strong 5-HT2a blockade Rapid D2 dissociation—haldol can block for days to weeks

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Possible synergistic effects Controversial Greater likelihood of side effects Even efficacy shows mixed results Examples Adding clozapine Adding lamotrigine No significant differences in five studies Possible reduction of alcohol craving for individuals with schizophrenia Adding antidepressants for negative symptoms Adding cognitive enhancers—no positive findings Adding FGAs—may negate benefit of SGAs Pharmacokinetics Lithium increases ziprasidone levels Valproate decreases ziprasidone levels Fluvoxamine increases clozapine and olanzapine levels by as much as four times Lamotrigine increases risperidone and olanzapine levels slightly Importance of p-glycoprotein Found in vessels of blood-brain barrier Prevention of harmful agents entering into brain Altering them has advantages and disadvantages Risperidone and its metabolite are potent inhibitors of p-glycoproteins Thus, other drugs will flow through more easily Long-acting forms Haloperidol decanoate Paliperidone ER Metabolite of risperidone Daily dose 3 to 12 mg Osmotic control-released oral delivery system, OROS General approaches Clozapine trial Switching technique Decrease first dose Gradually add second drug Use non–weight gaining SGA Add FGA Adding other medication classes ECT for behavioral disruption or augment for clozapine-resistant individuals Future medications COMT polymorphism D3 receptor polymorphisms may predict TD and EPS 5-HT2c predicts weight gain Glutamate NMDA receptor enhancers D-cycloserine Glycine agonists Amphokines Nicotinic-cholinergic agonists Alpha 7 ACh receptor agonists for glutamate hypofunction—thus improving cognition Stimulants—improving attention Intensive treatment of comorbid PSA Homocysteine excess in pregnancy Inhibiting cannabis-1 receptor Specific agents Asenapine (currently available) 5-HT and NE also Clozaril-like

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Iloperidone D1 and 5-HT2A receptors Low weight gain, diabetes mellitus, EPS, no prolactin Prolongs QTc

SUBSTANCE ABUSE IN INDIVIDUALS WITH SCHIZOPHRENIA High in patients with schizophrenia Possibly self-medicating frontal lobe dysfunction (nicotine) Possibly medicating deficits discussed CB1 receptors in the frontal lobe Family history of schizophrenia or DA pathway polymorphism May be more sensitive to THC psychosis Agents which may exacerbate psychotic symptoms Stimulants Cocaine Cannabis PCP Prevalence Nicotine—81% to 88% of individuals with schizophrenia smoke cigarettes Other agents—40% to 60% Risk factors Young age Male Less educated Less peer support Poorer treatment outcome Treatment Long-term strategies should be implemented Medication and therapy Initial goal is to stabilize psychosis and then focus on substance use Medical considerations Hepatic Cardiac Drug interactions Side effects of drugs Specific agents Alcohol

Naltrexone

Opioids

Methadone

Nicotine

Nicotine patch Bupropion

Collaborative team approach

NONPHARMACOLOGIC TREATMENT Approaches Psychoeducation 10 studies Decrease in relapse or readmission rates (NNT 9) Compliance significantly improved in one study Positive effect on the patient’s well-being

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Psychiatry Bullets No impact on insight/med adherence Assertive community treatment 17 trials More likely to remain in contact with services Less readmission (NNT 10.3) and shorter hospitalization stay More likely to live independently, less unemployment, more happy Better than hospital-based rehabilitation Cognitive behavioral therapy 13 trials CBT+standard care increased discharge rates NNT 3 No improvement in relapse or readmission More medication adherence Family intervention 13 trials Decrease rate of relapse NNT 6.5 Tend to be medication adherent Enhance family communication Enhance family problem solving skills Cognitive rehabilitation Three trials Improved self-esteem No difference in mental state, social, or occupational functioning

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Chapter

4

Depression

OVERVIEW OF EMOTIONS (Understanding emotions spotlights the complexity of how treatment interventions theoretically work) The three components of emotion Physiologic arousal Changes in heart rate, blood pressure, respiratory rate Changes in muscle tension Changes in perspiration (skin conductance response) Changes in perceived body temperature Changes in sensory sensitivity (pain) Behavioral expression—social interactions and “hard wired” Facial expression Tone of voice Posture Conscious experience—subjective feeling of an emotion “Types” of emotions—“How many emotions do humans have?” Plutchik (researcher in the mid-1900s) Anger Fear Sadness Joy Disgust Surprise Curiosity Acceptance Ekman (researcher in the late 1900s) observed populations in the tropics Anger Fear Sadness Happiness Disgust Neurobiologically based components of emotions Perception/evaluation—based upon past experience “hard wiring” Subjective experience—conscious experience that is positive or negative Conditioning/learning—situation/experience linked to emotional reaction Expression—somatic and autonomic activity elicited Role of emotions Safety Social Decisions/guiding behaviors 31

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Words on fear and anxiety Hard wired and species-typical response (not learned or conditioned) Involvement of Identification of fear-inducing agent “hard wired” Defensive behaviors Autonomic arousal Hypoalgesia Potentiation of somatic reflexes Hypothalamic-pituitary-adrenal (HPA) axis activation Response triggers can be learned or conditioned Amygdala and HPA axis play critical roles

ETIOLOGY OF DEPRESSION Neurotransmitter construct monoamine (and receptor) hypothesis Explanation Depression is due to a deficiency of monoamines (NE/5HT) in neuronal synapses Evidence Certain drugs that deplete monoamines cause depression Certain drugs that increase monoamines improve depression Problems Levels of monoamines increase immediately, but response is delayed An increase in the monoamines and a physiological change in the postsynaptic neuron receptors are involved in this hypothesis Specific pathways NA—noradrenergic pathway Locus coeruleus → prefrontal cortex and limbic Depletion affects Mood Concentration Interest Energy Causes psychomotor retardation Functions Frontal projections Mood Arousal/attention Limbic projections Energy Agitation/anxiety Emotions (motivation/pleasure) Cerebellar projections—tremor Brain stem projections—blood pressure, appetite 5HT—serotonin pathway Raphe nucleus→ PFC and limbic areas Depletion affects Anxiety Mood Functions Frontal cortex projections Mood Basal ganglia projections Akathisia/agitation/anxiety Obsessive compulsive activity Limbic projections Anxiety

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Hypothalamic projections Appetite Brain stem projections Insomnia Nausea/vomiting Temperature regulation DA—dopamine pathways Functions Nigrostriatal (basal ganglia) Movement Mesolimbic (midbrain—nucleus accumbens) Pleasure Perception integration (delusions/hall) Tuberoinfundibular (hypothalamus and anterior pituitary gland) Prolactin Mesocortical (midbrain to frontal cortex) Positive and negative symptoms Cognition Support of the neurotransmitter construct Antidepressants will eventually lead to down-regulation of receptors which the monoamines bind The time course of this down-regulation corresponds to the delayed onset of the antidepressant action The time course also corresponds to the time it takes patients to become tolerant to side effects Anatomical construct Areas of interest Limbic System Cingulate gyrus Fornix Septal nucleus Mammillary body Amygdala Hippocampus Insular cortex Frontal lobe systems OFC (orbitofrontal cortex) VMPFC (ventral medial prefrontal cortex) Pain, aggression, social, and sex behavior Autonomic and neuroendocrine DLPFC (dorsal lateral prefrontal cortex) Cognitive control, solving complex tasks, memory manipulation Low activity associated in depression High activity in this area suggests low activity in VMPFC (via cingulate and hippocampus via glutamate and GABA but 5HT and NE possibly control direction of activity) LOPFC (lateral orbital prefrontal cortex) Depression, OCD, panic, PTSD Corrects and inhibits maladaptive, preservative, and emotional Spotlight on the limbic system Amygdala Importance Coordinating center for the emotional expression of fear Afferent and efferent pathways active Unconscious emotional memory Fear conditioning

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Psychiatry Bullets

Stimulation causes fear/withdrawal/rage Kluver-Bucy syndrome Afferents and effects Lateral hypothalamus → sympathetic activation Dorsal motor nucleus of vagus nerve → Parasympathetic activation Parabrachial nerve→ dyspnea/hyperventilation Ventral tegmental area Locus coeruleus Dorsal lateral tegmental area → behavioral arousal/EEG arousal (hypervigilance) Nucleus reticularis pontis caudalis → increased startle Midbrain central gray → freezing, fear of dying Trigeminal/facial motor nerve → facial expression of fear Paraventricular nucleus → HPA activation Hippocampus—and its role in depression If the amygdala is the activating force, then the hippocampus associates emotional valence to the memory Roles Cognitive functioning Emotions Neuroendocrine functioning Learning Communication with hypothalamus and pituitary Smaller volume can be an obstacle to future treatment Neuroendocrinological Construct Monoamines Serotonin and norepinephrine influence GABAergic activity as well as glutamatergic activity in the prefrontal and limbic cortices. Excessive glutamatergic activity results in decreased locus coeruleus and raphe nucleus activity, which then reduce serotonin and norepinephrine activity. Excessive glutamate leads to production of glucocorticoids, which have been known to have toxic effects on the hippocampus Dysfunction of the hippocampus contributes to cognitive impairment and emotional and neuroendocrine dysregulation Cortisol and depression Early trauma (parental loss or abuse) can lead to permanent changes HPA axis Increased HPA axis activity Increased hypothalamic production of cortisol releasing factor (CRF) Increased pituitary secretion of Adrenocorticotropic Hormone (ACTH) leading to Increased adrenal secretion of cortisol Increased number of CRF neurons Hypersensitive and increased CRF and cortisol responsiveness Thus, even mild stress can lead to an exaggerated CRF and cortisol response Chronic exposure to above normal cortisol leads to Hippocampal damage Hippocampal damage correlated to MDD HPA axis and fear General adaptation syndrome Nonspecific stimuli Hypothalamus → cortisol releasing hormone (CRH) → pituitary → Adrenocorticotropic hormone (ACTH) → Adrenal cortex → cortisol (which (increases energy) → B endorphin (which promotes analgesia) → Sympathetic NS → NE and E Fight-or-flight response NE (norepinephrine) Increased heart rate and blood pressure

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Increased lipid breakdown (lipolysis) Peripheral vasoconstriction E (epinephrine) Increased heart rate and blood pressure Increased lipid breakdown (lipolysis) Peripheral vasoconstriction Coronary dilation/bronchial dilation Muscle’s glycogen broken down to glucose Antidepressants’ association with reparation and growth construct (Antidepressants enhance the connectivity of impaired networks) The amygdala is the “activating” force and the hippocampus is the “modulator” of emotional response The hippocampus Appears to be a center for making and storing emotional memories Toxicity due to excessive input from VM PFC and glucocorticoids (physically changes the hippocampus) Dysfunction may contribute to cognitive impairment, emotional dysregulation, neuroendocrine dysregulation Hippocampal volumes tend to be smaller (?brain plasticity) In individuals with childhood PTSD In individuals with longer duration of untreated depression Neurons under stress are less arborized (cortisol toxicity) Role of Mediators—BDNF (brain-derived neurotrophic factor) Functions Assists in survival of existing neurons Encourages growth and differentiation of new neurons and synapses Adult neurogenesis occurs normally in olfactory bulb and hippocampus Do antidepressants increase hippocampal neurogenesis/neuroplasticity (since depression causes decreased hippocampal volume)? Role in depression Stress and glucocorticoids suppress BDNF expression in the hippocampus at the mRNA and protein level Antidepressants enhance BDNF expression and its receptor Trk3 in the hippocampus Antidepressant-treated patients have enhanced BDN Infusing BDNF into animals’ hippocampus has an antidepressant effect Increases in BDNF promote synaptic plasticity and new spine formation in the hippocampus Neurogenesis continues to occur in key brain areas (hippocampus) BDNF associated with production of new neurons and their growth and development Neurotrophins modify synaptic transmission in an activity developmental manner Downregulated in MDD and increased in antidepressant treatment Has a hypothetical neurotrophic effect that influences mood and perception of pain Increased levels increase the “3 N’s” Neuroplasticity—cells can communicate effectively Neurogenesis—proliferation of new cells Neuroprotection—increases cellular resistance Stress/glucocorticoids/glutamate → decreases BNDF, decreases synapse and neuronal size Animal models—stress and pain lower BDNF gene expression Antidepressants and neurogenesis Chronic antidepressant treatment in adults increases hippocampus neurogenesis Disrupting antidepressant-induced neurogenesis blocks behavioral response to antidepressants

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Genetics Construct The 5-HT transporter (5-HTT) promoter gene polymorphism (5-HTTLPR) ss represents the short allele promoter region ll represents the long allele promoter region Having the ss allele/variant Associated with Increased amygdala reactivity response ( f MRI demonstration) Decreased anterior cingulate filtering response Higher vulnerability for adult major depression (especially in context of environmental stressors) Associated with poor antidepressant efficacy to Fluvoxamine Paroxetine Associated with greater adverse effects from Fluoxetine Paroxetine Associated with better efficacy in Asians from Fluvoxamine Paroxetine Having the ll allele/variant Associated (in STAR *D) with longer duration on citalopram 5-HT 2A receptor and 102 T/C SNP Having C/C variant Associated with poor clozapine response Associated with paroxetine adverse effects In patients with MDD there are state-dependent increases in activation of the amygdala and increased amygdala activation influences perception of perception and cognition (?worry/rumination) An increase in the monoamines and a physiological change in the postsynaptic neuron receptors are involved in this hypothesis Other Etiologies Impaired regulation of hormonal release Decreased growth hormone (GH) Thyroid-stimulating hormone (TSH) Substance P neurokinin 1 (Subs P preferring receptor), therefore, neurokinin receptor antagonist Found in stress-response brain areas Converges with NA, DA, 5-HT pathways associated espec 5-HT Therapy changes our limbic responses “top down” and medications are “bottom up” Depression as a “Metabolic Syndrome” Construct Medical illness and relationship with depression Some facts HTN if also depressed associated with 3× morbidity risk CAD “ 40% increased cardiac risk Post-MI “ 33% at 3 months—mortality 4 – 6× Poststroke “ 20% – 25% Diabetes mellitus “ 15% – 20% poor glycemic control Arthritis “ 40% – 60% increased mortality Other connections Post MI patients with depression more likely not to exercise Smokers with depression 40% less likely to quit over 9 years CAD with depression less likely to adhere to low dose Aspirin patients with depression 3× more compliant Systemic consequences of depression Hypothalamus stimulates the pituitary gland to release excessive ACTH

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Adrenal gland releases excessive catecholamines and cortisol catecholamine increases lead to myocardial events, decreased heart rate variability, and possibly ventricular arrhythmias Platelet activation increase which leads to cytokines and interleukins release, which may lead to atherosclerosis and hypertension Cortisol antagonizes insulin leading to dyslipidemia, diabetes, and obesity Suppresses the immune system Recovery decreases with the duration of major depressive episodes 54% recovery rate after 6 months; 16% after 1 year Progression of depression—“kindling” and stress After six to seven episodes of depression, stress has little impact on relapse Thus, the number of depressive episodes increases the risk of relapse

RISK FACTORS FOR DEPRESSION Suggested risk factors Dysthymia is associated with 70% – 80% chance of MDD Loss of a parent before the age of 11 years Childhood onset of depression Medical illness (pancreatic cancer, multiple sclerosis, brain tumors) Stress/learned helplessness Screening for risk factors Screening options Two question screening (Either positive response is a positive screen): Over the past 2 weeks have you felt down or hopeless? Over the past 2 weeks have you felt little interest in doing things? PHQ-9 Nine-item questionnaire Self-administered or by a clinician

SUICIDE Risk factors Increases with age (especially after the age of 85 years) Psychiatric Illness (depression, bipolar, dysthymia, OCD, panic disorder, schizophrenia, alcoholism) Bipolar disorder associated with higher risk factor Young males with schizophrenia with depression not actively hallucinating associated with higher risk factor Acute risk factors (within 1 year of assessment) Severe anxiety Panic attacks Global insomnia Recent alcohol abuse Severe anhedonia Chronic risk factors (within 2 – 10 years of assessment) Suicidal ideation (assess risk of method also) Prior suicide attempts (assess severity also) Hopelessness * predictor of strong MDD Other risks The individual believed that the risk was high Male—especially if Caucasian and older than 45 years

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Psychiatry Bullets Ethnicity (Caucasian>Native Americans>Hispanics>Blacks) Access to firearms Lack of intact family, living alone Mother with mood disorder Poor communication with family Father crime history Family history of suicidal behavior Failing/disciplinary/suspension/dropping out Lack of college education Occupation (chemistry, farming, law enforcement, women in medicine) Hopelessness External locus of control Parental death (loss of mother more so than father) Family history of psychiatric illness Family history of suicide Poor physical health NOT socioeconomic status Differential diagnoses: Self-injurious behaviors High-risk behaviors Polysubstance use Comorbidity Major depression Alcohol abuse/dependence Illicit drug use Conduct disorder Treatment Containment Health insurance Quality of care in the emergency department If family dysfunction—family therapy Treat psychiatric conditions

SUBTYPES Severe depression What is severe depression? Clinical setting Psychotic Suicidal Melancholic Receiving inpatient care Comorbidity exists Functional impairment Treatment resistance Research setting—defined by research measures Discipline-specific Relevance of severity Less likely to remit Longer treatment periods Marker for comorbidity High rate of suicidality Few spontaneous remissions. DSM-IV-TR Measuring severity

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QIDS PHQ-9 Treating severe depression Antidepressants Combination of medication and therapy Electroconvulsive therapy (ECT) Vagal nerve stimulation (VNS) Repetitive transcranial magnetic stimulation (rTMS) Deep brain stimulation therapy (DBS) Severity as a predictor of antidepressant medications Depressed inpatients had a more robust response to TCAs (compared to placebo) Desipramine response better in those with higher HAMD scores Amitriptyline better than placebo with HAMD>12 Mild depression placebo responses are better than with severe depression Studies Escitalopram and paroxetine SADHART CREATE STAR*D ECT and rTMS Psychotherapy and combined treatment Atypical depression History/development of the clinical concept The “atypical depression” concept arose from clinical observations that some depressed patients had better response to MAOs than TCA DSM-IV criteria arose from research at Columbia University Atypical features specifier (DSM-IV, APA, 1994) Greater than two symptoms with mood reactivity: Significant weight gain or increase in appetite* Hypersomnia* Leaden paralysis Long-standing interpersonal rejection* * appear to be very common in atypical depression Atypical depression—community data 2002—4.8% prevalence rate 2005—triadic concept (female, eating, sleeping) Females affected more than males Bipolar disorder type II Rates of atypical depression Features in 22% – 40% of MDD patients In community, private, tertiary settings, recommend thinking prevalence as 25% – 30% STAR-D reports that 18% of those with depression met criteria for atypical depression; features assessing for atypical depression symptoms is not fully found in standartized testings Primary Care Setting study Mean age 46 Men 1/3 Women 2/3 Mean HAMD scale 18 (does not include increased appetite, hypersomnia, and rejection sensitivity) 26% with atypical Difficulties in comparisons of various studies Criteria of atypical depression vary Sampling methods in studies vary

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40

Psychiatry Bullets Operational criteria in ICD-10 are missing HAMD is most frequent scale used in studies and does not include atypical symptoms of hyperphagia or insomnia (alternative is IDS-C) Pharmacotherapy MAOI TCA Newer AD SGA Treatment with monoamine oxidase inhibitors (MAOIs) Monoamine oxidase isoforms MAO A Deaminates 5HT, E, NE (and melatonin) Found in the brain and gut MAO B Deaminates phenethylamine and benzylamine Platelet as a marker Both MAO A and B Deaminates tyramine and dopamine Early MAOIs Inhibits MOA irreversibly and nonselectively Forms unbreakable bond with enzyme (It takes 14 days to synthesize new MOA) Decreases breakdown of NE and 5-HT Increases synaptic concentrations of NE and 5-HT Receptor and signal transduction changes In current use Isocarboxazid (Marplan) Tranylcypromine (Parnate) Phenelzine (Nardil) l-Deprenyl (Selegiline) Limitations of isocarboxazid, tranylcypromine, and phenelzine Dietary restrictions Risk of serotonin syndrome via drug-drug interactions Hypertensive crisis (due to undergraded tyramine) leading to stroke/death High side effect burden Orthostatic hypotension Edema Weight gain Sexual dysfunction Selegiline FDA approved for Parkinson’s (at lower doses—MOA-Bi) FDA approved for depression(at higher doses MOA-Ai) STS—Transdermal delivery Bypasses first pass and intestinal absorption Nonselective inhibition in brain (MAO A and B) Dietary and drug interactions Doses <6 mg/24 hours not problematic MAOI diet at >6 mg/24 hours Caution when switching from SSRI/SNRI A meta-analysis of randomized controlled trials of atypical depression demonstrates a robust response to phenelzine (72%) compared to imipramine (44%) compared to placebo (26%) Pharmacological treatment of atypical depression Modern antidepressants SSRIs

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41

Varied response 65% response rate for fluoxetine Moclobemide (MAOI not approved for use in the US) superior to fluoxetine Phenelzine = Fluoxetine Fluoxetine compared to imipramine No difference (but fluoxetine was better tolerated) SNRIs 5-HT1a agonists Buspirone Gepirone (not approved for use in the US) Partial 5-HT1a agonist Response rate at 8 weeks—62% (placebo’s response rate—20%) Dosed at 30 – 120 mg/d Alternative Chromium picolinate Possible effectiveness Giving immediate release may improve mood Inconsistent findings Typical dose 600 mg/d Mechanism of action is not known Increases insulin sensitivity via enhancing central NE and 5H activity Downregulates postsynaptic 5-HT2a receptors and activation of these receptors contributes to differences with sleep and sexual function Phosphoinositol second messenger system used for insulin resistance (and carbohydrate craving found in atypical depression) St John’s wort A small study showed that it can be helpful with increased sleep and appetite A larger study is pending although promising a similar response TCA MAOIs are considered superior Imipramine is the best studied Special populations—elderly Best estimate incidence of atypical depression 28% SNRI study (Venlafaxine XR) in women especially Unmet needs in treatment of atypical depression Limited evidence of efficacy of newer classes of antidepressants Limited studies of efficacy Limited studies of nonpharmacological treatment

DIFFERENTIAL DIAGNOSES Medical Treatment side effects Comorbidity (hypothyroidism) Psychiatric disorders—Bipolar conditions Comorbid psychiatric conditions Anxiety (panic disorder, generalized anxiety disorder) Polysubstance use/abuse/dependence New-onset anxiety in the elderly is likely to be depression Bereavement/grief Normal bereavement Associated with sadness, insomnia, poor concentration in waves Usually lasts less than 2 months Not usually associated with

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Psychiatry Bullets

Psychomotor retardation Worthlessness or guilty preoccupations Suicidal ideation Hallucinations Treat especially if there is a history of past depression Symptom manifestation in the chronically medically ill Negative thinking Poor concentration Depressed mood Lack of interest Impaired daily functioning likely to overlap with chronically ill conditions Impairment of appetite, sleep are also often unreliable

TREATMENT Historical observations Reserpine (antihypertensive) found to cause depression (amine depletion) Iproniazid (a drug for tuberculosis) has antidepressant effects due to its MAOI activities Imipramine (antihistamine—TCA) with antidepressant effects Doxepin (powerful antihistamine—TCA) with antidepressant effects Blunted TSH response to TRH challenge secondary to down-regulation when increased TRH reaches it Blunted GH response to clonidine (alpha 2 agonist) Substance P/neurokinin 1 A general approach Monotherapy does not help in 30% of conditions (but does help 70%) Improved adherence → improved outcomes (know patient’s preferences) “Do something”—“Start low, Go Slow, But GO” Antidepressant selection Individual’s response history Family members’ response histories Side effect profiles Cytochrome P45 Izoyme inhibition (2D6) SSRIs versus TCAs Discontinuation usually due to high doses and rapid cessation Sexual dysfunction side effects (30% – 40% chance if on SSRIs) Drug holiday/substitution—consider 24 – 30 hours t½ Augmenting with bupropion/buspirone Residual symptoms are high risk for recurrence (and early relapse) Other augmenting agents SGA (consider long-term side effects) Modafinil Recurrence (after recovery from MDD) Duration Coordinated care Team approach Case manager Support, self-help, patient visit groups Psychiatrist Remind individuals of upcoming appointments Education About illness and offer available therapies (CBT) Exercise moderately (relieve tension and improve sleep)

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43

Avoid caffeine Avoid alcohol and nicotine (excess) Sleep hygiene Support—providing HOPE Other ECT, TMS, VNS, therapy Electroconvulsive therapy (ECT) Mechanism of action (essentially not known) Bioaminergic Metabolic activation (mobilize cortical hypometabolism) Impact sleep architecture (soporific) Anticonvulsant Indications Mood disorders Depression Active symptoms No positive findings for maintenance Refractory Can be a first-choice treatment Mania Acute symptoms No positive findings for maintenance Refractory Can be a first-choice treatment If complicated by catatonia Psychotic disorders Acute symptoms If complicated by catatonia Can be a first-choice treatment Other Neurological disorders EPS Seizures Emergent states Contraindications (none absolute) Recent MI or cardiac instability Increased intracranial pressure Recent stroke (especially hemorrhagic) Cerebral aneurysm/AV malformations Severe pulmonary disease ASA score ³4 (American Society of Anesthesiologists six category physical status classification) Obtain informed consent Preparation Psychoeducation Medical CXR EKG Basic metabolic profile/CBC Other pertinent consultations (cardiac) When necessary Pseudocholinesterase levels Concerns for high prelevels Spinal films History of osteoporosis Neuroimaging

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44

Psychiatry Bullets Concerning medication effects MAOI Hypertensive crises Lithium Delirium Depakote Even at a therapeutic range, ECT may reverse anticonvulsant effects Premedication NPO Anasthesia Methohexital 0.75–1 mg/kg Propofol 0.75–1.5 mg/kg Etomidate 0.15–0.30 mg/kg Muscle relaxant Succinylcholine 0.5–1 mg/kg (care as it is a pseudocholinesterase—cured with curare) Other Atropine (reduce mucus) Watch for rebound bradycardia Oxygen ?Lowers seizure threshold (increases pH) Beta-blockers to Lowers blood pressure Benzodiazepines Lowers anxiety Electrode placement Unilateral Nondominant lobe Usually first-line placement Bilateral Individuals present Psychiatrist Anesthesiologist or CRNA Monitor Vital signs Typically increases Observe for generalized seizures EEG Muscle twitch Prolactin levels Increases during seizures Duration of seizures Standard 30–60 seconds but <90 seconds No correlation between length of seizures and benefit If no seizure obtained Repeat process Identification for failed procedure Discontinue medications that raise seizure threshold Increase energy input But cognitive impairment is correlated with energy input Increase oxygenation Caffeine iv 120–140 mg Effectiveness Study comparing to sham ECT reveals effectiveness Remission rate >80% (time-limited)

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Relapse rates high (approximately 70%) Response rate unknown but comparable to adequate pharmacological treatment Less effective Mixed mood episodes Based upon case studies Schizophrenia—unless Acute symptoms Catatonia Past positive response to ECT Ideal candidate Neurovegetative symptoms Absence of personality disorder Minimal reactivity Psychotic symptoms Frequency Two to three times per week Gradually phase out over months Improves high relapse rates Integrated with other elements of treatment Adverse events Cognitive Postictal amnesia Retrograde and anterograde Impaired short-term memory No structural findings No changes in neuropsychological functioning Postictal delirium Headaches Oral complications prevented by bite blocks Tongue bites Loose teeth Status epilepticus (often when benzodiazepines unavailable) Grand mal seizure (succinylcholine not used or underdosed) Transcranial magnetic stimulation (TMS) Principles of mechanism of action Electricity in insulated coils induces magnetic fields Magnetic fields pass through the cranium for 2–3 cm and induce electric fields in the brain Nerve cells are stimulated to fire and release 5-HT NE DA Deep brain stimulation (DBS) Principles of mechanism of action Implantation of implanted pulse generator (IPG), a lead, and an extension The IPG is implanted in the clavicle or abdomen The lead is implanted in the brain The extension connects the lead to the IPG Cranial electrotherapy stimulation Principles of mechanism of action Suppression of thalamocortical activity (CES activates 5-HT in the raphe nuclei, which will then inhibit brainstem ACh and NE systems) Suppression of agitation/reduction of aggression Induces alpha EEG and decreases delta rhythm More alert More relaxed 5-HT itself Modulates pain sensation in the dorsal horn of the spinal cord Alters pain perception in the limbic forebrain

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46

Psychiatry Bullets Cognitively Emotionally FDA-approved for Anxiety: Effect Size 0.58 Depression Insomnia: Effect Size 0.64 in Side effects Self-limiting Headache

0.1%

Skin irritation at electrode sites

0.07%

Enduring for hours or days (especially if history of vertigo) Headaches Vertigo Nausea Disorientation (if abruptly discontinued) Contraindications Pacemakers, defibrillators Pregnancy STAR*D The STAR*D Trial www.star-d.org Overall aim: Define preferred treatments for treatment-resistant depression Overview I Duration 7 years (10/99 – 9/06) NIMH funding National Coordinating Center, UT SWMC (Dallas) Data Coordinating Center (Pittsburgh) Overview II 14 Regional Centers 41 Clinical Sites 18 Primary Care Settings (and, not research based) 23 Psychiatric Care Settings (and, not research based) Level I Obtain consent Citalopram given (chosen as it was available generic, easy to use) Follow up (if satisfactory response) Level II (if not satisfactory or <50% change from baseline) Level II Randomize—trying to mimic clinical practice; thus, ask the patients what they were willing to do Augment Augment to psychotherapy Switch Switch to psychotherapy Choices Sertraline Switch Bupropion SR Venlafaxine XR Cognitive behavioral therapy (CBT) Augment Citalopram + Bupropion SR Citalopram + Buspirone – chose it “because we thought it would be a dog” Citalopram + CBT

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47

Study methods Independent, blind, treatment evaluators obtain research outcomes Multiple research outcome domains Treatment protocols provide consistent, adequate treatment before declaring resistance “It is useful to measure what you treat quickly” Participants MDD Nonpsychotic Representative primary and specialty care practices (nonacademic) Self-declared patients Inclusion criteria Clinician deems antidepressant medication indicated 18–75 years of age Baseline Hamilton rating scale for Depression17(HRSD17 ≥ 14) 17-item scale Scores ≥ 14 Most concurrent axis I, II, III allowed! This deviates from most other studies currently performed Multiple research outcomes Symptoms Function Side effect burdens Patient and clinician satisfaction Utilization and costs of health care services Why remission was the end point? Nonremission is common 35%–45% remission 10%–20% response with residual symptoms 15% partial response 25% nonresponse 7%–15% intolerant Consequences of nonremission Poor function (work, family) Poor prognosis (increased recurrence) Psychiatric or general medical complications Health service utilization Death from Medical comorbidities Suicide Treatment resistance—a strong predictor of relapse or recurrence Clinical procedures Open treatment with randomization Symptoms/side effects measured at each clinical visit Clinicians guided by algorithms/supervision Dose adjustments “mandatory” to achieve remission Education for all patients Quality control of treatment Clinical research coordinator support Clinician training Clinical manual Web-based monitoring system Routine measurement of symptoms (QIDS-C16)

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Psychiatry Bullets

Findings Level I Clinical baseline Features N = 2,876 Recurrent depression

75%

Onset <18

37.8

Family history of depression

55.6

History of suicide attempt

25.3

Anxious depression

53.2

Majority had concurrent axis I at baseline 34.8% Treatment Pushed citalopram (41.8 mg, for 10 weeks) Categorical symptom outcomes Response (without remission 50% decrease) Similar outcomes in primary settings Of those that responded, 2/3 responded in 6 weeks; 1/3 will get there in time Of those that remitted ½ remitted by 6 weeks ½ even at 12 weeks Risk factors—medical conditions Conclusions weeks Studies of remission require longer duration of studies 30% remission rate (across all treatment) Follow-up—12 months If you remitted, a greater proportion stayed better over time (½ “lose it”—30% reach remission, but 50% don’t remain or 15% get better) Level II Medication switch Treatment outcomes 25% will get to remission ACROSS ALL Also the timing of remission was the SAME CBT––The same rate of remission as meds Days to remission similar Acceptable switch option Acceptable augmentation option Follow-up required Not as popular as expected Medication augmentation Treatment outcomes Buspirone worked as well as Venlafaxine XR Timing to response was also the same Serious side effects All Death GMC (medical) GMC (medical––hospitalized) All psychiatric side effects Psychiatric hospitalization Conclusions Cumulative remission rate is over 50% I and II Patient preference plays a big role in strategy selection Follow-up—12 months same as Level I Level III Randomize Switch Mirtazapine Nortriptyline

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Augment Lithium Thyroid (T3) Few people remitted with any method (20%) T3 augmentation was much better tolerated by patients Level IV Randomize Tranylcypromine (MAOI) Venlafaxine XR + Mirtazapine Very few people remitted, and tranylcypromine was not tolerated

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Chapter

5

Bipolar Disorder

OVERVIEW Lifetime prevalence of bipolar I is 1.0% and bipolar spectrum is 4.4% Age of onset is adolescence Median age of onset 18 years (STEP BD 2000 data) New onset rare after 50 years 30% of cases are untreated for the first 10 years (median 6 years lapse in treatment) Fourth leading cause of neuropsychiatric disability worldwide High suicide rate—19% (lower if never hospitalized) Females = males incidence Strongly comorbid with Substance abuse 60% Anxiety disorders >50%

ETIOLOGY Genetic Twin studies 60%–93% variance in bipolar disorder Shared environmental factors account for 30%–40% variance Unique environmental factors account for 10%–21% variance Genome-wide association scans Family study—increased rates of affective disorder (depression), anxiety, and behavioral disorders (attention deficit hyperactivity disorder [ADHD]) in offspring Monoamine hypothesis 5-HT Roles in mood/sleep/appetite/circadian rhythm/cognitive Receptor subtypes 5-HT1A—(buspirone is an agonist) ANXIETY 5-HT2A Findings Lower 5-H1AA levels in brainstem and CSF Acute depletion of tryptophan associated with relapses from depression Fewer 5-HTT in prefrontal cortex Antidepressant effects NE activity elevation DA activity elevation GABA Cholinergic Inputs reduce REM latency 51

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Psychiatry Bullets

Anticholinergic effects are antidepressant Lycine—an anticholinergic precursor that can cause depression Glutamate NMDA receptors Antidepressant effects of glutamate NMDA receptor antagonists Mitochondria Decreased mitochondrial functioning Leading to neuronal dysfunction and apoptosis Neuropeptides/hormones Cortical-hypothalamic-pituitary axis hyperactivity Hypersecretion of CRF leading to downregulation of hypothalamus Hypothalamic-pituitary-thyroid axis Blunting of TSH response to TRH challenge (downregulation of TRH receptors in the pituitary) Hypothalamic-GH axis Brain growth factors GH BDNF Substance P and neurokinin-1 receptors Alteration of neuronal circuits Frontal lobe dysfunction—“Brakes” Limbic cortex dysfunction—“Accelerator” Neuroimaging Prefrontal lobe dysfunction Reduced blood flow and glucose metabolism Orbital and medial PFL Limbic dysfunctions Other Abnormal G protein, protein kinase C, and second messenger activities (their potential roles in neuroplasticity) Neuronal death occurs with repeated mania Lithium promotes neuronal growth Smaller hippocampal sizes in bipolar patients Kindling––SENSITIZATION Repeated stressors lead to more exaggerated responses With regard to mood disorders Clinically (Robert Post) More mood episodes leads to even more mood episodes Cycle length decreases with time Psychosocial triggers decrease with time Physiologically, seizure-like focus in limbic areas Does not appear to be the same kindling as seen in seizures Treatment—anticonvulsants more effective than lithium for rapid-cycling patients Supportive observations for the kindling model Episodes more frequent with time Well periods shorten with time Psychosocial triggers decrease with time Rapid cycling increases with time Treatment responsiveness decreases with time Circadian rhythms––FAST PACEMAKERS Stress diathesis model (GENES and ENVIRONMENT) Underlying vulnerability plus stress leads to observed illness Medications reduce underlying vulnerability and therapy reduces stress A look at the genes—inquire about family history beyond first-degree relatives (i.e., cousins, aunts, uncles, etc.) A look at environment Ask not just concerning immediate shared family experiences Random events

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Intrauterine/prenatal Genotype/environmental interaction

COURSE Some statistics 1 /3 get completely better with monotherapy mood stabilizers 2 /3 need polypharmacy ½ have partial recovery ¼ do not recover Predictors of poor prognosis Polysubstance abuse/dependence Psychosis Early age of onset Predominant depression Mixed states Many episodes Good prognosis Euphoria Unipolar mania Late age of onset Few episodes Clinical course (13-year follow-up study) Approximately, 50% will start asymptomatic (50% with symptoms) and then 68% will be depressed 19% will have hypo/mania 16% will have mixed symptoms Comorbidity is the rule Migraines Pain disorder Diabetes Cardiovascular disease Obesity Substance use Eating disorder Anxiety disorder Impulse ADHD Personality disorder Phenomenological issues Mixed episodes Full episode criteria in both poles Contrast with dysphoric mania or agitated depression Spectrum model Pure depression

Agitated depression

Depressive mixed state

Dysphoric mania

X

X

X

Pure mania

Mixed states Gradations of “Mixedness” (and 60% of BP is mixed!!!) Rapid cycling

>4 episodes/year (not hour to hour)

Seasonality

Mania in summer, depression in winter

Remission

¾ remit (thus ¼ never remit)

Unipolar mania

Never had depression—most responsive to lithium

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54

Psychiatry Bullets Childhood presentation Preadolescence (<12 years of age) 80% continuous rapid cycling 1 week of hypomania/mania identifiable Family history in first-degree relative Adolescence (≥13 years of age) 60% mixed Chronic Similarities with ADHD 90% of bipolar conditions diagnosable with ADHD Adults 33% diagnosable with childhood ADHD Different developmental presentations of the same underlying disease Stimulants and mania They are associated with an earlier age of manic onset (small studies do not conclude this) Modafinil may also be activating Effects of childhood use of amphetamines in adulthood (based upon animal studies) Decreased response to rewarding stimuli Increased depression and anxiety Decreased dopaminergic neuronal activity Increased corticosteroid response after stress Decreased long-term survival of new neurons in the hippocampus

MISDIAGNOSIS Clinician factors Lack of assessing family members—ask that family be involved Poor assessment of manic symptoms Overemphasis on symptoms rather than Course Family history Treatment response Disease factors Lack of insight (impaired insight is part of the illness) Frontal lobe involvement suggesting poor executive functioning Ask that family be involved in treatment Poor memory Unreliability of hypomania Overlapping features with borderline personality disorder/traits Rule out mood disorders prior to diagnosing personality disorders Findings more often associated with borderline personality Trauma Self-injury Chronicity—not state dependent Interpersonal characteristics Countertransferential effects Prodromal mood symptoms Overlapping symptoms with depressive disorders Findings more often associated with bipolar disorder Atypical symptoms (using DSM-IV-TR criteria) Psychotic symptoms Postpartum manifestation Earlier age of onset Bipolar at 19 years Unipolar at 30 years

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Brief episodes Bipolar 3–6 months Unipolar 6–12 months Poor antidepressant response Effectiveness “wears off” Three antidepressant trials ineffective Antidepressant-induced mania No prevalence of pervasive developmental disorder Recurrent major depressive episodes >3 in a lifetime Overlapping symptoms Depression—90% of bipolar disorders Psychosis 60% lifetime prevalence 15% point prevalence Anxiety—50%–90% of bipolar disorder (mostly during depressed phase) Long-term frequency of depressive symptoms Most people with bipolar disorder (even treated) live in depression Causes of treatment refractory depression quantitated by Sharma (2005) 50% misdiagnosis 50% other Other diagnoses Personality disorders Substance abuse Psychosocial stressors (neurotic depression) Treatment intolerance Side effects “Nocebo effect” (the patients who develop side effects to any medication intervention) Patient nonadherence Rapid metabolizers Inadequate dosing True treatment resistance

ASSESSMENT Scales MDQ study overall prevalence at 3.4% Sensitivity—0.81 Specificity—0.67 Predictive value 45% (right 45%, wrong 55%) Bipolar spectrum diagnostic scale Manic-depressive spectrum Clues in the history Antidepressant-induced mania or hypomania Family history in a first-degree relative Hyperthymic personality (baseline, nondepressed state) Recurrent major depressive episodes (>3) Early age of onset (<25 years old) Atypical depressive symptoms Brief major depressive episodes (<3 months) Psychotic major depression Postpartum depression

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56

Psychiatry Bullets Antidepressant wear-off Acute but not prophylactic response Rapid onset of action No response to three or greater number of adequate antidepressant trials Validators of diagnosis (these are classically used in research—not in DSM-IV-TR) Phenomenology Cross-sectional symptoms DSM-IV criteria Family history Course Age of onset Number of episodes Outcome Treatment response Poor substitute for biological markers

DIAGNOSIS Types Subtypes 1. Type I—mania 2. Type II—hypomania + DD 3. NOS 4. Cyclothymia—hypomania + subthreshold depression a. Adults—2 years duration required b. Adolescents—1 year duration required Diagnosis Mood elevation Euphoria or irritability Dysphoria (mixed) Depressed mood +/– irritability DIGFAST Mnemonic Distractibility Insomnia Grandiosity Flight of ideas Activities Speech Thoughtlessness Mania Three symptoms plus euphoria Four symptoms plus irritability Hypomania—no dysfunction Duration 1 week mania 4 days hypomania Hospitalization with any duration Clinically, at least 2 days for hypomania Possible criteria of lasting less than one day proposed

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Cardinal symptoms Distractibility Insomnia: decreased need for sleep as opposed to inability to sleep Grandiosity Flight of ideas (ruminations/worries are of the same theme—flight of ideas is almost tangential) Activities (work, school, home, social, sexual) Pressured speech, increased talkativeness Thoughtlessness Sexual indiscretions Recklessness Sudden traveling Spending sprees If irritable, fights and arguments

SUGGESTED DEFINITIONS OF BIPOLAR DISORDER Bipolar spectrum disorder A. Criteria Antidepressant-induced hypo/mania Diagnosed or treated bipolar disorder in a first-degree relative B. Criteria Major depressive characteristics <3 months Recurrent >5 episodes Atypical Psychosis Postpartum Early age of onset <20 years Antidepressant tachyphylaxis (or acute but not preventative response) Nonresponsive to full trials of three antidepressants Hyperthymic personality at baseline Diagnosis of bipolar spectrum → 1A + 1B or 5B alone Hierarchy of diagnosis (e.g., once a mood disorder is diagnosed, lower diagnoses must not be diagnosed) Mood disorders Bipolar disorder Unipolar disorder Psychotic disorders Schizo-affective disorders Schizophrenia Anxiety disorders Other Personality disorders ADHD

DIFFERENTIAL DIAGNOSES Secondary to Clear psychosocial stress Other medical illness

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Psychiatry Bullets

Substance use

Cocaine

Medications

Steroids

Neurological conditions

Multiple sclerosis Frontal lobe syndromes Temporal lobe epilepsy Stroke

Endocrinological conditions

Hyperthyroidism Cushing syndrome

Infections

HIV

Autoimmune disease

Lupus

Metabolic states

Hypoxia

Psychiatric conditions Depression Schizophrenia Schizo-affective disorder ADHD Borderline personality disorder Primary substance abuse PTSD Panic disorder

TREATMENT Symptomatically—as elaborated below Address comorbid issues Psychiatric conditions Medical conditions Address other issues Stress Tobacco use Weight Burden/side effect from medications prescribed Support Family Avocational Educational Financial issues Address overall functioning

NONPHARMACOLOGIC Diagnostic clarification Management Charting of entire life events relating to symptom presentation Treat substance use Treat side effects vigorously Psychotherapy (focus on adherence, education, and integrity of sleep cycle) Anticipate polypharmacy Patients live in depression 2/3 of time—but watch for induction/switching High suicide risk

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59

PHARMACOTHERAPY: MOOD STABILIZERS Lithium Lithium carbonate ER ½ 24 hours Dose once daily if decreased renal function observed Usage for Acute mania Maintenance Combination with paroxetine or imipramine If lithium levels are >0.8 mmol/L, then Li = Li + antidepressants But antidepressant addition may still be important (controversial) Sachs et al., NEJM (2007) Mood stabilizer with placebo is equivalent to mood stabilizer with bupropion (you may still capture those who will respond with the medication combination) Side effects Checking creatinine clearance is more sensitive than just Cr Check TSH—depressive episode predictor Specifics CNS—poor memory, slowed function Cardiovascular—arrhythmia, hypotension, bradycardia Gastrointestinal—anorexia, nausea, vomiting, diarrhea Genitourinary issues Issues Blood levels Gastrointestinal activation Tremor Fetal abnormalities Warnings Lithium toxicity if patients have cardiovascular or renal disease Nephrogenic diabetes insipidus Encephalopathic syndrome associated with lithium Carbamazepine Carbamazepine ER (Equetro) Only mood stabilizer that addresses mixed symptoms YMRS change for mixed symptoms Indications—mania and mixed Side effects Nausea, vomiting, dry mouth Blurred vision, speech disorder Dizziness, ataxia, somnolence Pruritus Issues Dizziness Gastrointestinal activation Drug-drug interactions Warnings Aplastic anemia Agranulocytosis Depakote Forms Divalproex Depakote ER Acute mania only Equivalent to lithium and both are superior to placebo Unstudied

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Psychiatry Bullets

Lithium is better for euphoric mania Depakote is better for dysphoric mania PCOS (polycystic ovarian syndrome)—depakote forms usage increases risk 10 fold Did not separate from placebo during maintenance phase of bipolar Side effects Nausea, GI pain, vomiting, dyspepsia Somnolence, athenia, dizziness, headaches Rash Findings and issues—symptom relief by day 4 or 5 Lamotrigine Profile Metabolism Hepatic—glucuronidation Renal—94% excretion Absorption per oral—completely absorbed Protein binding <55% t½ 24–33 hours (longer if in the presence of carbamazepine or divalproex as much as twice) Dosing Rash if lamotrigine is effective, consult a dermatologist 10% have a rash 1/100 0.1% develop Stevens-Johnson syndrome 1/1,000 Concerns for Stevens-Johnson syndrome if The individual is a child Mouth/mucosal involvement Painful If eosinophil counts are elevated If creatine clearance is higher If there is truncal involvement of rash FDA approved for maintenance only Out of five trials for use in depression, only one was positive (maybe due to the time necessary to develop therapeutic doses) Mania—does not appear to address manic symptoms Lamotrigine and lithium individually more robust response compared to placebo (but lamotrigine better for addressing depressive symptoms and lithium better for manic symptoms)

PHARMACOTHERAPY: ATYPICAL ANTIPSYCHOTICS Olanzapine Indications Mania Clinical features CATIE trials suggest that this is the most efficacious agent Side effect Metabolic syndrome Aripiprazole Indications—all phases of bipolar disorder Clinical features Not anticholinergic, mildly antihistaminic Switching from a highly anticholinergic/antihistaminergic medication (olanzapine or clozapine) may cause increased cholinergic/histaminergic effects (treat with diphenhydramine and hydroxyzine)

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Partial D2 receptor agonist Aripiprazole reduces 30% of dopaminergic activity (haloperidol reduces 100% of dopaminergic activity) suggesting that drug-naïve patients are likely to respond to aripiprazole since previous exposure to D2 receptor has blockers already upregulated receptors Better to do a slow cross taper (perhaps over 2–3 months!!!) Used to counter side effects connected with DA antagonism (prolactinemia) Intramuscular treatment study This trial did not include concomitant use of lorazepam since lorazepam was one of the independent arms Aripiprazole 9.75 and 15 mg and lorazepam 2 mg intramuscularly significantly better compared to placebo (after a 1-hour time period) One of the studies leading to FDA approval in treatment of mania High initial dose of aripiprazole was used (30 mg)—a dose not typically used in clinical settings (both aripiprazole and placebo arms were used along with lorazepam) Side effects Nausea Akathisia Activation Onset of action by day 4 Quetiapine Indications—all phases of bipolar disorder (Seroquel XR) Issues Sedation Slower onset of action Clinical Higher doses (600 mg or greater) suggested for acute mania Bipolar depression—the only one with FDA approval for monotherapy Doses of 300 and 600 mg separated from placebo responses More robust for bipolar type I compared to bipolar type II Risperidone Indications Mania: monotherapy Mixed or bipolar depression: combined with lithium Side effects EPS (dose dependent) Prolactin Ziprasidone Indications Mania Mixed Maintenance Side effects Asthenia Abnormal vision Somnolence Issues Unpredictable initial response (dosing possibly related) Onset within hours

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Psychiatry Bullets

Comparing Agents: FDA-Approved Medications Mania

Mixed

Maintenance

Depression

Ariprazole

×

×

×

−

Ziprasidone

×

×

−

−

Risperidone

×

×

−

−

Quetiapine

×

−

−

×

Chlorpromazine

×

−

−

−

Olanzapine

×

×

×

−

Valproate DR ER

×

−

−

−

Carbamazepine ER

×

×

−

−

Lamotrigine

−

−

×

−

Lithium

×

−

×

−

Symbyax

−

−

−

×

Antipsychotics

Anticonvulsants

Other

Comparing Agents: Side Effects Profiles O

R

Q

Z

A

Weight gain

+++

++

++

+/0

+/0

Dyslipidemia

+++

+

+

0

0

++

+

+

0

0

+++

++

+++

+

+

Metabolic

Hyperglycemia Neurological Sedation

+

++

0

+

+

CVS— Hypotension

EPS

++

+

−

±

±

Endo—Prolactin

+/0

++

0

0

0

Anticholinergic

±

+

±

±

±

Treatment from a symptomatic point of view BP depression Monotherapy Lithium FDA approved for bipolar depression (long-term use) Eight placebo-controlled studies, all before 1980 (out of nine studies) Small studies Response rate—overall 79%, unequivocal 36% Onset of action 6–8 weeks Valproate—two small studies (− and +) Lamotrigine Four negative studies, one positive study

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Suggest adding along to a mood stabilizer (lithium) Possible role in treatment-resistant bipolar depression Possible role in preventing an episode of depression Not found to be helpful in preventing an episode of mania FDA approved for prevention of relapse of bipolar depression SGA Quetiapine (300–600 mg)—FDA approved for bipolar depression Aripiprazole Two negative studies Modafinil Antidepressants Few studies, small studies, MAOI focused Significant concerns for switching Combination Adding antidepressants: STEP-BD reveals no benefit with antidepressants for bipolar depression with mania History of switching is a risk for future switching Olanzapine—fluoxetine: FDA approved for bipolar depression Psychotherapy An arm of treatment offered to test subjects STEP-BD reveals benefit Types CBT Family-focused therapy Psychoeducation Rehabilitation BP acute mania Anticonvulsants Lithium Prevention Valproate Carbamazepine extended release SGA Entire list FGA Haloperidol Role as augmenting agents BP maintenance Lithium “the gold standard” Role in preventing manic episode Prevents suicide Divalproex SGA Olanzapine—similar to response rates of lithium Quetiapine XR BP rapid cycling Valproate Equivalent to lithium Lithium Equivalent to valproate BP mixed—“don’t use antidepressants” Recurrence (overall psychotherapy may have critical role in treatment) Depression Lithium Lamotrigine Mania Lithium

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Chapter

6

Anxiety

ANXIETY AND DEPRESSION (www.adaa.org, a web site for patients with anxiety disorders) OVERVIEW WHO findings Depression is the fourth greatest health problem Depression will be the second greatest problem by 2020 Depression is already the world’s greatest source of disability among adults DSM-IV classification Panic disorder with or without agoraphobia Social phobia Specific phobia Obsessive-compulsive disorder Acute stress reaction Posttraumatic stress disorder Prevalence 10% of the population Point

Lifetime

Social phobia

6.8%

12/1

OCD

1

1.6

PTSD

3.5

6.8

Agoraphobia

0.8

1.4

Panic disorder

2.7

5.7

GAD

3.1

4.7

Breaking down panic attacks, panic disorder, and agoraphobia Any panic attack

28%

Panic attack only

22%

Panic disorder only

4%

Panic disorder with

1.1% (females>males)

Agoraphobia

0.8%

65

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AGE OF ONSET COMORBIDITY WITH DEPRESSION Order of occurrence: Specific phobia>social phobia>agoraphobia>panic disorder*>GAD *depression occurs with panic disorder, others before Why? Affective spectrum disorder Inspired by neurosis construct Strong familial aggregation Challenges notion of individual heritability Neuroticism and internalizing disorder in twin studies There was a set of genes that explain increased suicide attempts STAR*D (NIMH funded) Profile Older, unemployed, less educated More severe depression More suicidal ideation More symptoms of panic, GAD, OCD, social anxiety disorder, PTSD, hypochondriasis, somatoform disorders Depression features associated with remission Anxious depression most likely not to remit Length of depression medium likely not to remit Recurrent depression least likely to remit Effect of comorbid depression on antidepressant Increases severity Increases chronicity Increases social impairment Increases vocational impairment Increases alcohol/substance use Increases risk of suicide Increases poor response to acute and long-term treatment Comorbidity with bipolar disorder—another NIMH-funded study Looking at bipolar and anxiety disorder (1/3 of bipolar patients have comorbid anxiety disorders and fewer days well, and the more anxiety disorders, the even fewer days well, and increased risk for relapse (especially social anxiety disorder [SAD] and PTSD)

HERITABILITY Behavioral disinhibition Behavioral disinhibition is associated with family history of anxiety disorder But only <30% of kids with behavioral disinhibition develop anxiety disorder Risk increases if the parent has an anxiety disorder, especially panic disorder Risk increases even more if parent has childhood onset of anxiety disorder Family study of anxious school refusal/phobia School refusal/phobia is related to anxiety disorder Two common reasons for school refusal/phobia Separation anxiety disorder—look for family history of panic and agoraphobia Phobia (especially social phobia)—look for family history of social phobia Family study of generalized social phobia—very familial Heritability of panic disorder Panic disorder runs in families Higher in monozygotic twins than dizygotic twins (concordance)

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High rates of 35% carbon dioxide sensitivity among first-degree relatives Remember giving patients 35% carbon dioxide can induce panic attacks What is inherited? “Phobia-proneness” genes for internalizing disorders like mood and anxiety disorders But does not adhere to our diagnostic criteria Agoraphobia—maybe this is more inherited—a study Relationship with chromosome 11p CCK BR locus CCK—cholecystokinin is associated with panic Alternate diagnostic conceptualizations: Panic—bladder/renal associated interstitial cystitis LOD3.57 at chromosome 13q (D13S793) Heritability of social anxiety-related concerns 48%

OVERALL TREATMENT APPROACHES Antidepressants Current FDA anxiety indications GAD Paroxetine Venlafaxine Escitalopram Duloxetine Panic disorder Fluoxetine Paroxetine and CR form Venlafaxine Sertraline SAD Paroxetine and CR form Venlafaxine Sertraline Posttraumatic stress disorder Paroxetine Sertraline Obsessive-compulsive disorder Fluoxetine Paroxetine Sertraline Fluvoxamine Clomipramine GAD PD

F

SAD PTSD OCD

F

P

V

Esc

D

P/cr

V

S

Pcr

V

S

P

S

P

S

L

Cl

F, fluoxetine; P, paroxetine; V, venlafaxine; Esc, escitalopram; S, sertraline; L, fluvoxamine; D, duloxetine; and Cl, clomipramine Specific studies on SSRIs Escitalopram and citalopram in panic disorder both effective Paroxetine—in social phobia is effective Predicting SSRI response 5-HTT promoter region polymorphism ss << sl ≤ ll social phobia responsiveness to SSRI This was not shown for MDD Anxiety disorders work more on 5-HT availability

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SNRI’s—Venlafaxine XR Demonstrating that NERI is not necessary as 75 mg just as good as 150 to 225 mg Benzodiazepines Examine risks Long-term use Dose escalation Not typically found with therapeutic doses Observe for individuals with Substance use disorder Personality disorder Dependence Commonly after 4 to 6 weeks of continuous use Risk Daily dose Prior dependence on sedative-hypnotics Withdrawal Shorter half-life agents result in greater rebound Speed of discontinuation effects symptoms Beware of discontinuation symptoms all Cognition Acute Decrease recent/immediate recall Dependent upon Dose Potency Chronic Reversible Decrease short-term recall Interaction with alcohol Examine benefits Rapid onset of action No sexual side effects Clonazepam in social phobia One study shows a superb response 50% of people with social phobia will not respond to SSRIs Combination with antidepressants Potential benefits: effectiveness SSRI + Clonazepam (specifically for panic disorder) Use these first before using a second-generation antipsychotic agent Gabapentin Mechanism of action Release of GABA (nonsynaptically) from the glia Binds to alpha-2-delta subunit (subunit of voltage gated calcium channel) NOT a benzodiazepine and does NOT work at that receptor Not FDA approved for any anxiety disorders Possible role in Social phobia (Pregabalin-tiagabine also effective) Agitation Rage Irritability Usual doses 750 to 1,200 mg daily (TID) Pregabalin Mechanism of action similar to that of gabapentin Possible role in GAD (pregabalin 300 mg equivalent to alprazolam)

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Buspirone Mechanism of action: 5-HT1A agonist Onset of action similar to that of SSRIs No FDA approval for any anxiety disorders Beta-blockers Helpful for Autonomic symptoms Objective symptoms SGA Low doses being used Same risk management approaches recommended Kava-kava Over-the-counter agent Withdrawn in Europe Hepatotoxicity Encephalopathy (due to hepatotoxicity) Liver failure Cognitive behavioral therapy (CBT) Useful alone or in combination with medication for Refractory symptoms Persistent dysfunctional cognitive, behavior, and anxiety sensitivity Comorbid conditions Facilitating medication discontinuance Panic disorder, social phobia, PTSD CGI response in panic disorder comparing medications, CBT, and combination Barlow et al. JAMA 2000 Both good acutely and maintenance You can use either treatment alone (60% will do well) NIMH web site www.adaa.org (Anxiety Disorder Association of America)

TREATMENT GUIDELINES APA Practice Guidelines (1998) for the Treatment of Panic Disorder Guideline Watch: Practice Guideline for the Treatment of Patients with Panic Disorder www. psych.org/psych_pract

RESIDUAL SYMPTOMS A complex concept in evolution Why do we care? Common Disabling Increased health care utilization Harbinger of recurrence … and MDD—a debate May be a variant of treatment resistance or partial response May represent residual symptoms present after supposed remission May have second comorbid condition responsible for the symptoms May be medication induced May have symptoms as a result of an underlying personality construct

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If due to Incomplete/partial response → treat core symptoms aggressively Untreated symptoms (not core) → develop symptom-focused approach Secondary to comorbid condition → treat comorbid condition Treatment emergent side effects → modify the treatment Personality → focus on personality (treat with CBT/DBT) 20% to 45% of patients who meet response criteria have persistent residual symptoms Common residual symptoms—not well studied 75% of partial responders had mild-to-moderate residual symptoms General somatic symptoms Fatigue Psychic anxiety Depressed mood Insomnia Guilt If residual symptoms are thought to reflect partial response Increase the initial antidepressant as tolerated Switch class of antidepressant Add augmenting agent Modafanil Bupropion Stimulants Bupropion Atypical antipsychotic Dopamine agonists Add evidence-based psychotherapy Add somatic treatment Manipulate the environment

SPECIAL CONSIDERATIONS Comorbidity Psychiatric disorders Depression Medical disorders Cancer COPD Infectious disease Chronic pain Autoimmune conditions Cardiovascular disease Irritable bowel syndrome Role of neurotransmitters in mood disorders NE

energy motivation anxiety/irritability mood/emotion/cognitive

5-HT

impulse anxiety/irritability mood/emotion/cognition/sex/appetite/ aggression

DA

drive motivation mood/emotion/cognition sex/appetite/aggression

CURRENT MEDICATIONS Current medications—are they optimized? Have common treatment interventions been explored? Other options—see augmenting agents above

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Reboxetine augmentation very selective SSRI and NERI can be helpful MAO-I Indications Reverse gastrointestinal signs (more eating, sleeping, anergia) Nonendogenous Mood reactivity Rejection sensitivity MAOI > TCA > PBO DA, NE > 5-HT Selegiline transdermal system (STS) (FDA approved)

COMORBIDITY OF MDD AND ANXIETY DISORDERS General 60% with MDD have anxiety disorder Anxiety disorder occurred first (watch for depression in the future) What are they? (how do they manifest?) Worry Psychic anxiety (ask about trauma—PTSD) Somatic anxiety Panic attacks Phobic symptoms Obsessive-compulsive symptoms

ANXIETY AND FATIGUE Fatigue—too little data Agents Stimulants Bupropion Modafinil—good for fatigue and sleepiness during the day; does not necessarily treat the depression itself Desipramine (more noradrenergic compared to other tricyclic agents) Practical thoughts Ask patients for presence of residual symptoms Do the symptoms bother the patient? What is the intensity? How frequently (times/day or week)? How does it affect quality of life? Quantify the symptoms with the patient Care Engages patients with the process of their own healing It gives the patients power over their own symptoms Objective monitoring of treatment Evidence-based psychotherapies Options Light (fatigue, concentration) Exercise (anxiety, somatic, fatigue) 20 to 30 aerobic minimally 3× week Massage (anxiety, somatic, sleep, fatigue) Other—yoga, acupuncture Effective most of the time Remission (defined as >50% improvement) 80% of remitters had residual symptoms

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ANXIETY AND INSOMNIA Insomnia Prevalence and impact Prevalence in adults (chronic insomnia) 10% to 15% (2000, 2003) Varying degrees of severity 20% to 30% additionally have transient or occasional sleep problems (two nights in a month of poor quality sleep) Morbidity (1997, 2000, 2005) Absenteeism Accidents at work and driving Memory impairment Greater health care utilization Chronic insomnia Sleep hygiene Limit caffeine Alcohol intake (rebound insomnia and withdrawal symptoms) Illicit drugs Psychotropic management (behavioral, lifestyle approaches not discussed) Indications Impaired daytime functioning Behavioral approaches alone insufficient Insomnia compromising mental health outcomes Best use Initially—nightly therapy (4 to 6 weeks) Intermittent use—longer term—several days to a week in a row and then stop Couple with behavioral therapy and sleep hygiene FDA approved Trade name

Onset in minutes

t½

Restoril

45 to 60

Intermediate

Halcion

15 to 30

Short

Ambien

15 to 30

Short

Ambien CR

15 to 30

Intermediate

Sonata

15 to 30

Ultra short

Lunesta

15 to 30

Intermediate

Rozerem

30 to 45

Intermediate

ANXIETY AND PULMONARY DISEASE COPD or asthma with depression associated with: Poorer adherence to meds Poorer lifestyle choices (smoking, exercise) More severe symptoms Poorer disease outcomes (thus, COPD/asthma is a risk factor) Treatment of asthma and comorbid anxiety disorder Evidence-based therapies SSRIs and SNRIs Benzodiazepines are usually not contraindicated; but—avoid prn! Consider drug-drug interactions Use psychotherapy Lifestyle modifications Adjustment to chronic illness B agonists may make anxiety worse

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PATHOPHYSIOLOGY OF ANXIETY DISORDERS Neurotransmitters GABA GABAa site—specifically delta and gamma subunits Glutamate Ionotropic—fast excitatory transmission AMPA Kainate NMDA Antagonists are anxiolytic Metabotropic—modulatory and couple with phospholipase C or AC Group II mGluR2 and MGluR3 agonists reduce glu transmission Serotonin Norepinephrine Brain regions Frontal cortex Lack of effective functioning Ineffective ability to utilize executive functioning effectively Limbic cortex: Increased activity Amygdala: Increased activity

SUBTYPES OF ANXIETY DISORDERS PTSD Historical overview Focus on adults (war: battle fatigue, shell shock, nervous breakdown) 1970s research on childhood trauma Chowchilla incident: 26 kids were kidnapped on a bus and held for 17 hours before escaping PTSD in 1980 DSM-III Lifetime prevalence 7.8% Neurobiology Structural changes—reduced hippocampal volume Cause versus effect Overlap with depression Functional changes Paralimbic area Prefrontal cortex (PFC) The anterior cingulate (AC) is a filtering device for external stimuli Thus, there is a reduced functioning of the AC Lack of filtering Contributes to startle response Neurophysiological changes—HPA axis CRF, cortisol, DHEA Sympathetic nervous system Neural correlates of traumatic memory in PTSD Increased activity in amygdala and thalamus Decreased activity in AC (using procaine) procaine is novocaine which can cause panic attacks Diagnostic criteria and clinical findings TR—Event leading to fear, helplessness, horror, disorganization, and agitation Reexperienced: recall/play, dreams, flashbacks/reenactment, and distress reactivity

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Persistent avoidance: thoughts, activities, recall, interest, detachment, restriction, sense of foreshortened future Persistent arousal: Difficulty falling asleep, irritability, decreased concentration, hypervigilance, startlement More than a month; impairment Acute (<3 months), chronic (>3 months), delayed (at least 6 months after the stressor) Exposure to a stressor Consider verbal exposure, trauma from a distance, displacement Children are prone to malleable memories; ask parents/adults Rape and exposure lead to more symptoms than disasters or accidents Reexperiencing Traumatic play Reenactment behavior (repetition compulsion like) Traumatic reminders (circumstances, precipitants, signs of danger, objects, situations) Avoidance of stimuli/numbing Increased state of arousal PTSD complexity (diagnose to population frequency) Risk factors Female gender (twice as common in women) Age (an inverse relationship) Education Intelligence Socioeconomic status Family history (of anxiety, alcoholism, depression, and attention deficit symptoms) Reported childhood abuse, combat, rape (30% of victims develop PTSD) Reports of other adverse childhood events Extent of trauma (the more combat exposure, the more PTSD symptoms) Poor social support/ quality of attachment Post trauma life stress Previous psychiatric disorder (conduct, mood, ADHD) Coping styles/strategies Developmental considerations Toddlers cannot articulate Loss of acquired/new skills (talk, enuresis) School behavior/mood, forgetting to do things Adolescence Comorbidity MDD

50%

Alcohol (M>F)

50/30% assoc with 5-HTT phenotype!

Drug (M>F)

30/25%

SAD

25%

Agoraphobia

12/25%

GAD

15%

Etiology Psychoanalytic—attacking the ego, rendering it helpless Social learning theory—fight/flight/freeze Neurobiology (neurotransmitters) NE, 5-HT, DA, GABA, corticosteroids, and endogenous opioids Assessment: Careful history Ask parents/loved ones Clarify the stressor

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Trauma history—type, age, and duration PTSD symptoms (>1 month) Reexperiencing (Flashbacks, nightmares, psychological, and physical reactivity) This is usually considered a core symptom Avoidance/numbing (usually functionally impairing) Hyperarousal (usually needs separate medication) Difficulty concentrating Memory difficulties Insomnia Safety Suicidal ideation Homicidal ideation Personal characteristics Resilience Genetics regarding the 5-HTT promoter region Social support Fewer risk factors Coping skills Interpersonal relatedness Faith Psychosocial situation Home environment Social supports Stressors Acute Ongoing Treatment Nonpharmacological treatment Prolonged exposure Originally developed for rape-related PTSD Effective and sustained benefit over time Imaginal exposure (focus on feelings—not events) Patient imagines and describes trauma and associated symptoms Effective in reducing PTSD symptom severity In vivo exposure Uses systemic desensitization to trauma triggers Effective in decreasing symptom severity Benefits sustained over time Stress inoculation training (SIT) “Tool box” for managing trauma Contents Breathing exercises Components of relaxation Role play Covert modeling Thought stopping Self-dialogue Effective in reducing PTSD symptoms Imagery rehearsal therapy Brief Decreases chronic nightmare (a refractory symptom and SSRIs may worsen them) Improves sleep quality (avoid deep sleep, cannot sleep deeply) Cognitive processing therapy (CPT) Manualized treatment developed for treating PTSD Corrects maladaptive cognitions Emphasis on written dialogue

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Psychiatry Bullets Exposure and education about issues of Safety Trust Esteem Intimacy Reduces severity of PTSD and depression symptoms Gains maintained over time Efficacy Eye-movement desensitization and reprocessing (EMDR) Exposure-based therapy using Eye movements Trauma Memory recall Verbalization Effective as other therapies (small studies) Eye movement component may be unnecessary Psychodynamic Focus Countering demoralization Understand meaning of trauma Integrate trauma into the patient’s life narrative Trust and boundaries Most helpful in improving numbing and avoidance One small randomized controlled study supports efficacy Debriefing Group and individual Staged Semistructured interview Addresses Facts Related emotions Not effective (individual) (group not studied) Role in acute stress disorder (thus, use early) New directions Imagery rehearsal therapy → nightmares and insomnia Guided imagery → PTSD Group treatments→ PTSD (early use) Secondary prevention (increase resilience) Critical incident debriefing (not helpful; more studies) Resources Effective treatment for PTSD Gender and PTSD PILOTS database Department of Veteran Affairs Web site PTSD treatment guidelines This is evidence-based APA treatment guidelines (www.apa.org) NIMH (www.nimh.org) Children Debriefing children in classrooms describing and clarifying Play (drawing/squiggle game) to repair Role play Family therapy Pharmacological Goals Reduce core symptoms

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Reexperiencing Avoidance or numbness Hyperarousal symptoms Treat associated comorbidities (MDD especially) Improve quality of life and resilience to stress via reducing disability and stress vulnerability Facilitate nonpharmacologic therapies First-line SSRIs (FDA-approved sertraline and paroxetine). Long-term studies did not support gender preference Efficacy in long-term studies Latest combining therapy and medications better than either alone Antidepressants Sertraline Flexible dose After 12 weeks Augmenting with prolonged exposure (better) (resilient to reexperiencing symptoms) Paroxetine—fixed dose Fluoxetine—6 month study → protects against relapse Others studied Nefazodone

100 to 600 mg

open label/RCT

Mirtazapine

15 to 45 mg

“

Venlafaxine

75 to 300 mg

“

Bupropion

75 to 300 mg

Citalopram Escitalopram

“ less data

in combat veterans helpful

Benzodiazepines No controlled studies support efficacy in acute/chronic PTSD Controversial monotherapy use (increased risk of PTSD) Use to help reduce anxiety, improve sleep acutely Side effects and high substance abuse comorbidity Impairs cognition—thus, difficulties with memories Mood stabilizers Helps flashbacks? But, in general most studies are negative Medications studied Valproate

Open-label study

Carbemazepine

Open-label study

Lamotrigine

Small randomized control study

Topiramate

Open-label study

Tiagabine Lithium

Open-label study

Phenytoin Antipsychotics Helpful for Treatment of refractory patients Comorbid psychotic symptoms 40% of veterans may have comorbid psychotic features Larger controlled studies pending

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Second generation antipsychotics—some studies Olanzapine Augmentation if antidepressants insufficient One negative trial Quetiapine Helps in treatment of refractory veterans Risperidone Augmentation helps Aripiprazole Monotherapy (pending) Augmentation helps Adrenergic inhibitors Alpha 2 agonists mixed results Clonidine (role in startle and panic awakenings) Guanfacine Alpha 1 antagonist prazosin 5 to 10 mg or higher Role in startle and panic awakenings B blocker—propranolol 40 to 160 mg For peripheral autonomic arousal Other medications Topiramate Role in decreasing nightmares Sleep disturbances Common—polypharmacy often directed at sleep problems EEG findings (limited findings) Awakenings from REM phenomenon Movement suppression during sleep Epidemiological samples—“remarkably normal sleep” More brief arousals from REM sleep With perception of poor sleep Treatment Addressing nightmares and fear for safety Address security, make bedroom safe Install night lights and remove potential hazards “Dream-scripting” CBT technique Special treatment considerations for service members Goals of treatment Increase resilience Encouragers include providers, service leaders, and family Encourage calm responsivity Encourage overall positivity Encourage optimism during duress Encourage recovery Focus on reintegration Of service members and family Awareness especially 3 to 6 months after returning home Monitor Comorbidity PTSD Depression Substance use Family members At risk for operational stress Often moves with the service member (consider duration) Consider the unit in which the service member is involved Also viewed as “family”

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Chapter 6 Anxiety Options for treatment Nonpharmacological CBT—Focusing on resilience, recovery, and reintegration Yoga Acupuncture Mindfulness training Relaxation therapy Exercise Spiritual support Pharmacological (as noted above)—consider side effects Resources www.realwarriors.net www.dcoe.health.mil www.ncptsd.gob Defense Centers of Excellence (DCoE) Outreach Center 1-866-966-1020 (available 24 hours/7 days)

GENERALIZED ANXIETY DISORDER (GAD) Symptoms Core Excessive anxiety and worry about a number of events for the majority of days over 6 months Difficulty in controlling the worry (obsessional quality) Associated with physical and psychological symptoms Significant distress or impairment Not due to substance or a general medical condition Associated symptoms ≥3 Psychic symptoms Irritability Difficulty in concentration or mind going blank Sleep disturbance Somatic symptoms Restlessness or feeling keyed up on or on edge Fatigue Muscle tension Common presenting somatic symptoms in GAD Muscle tension, trembling, twitching, aching, and soreness Cold, clammy hands Dry mouth Sweating Nausea or diarrhea Urinary frequency Epidemiology Prevalence 1 year: 3% Lifetime: 5% (chronic) Age of onset: adolescence—30 years 2:1 females:males Comorbidities—high rates Any disorder: 90% MDD: 60% (explains why antidepressants work) Alcohol use: 35% (generally secondary) SAD: 30% (generally secondary) Panic disorder: 25% (generally secondary)

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Impairment comparable to depression—CONSIDERABLE Impaired occupational functions: 15% Impairment in social functioning: 25% Risk Factors Childhood depression Mother with phobic anxiety Developmental problems Psychosocial stress Differential diagnoses Generalized anxiety disorder SAD Panic disorder Obsessive-compulsive disorder Adjustment disorder with anxiety—with the specific stressor within 3 months of stressor and asymptomatic after 6 months Remission THE GOAL (just like in depression) Anxiety remission

HAM-A ≤7 or ≥70% improvement in symptoms

Depression remission

HAMD17 ≤7

Disability remission

Sheehan disability scale ≤5

Prevent recurrence

HAM-A/D17 ≤7

Pharmacotherapy Benzodiazepines Risks and benefits Benefits Effective (data with diazepam and alprazolam) Rapid onset of action Syndromic benefits of higher sustained doses (max) Easy titration Can be used PRN Can be used for augmentation Risks Side effects Sedation Decreased reaction time Incoordination Memory impairment Dependence Cross-tolerance with ETOH/abuse potential No effective for comorbid depression Sexual side effects (especially diazepam) Withdrawal syndrome First several days → Anxiety, insomnia, and restlessness First 10 days → Confusion, tachycardia, hallucinations, depersonalization, and alteration in conscious 2 to 3 weeks → Tremor, anorexia, sweating, lethargy, nausea, anxiety, agitation, insomnia, myoclonus, tachycardia, and high blood pressure Earlier/3 weeks → Perceptual hyperacusis and photophobia GABA Generally The inhibitory neurotransmitter of the brain Three receptor types GABA-A GABA-B GABA-C

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Roles in Sensitivity for neuronal firing (seizures) Emotion, cognition, pain, sleep, and motor function Buspirone Efficacy demonstrated in individual studies and meta-analysis Delayed onset of therapeutic benefits (5 weeks in 1 study) Excellent tolerability and low side effect burden No sedation, cross tolerance with alcohol, abuse potential Modest effect for depression (most commonly used as an augmenting agent with antidepressants) Tends to be underdosed (>30 mg required) (another use is agitation in dementia) 5-HT1A agonist Gabapentin Pregabalin Promising effects SSRIs/SNRIs Generally Efficacy determined in controlled studies Delayed onset of therapeutic benefits 2/3 of patients respond by 8 weeks Significant functional improvement Generally well tolerated Effective in other anxiety disorders and depression Flexible dose paroxetine (20 to 50) > placebo in patients with GAD Sertraline (25 to 50 mg) > placebo (kids) (better if highly depressed) Venlafaxine XR (75 to 150 mg) > pbo Increasing dose became increasingly effective This was a 6-month study (remission increases with time) Equivalent to benzodiazepine and > buspirone 30 mg Symptom improvement by week 1 Psychotherapy General Evidence in randomized controlled trials (CBT) Other types Psychoeducation/support Psychodynamic for those with a history of trauma CBT A study Many rating instruments Continuing efficacy Cognitive model for anxiety disorders Anxieties associated with patterns of thinking Increase in anxiety results in thoughts/images of social harm and/or physical harm Panic attacks → physical harm Social phobia → social failure GAD → loss of control/vigilance Prognosis Generally very good Risk factor for social phobia, MDD, GAD, and panic

SOCIAL ANXIETY DISORDER Symptoms for at least 4 weeks with an onset before 18 months ≥3/8 symptoms Clinical findings Procrastination in AM, somatic (GI, HA), difficulty attending school Decreases with age

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Comorbidity Specific phobia OCD ADHD Treatment SSRIs and SNRIs MAO inhibitors TCAs Benzodiazepine Role in Prevention of SAD relapse Adjunctive role Beta-blockers Performance anxiety CBT for SAD Efficacy studies Individual or group CBT is effective Comparable to pharmacotherapy as supported by RCTs Phenelzine v group CBT (1998, 1999) Fluoxetine v group CBT (2004) Integrating CBT into pharmacotherapy Information Elements of the anxiety experience Role of maladaptive thoughts in escalating the anxiety role Exposure—encouraging step-by-step exposure to fear and avoided situations and sensations

SEPARATION ANXIETY DISORDER Normal Beginning at 6 to 7 months Peaking at 18 months Decreasing after 30 months Abnormal Persistent, excessive, associated with significant distress or impairment

PANIC DISORDER Prevalence Comorbidity Affective conditions Substance use Other anxiety disorders Phobias Obsessive-compulsive traits Relapse can occur in 2 months to 2 years after medications have stopped Treatment Generalizing principles Focus on unexpected limited symptom attack (not panic attack) that would reinforce the panic attacks Dizziness Chest pain Choking spells Symptoms of GI discomfort

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Chronic treatment will be required (acute, long-term, relapse) Patient education Treatment choices CBT treatment—80% to 90% panic free within 6 months Types Exposure therapy: In vivo, imaginal, interoceptive Systemic desensitization SSRIs Overall Better outcomes than with TCAs Benzodiazepines Recommend higher doses “Start low, go slow, but go” Suggesting titrating dose up till side effects FDA-approved agents Paroxetine/CR 40 mg needed (compared to 10 and 20 mg) Sertraline Fluoxetine Venlafaxine/XR Note: others are not necessarily ineffective Citalopram Escitalopram Fluvoxamine SNRIs TCA Effective Consider adverse events MAOIs Effective Consider adverse events Benzodiazepines Half-life is not a good predictor of treatment outcome Half-life does not correlate with duration of therapeutic action Other Divalproex (if effective, reconsider comorbidity with bipolar) Tiagabine Not appearing to be effective Gabapentin Pregabalin SGA Even when used with patients comorbid with bipolar disorder, effectiveness was not noted Bupropion Not effective for panic disorder Consider it as exacerbating anxiety 5-HT1A agonists—not appearing to be effective Buspirone Gepirone Combination SSRIs + Benzodiazepine Addresses possible activation seen in early stages of SSRI treatment Improved adherence to the SSRI Watch for any signs of withdrawal SSRIs + CBT

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Differential diagnoses Hyperthyroidism/hypothyroidism Mitral valve prolapsed Cardiac arrhythmias Coronary insufficiency Pheochromocytoma Hypoglycemia Vertigo Substance withdrawal

OBSESSIVE-COMPULSIVE DISORDER Diagnostic criteria (NB: children may not see symptoms as problematic) Clinical findings Age of onset for boys—9 years for girls—11 In children, boys to girls 3:2; adolescents 1:1 Early onset—male family history with OCD/tic disorders Excessive cleaning, repeating, checking, counting, ordering, hoarding Compulsions without obsessions common in young kids Subtypes can change over time (no particular pattern) Practice Parameter AACAP 1998; CYBOCS Subtypes Early onset: male, ADHD, family history, tic (familial variety) and obsessions are ego-syntonic PANDAS severe symptoms, then remit OCD/tic symptoms presents Often prepubertal GABHS infection Check throat culture antistreptolysin O antiDNAse B streptococcus ANA Differential diagnoses Depression Anxiety Autism Mental retardation Panic disorder Brain damage Anorexia nervosa Bulimia nervosa Tourette syndrome Epidemiology Prevalence 0.8% Lifetime 1.9% or 3% for adolescence Etiology Frontal-limbic-basal ganglia dysfunction Parkinson, Huntington Chorea, Sydenham (antibodies to the basal ganglia after a streptococcal infection) with increased OCD Decreased caudate nucleus activity Treatment Selection AACAP parameters

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Behavioral CBT (exposure with response) gold choice treatment Pharmacological Clomipramine Sertraline >6 years of age Fluvoxamine >7 years of age Fluvoxamine >8 years of age Citalopram—no studies Escitalopram—no studies Venlafaxine POTS (pediatric OCD treatment study): cognitive behavioral therapy (CBT), sertraline, and combination for children and adolescents with OCD Design Randomized controlled trial 3 U.S. centers Methods 12 weeks Individuals aged 7 to 17 years N = 112 Conclusion Combined treatment superior to CBT or sertraline alone Effect sizes Combined: 1.4 CBT alone: 0.97 Sertraline alone: 0.67 Augmentation strategies Clomipramine is highly serotonergic (and its metabolite is highly noradrenergic) Both vulnerable to first pass iv clomipramine bypasses liver Effective for treatment OCD resistant Adding low dose fluvoxamine taking advantage of 3A4 and 2C19 metabolism interference Neuroleptics Buspirone Additional SSRI Lithium Fenfluramine Stimulants Other Bupropion Valproate might be helpful for refractory (if in context of complex partial seizures) Adjunctive (will not work alone) Adding benzodiazepines does not work unless anxiety is an independent disorder Synergistically How long to treat? Never for the rest of life until they recognize that they are different When to stop springtime? Summer camp winter holiday How to stop? No breakthrough symptoms no seasonal slumps Slowly Watch closely—wait for 1 year Psychodynamic and psychosocial; self-esteem, life effects, compliance Family therapy (discord, roles/boundaries) Investigational

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Deep brain stimulation Current indications Parkinson tremor Dystonia PANDAS Pediatric autoimmune neuropsychiatric disorders associated with strep Not a validated disorder “Most treatments should be done as part of a research trial” Plasmapheresis results of small (N = 10) study—no benefit Penicillin prophylaxis results of a study in 1999 revealed that prophylaxis with penicillin and azithromycin was helpful in reducing the streptococcal infections and the neuropsychiatric symptoms exacerbations If there is a suspicion, perform a throat culture—If positive treat (consider for an extended period like 20 days instead of 10 days) Effectiveness of obtaining titers—for research only? Prognosis: most patients can expect improvement although a small number do experience chronic and debilitating symptoms

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Chapter

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Substance Use Disorders

GENERAL PATHOPHYSIOLOGY Brain areas Addiction Brain areas Mesolimbic dopamine pathway Nucleus accumbens Neurotransmitter Dopamine Mechanism Dopamine transmission does not decrease with repeated use of the substance Seeking and craving Brain areas Amygdala Frontal cortex Neurotransmitter Glutamate Circuits Motor memory Limbic priming Basolateral aspect of the amygdala associated with cue priming Extended aspect of the amygdala associated with stress priming Genetics Twin studies Family studies Adoption studies Gene expression Lowered acetaldehyde dehyrogenase in Asian ethnic groups (Alcohol’s rate-limiting step of metabolism; a less efficient enzyme leads to a buildup of toxic metabolites) Environment Social learning Family habits/issues Risk factors in teens and adolescents Family conflict Use of tobacco at an early age Peers’ usage Low scholastic priority Stressful/traumatic events Lack of supervision Delinquency 87

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Preventative measures for teens and adolescents Investment in scholastic activities Consistent family patterns, expectations, dynamics Anger management Emphasize prosocial behaviors in all realms of life Comorbidity with other psychiatric disorders Self-medication hypothesis Conduct disorder is the highest predictor for substance abuse in adolescents with ADHD

DEFINITION Substance abuse (does not apply to caffeine or nicotine) DSM-IV TR definition (One or more within the last 12 months) Maladaptive pattern of substance use leading to clinically significant impairment Failure to fulfill major-role obligations (work, school, home) Physically dangerous (MVA, machinery) Legal problems (OUI) Recurrent physically hazardous behavior Continued use despite social problems Does not meet criteria for substance dependence Substance dependence Maladaptive pattern of use, distress within 12 months—three or more: Tolerance Need for larger amounts Decreased effect with same amount Withdrawal Classic withdrawal syndrome associated with the agent The same substance is taken to relieve or avoid the withdrawal symptoms Larger amounts and longer periods than intended Persistent desire or unsuccessful effort to cut down or control the usage Great deal of time is spent on obtaining the substance Important (social/job/recreational) activities are given up or reduced because of usage Use continued despite knowing problems Specifiers With physiological dependence/without physiological dependence Early full remission/early partial remission/sustained full remission/sustained partial remission On agonist therapy in a controlled environment Substance intoxication (does not apply to nicotine)—reversible, substance-specific syndrome with maladaptive behavioral or psychological changes developing during or shortly after using the substance)

SUBSTANCE WITHDRAWAL ETIOLOGY AND PATHOPHYSIOLOGY Biological factors Genetics Dopamine receptor alleles Hyporesponsiveness to alcohol and sedative drugs Neurobiological substrates for positive and negative reinforcement Psychological High rates of depression High rates of sensation seeking (control of aggressive impulses)

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Social factors Peer influences Family influences Gateway drugs (tobacco, alcohol, cannabis) use during early teens leads to substance dependence in early 20s; (ideal delay of 1–2 years during adolescence may be preventative) Life stressors Risk factors Male gender Alaskan-Inuit ethnicity Some college education (as opposed to none) Unemployment

SPECIAL ISSUES IN THE PSYCHIATRIC EXAM Source of information Better to ask individuals other than the patient Family Friends Work School Exact amounts difficult (naloxone challenge, barbiturate tolerance test) Underreporting likely (especially if the patient is not the referring party) Aberrant behavior Intoxication Violence Suicide (overdose) Elicit precipitant that led the patient to seek treatment now Keep evaluation focused on specific data needed to evaluate the substance use Stay away from affect since it is often a defense from the core issues Impaired cognitive functioning (driving can only occur after impairment is over) Uncontrolled affective displays

COURSE AND NATURAL HISTORY Most individuals who experiment with drugs do not develop dependence Gateway agents used during early teens (as noted previously) Risk factors Conduct disorder (especially if linked with substance dependence) Crime Dysfunction at home Poor education Studies suggest that different drugs are popular at different times National Institute on Drug Abuse (NIDA) High school senior surveys Drug abuse treatment outcome studies (DATOS)

ASSESSMENT Domains and stages to be assessed Consider health, aggression, family, school, peer, work, recreation Consider progression of substance

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Consider stages Experimental/social → misuse → abuse disorder → dependence Standardized assessment instruments Cut down/Annoyed/Guilt/Eye opener (CAGE) Car/Relax/Alone/Forget/Family-Friends/Trouble (CRAFFT) Drug Use Screening Inventory (DUSI)—149 yes/no questions Problem Oriented Screening Instrument for Teens (POSIT)—139 true/false questions (free on NIDA) Personal Experience Screening Questions (PESQ)—38 questions including lie scale Personal Experience Inventory (PEI)—300 questions including validity questions Adolescent Drug and Alcohol Assessment (ADAP) Addiction Severity Index/Teen Addiction Severity Index (ASI[T-ASI]) Urine toxicology

ALCOHOL Epidemiology Overall use per capita is decreasing, but majority are heavy drinkers Lifetime prevalence Males 15%–20% Females 5%–7% Prevalence in the United States amongst adults Alcohol abuse/dependence: 18.6 million (8 million are dependent) Diagnosed: 2.5 million Treated: 1.5 million Treated with pharmacologic agents: 140,000 Gender Females More drink at a later age Progression to abuse more rapid–“Telescoping” More likely to abstain More associated with depressive symptoms Higher blood alcohol levels Lower amounts of alcohol dehydrogenase in gastric mucosa More body fat relative to body water (greater intoxication) Look for signs of physical, sexual, and emotional abuse Developmental issues Adolescence Binge drinking (Motor vehicle accidents) (Suicide) National patterns of adolescent substance use—the “MTF” “Monitoring the Future” is a study sponsored by the NIDA tracking substance abuse by US adolescents since 1975. Surveys 50,000 8th, 10th, and 12th graders in 400 schools—www. monitoringthefuture.org Findings The rates of both alcohol and tobacco use increase with age Lifetime and daily rates of alcohol use are higher than that of tobacco Alcohol used by 47% of high school seniors compared to 23% for tobacco Alcohol is most commonly used agent By 18 years, 92% boys and 73% girls have tried 6% of adolescents binge drink 4% of adolescents drink daily (Cannabis is the most commonly used illicit agent) Illicit drug use in 20% of 8th graders and 30%–40% of 12th grades Prescription pain meds and sedative/barbiturate use rates are increasing College students 46% have used tobacco

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43% have alcohol (with 20% reporting frequent high-risk use) 32% have used cannabis 4%–8% have used “club drugs” and other hallucinogens Elderly—1/3 late-onset alcoholism Ethnic patterns of drinking and types of alcohol problems in the United States White males > Hispanics > Blacks > Asians The toll of alcohol dependence >8.1 million in the United States meet DSM-IV-TR criteria for alcohol dependence $185 billion/year Premature death Lost work days Fetal alcohol syndrome (leading cause of preventable cause of mental retardation)— 120,000 deaths/year in the United States Definitions DSM-IV TR definitions Alcohol dependence ≥3 symptoms in 12 months Tolerance more alcohol is needed for intoxication less effective Withdrawal ≥2 signs and symptoms of withdrawal Larger number over longer time Great deal of time drinking or recovering from drinking Social/work/fun given up More drinking despite knowledge of having the problem Qualifiers Early remission Partial remission Full remission Sustained remission in a controlled environment Alcohol intoxication—metabolism is 1 oz/hour or 7–10 g/hour Alcohol withdrawal 10%, delirium tremens in 5%, and generalized seizures in 3%–5% Alcohol-induced persisting amnestic disorder Wernicke’s—confusion, ataxia, nystagmus, gaze palsy Korsakoff’s impaired memory anterograde amnesia ± confabulation Acute: 100% reversible—treatment is thiamine 100 mg TID Chronic: 20% reversible—treatment is thiamine 100 mg TID Blackouts—not technically in DSM-IV-TR Alcohol-induced mood disorder Alcohol-induced persisting dementia—repeated Wernicke’s leads to frontal lobe atrophy and increased ventricle Controversial as others can cause this (Liver/pancreatic/kidney dysfunction) Alcohol-induced anxiety disorder Alcohol-induced psychotic disorder—usually within a month of intoxication or withdrawal (and fully alert and oriented) Alcohol-induced sleep disorder—can occur after 1 month of abstinence Alcohol intoxication—increase NREM, decrease REM, restless/vivid dreamsnightmares/REM rebound Alcohol withdrawal—fragmented sleep and REM increase Alcohol-induced sexual dysfunction Theoretical subtypes Cloninger’s Type I: Late onset, rapid tolerance, guilt/anxiety about drinking, high reward dependence/avoids harm Type II: Early onset, family history, no guilt, low reward dependence, low harm avoidance, high new stimulation seeker: male → male transmission DA and NE triggered

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Type A and B definition Type A: late onset, tends towards decreasing dependence and problems, treatment focused on interactional treatment Type B: early onset, tends toward increasing dependence and problems, treatment focused on coping skills Gamma and Beta definition Gamma: Americans—out of control Beta: Europeans—in control, but must drink daily Miscellaneous definitions Antisocial: male poor prognosis Develop cumulative: increased use with precipitants Negative affect: female—mood regulator Develop limited: decreased use with better circumstances Comorbidity Prevalence 61% mood disorder 54% conduct disorder 43% anxiety 16% severe functional impairment Major diagnostic categories Depressive disorders Bipolar disorder Anxiety and PTSD Organic mental disorders Schizophrenia ADHD Conduct disorder and Asperger’s disorder Eating disorders Genetic predisposition Affective dysregulation Pharmacological vulnerability Personality disorder Asians with alcohol dehydrogenase insufficiencies and polymorphisms 12 month odds of ETOH dependence and mood and anxiety Any mood disorder: 4.1 (patients with a mood disorder have 4.1× greater risk of alcohol dependence) MDD: 3.7 Dysthymia: 2.8 Mania: 5.7 Any anxiety disorder: 2.6 Panic: 3.6 Social phobia: 2.5 Specific phobia: 2.2 GAD: 3.1 Antidepressants exert modest beneficial effect for major depression and alcoholism; thus, treatment should include therapy targeting the addiction Pathophysiology Converging actions of drugs of abuse on the VTA to the NA (limbic) (dopaminergic reward pathway) Opioid: euphoria GABA: release of tension DA: energy NE: final common pathway Glutamate alcohol artificially stimulates the reward system

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the brain has an overexpressed stress system (glutamate) and when alcohol is removed, the stress system (glutamate) can be overactive even after 1 year of not drinking (clinical symptoms: insomnia, irritability, inattention) Brain changes Frontal lobe—making judgments and controlling impulses Limbic system—impulses Extended amygdala—amygdale, stria terminalis, nucleus accumbens “artificial stimulus of the reward system” Relapse prevention is the central concern of alcoholism treatment “Any alcoholic can stop at any time—it is the relapse that’s difficult” Opportunities for treatment Acute withdrawal—Protracted withdrawal (glutamate) Clinical status 1 year posttreatment 20%–30% resume dependence level of drinking (minority) Chronic medical disorders Diabetes mellitus: 30%–50% Hypertension: 50%–70% Asthma: 50%–70% Assessment Screening tools Michigan Alcoholism Screening Test (MAST) 25-item question CAGE AUDIT Alcohol Use Disorders Identification Test 10-item questions Psychiatric history and examination Sleep Impaired Decreased REM (resulting in later dreams) and stage 4 sleep Comorbidities with depression, anxiety, etc. Motivational stage of change Physical exam Look for end-organ damage and evidence of polysubstance abuse conditions Laboratory Immediate detection—Breathalyzer Blood alcohol levels (possible clinical findings based upon the individual’s history of exposure) 0.05—Loose disrupted 0.1—Clumsy 0.1–0.15—Intoxicated (0.08) 0.2—Depressed brain 0.3—Stuporous 0.4—Coma (1 drink = 12 oz beer = 4 oz wine = 1–1.5 oz liquor) Heavy use (none of the following are sufficiently sensitive or specific for routine screening of alcohol abuse) Glutamyl peptidase (GGT) Elevated in 75% of patients with alcohol dependence before liver problems manifest Increased in 30% of problem drinkers Normalizes after 4–8 weeks of abstinence Nonspecific reasons of GGT elevation (added under the section of GGT) Fatty liver Anticonvulsant medications and others SGPT/SGOT >2 Erythrocyte mean cell volume (MCV) Elevated in those who also smoke tobacco Found in 60% of those who use alcohol Females > males

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Nonspecific causes of elevated MCV Chronic liver disease Hypothyroidism Folate deficiency Normalizes after 3 months of abstinence Carbohydrate deficient transferrin (CDT) Suggests heavy use over 7–10 days; obtaining a baseline is recommended Mechanism of action—impairment of glycosylation of transferrin More helpful in monitoring abstinence or increased alcohol consumption MCV increase in 60% (women > men) Triglyceride increase Aspartate amino transferase (AST) Less sensitive than GGT More elevated relative to ALT for patients with alcohol-related conditions Alcohol metabolism Alcohol is converted to acetaldehyde via alcohol dehydrogenase Acetaldehyde is converted to acetic acid via aldehyde dehyrdrogenase (The site of action for disulfiram) Alcohol is metabolized in the liver 90%, kidneys and lungs 10% at 15 mg/hour (different factors affect metabolism) Treatment Examining neurotransmitters Relapse pathways Exposure to drug (reward/extinction) Exposure to conditioned cues (people/places/things) (craving/dysphoria) The basis for the 12-step program Exposure to nonspecific stress (anything that raises cortisol) Neurotransmitters Cortisol releasing factor (CRF) CRF role Hypothalamus controls pituitary-adrenal response to stress Brain stem CRF controls CNS response Alcohol Alcohol acutely activates HPA response to stress via CRF Chronic alcohol use produces tolerance to HPA response and sensitizes brain’s CRF responses CRF antagonists decrease excessive drinking associated in animal studies GABA: “The brain’s braking system” General information Primary inhibitory neurotransmitter in CNS GABAa most prevalent Many medications associated with GABA Alcohol and GABAa receptors Alcohol affects GABA and GABAa: incoordination, sedation, anesthesia and withdrawal are symptoms Decreased sensitivity to GABAa inhibition Creates imbalance in absence of alcohol “can’t put on the brakes” May contribute to excitatory aspects of withdrawal Glutamate: “The accelerator” General information Major excitatory NMDA most sensitive to alcohol Activated NMDA receptor allows positive ion influx NMDA receptors adapt to chronic alcohol exposure Up-regulates the number of receptors During withdrawal—hallucinations, hyperactivity, seizures

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Contributes to Tolerance Sensitization—increase in withdrawal symptoms after alcohol exposure and withdrawal Clinically → increased craving and risk of relapse NMDA receptors and alcohol withdrawal Excessive glutamate excitation “foot stuck on the accelerator” Increases risk of excitotoxic cell death (cognitive) 5-HT: modulates consummatory behavior DA: reward system (nucleus accumbens) Endo-cannabinoid: CB1 receptor (future antiobesity drugs may target this receptor) Endogenous opioid: hedonic tone (pain/temp) Endogenous opioids and their receptors Therapeutic targets B endorphins: mu receptor enkephalins: delta dymorphins: kappa Withdrawal treatment CIWA (Clinical Instrument Withdrawal Assessment) scale Autonomic hyperactivity Tremor Anxiety Hallucinations Agitation Nausea/vomiting Headache Seizure with an onset between 2 and 4 days Delirium tremens (onset typically 3–7 days following cessation) General guidelines Thiamine 100 mg iv with dextrose for 3 days and continue with 100 mg thiamine po daily Magnesium 240 mg (po) Benzodiazepine individually tailored usage while following CIWA Chlordiazepoxide recommended for its long-acting quality Caution necessary in the context of severe hepatic function Oxazepam often used in these situations Tapering of doses over time Phenobarbital or pentobarbital challenge Offer until no intoxication within a 12–16 hour time period Dose up to 60–100 mg (for pentobarbital 200 mg) If patient becomes severely intoxicated or is asleep, no treatment is required after that dose challenge If moderate symptoms (dysarthria, nystagmus, ataxia, not sedated), offer another 200–300 mg of phenobarbital or 60–90 mg of pentobarbital If no symptoms, offer 600–1,000 mg of phenobarbital or 180–300 mg of pentobarbital Then, reduce dose by 10% daily or every other day Pharmacological approaches following the treatment of withdrawal Overall goal for medication targets Reduce intensity of binges Assist in abstinence Decrease urge to drink Normalize dysregulated brain systems Reduce symptoms associated with relapse (negative effect, insomnia) Persistence and patience are required as it typically takes time (Individuals average seven attempts before “quitting” tobacco)

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Psychiatry Bullets FDA-approved medications Naltrexone (Revia) Campral (Acamprosate) Naltrexone IM Disulfiram Combinations Specific agents Disulfiram (Antabuse) Mechanism of action: alcohol dehydrogenase inhibition—Alcohol → acetaldehyde (toxic) → acetate Adherence and abstinence Adherence leads to abstinence Safety and tolerability Side effects (“desired effects”) usually within 15 minutes Facial flushing Palpitations Increased heart rate and blood pressure Nausea and vomiting Hepatotoxicity Contraindications for use Ischemic heart disease Pregnancy Drug interactions Anticoagulants Phenytoin Isoniazid Food/over-the-counter agents Summary Appears to decrease drinking days in alcohol Minimal evidence that it increases abstinence Limited data on implants Adherence is critical Naltrexone (Revia) Pharmacology Endogenous opioid system—pure opioid antagonist with rapid onset of action (within 2 hours of ingestion), but leaves quickly too; inhibits opioid effects at the mu receptor Antagonist—reduces rewarding effects of drinking “any organism that has a mu receptor will drink less—you do not have to have alcohol dependence” No tolerance or abuse potential Reversibly blocks the subjective effects of iv opioids Will precipitate withdrawal symptoms in opioid addicts Blocks self-administration of alcohol in animal models Blunts rewarding effects of alcohol in humans Clinical trials—allowed up to 200 mg/day (start low, go slow, but go) 50 mg/day—rate of total abstinence 50 mg/day—relapse to heavy drinking: significantly Side effects (nausea and headaches are brief and transitory) Nausea most common reason for discontinuation Headaches Dose-dependent hepatotoxicity Check LFTs initially and then at follow-up Black box warning (usually problematic at higher doses of 300 mg/day)

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Induction of opiate withdrawal Increased depression in depressed patients Interactions with NSAIDS Adherence (monitor GGT, which is sensitive to changes in drinking) Encourage adherence to promote effectiveness Side effects Nausea Headaches Dizziness Fatigue Insomnia Anxiety/nervousness Sleepiness Contraindications Current opioid use Pregnancy/breast-feeding Conditions requiring analgesic effects of opioids Summary Reduced heavy drinking for active drinkers Also good for abstinent patients Side effects (nausea, fever, decreased appetite, injection site pain) Liver transaminase elevation not usually problematic Naltrexone IM (Vivitro) Efficacy and tolerability Abstinence through 3 months Pharmacokinetics Sustained over 1 month im 380 mg versus po 1,400 mg Reduced fluctuations in plasma concentrations Reduces heavy drinking at 380 mg (>190 mg) Side effects Nausea: 33% (the GI tract is lined with opiate receptors) Fatigue: 20% Decreased appetite: 13% Dizziness: 13% Injection site pain: 12% Discontinuation due to side effects: 14% (identical to po form) Pearls Helpful for heavy users Helpful for treatment resistant illness Long-acting formulations (encourages adherence) can be helpful Good safety profile Good for short-term benefits (especially if patients are adherent) Acamprosate (Campral): 2 g/day Pharmacology General information Not active at GABAa Weak inhibitor of GABAb in nucleus accumbens Generally inhibits glutamatergic system in mammals Inhibits glutamate transmission presynaptically Negative reinforcing effects of alcohol, conditioned “pseudowithdrawal” may be cue-induced Glutamate (NMDA) receptor modulator Taurine analog—normalizes alcohol-induced hyperexcitability

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Psychiatry Bullets Normalizes glutamate neurotransmission related to alcoholism (the patient should have alcohol dependence since you need this abnormal neuroadaptive response present for this medication to work) Not metabolized by the liver Absorbed drug is excreted unchanged by kidneys If renal insufficiency exists, halve the dose Hepatic impairment does not affect the medication No known drug interaction Steady state in 5 days—unlike naltrexone Clinical trials findings Total abstinence—even a year after treatment Days to first drink: length of abstinence 5 months Reduction of drinking: fewer drinks/week for a year Reverses problems with sleep architecture Side effects Asthenia/depression Nausea Pruritus Flatulence Diarrhea (most problematic) but not significant Bloating Rash Contraindications Severe renal impairment History of hypersensitivity to acamprosate Benefits Long-term abstinence Excellent safety profile No serious side effects Encourage adherence even after relapse as improvement will occur anyway Risks No observed health risks in >1.5 million patients since 1989 Motivate patients to have abstinence as a goal Acamprosate + Naltrexone combination Rationale Safe and effective Different mechanisms of action Different effects on drinking Naltrexone—reduces heavy drinking Acamprosate—helps with abstinence Studies Pharmacokinetics and pharmacodynamic drug interactions studies Naltrexone increases the bioavailability of Acamprosate But, the combination did not affect Naltrexone Rate of relapse to heavy drinking was best addressed with combination Project COMBINE results Design: Naltrexone at 100 mg/day Acamprosate at 3,000 g/day Combined Naltrexone + Acamprosate Neither Half received psychotherapy One cohort received psychotherapy alone Conclusions % days abstinent

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All arms did well 75% at 4 months Worst outcome—CBT only arm Best outcome—combination arm % relapse to heavy drinking All did well BEST combo The rate of nausea, vomiting, diarrhea all high even placebo group (“recovery hurts”) Side effects Nausea/vomiting Diarrhea Decreased appetite Somnolence AST/ALT five times upper limit Discontinuation due to side effects Treatment algorithm Monotherapy with Acamprosate or Naltrexone after 3 months approx Alternative monotherapy (allow 2 days abstinence for Acamprosate) after 3 months Combination of Acamprosate and Naltrexone Disulfiram monotherapy Disulfiram + Acamprosate (Never disulfiram combined with naltrexone as they both have black box warnings for hepatotoxicity) Serotonergic agents Alcohol dependence Animals: it does reduce use in animal studies Humans: no difference, overall Type A later onset fair better with SSRI (sertraline study) Type B <18 month, family history, father with antisocial personality disorder, individual psychiatric history (SSRIs not as helpful) Abstinence Ondansetron (5-HT3 antagonist) Study: failure but Type B individuals performed better Conclusions 5-HT dysregulation in alcohol is complex, affective disorder comorbidity may benefit 5-HT3 for Type B Anticonvulsants Topiramate Fewer heavy drinking days Greater likelihood of days abstinent Dopaminergic Haloperidol reduces euphorigenic effects and craving But, outcomes are inconsistent and individuals develop dysphoria Other neurotransmitter sites (not approved by the FDA) Other agents Selective 5-HT3 antagonist (ondansetron) Anticonvulsants CB1 antagonists Baclofen (GABAb agonist) Nonpharmacological approaches Treatment strategies for experimental or social use Education Counseling Treatment strategies for substance misuse Individual and group

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Psychiatry Bullets Family: parent management training and contingency contracting Abstinence contract Motivational learning Treatment strategies for substance abuse and dependence Family: coherent with clear rules but not hierarchal Multisystemic Alcoholics Anonymous 12-step approach Therapeutic communities: move through stages of individual/community development CBT Motivational Prochaska motivational interview Use through Abstinence Maintenance Prevention of relapse Community-reinforcement approach Level of care Alcoholics anonymous Consideration of special groups Psychiatric comorbidity Adolescents Geriatric Gender Ethnic Counseling Day-to-day life Lifestyle without alcohol Identify risk factors to prevent relapse Web sites www.alcoholfree.info: Patient education and self-help www.asam.org: Patient assessment and levels of care criteria www.niaaa.nih.gov: Provider guide to treatment (including CBT guide) www.alcoholics-anonymous.org: AA guide to medications www.aaap.org: Specialists’ reference

CAFFEINE Caffeine use disorders Caffeine intoxication Caffeine-induced anxiety disorder Caffeine-induced sleep disorder (No disorder named for caffeine withdrawal) Introduction Most widely used psychoactive substance in the world >80% of adults and kids consume regularly Methyxanthines Caffeine Theobromine (chocolate) Theophylline (treatment for asthma) Caffeine intoxication (also caffeine tolerance) Definition Set of symptoms developing during or shortly after caffeine use ACUTE versus CHRONIC Symptoms

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Nervousness Restlessness Insomnia Periods of inexhaustibility Diuresis Excitement GI disturbance Muscle twitching Psychomotor agitation Flushed face Tachycardia or cardiac arrhythmia Rambling flow of thought and speech Acquired tolerance Inadvertent overdosing—IV theophylline, NODOZ, caffeinated water Pathophysiology Adenosine receptor antagonist Effects of adenosine antagonism Increased synaptic activity in the brain Neurotransmitter release Vasoconstriction Tachycardia Bronchodilation Assessment Caffeine intoxication Caffeine-induced anxiety disorder Caffeine-induced sleep disorder Flow diagram for diagnostics Heavy use of caffeine or acutely greater than normal use No—no disorder Yes Symptoms for caffeine-induced disorder Anxiety Panic disorder Obsessive-compulsive symptoms Sleep disorder → caffeine-induced sleep disorder Differential diagnosis better understood Epidemiology—not well-known, caffeine intoxication in 7% of the population Course short t½ of 3–6 hours Treatment Careful history of beverages and medications Rule out chronic use of high doses of caffeine Caffeine withdrawal (not a disorder in the DSM-IV TR) Definition Headache—most common symptom Fatigue, lethargy, sluggishness Sleepiness, drowsiness Dysphoric mood Difficulty concentrating Work difficulty, unmotivated Depression Anxiety Irritability Nausea Vomiting Muscle aches or stiffness

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Psychiatry Bullets Assessment Awareness and incorporation into psychiatric review of systems Presurgical or “non per oral” states Inpatient psychiatric hospitalizations Differential diagnosis Viral illness Sinus conditions Headaches (migraine, tension, postanasthesia) Other drug withdrawal (stimulants or cocaine) Idiopathic drug reactions Course 12–24 hours after discontinuation; especially peaks 24–48 hours, can last 2 days to 1 week Treatment—taper Caffeine dependence not a disorder in the DSM-IV TR Definition See DSM-IV-TR for substance dependence Strain et al. 1994 found caffeine dependence associated with psychiatric and physical symptoms Etiology Caffeine’s subjective effects Low doses (20–200 mg) well-being, alert, energy, concentration, and motivation High doses (800 mg) anxiety, nervousness Caffeine reinforcement due to the positive effects noted above Genetics and caffeine use Monozygotic and dizygotic rates of heavy use found with Caffeine tolerance Caffeine withdrawal Caffeine use and alcoholism possibly linked (alcohol use and nicotine use are often coexistent) Caffeine use and nicotine/cigarette Greater caffeine use among tobacco users Caffeine in psychiatric patients Schizophrenia Substance use disorder Anorexia nervosa Assessment Incorporate in psychiatric review of systems Differential diagnosis Caffeine intoxication Caffeine withdrawal Caffeine dependence Epidemiology US average daily consumption is 280 mg Course—no studies Treatment 75% of primary care providers recommend to their patients to stop/taper usage Caffeine-induced anxiety disorder is a DSM-IV TR condition Etiology and pathophysiology—Individuals with anxiety disorders should avoid caffeine Assessment and differential diagnoses Associated with caffeine Presence of caffeine tolerance, withdrawal, and dependence But the anxiety should be excessive compared to caffeine intolerance or withdrawal Epidemiology and comorbidity—no studies Course—nothing is known Treatment—benzodiazepines during taper

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Caffeine-induced sleep disorder Definition In the context of caffeine withdrawal or intoxication Sleep disorders Insomnia Hypersomnia Parasomnia Mixed Etiology and pathophysiology Based upon time of caffeine, person’s caffeine tolerance, other substance use Delays sleep onset, REM, total sleep time Alters normal stages of sleep Decreases quality of sleep Assessment and differential diagnoses Amount used less than 100 mg/day: no disorder greater than 100 mg/day and: (consider caffeine use disorder) Individual wants to quit Difficulties related to caffeine usage Withdrawal symptoms Tolerance symptoms Compulsive usage Greater than 100 mg/day, after 24 hours and: (consider caffeine withdrawal) Headache Drowsiness Dysphoria Nausea and/or vomiting Problems related to caffeine Sleep disorders may be exacerbated by caffeine Epidemiology, comorbidity, course and treatment no data ICD-10 places caffeine disorders and amphetamines under “other stimulants” Flow diagram during review of systems

CANNABIS Cannabis related disorders Cannabis abuse Cannabis dependence Cannabis intoxication Cannabis-induced psychosis Cannabis-induced anxiety disorder Cannabis related disorder NOS Most common illicit substance Adolescent use lower than compared to 2001 (adolescent opioid use has increased since 2001) Use patterns Male, white > 26 years Female = male 12–17 years Botany and pharmacology Cannabis: female sativa plant has high Delta-9-THC the primary psychoactive ingredient Marijuana is created from this plant’s dried leaves Hashish is more potent (prepared by extracting and drying the resin with or without flowers)

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Hashish oil is distilled hashish and is more potent than its nondistilled form Potency has increased over the last 30 years Effects can last minutes to hours after smoking (and faster), 8–24 hours if eating Highly lipophilic: crosses placenta and breast milk Liver hydroxylation into 20 metabolites Excreted in urine Resorbed in Bile, urine, sweat, hair, fat (released slowly here) G-protein coupled cannabinoid receptors CB1 (brain) and CB2 (immune) Found in Basal ganglia, hippocampus, cerebellum, not cortex Inhibits adenyl cyclase, decreasing cAMP, inhibits calcium and potassium transport Mediates the excitatory effects of mitogen-activated protein kinase Modulatory role in Mood Motor control, perception (including pain), appetite, sleep, memory, cognition, reproductive, immune Can potentiate alcohol, barbiturates, caffeine, amphetamines Etiology and pathophysiology Cannabis use disorder Frequent use is an important predictor of developing the disorder Mesolimbic dopaminergic pathway (VTA → NA) Naloxone—an opioid antagonist at the µ1 receptor in VTA blocks this increase in DA Regular use (short as 1–3 weeks) can produce tolerance Discontinuation of cannabis increases CRF in amygdala and decreases DA in limbic structures Withdrawal symptoms Irritability, anxiety, physical tension, decreases mood/appetite, restlessness, tremor, sweating, insomnia, increased aggression, vivid dreams (milder but longer than opioid withdrawal) Starts days after discontinuation, peaks at 3rd day, complete after 1 week (does vary with individuals) Cannabis-induced disorders Euphoria due to mesolimbic dopaminergic reward pathway Physiological signs and symptoms Noradrenergic, cholinergic, serotonergic, opioid Anxiety and psychosis may occur in those who have a predisposition Assessment and differential diagnosis Cannabis-related disorder A positive toxicology screen merely suggests that the following could be possible Cannabis dependence (Usually comorbid with other Axis I or legal issues, ask about family history, performance at work/health/home, attempt to stop, tolerance) With physiological dependence Without physiological dependence Early full remission Early partial remission Sustained full remission Sustained total remission In a controlled environment Cannabis abuse—large continuum Cannabis intoxication ± perceptual disturbances

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Establish recent cannabis use (positive toxicology screen not really always helpful) Production of clinically significant maladaptive behavior or psychiatric changes Some physical signs of cannabis abuse Tachycardia, high blood pressure, thirst, increased appetite, constipation, decreased intraocular pressure, mydriasis, mild bronchoconstriction followed by brochodilation, increased reaction time, impaired coordination, distorted time and perception, decreased libido, mild analgesia, mild antiemetic effects Ataxia, ptosis, miosis, drowsiness, bradycardia, low blood pressure, hypothermia, peripheral vasoconstriction Some psychological signs Common and quick Euphoria, distortions (also with time), enhanced sensations Uncommon and quick Dysphoria, anxiety, panic disorders, restlessness, depression, derealization, paranoia Some neuropsychiatric deficits Short term memory difficulties, sustained/divided attention, complex decision-making Symptoms are not due to any other mental disorder Cannabis-induced delirium should resolve in 1–2 days Cannabis-induced psychotic disorder With delusions with onset during intoxications With hallucinations with onset during intoxications (consider underlying Axis I condition) Cannabis-induced anxiety disorder With onset during intoxication With generalized anxiety With panic attacks With obsessive compulsive symptoms With phobic symptoms Epidemiology and comorbidity Cannabis use disorder Adolescents’ (as cannabis is one of the gateway agents) usage typically ceases by 30 years of age (90%) Look for polysubstance use Look for Axis I—bipolar, anxiety, antisocial personality traits Cannabis-induced delirium—see above; REASSURANCE is the best as it is self-limiting Course Cannabis use disorder Self-limiting “Amotivational syndrome” (controversial) Lack of direction, motivation, ambition Cannabis-induced delirium—self-limiting—see above Treatment Cannabis use disorder Standard approaches to treatment Longest retention in a facility—best prognosis Prochaska’s motivational interviewing Abstinence is the goal Treat other addictions as well (hospitalize, if necessary) Special features influencing treatment Replace cannabis with better coping skills

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Psychiatry Bullets Treat Axis I conditions Refractory patients and nonresponse to initial treatment Anticipate relapse—get friends/families/work involved Treat underlying conditions Cannabis-induced delirium No particular treatment other than the condition itself ICD-10: SAME

COCAINE Pathophysiology: Blocks dopamine reuptake Cocaine use disorders Cocaine dependence Cocaine is psychologically addictive Maybe not physiologically addictive Cocaine abuse Maladaptive pattern of substance use Recurrent and significant adverse consequences related to repeated use Cocaine initiation may herald psychosocial difficulties Cocaine intoxication Intense euphoria Powerful reinforcer Anxiogenic Route (iv/smoked) leads to greater tolerance (not necessarily euphoria) Cocaine-induced delirium Cocaine-induced psychosis Cocaine-induced mood Cocaine-induced sexual disorder Cocaine-induced sleep disorder Forms: Erythrooxylon coca Cocaine HCl—powder (in), mixed with water (iv) Freebasing—cocaine HCl heated in ammonia/baking soda plus water—smoked Crack—precooked form of cocaine alkaloid Cocaine intoxication Cocaine abuse Cocaine dependence—pervasive pattern of frequent use and psychosocial effects/ medical Binge use can lead to a mild withdrawal syndrome char by depression (dysphoria and anhedonia) Epidemiology MTF study—overall use is a downward trend Rising use in crack-cocaine and “Crystal Meth” (“Ice”) specifically in the west coast “Pharm parties” use of prescription drugs intranasally and po increasing But 0.5% of the population over the age of 12 are using it Gender differences Males were studied more Females closing the gap Pregnancy Vascular injury to CNS Placental abruption Preterm labor Low birth weight Abuse and neglect But children exposed to cocaine in utero do not have permanent sequelae

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Psychiatric disorders Comorbidity with mood, schizophrenia, PTSD, ADHD Mood → cocaine use Cocaine use → ADHD Treat both conditions simultaneously Course and natural history Energy, self-esteem, decreased anxiety and social inhibition, emot enhancement, pleasurable experiences are heightened but not distorted (hallus are absent) Euphoria Highly reinforcing Cocaine complications Cocaine intoxication Paranoia Grandiose delusions Hallucinations (auditory, visual, tactile) Pressured speech Cocaine withdrawal >2 weeks dysphoria; ≥2: Fever Nightmares Sleep change (typically increased) Increased appetite Psychomotor change Suicidality Medical complications of cocaine abuse Nasal/mucosal problems; infectious embolisms; acute dystonias, tics; migraine-like headaches; cardiovascular strokes Cardiac arrhythmias; death (seizure, respiratory depression, cardiovascular disease, myocardial infarction) Treatment Psychotherapy Address craving and behaviors attached to craving Consider patient provider relationship Pharmacotherapy No specific agent effective for chronic use Treat/address ADHD symptoms Treat psychotic symptoms with antipsychotics

STIMULANTS Amphetamine General: Cannabis 1st; Amphetamine 2nd (most widely used illicit drug) History Preparations: prescription source; over the counter (banned 2006); “street” source Amphetamine dependence Amphetamine-induced intoxication Heart rate changes Dilated pupils Blood pressures changes Chills Perspiration Nausea/vomiting Decreased weight Weakness Chest pain

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Arrhythmia Confusion Seizures Coma Dyskinesias Amphetamine withdrawal Change in affect in the evening Increased appetite Sleep changes Nightmares Fatigue Amphetamine-induced intoxication Amphetamine-induced psychosis Amphetamine-induced mood disorder Amphetamine-induced anxiety Amphetamine-induced sexual disorder Amphetamine-induced sleep disorder Acidic urine decreases the half-life, thus increasing elimination Metabolized by the liver and excreted in the urine Increased prescription drug misuse/abuse/diversion “Pharm parties”

ANABOLIC STEROIDS Anabolic steroid disorders: (DSM-IV TR other substance-induced) Anabolic steroid withdrawal Anabolic steroid-induced mood disorders Anabolic steroid-induced psychosis Anabolic steroid related disorder NOS Used in treatment Testosterone decrease Hypogonadal hereditary angioedema Anemia secondary to Fanconi’s (bone marrow anemia) Renal failure AIDS (wasting syndrome) Metastatic breast cancer Osteoporosis Endometriosis Premenstrual symptoms Side effects/toxicity Acne Hyperlipidemia Blood pressure Myocardial infarction/cardiomyopathy/strokes Hepatic: jaundice/increased liver transaminase Muscle hypertrophy Sterility Gynecomastia Testicular atrophy Hirsutism Mood lability/aggression (“Roid Rage”)/psychosis Withdrawal symptoms Fatigue Depression

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Need for more steroids 1988: 6.6% lifetime use in hs seniors Typical cycle of use: 4–18 weeks on steroids 1 month–1 year off

HALLUCINOGENS Hallucinogen and MDMA-related disorders Introduction Hallucinogen intoxication Hallucinogen persisting perception disorder Hallucinogen-induced delirium (NO withdrawal delirium) Hallucinogen-induced psychosis Hallucinogen-induced mood disorder Hallucinogen anxiety disorder Hallucinogen dependence Hallucinogen abuse Epidemiology 10% high school seniors have used hallucinogens LSD is the most common (synthetic) Shrooms (psilocybin) peyote cacti Increase in accidental deaths from MDMA (Ecstasy, E, XTC) natural forms (psilocybin, DMT) Other hallucinogens LSD is most commonly used (but lower use compared to 20–30 years ago) Ketamine (K, Special K) is gaining greater use General findings No physiological dependence but incredible tolerance, no physical addiction No withdrawal or death from overdoses of LSD MDMA or E or XTC, natural psilocybin, DMT Neurotoxic and serotonergic or 5-HT ± ? Etiology and pathophysiology: somatic first → mood → psychological 0–30 minutes Dizzyness, nausea, weakness, anxiety 30–60 minutes Blurred vision, visual hallucinations, pseudohallucinations, after-imagery decreased concentration, dissociation, depression, out of body sensation, synesthesia 60–240 minutes Intensified after-imagery, false perceptions of movement, flood of emotions 4–12 hours Return to previous state but with arousal, headache, fatigue, sense of profundity Drug response variability Experience, environment, personality, previous psychiatric disorders, genetics No dependence, but rapid tolerance (4–7 days for LSD) LSD binds to 5-HT2 receptors LC Decreases spontaneous activity and activates NMDA receptors (enhances sensory responses) Cortex Induce glutamine and inhibits GABA SSRIs Blunt hallucinogenic effects via 5HT1 receptor agonists GABA An antianxiety agent (like benzodiazepines), stops the “high” (inhibits the LC)

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Psychiatry Bullets Opiates Reduce glutamatergic action in the cortex, stops the “high” (thus, heroin addicts do not use LSD) Diagnosis for acute intoxication Have a high index of suspicion because gas chromatography is costly Autonomic arousal (hyperreflexia, tachycardia, dilated pupils) Hypersensitivity to visual and auditory stimuli Reduced motor functioning (individuals are not usually aggressive) LSD-related psychosis can be prolonged Differential diagnosis Other agents PCP, cocaine, amphetamines, anticholinergics, inhalants Schizoaffective/schizophrenia/pyschotic disorders Head injury Withdrawal states Sedative/hypnotic Anxiolytic Alcohol Hypoglycemia/hyperthermia/seizures/vascular events/CNS Treatment for acute intoxication Benzodiazepines (PCP acute symptoms are treated with antipsychotics) or “talk them down” PALM TEST—draw a line—what colors—if bright then LSD, if aggressive PCP Hallucinogen persisting perception disorder and hallucination intoxication Imperative to rule out other possible conditions Treatment Benzodiazepines Palliative (Olanzapine, Sertraline, Naltrexone, Clonidine) Not as desirable (risperidone, THC) Reduce the difference between internal and external environments with sunglasses (darkness is not desired)

MDMA Epidemiology Increasing use (increasing perceived harmlessness) 1990 “Raves”—much higher doses, other drugs (ETOH, THC, opiates) Most need 1 day to recover Pharmacology—toxic to serotonergic neurons (reduced 5HT, 5HIAA), damage but reversible Suspect if College student Tobacco use Binge alcohol use Acute positive psychological effects—“feels good” about others Physical consequences Nausea, vomiting, anorexia, high blood pressure, palpitations, diaphoresis, headaches, ataxia, muscle aches, hot/cold flashes, urinary urgency, nystagmus, blurred vision, dry mouth, bruxism (5HT1B receptor agonist of trigeminal nerve), increased body temperature Clinical manifestation of long-term MDMA toxicity Depression OCD Anxiety No libido

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MDMA somatic toxicity Strokes Myocardial infarctions Arrhythmias Death Due to electrolyte abnormalities (“Raves” are very warm and the individuals are diaphoretic) Treatment—SSRIs? ICD-10 almost the same

PCP Forms Phenycyclidine Animal tranquilizer Anesthetic hallucinogen Angel dust Ketamine/K/Special K Phencyclidine use disorders (aka angel dust ketamine) Phencyclidine abuse Dependence Induced anxiety disorder Induced mood disorder Psychotic disorder with delusions Psychotic disorder with hallucinations Intoxication Intoxication delirium Introduction Originally created as an anesthetic; but, psychosis lasted hours to days One hit can last several hours in an individual, and weeks in those with schizophrenia Symptoms CNS effects Sympathomimetic Neuromuscular effects Kidney effect Act on NMDA glutamate via receptor noncompetitive blockade (prevents calcium influx) Epidemiology Overall, declining use—highest amongst 18–20 year olds—2% of population Greater prevalence in males (two times) Greater prevalence in ethnic minorities Greater prevalence in age range of 20–40 years Death NOT secondary to overdose or drug interaction, but accidents/homicide Etiology and pathophysiology Withdrawal, negativism, catatonia, concrete/bizarre thought process Problems with symbolic thinking process and attention like issues found in individuals with schizophrenia (not the case for LSD or amphetamine intoxication) Phenomenology and variations in presentation Cardiovascular High blood pressure—most common finding—usually self limiting 4% developed severe symptoms) Tachycardia in 30%

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Psychiatry Bullets Neurological Nystagmus, hyperreflexia, motor abnormalities/ataxia, nystagmus vertical or horizontal, seizures, coma, dysarthria, facial grimacing, generalized rigidity, localized dystonia, athetosis Cholinergic or anticholinergic signs Hypothermia or hyperthermia Myoglobinuria Psychological Can last 4–6 hours Hallucinations Delusions Paranoia Thought disorder Catatonia (with intact consciousness) Impulsive Violent (Ketamine intoxication is much shorter duration than PCP) Assessment Special issues in psychiatric exam and history—overly sensitized—minimize stimulation Physical exam and labs Vital signs (temperature, blood pressure, respiratory rate) q2–4h, consider its analgesic effects (minimizes presentation) Alkaline urine hides PCP Venlafaxine and its metabolite, DMX can cause false +tox Check urine for heme (myoglobinuria) Differential diagnoses Nystagmus and high blood pressure (and increased body temperature—think PCP) Rule out Schizophrenia spectrum disorder (especially if beyond 4–6 weeks) LSD (synesthesia) Others: (postictal state, primary metabolic issues) NMS Course and natural history Usually receding 5–21 days; possible to have flashbacks (stored in lipid cells) Physical signs and symptoms clear, then psychosis clears (1 day to 6 weeks) Overall goals of treatment Treat medical concerns Treat violent/impulsive behavior Avoid anticholinergic agents (chlorpromazine) if using antipsychotic agents Physician-patient relationship LSD—talk them down; REASSURANCE PCP—avoid talking them down; REDUCE STIMULI Pharmacotherapy and somatic treatments: none really—symptomatically ICD-10 – PCP included in the hallucinogen class

OTHER HALLUCINOGENS Other agents: MDMA (see following pages) Khat Club drugs (LSD, GHB, MDMA) GHB Nitrite inhalants: poppers/sex Nitrous oxide: laughing gas

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Nutmeg: LSD Catnip: LSD Betel nuts: mild euphoria Kava: sedation incoordination hepatitis lung issues decreased weight Ephedra: arrhythmias Chocolate: Anandomide (THC receptors)—5-HT phenylalanine Ecstasy, XTC, X, E 3,4-methylenedioxy-n-methylamphetamine Effects in 30–60 minutes lasts 3–6 hours: euphoria, comfort, empathy, sense of connection, high heart rate and blood pressure, cognitive impairment GHB gamma-hydroxy butyrate Powder, clear liquid, tablet, capsule mixed with alcohol Alcohol like effects and growth hormone–like muscle-building Effects in 20 minutes lasts 3–4 hours Higher risk for seizures, unconsciousness, coma Websites www.theantidrug.com; www.dancesafe.org

INHALANTS Introduction Types Industrial/household Propellant gases (butane, fluorocarbons) Household aerosolized Medical gases (anesthesia) Aliphatic nitrites (whipped cream) Used as an inhalant for sexual enhancement Volatile hydrocarbons Toluene n-hexane methylbutyl ketone trichloro/ethylene, ethane, dichloromethane, gasoline, butane—not anesthesia or amyl nitrates Inhalant use disorders Dependence: Mostly psychological, some weak physiological General disorientation Sleep disturbances Headaches Muscle spasms Irritability Nausea Fleeting illusions Abuse: accidents Problems with family and school Inhalant intoxication (death) Disinhibition Slurred speech within 5 minutes and can last 30 years Excitedness Light-headedness Visual disturbances Incoordination Dysarthria Unsteady gait Euphoria Watch for decreased reflexes, stupor, coma, death—(due to arrhythmia) Mechanism of action

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CNS depressant GABA? Membrane fluidization (ETOH) Chronic use Peripheral neuropathy Headaches Parasthesias Tubular acidosis (kidney effects) Parkinson symptoms Decreased concentration/memory/IQ Irritant to liver; chest pain, bronchospasm (also seen in copper, zinc, and heavy metals) Epidemiology—worldwide, 8th graders Toxicology—death can happen quickly and on the first try (due to metabolic acidosis and renal failure) Treatment—most drugs are not helpful Different DSM-IV TR diagnoses Inhalant-inducedpsychotic disorder, with delusions Inhalant-inducedpsychotic disorder, with hallucinations Inhalant intoxication delirium Inhalant-inducedpersisting dementia Inhalant-induced psychosis Inhalant-induced mood Inhalant-induced anxiety Inhalant-induced intoxication Inhalant-related disorder NOS

NICOTINE Conditions Nicotine dependence Nicotine withdrawal Nicotine-related disorder NOS Introduction 20% of US population smoke tobacco Causes 440,000 deaths/year in the United States Six FDA-approved medications (Zyban and nicotine replacements: patch/gum/spray/ lozenge/inhaler) Behavioral psychotherapies Medications and behavioral intervention can assist 45% of attempters to quit Under 44% of smokers receive mental health care Definition of nicotine withdrawal Symptoms that develop after abrupt discontinuation/reduction of nicotine after at least several weeks of daily use Four or more Dysphoria or depression, insomnia, irritability-frustration-anger, anxiety, difficulty with concentration, restlessness, impatience, increased heart rate, decreased weight Other nicotine withdrawal symptoms Craving, craving for sweets, impaired vigilance tasks, degree is based upon severity of habit Typical profile Lower socioeconomic status Males (more successful at cessation) Increasing rate with adolescent girls (typically starts 14–18 years) More dependent personality traits Co-occurring psychiatric or substance use disorders

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Receives mental health care (two to three times more than general population) Schizophrenia (70%–90%) Affective disorders (70%) Alcohol issues (60%–90%) Other substance (70%–95%) Cause of death usually smoking related injuries when polysubstance abuse is present Etiology and pathophysiology t½ 2 hours Early starters (90% by 18 years of age) Gateway drug—powerfully addictive (1/3–1/2 of all kids become habitual users) Multiple effects Mesolimbic DA pathway (reward/euphoria) Locus Coeruleus (mediator of stress reaction/vigilance and relation to higher mental/ cognitive functions) Specific nicitonic cholinergic receptors Hypothalamus, hippocampus, thalamus, midbrain, brainstem, cortex Endocrine-neuroendocrine system Catecholamine, serotonin, corticosteroid and pituitary hormones Release of ACh, NE, 5-HT, DA, vasopressing, growth hormone, corticotrophin, cortisol, prolactin endorphins Mediated by hypothalamic-pituitary axis Stimulant and depressive effects centrally and peripherally Cardiovascular, gastrointestinal, musculoskeletal Cholinergic (sympathetic/parasympathetic) and learning Improves mood and decreases anxiety Decreases distress in anxiety provoking situations Decreases aggression Improves cognitive functioning and performance Increases memory Helps disregard irrelevant stimuli Decreases appetite for carbohydrate Tolerance can take effect Withdrawal symptoms Anxiety, depression, bradycardia, decreased concentration, increased appetite and weight gain, insomnia, irritability/anger, restlessness Course and natural history 70% want to quit at sometime in lifetime 33% try to quit every year Median success rate for quitting 7% 3% quitting on own are successful 15%–45% 1 year abstinent rates High relapse rates (similar curve to opiates) Depression now and history is a predictor of relapse Individual factors Addiction Social and environmental circumstances Nicotine withdrawal Severe 1–3 days after Continuing 3–4 weeks maybe 6 months or more Nicotine dependence Chronic relapsing illness with intermittent episodes of remission (65%) Less than 25% quit with first attempt Average five to six attempts before success Predictor of success—previous success Relapse can occur after long cessation Evaluation and assessment

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Current and past tobacco use (consider multiple sources of nicotine) Current motivation to quit Objective measures Carbon monoxide levels of the breath Cotinine levels (saliva, blood, urine) Assess prior quit attempt (amount and what happened) Why quit? How long abstinent? Why relapsed? What treatment was used (how used? how long?)? Assess withdrawal symptoms and dependence criteria Psychiatric conditions and use of other substances/alcohol Medical conditions Seizures Eating disorders Pulmonary status Common triggers (car, people, mood, home, phone calls, meals, etc.) Perceived barriers and supports Preference for treatment strategy Overall approach to treatment Medications and therapy combined are best (consider health insurance limitations) Six FDA-approved medications Nicotine gum, inhaler, spray, patch Bupropion SR (Zyban) Clonidine Varenicline (Chantix) Good psychosocial treatment Phases of treatment Engagement American Cancer Society American Lung Association American Heart Association Local hospitals Quitting Quit date Preventing relapse Especially in the first few days (time of likely relapse) Nicotine replacement plus Zyban becoming more vogue Nicotine anonymous Self-help 50% are able to quit (>90% without professional help) COLD TURKEY is most common way—tapering leads to inconsistent loyalties Professional help may be inconvenient and time consuming Brief face-to-face with primary care provider can increase cessation by 2–10 fold especially if a serious medical condition exists Specific medications Nicotine replacement (prevents withdrawal, little abuse liability) Gum—first Releases nicotine and absorbed through buccal mucous membrane 2–4 mg doses and 9–16 pieces/day Better with conjunction with behavioral therapy Definitive schedule better than PRN dosing Tapering after 4–6 months of use Not great for individuals with TMJ, dental problems, dentures Highly motivated individual and understands complex instructions Crunched a few times and then park it in gum/cheek Not intended to be used like chewing gum

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Avoid acidic (coffee, soda, orange juice) as it interferes with absorption/ release Patch Sustained release through the skin Higher doses related to higher cessation rates Eliminates conditioning of repeated nicotine use Easier to be adherent 7 mg and 14 mg and 21 mg dose forms Delivery 0.9 mg/hour of nicotine (steady state 13–25 ng/mL) Usually 6–12 weeks or longer No titration dose Safe to use with poor dentition Well tolerated (skin irritation, erythema, serious) Combination with gum replacement form Nasal spray 0.5 mg to ear nostril 1–3×/hour for 15–20 sprays day (8–10 mg) Higher blood level than gum per patch Nicotine inhaler 8–10 ng/mL Allows mimicking of upper airway stimulation when smoking Absorbed via oropharyngeal mucosa Effective Side effects Local irritation Cough Headache Nausea Dyspepsia Multiple dosing Not discreet Zyban—DA/NE reuptake inhibitor Varenicline (Chantix) Psychosocial treatment underused, understudied, effective Motivational enhanced therapy (MET) CBT 12 step Medication and psychosocial treatments Nicotine replacement doubles quit rate (versus placebo) Face-to-face behavioral treatment doubles quit rate (versus minimal psychosocial intervention) Also increases adherence by 50% Triples outcome rate ICD-10 for nicotine dependence includes craving, malaise, increased cough, mouth ulceration NOT decreased heart rate

OPIATES Opioid use disorders Opiate dependence Opiate abuse Opiate intoxication Opiate withdrawal sleep disorder Opiate sexual disorder Opiate delirium Opiate psychosis

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Opiate mood disorder Opiate anxiety disorder Introduction Receptors Gamma: analgesia Mu Morphine is the prototypical agonist Effects—analgesia and euphoria, respiratory depression, constipation Kappa: analgesia, sedation, diuresis Agents Natural—morphine Semisynthetic—heroin (more potent and lipid-soluble than morphine) Synthetic—meperidine, codeine, hydromorphone, methadone, oxycodone, fentanyl Buprenorphine—a partial agonist MPTP-induced Parkinson’s MPTP + opioid → irreversible Parkinson’s MPTP → (MO) → MPP+ → SN(DA neurons) kills cells Use Analgesia Anesthesia Antidiarrheal Cough suppressants Epidemiology of opioid abuse and dependence Heroin most commonly abused drug of this class 1.3% of US population has used it once 12%–15% of adolescents use it for nonmedical uses Increasingly pure and available Increase in prescription abuse Number of methadone related deaths due to overdose is increasing Often unintentional Often in context of drug-drug interactions Oxycontin can contain as much as 80 mg/tablet Chewing/biting on oxycontin eliminates the slow release effects Etiology and pathophysiology of opioid-related disorders Risk factors Social/peer group Availability History of childhood conduct disorder or adult Asperger’s disorder Family of origin psychopathology (alcoholism and antisocial personality disorder) Heroin—IV/in; tar heroin-smoked; morphine, meperidine(Demerol) IV; fentanyl IV; codeine/perc po Clinical picture of opioid-related disorders Intoxication (minutes to a few hours) Initial euphoria Then dysphoria Evening psychomotor retardation or agitation Impaired judgment/impaired social or occupational function Papillary constriction Anoxia and pupils are dilated in severe overdose coma/obtunded Respiratory depression Slurred speech Inattention Dry secretions (mouth and nose) Slow gastrointestinal activity or constipation Withdrawal

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Anxiety Restlessness Ache Craving Irritability Increased sensitivity to pain Triad Dysphoria/depression Nausea/vomiting/diarrhea Muscle aches/lacrimation/rhinorrhia Also Diaphoresis Yawning Fever Insomnia Pupillary dilatation Piloerection NB: Fever and piloerection are signs of severe drug use Timing Heroin: occur 6–24 hour; peak 1–3 days; subsides 5–7 days LAAM/methadone: 2–4 days (anxiety, dysphoria, anhedonia, insomnia, craving) Subsides weeks to months Increases QTc duration: thus, caution should be taken when used in treatment Dependence Inappropriate use Exceeds use Tolerance Abuse Less use than dependence No signs of tolerance or wd Assessment and clinical picture Physical exam Tracks, skin popping (individual injects in subcutaneous tissue) Cellulitis tetanus Bacterial endocarditis Hepatitis B/C, HIV Irritation of nasal mucosa Difficulties in sexual functioning Premature ejaculation (opiate withdrawal) Impotence (opiate intoxication/use) Reproductive difficulties and irregular menses Laboratory values Detection Most forms in 12–36 hours LAAM methadone days Fentanyl not in standard urine test (needs specialized procedures) Oxycodone, hydrocodone, hydromorphone on gas chromatography Toxicology screen may be positive for other conditions Hepatitis B/C Liver transaminases Low platelets, anemia, neutropenia HIV Differential diagnoses Opiates withdrawal

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Pupillary constriction (not dilation like with alcohol, hypnotics, or sedatives) Watch with naloxone treatment Psychiatric signs and symptoms—depression and anxiety Course and natural history of opioid dependence Long history of abuse/dependence, etc. “Burn out” in 40s and older Treatment Opioid agonists Methadone mu receptor agonist and NMDA glutamate receptor agonist Suppresses opioid withdrawal for 24–36 hours after a single dose Higher doses recommended for treatment (80–120 mg/day) Best results if combined with psychosocial therapy LAAM Approved by the FDA in 1993 Longer acting than methadone 48–72 hours after a single dose Partial agonists Buprenorphine FDA-approved buprenorphine forms Buprenex—buprenorphine only FDA-approved since 1981 as an analgesic But illegal to use for opioid detoxification or maintenance treatment in United States 0.3 mg im/iv q4–6h Subutex—buprenorphine po (SL) only FDA-approved for opioid dependence (2 or 8 mg only) Not FDA-approved for pain Target dose is 8–16 mg/day (receptor saturation at 16 mg/d) Suboxone = buprenorphine + naloxone (2 mg/0.5 mg or 8 mg/2 mg) FDA-approved for opioid dependence Not FDA-approved for pain Target dose is 4–16 mg/day (available in 2 mg/0.5 mg or 8 mg/2 mg) Opioid partial agonist made inactive—if not parenteral Likelihood of death due to overdose significantly decreased Overdose (all forms SL SC IM IV) Risk minimal Low risk High doses do not cause respiratory depression But beware when ingested in large amounts with other CNS depressants Death from respiratory depression (France) (crushed with IV high potency benzodiazepines) Warning should be given if combined use (but no absolute contraindication from any/all benzodiazepines) Antagonists Naloxone Opioid antagonist Short acting High mu affinity Reverses opioids (especially respiratory depression) and can precipitate withdrawal No intrinsic agonist activity Opioid antagonist short acting with high mu affinity Naltrexone: Partial opioid antagonist Nonopioid alternatives Alpha 2 adrenergics

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clonidine Suppresses autonomic signs/symptoms of withdrawal Side effects Sedation Hypotension Lofexidine (originally antihypertensive) Less sedation and hypotensive Peaks and flattens earlier than methadone Guanfacine—more studies needed Benzodiazepines NSAIDS Psychosocial/behavioral therapies Helping with life issues Helps with cessation of all addictions 1993 study demonstrated that enhanced behavioral therapy Self-help groups Contingency management Adherence to appointments appear to be most difficult Individual drug counseling Therapeutic communities Residential settings 6–18 months Rare use of agonists/antagonists Psychotropic use Addressing comorbidity Psychiatric Depression Mood Insomnia Sexual functions Not often bipolar or schizophrenia PTSD Medical HIV HepB C Methadone increase plasma levels of zidovudine (looking like methadone withdrawal) Nevirapine lowers methadone levels Death due to overdose/accidents/injuries/medical complications Fetus Prematurity Low birth weight Found in breast milk (but 180 mg no adverse effects) HIV in 1/3 of infants (but 1/10 if moms are given zidovudine) HIV in breast milk, too Integrated treatment: helpful Harm reduction Needle exchange Education of hygienic measures ICD-10—craving, gastrointestinal cramps, tachycardia (not fever or dysphoria like in DSMIV-TR)

SEDATIVES, HYPNOTICS, AND ANXIOLYTICS Introduction Etiology GABA receptors

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Psychiatry Bullets GABA a receptor on the GABA cell Over time the GABA a receptor may uncouple (thus less effective) Epidemiology—essentially not known Patterns of abuse (high, intensify other drugs, self-medicating the withdrawal of others substances, reduce side effects of other drugs) Barbiturates IV (infectious sites) irritating to tissue vasoconstriction (gangrene) Methaqualone Quaaludes removed from US market in 1984 Benzodiazepines (BNZP) Flunitrazepam (Rohypnal, Narcozep) “date rape drug” from mid-1990s Combined with other BNZP → synergistic respiratory depression GHB—has sedative/hypnotic properties Zolpidem (Ambien) Rapidly absorbed Short t½ (2.2 hours) Binds to subunit of GABA-bnzp complex Zaleplon (Sonata) Binds to subunit of GABA-bnzp complex on the omega 1 receptor Short t½ (1 hour) Acute intoxication with sedative hypnotics Slurred speech Incoordination Ataxia Sustained nystagmus Impaired judgment Mood lability Progressive respiratory depression/coma (quicker for barbiturates and other SH) Dependence Withdrawal typically within 1 day for short acting and 1 week for long acting Anxiety Tremors Nightmares Insomnia Anorexia Nausea and vomiting Postural hypotension Seizures Delirium—usually following insomnia Hyperpyrexia Death Iatrogenic dependence Assessment Drug use history Consider possibility in polysubstance abusers In the context of the conditions needed for treatment Ask family/friends Street sources are not “controlled” Physical exam Intoxication: sustained horizontal nystagmus (reliable) Withdrawal: abnormal diaphoresis, increase in pulse and blood pressure Labs Valium (Diazepam) and Librium (Chlordiazepoxide) weeks Xanax (Alprazolam) and Clonazepam may not show up on urine toxicology screens

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Treatment Detoxification Decreasing doses of the agent of dependence Substitute phenobarbital (or other long-acting barbiturate) Good for individuals with polydrug dependence Phenobarbital Safer than short-acting barbs Lethal doses much higher than toxic doses Toxicity—sustained nystagmus, ataxia, slurred speech Maximum daily dose is 500 mg/day Calculate daily equivalent dose Watch for toxicity especially sustained nystagmus If 1 symptom holds one dose, if all three hold two doses for 2 days If intoxication occurs 1–2 hours after im dose—intoxication is not severe Decrease phenobarbital 30 mg/day unless withdrawal is noted (increase by 50%) Replace with long-acting benzodiazepine Stabilization phase—see above Withdrawal phase—see above Psychotherapy Watch for physical symptoms, emergence of psychiatric symptoms, family/ occupational functioning Not insight oriented but supportive 12-step recovery Additional Treat psychiatric morobidity Abuse potential of benzidiazpines → not really, think more for self-medicating withdrawal from opiates Treatment of high-dose benzdiazepine dependence→ use Phenobarbital equivalents Low-dose benzodiazepine withdrawal syndromes Discontinuation (increasingly symptomatic usually at 10%–20% of peak dose) Symptom rebound (especially insomnia) lasting a few days to a few weeks (transient) Symptom reemergence (recrudescence) anxiety returns to what it was and should be treated Severe protracted withdrawal Risk factors Family history of alcohol or other sedative use Alprazolam use Treat (e.g. 20 mg valium (diazepam) needs 200 mg phenobarbital) Give clonidine or beta-blockers to address side effects ICD-10—Sedative/hypnotics intoxication includes erythematous skin lesions or blisters Sedative/hypnotic withdrawal has craving, postural hypotension, headaches, malaise/ weakness, paranoia (not on DSM-IV TR)

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Chapter

8

Personality Disorders

ASSESSMENT Multiple resources Interviewing of the individual over time Multiple historians other than the individual Medical records Other providers Family members Friends/associates Psychological testing “Rule-out” Axis I, III, and IV Assess for other psychiatric conditions Assess for medical conditions Assess for psychosocial stressors

DEFINITION TR: unusual situation <18, features >1 year maladaptive (Antisocial personality disorder: severe chronic CD and pattern of irresponsibility and as behavior <15 years) Rutter: institutionalized children have problems until late 20s

PERSONALITY DEVELOPMENT Family history OCD and compulsive traits Antisocial personality disorder ADHD and traits Character as a consistent pattern: Projection → paranoia Action/proneness → acting out Reaction formation → obsessive Repression → hysterical

LONGITITUDINAL STUDIES 3 months to 2 years stable: Mood Adaptability Approach

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Intensity (not: activity, distraction) Temperament Sense of identity established at 6 to 12 years Have a sense of “me-ness” Lower level defenses: splitting, denial, projection, good/bad, omnipotent But, will develop higher level defense mechanisms with time

TYPES (REFER TO DSM-IV TR) Paranoid personality disorder Assessment approach Individual may not likely seek treatment Therapeutic alliance strengthened if clinician can be Straightforward Factual Not overly warm style (avoids exacerbating paranoia) Treatment Group therapy addressing social skills CBT addressing anxiety management Psychopharmacological Antipsychotic agents to address potential psychotic decompensation Schizoid personality disorder Assessment approach Individual may not likely seek treatment Therapeutic alliance strengthened if clinician can be Interested Caring Nonconfrontational Treatment Supportive therapy Treatment if Axis I condition also present Group therapy addressing social skills Schizotypal personality disorder Assessment approach Individuals may not likely seek treatment Therapeutic alliance strengthened if clinician can be Straightforward Factual Treatment CBT addressing cognitive distortions and social skills Psychopharmacological treatment Antipsychotic agents to address potential psychotic decompensation Histrionic Treatment Frequent therapy Parental counseling (especially in female patients) Borderline Assessment approach Individual often found in treatment settings Therapeutic alliance strengthened if the clinician can be Consistent Expectant of the patient to be angry and disruptive

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Anticipatory of defenses Splitting Devaluing Idealization Denial Projection Treatment Supportive therapy providing “corrective emotional experience” Psychodynamic therapy with same intent Supportive group therapy with same intent CBT to address social skills DBT (dialectical behavior therapy) Developed by Marsha Linehan Cognitive behavioral techniques and mindful awareness Skills taught Core mindfulness Interpersonal Emotion regulation Distress tolerance Psychopharmacological agents to address Mood lability Cognitive distortions Aggression Narcissistic Assessment approach often requiring time (years) Treatment “Cornerstone” treatment: individual psychodynamic psychotherapy Empathy toward patient’s sensitivities and disappointments Insight directed toward maladaptive grandiosity Antisocial personality disorder Assessment approach Awareness of the possibility of this condition Monitoring of dynamics in the individual’s setting Inpatient hospital setting amongst other patients Treatment team dynamics of observations of the patient Family, social, occupational, etc. dynamics Treatment Treatment if Axis I condition present Supportive therapy to enhance awareness of behaviors Avoidant personality disorder Assessment approach Differentiate from Schizoid personality disorder—avoidant individuals avoid secondary to fearing rejection and/or criticism Social phobia—social phobia individuals have more specific fears Therapeutic alliance can be strengthened if the clinician can be Supportive of patient’s sensitivity Nonconfrontational Aware of potential for countertransference Overprotectiveness Too little or too much expectation for change Treatment Social skills training focusing on assertiveness CBT to address distortions of patient’s abilities Group therapy addressing social skills

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Dependent personality disorder Assessment approach Individuals often seek help for depression or anxiety Therapeutic alliance strengthened if the clinician is not overly directive or protective Treatment Group therapy addressing social skills CBT addressing increased independent functioning Couples therapy to strengthen more adaptive independence Family therapy to strengthen more adaptive independence

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Chapter

9

Somatoform Disorders

SOMATIZATION DISORDER Assessment Critical assessment for other conditions necessary: Medical conditions Axis I conditions Schizophrenia Anxiety disorders Mood disorders Medical records Family members Multiple providers Treatment Empathy toward individual’s sense of suffering Information Reassurance

UNDIFFERENTIATED SOMATOFORM DISORDER Assessment Symptoms are not consistent with somatization disorder Assess for Major depression Anxiety disorders Treatment Supportive therapy Time

CONVERSION DISORDER Assessment Nonintentional production of symptoms Specific symptoms Motor Impaired coordination/imbalanced Paralysis/localized weakness Difficulty swallowing/ “lump in the throat” Aphonia Urinary retention

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Sensory Hallucinations Loss of touch or pain sensation Double vision Blindness Deafness Seizures/convulsions with voluntary motor/sensory components Look for history of conversion symptoms Treatment Treat symptoms Reassurance Relaxation technique education Hypnosis

HYPOCHONDRIASIS Assessment Address physical disease (if present) Monitor for Mood symptoms Anxiety symptoms Other obsessive or compulsive inclinations Treatment Mood, anxiety symptoms, and obsessive/compulsive symptoms Team approach with other medical providers

BODY DYSMORPHIC DISORDER Assessment Monitor for Anorexia nervosa Gender identity issues Peaks during adolescence and early adulthood 2% of those who seek corrective cosmetic surgery have this condition Treatment Recognition Behavioral therapy addressing interpersonal relationship improvement Psychodynamic therapy addressing self-esteem Pharmacological therapy to address Distortions Depression

SOMATOFORM DISORDER NOS

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Dissociative Disorders

DISSOCIATIVE AMNESIA Assessment Peaks at age 30 and 40 Comorbidity Conversion disorder Bulimia nervosa Alcohol abuse Depression Histrionic, dependent, borderline personality disorders Treatment Time (most spontaneously revert) Hypnosis “screen technique” Relive a traumatic event as if watching it on TV or as a movie Mastery over event Observer—not a participant of the “reliving”

DISSOCIATIVE FUGUE Treatment—integrating dissociated memories/behaviors

DISSOCIATIVE IDENTITY DISORDER (FORMERLY KNOWN AS MULTIPLE PERSONALITY DISORDER) Assessment Emerges typically between adolescence and in the 30s (rarely in the 40s) Patient’s lack of awareness History of sexual and physical abuse Projective psychological testing Monitor for Depression Substance issues Borderline personality disorder Seizure disorders Treatment Maldonado’s “Rules of engagement” Free access to all pertinent records Review of all available and pertinent records Freedom to discuss all past and current pertinent information with previous therapists 131

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Complete organic/neurological workup Contract for safety Increased communication and cooperation amongst alters “No secrets” policy Establishment of hierarchical pattern of communication Establishment of hierarchical pattern of responsibility Limited exploration followed by therapeutic condensation of memories “All details are not needed” policy Rules regarding contact during hospitalization and continued therapy after discharge Videotaping Ultimate goal: “full integration” “One day you will make me obsolete” principle Psychotherapy to mastering past traumatic events Hypnosis Eliciting different personality states Eliminate regression and encourage cohesion of personalities CBT to address integration of personalities Pharmacological agents addressing Depression Seizure disorders

DEPERSONALIZATION DISORDER Rule out PTSD Treatment Hypnosis “Imaginary screen” to picture problems

DISSOCIATIVE TRANCE DISORDER Differentiate from Dissociative trance disorder Do not involve distinct identities Acitivities are simple Memory is not affected; amnesia is fragmented Possession trance Distinct alternate identity Deity Ancestor Spirit Activities are complex Amnesia may be lengthy Treatment Rule out physical conditions Treatment of any comorbid psychiatric conditions Education Cultural sensitivity

DEREALIZATION

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Chapter

11

Factitious Disorders and Malingering

FACTITIOUS DISORDERS Assessment Intentional production or feigning of symptoms—psychological or physical Unconscious production of these symptoms Types Factitious disorder Munchausen Wanderers Multisystem complaints Multiple hospitalizations Non-Munchausen Often passive, immature, young adult female patients Often trained/employed in health care–related fields Conforming lifestyle Family support and involvement Single-system complaint Factitious disorder by proxy (diagnosis given to the victim of the proxy) Treatment Establishing safety of the patient (factitious disorder by proxy) Multiprovider interventions Awareness of potential countertransference Anger Aversion Violation of confidentiality Overidentification with patient Activation of rescue fantasies

MALINGERING Assessment Motivation is clear Monitor for frequent and/or unusual inconsistencies Treatment Confrontation Expectation of refusal of assessment/diagnosis Awareness of potential countertransference Anger Aversion Violation of confidentiality 133

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Chapter

12

Eating Disorders

OVERVIEW Continuum of eating disorders Anorexia Restricting type Purge type Bulimia Binge/purge Binge eating disorder Obesity Types Anorexia nervosa Bulimia nervosa Binge eating episode Genetics and environment Genetics Heritability: 0.5 to 0.8 COMT s/s variant? What is inherited? Perfectionistic/obsessive compulsive disorder symptomatology Height (BMI) Actual eating disorder Environment Coping strategies of family members Environment stressors

ANOREXIA NERVOSA OVERVIEW Diagnostic criteria Subtypes Binge-purge: drugs (laxatives, diuretics), depression, impulse, and suicide Restricting: food restriction and compulsive exercising for weight loss Epidemiology 0.2% to 1.5% lifetime prevalence 90% to 95% female Age of onset typically in adolescence but ranges from 8 to mid 30s Associated with highest mortality rates of any mental disorder

135

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Course Remitting Recurrent Chronic Clinical features Physical symptoms Cold intolerance, dizziness, constipation, gastrointestinal discomfort, and hyperactivity Exam Cachexia, breast atrophy, dry/yellow skin, Russell’s sign, bradycardia, lanugo, and alopecia Medical complications Cardiovascular complications Signs and symptoms Low voltage, bradycardia, T-wave inversions, ST depression, supraventricular premature beats, or ventricular tachycardia Watch in purging or diuretic abusers Also watch in cases of hypokalemia and hypochloremia Hypercholesterolemia Hematological changes: mild anemia or leucopenia and low platelets Gastrointestinal complications Decreased GI motility and gastric emptying time (GET) Pancreatitis (sometimes) Elevated LFTs and amylase if fatty degeneration of the liver exists Low fasting blood sugar Elevated serum salivary amylase Acute gastric dilation/rupture + acute vascular compression of duodenum Renal complications High BUN levels, polyuria, and peripheral edema during refeeding Neurological abnormalities—rarely (large ventricles and sulci), smaller gray matter Endocrine complications Amenorrhea precedes weight loss (20% to 30%) Thyroid Diabetes mellitus (careful use of insulin necessary) Skeletal complications Reduced bone density—osteoporosis (90% of bone mass in adolescents) Hypercortisolism and hypoestrogenisms → osteopenia Psychological assessment Severe body-image distortion Obsessive tendencies Interpersonal insecurity Minimal emotional expressivity Perfectionism Identity confusion Excessive conformity and guild Rigid control over impulses Competitiveness Envy Ambivalence of sexual and emotional maturation Psychiatric conditions: mood disorder, kleptomania, polysubstance abuse, and OCD Personality disorders Starvation effects Psychological Constant preoccupation with food and weight Heightened craving for food Heightened anxiety/obsessiveness Poor concentration Depressed and labile mood

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Feelings of inadequacy and irritability Social withdrawal Physical Electrolyte imbalance leading to cardiac arrhythmias Delayed gastric emptying time—bloating after meals Lowered metabolism, fatigue, and edema Ovarian abnormalities, fatigue, and edema Osteoporosis, dry skin, hair loss, and lanugo Insomnia, hypersensitivity to noise and temperature DIFFERENTIAL DIAGNOSIS Diabetes mellitus Crohn disease Colitis Thyroid conditions IBS Acid peptic disease Addison’s Motility disorder Brain cancer Conversion Schizophrenia ETIOLOGY High-risk populations Models Ballet dancers Athletes Chronically ill Diabetes Cystic fibrosis History of sexual abuse PATHOGENESIS Genetics COMT s/s variant Family history Mood disorders Eating disorders Environment Parental roles Family perspectives: individual with anorexia nervosa as the identified patient Sociocultural factors TREATMENT Practice guidelines American Psychiatric Association (APA) Practice Guidelines National Institute of Clinical Excellence (NICE) Guidelines Address multiple possible comorbidities Depression Substance use issues Anxiety disorders/PTSD/obsessive tendencies Setting of treatment Outpatient psychiatric treatment involving a specialist First episode—no previous treatment or relapse after resuming weight Continuing treatment following inpatient/partial hospitalization Weight loss is gradual over 3 months Weight loss within 75% to 80% of BMI Normal serum electrolytes Must consider inpatient care if: >20% original body weight loss in <3 months

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Weight <75% BMI Abnormal electrolytes (decreased K/Cl; metabolic alkalosis) Evidence of dehydration Abnormal EKG Depression with psychosis or suicidal tendency Incapacitating obsessions not related to the eating disorder Nonfunctioning otherwise Essential features Cognitive behavioral therapy Two core assumptions about anorexia nervosa Food avoidance activated by distorted thoughts of food and weight Anorexia nervosa serves a positive function Creation of life events chart Patient and therapist work together; homework given Visual account of relationships between interpersonal functioning, self-esteem, life events, and development/maintenance of eating problems Tasks Involve patient in short-term and long-term goals to reduce fear of treatment Establish regular weekly weighing Educate patient about negative effects of Dietary restriction Low weight Binge-eating/purging Introduce regular eating pattern and strategies to cope with anxiety Education Cognitive view of maintenance of the illness Psychological and physical effects of starvation—cost/benefit analysis Monitoring Weekly weighing Food records Cognitive restructuring and problem solving For interpersonal problems and eating behavior Family therapy (if patient is <18 years of age) Therapist with medical backup Medication—SSRI for depression/OCD behaviors Family Maudsley (to be implemented after weight restoration) Three phases of treatment of 20 sessions over 6 to 12 months Parents are in charge of weight restoration Assumes parent Available and willing participants Has a partner Assumes patient Available and willing participants Not with severe illness (weight > 70% to 75% ABW) Systems family therapy Focuses on patterns of behaviors and beliefs Studies family member’s roles and relationships Examines how patient’s developmental stage is accommodated by the family Pharmacology Only used adjunctly after weight restoration SGA ?Olanzapine Addresses overwhelming anxiety and obsessionality Study involving outpatient use with efficacy

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SSRIs are ineffective 5-HT levels are depleted l-Tryptophan availability is low (from food) Cyproheptadine Weight gain Antidepressant effect Tranquilizers—reduce anxiety Resistance to treatment adherence in anorexia nervosa Illness provides a useful function in life Escape from developmental issues Escape from life stresses Highly reinforcing—terrifying to relinquish Egosyntonic nature—patient denial Reinforcing factors that interfere with treatment Coping styles Developmental transitions Fears of maturity and autonomy Distressing life events Feelings of ineffectiveness Helplessness Poor self-esteem Disturbed relations with others Elevation of self-esteem and control PROGNOSIS Outcome 5% includes suicide Risk factors for poor outcome Low weight Social functioning Polysubstance abuse Binge-purge Mood disorder COURSE as above

BULIMIA NERVOSA Prevalence and epidemiology 2% to 3% lifetime prevalence for females (0.1% to 0.3% for males) Female:male ratio 10:1 Peaks during adolescence and young adulthood Course Remitting Recurrent Chronic Risk factors Familial Family member/relative with anorexia nervosa, bulimia nervosa, or obesity Family member/relative with depression/ alcohol-drug abuse/dependence Individual biological factors Mildly overweight Early menarche

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Individual psychological factors Perfectionistic Low self-esteem Affective disorders, alcohol/drug use Individual behaviors Dieting Activities that emphasize weight control Early feeding problems Cultural Industrial country “Thin is beautiful” United States has had a general significant weight increase Stressors Death of close friend/relative Sexual abuse or history of trauma Developmental features Lack of experiences to foster personal independence Sense of personal ineffectiveness Social ineffectiveness Poor self-esteem Warning signs Low weight or large fluctuations in weight Purging to lose weight Persistent concerns with weight loss Persistent attempt to lose weight despite normal or low weight Social withdrawal and isolated eating Unexplained amenorrhea Definition and diagnostic criteria DSM-IV TR criteria—eating within 2 hours large amounts, sense of a lack of control; compensatory behavior (diet pills, laxatives/enemas, exercise) two times a week for 3 months; influenced by body shape and weight and not during AN Types Purging Nonpurging Etiology Biological Family history (twin studies) Neurotransmitters (5-HT, DA, NE) Neuropeptides (CCK, opioids, neuropeptide Y, peptide YY, hypocretin/orexin) Leptin (plasma levels are higher) IDDM Psychological and family Attachment quality to mothers Cluster B personality disorder characteristics Image issues History of sexual abuse Risk factors: Cultural effects Dissatisfied with body Depression Signs and symptoms Chipmunk face (parotitis), fluid retention, irregular menses, bradykinesia, and shortness of breath

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Fatigue, hypotension, cold intolerance, muscle pain, gastrointestinal dysfunction, and epigastric symptoms Fullness, polyuria, dry cold skin, dental erosions, and Russell’s signs (back of hand erosions due to personally inflicted vomiting) Ruptured esophagus/stomach, cardiomyopathy (ipecac use), and cardiac arrhythmias Cardiomyopathy especially if ipecac use is present Subconjunctival hemorrhages, kidney failure, and low T3 levels Reduced insulin and glucose, increased lipolysis Sleep, libido, sex, dysphoria, irritability, social withdrawal, obsessional Psychological symptoms Preoccupied with weight, food, and body size Anxiety Depression, guilt, and impulse control issues Perfectionism Families focused on perfectionism, history of sexual abuse Labs Fasting (decreased volume and kidney function increase aldosterone release Potassium is excreted leading to hypokalemia and retention of Carbon dioxide—or if in metabolic acidosis, loss of carbon dioxide) Anemia Low potassium and chloride, high sodium Low protein (bloating) Low magnesium (cardiac and vascular, bone, kidney, thyroid) and zinc Osteopenia (if prolonged, restrictive type or Ipecac usage) Cardiomyopathy, congestive heart failure (perform ECHO) Chest pain, shortness of breath Generalized muscle weakness Hypotension, tachycardia, and EKG changes Increased liver function Increased sedimentation rate Irrational beliefs regarding “thinness” Differential Diagnosis Upper gastrointestinal disorder Neurological (Kleine-Levin, Kluver-Bucy) Hormonal (hyperparathyroidism) MDD Personality disorder Other eating disorders Comorbidity Treatment CBT (studies demonstrate efficacy) Interpersonal therapy Dialectical behavioral therapy Psychodynamic (should be used in conjunction with other treatments) Psychoeducation Family therapy (Maudsley version) Pharmacological agents Antidepressants SSRIs Fluoxetine is the only FDA-approved medication Fluoxetine doses should be high (60 mg/day) as the serotonergic system is blunted Bupropion is contraindicated TCAs (desipramine and imipramine) MAOIs (phenelzine)

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Antiepileptics (topiramate) Opiate antagonists (naltrexone) Antiemetics (ondansetron) Other Topiramate Sibutramine Zonisamide Binge eating agents Topiramate Sibutramine Zonisamide SSRIs (fluoxetine, etc.)

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Chapter

13

Sleep

NEUROLOGICAL UNDERSTANDINGS Neurotransmitters Acetylcholine (ACh)

Cortical activation

Norepinephrine (NE)

Heightens arousal from external stimuli

Serotonin(5-HT)

Affect and mood modulation

Histamine

Fired on only when awake

Hypocretin

Stabilizes arousal circuits when awake

Dopamine

Behavior modulation

Sleep neurotransmitters Wake Dopamine Norepinephrine Serotonin Histamine (antihistamine increases drowsiness) Acetylcholine Glutamate Hypocretin Orexin NREM Serotonin Adenosine GABA Theophylline and caffeine decrease sleep Benzodiazepines promote sleep REM Cholinergic nicotinic muscarinic receptors Nicotine promotes REM sleep TCA (anticholinergic properties) depresses REM sleep Brain areas Wakefulness is maintained by the coordination of two centers: Hypothalamus and the reticular activating system The hypothalamus integrates information Metabolic state Memory Mood Drives Environment 143

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The ascending reticular activating system Receives information from somatic and visceral sources Sends projections to subcortex and cortex The suprachiasmatic nucleus (SCN) is the sleep center of the brain. Major “afferents” into the SCN are Glutamate (via light) Serotonin and norepinephrine Melatonin (via the pineal gland) If the SCN is in the WAKE/ON mode activating neurons in the TMN or tuberomammillary nucleus: One is in a state of “external vigilance”(anxiety and fear) “calm alertness” (cognition/executive functioning) Histamine and hypocretin/orexin have been secreted from the TMN TMN cells almost solely produce histamine Projections of histaminic neurons go to the basal forebrain and cortex No histamine is “fired” during sleep Hypocretin/orexin theorized to stabilize wakefulness by suppressing REM and lowering the threshold for arousal Loss of this signaling causes “inappropriate transitions into REM” If the SCN is in the SLEEP/OFF mode activating neurons in the VLPO Or ventrolateral preoptic nucleus to inhibit the TMN Normally, ACh is present during wake stages GABA and ACh are released into the cortex A subpopulation of these cholinergic cells continue to fire during REM Brain structures Pons and midbrain (caudal) generate basic features of REM In general, REM sleep Anterior paralimbic cortex Error detection Motivation to action Ventral striatum/basal forebrain/basal ganglia Premotor

NREM

Motor cortex

Central pattern generation

Primary sensorimotor cortex

Sensorimotor

Cerebellum

Cognitive planning

Insular cortex

Interface w/ internal stimuli

Mesial temporal cortex (hippo/amy/uncus)

Emotion/memory

Brainstem reticular formation

arousal/approach

Brainstem → limbic/VM PFC → PFC Areas of decreased metabolism (relative to waking)––thalamus

Depression REM Depressed patients have increased REM sleep REM is a limbic activator NREM—changes in waking and NREM cerebral blood flow Insomnia Increased metabolism of the brain Arousal systems do not deactivate

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Chapter 13 Sleep Physiology of sleep states REM Peripheral muscle tone paralysis Neuronal firing/neurotransmitter release and uptake/metabolic rates like the active state Vigorous mental activity (dreams) NREM (during the first 6 months of life, the NREM stages emerge) Peripheral muscle tone stops Slower respiratory (RR) and heart rate (HR) Stages 1 Looks like REM But, respiratory rate, heart rate, and eye movements patterns are inhibited 2 K complexes Sleep spindles 3 and 4 Slow, high voltage synchronized delta waves Sleep requirements In general: Birth

2 years

16 years

Diurnal

50%

10%

0%

Nocturnal

50%

90%

100%

Sleep Time

18 hours 13 hours

7 hours

Development of sleep-wake organization Newborns

Adults

REM/NREM

50%/50% No Stage 4NREM

20%/80% Stages 3&4 comprise of 20NREM

Length of cycles

Every 50 minutes

Every 90 minutes

Wake-Sleep state

Sleep begins with REM

Sleep begins with 4NREM

Even REM/NREM through-out sleep

First 1/3 of sleep is 4NREM Later part of sleep is REM Diurnal influences more notable

Aging Waking metabolic declines associated with aging But, areas where metabolism declines from wake→ sleep are less in aging

SLEEP DISORDERS—ADULTS Adult population Epidemiology

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Difficulty falling asleep

4% to 17%

Difficulty remaining asleep

12% to 32%

Early morning awakening

5% to 16%

Nonrestorative sleep

3% to 15%

Pain during sleep

4% to 14%

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Insomnia Concerns Prevalence in adults over 10% (30% with disturbed sleep) Risk factor for psychiatric disorders Predictor of relapse from mood disorders Risk factor associated with a first myocardial infarction Predicted falls in the elderly (compared to hypnotic medications) Differential diagnoses Primary psychiatric disorder Major depression Bipolar disorder GAD PTSD Schizophrenia Panic disorder OCD Borderline personality disorder Dementia ADHD Substance abuse/dependence Medical conditions Cardiac Angina Paroxysmal nocturnal dyspnea Pulmonary COPD GI GERD Endocrine Hypothyroidism/hyperthyroidism Diabetes Menopause Neurologic Dementia Parkinson’s disease Strokes Migraines Urinary Renal issues Nocturia Substances Caffeine Alcohol (rebound insomnia) Medication—induced Antidepressants Stimulants Steroids/bronchodilators Decongestants Dopamine agonists (akathisia) Restless legs (RLS) and periodic limb movement disorder (PLMD) RLS Clinical features Urge to move Worsens at night/rest/inactivity Relieved with movement

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Family history Monitor for Iron deficiency Renal insufficiency/failure Pregnancy Medication induced Treatment via dopamine agonists Periodic limb movement disorder Clinical features Repetitive stereotyped movements of the foot/leg “Kicking” at night Sleep disorder Circadian disorder Elderly (secondary to medical conditions) Management of insomnia Aims of treatment Reduce nocturnal arousal Sleep onset Sleep maintenance Multiple mechanisms Maintain daytime alertness Long-term therapy indicated Hierarchical levels of arousal Sleep hygiene → DLPFC Psychotropics → limbic/VMPFC Sedative/hypnotics → brainstem reticular formation → basal forebrain → hypothalamus Nonpharmacological approaches for insomnia Sleep hygiene → promote habits to help sleep → provide rationale for subsequent instructions Stimulus control → strengthen bed and bedroom sleep as sleep stimuli Sleep restriction → improve sleep continuity (by limiting time in bed) Relaxation → reduce arousal (and decrease anxiety) via meditation, muscle relaxation, yoga, and biofeedback CBT → challenge dysfunctional beliefs and misperceptions Circadian → reset/reinforce biological rhythm Rhythm Entrainment Pharmacological approaches for insomnia Nonhypnotic Types Diphenhydramine Sedating antidepressants (TCAs, trazodone, mirtazapine) Second generation antipsychotics (quetiapine) Anticovulsants (gabapentin) Risks and benefits Benefits Low abuse potential Addresses anxiety Inexpensive Nonscheduled Risks Efficacy unproven, priapism Residual sedation, anticholinergic side effects, weight gain, toxicity

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Psychiatry Bullets Possible glucose and lipid abnormality (second generation antipsychotics) Cognitive impairment (anticonvulsants) Hypnotics FDA Approved

Medication

Active

Dose (mg)

Onset

t½

Metabolite Duration

Flurazepam (Dalmane)

15 30

Rapid

47 to 100

Y

Estazolam (Doral)

7.5 (15)

Rapid

39 to 100

Ya

Benzodiazepine

Prosom

0.5 (12)

Rapid

10 to 24

N

Temazopam (Restoril)

7.5 15

Interim

3.5 to 18.4

N

Triazolam (Halcion)

0.125 (0.25)

Rapid

1.5 to 5.5

N

Eszoplicone (Lunesta)

123

Rapid

6

N

6w/6m

Ambien CR

6.25 (12.5)

Rapid

2.8

N

3w

Zolpidem (Ambien)

5 (10)

Rapid

2.6

N

35d/3m/6m

Zaleplon (Sonata)

5 10 20

Rapid

1

N

2w/4w

Nonbenzodiazepine

Indiplon

2w

Melatonin receptor agonists Ramelteon (Rozerem)

8

Rapid

1 to 5

Y

12m

Benzodiazepine receptor agonists Mechanism of action Hypnotic Anxiolytic Myorelaxant Anticonvulsant Side effects Sedation Anterograde amnesia Ataxia/falls Respiratory depression Tolerance/dependence/abuse Triazolam issues Discontinuation rebound Dose escalation Nonbenzodiazepine receptor agonists No evidence of Tolerance Rebound Melatonin receptor agonist (ramelteon) Mechanism of action MT1 and MT2 receptors agonists (in hypothalamus) to maintain normal sleep-wake cycle t½ dose is the same no matter what the dose Efficacy Sleep onset Chronic insomnia Transient insomnia

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Excessive daytime sleepiness Differential diagnoses Inadequate sleep Voluntary restriction Shift work Delayed sleep phase disorder Poor quality sleep Sleep apnea Obstructive—due to blockage of the airway Clinical features Risk factors Obesity Age (increasing) Large neck Acromegaly Micrognathia Oropharynx Excessive daytime sleepiness Restless sleep Night time diaphoresis Dry mouth/sore throat Intellectual impairment Impotence AM headaches Bed partner unable to sleep Treatment CPAP—continuous positive airway pressure Weight loss Surgery to upper airways Tracheostomy Sleep consult Central—due to brainstem or systemic illness PLMD Medication-induced Environmental factors Excessive sleep drive Narcolepsy Idiopathic hypersomnia Medication-induced

SLEEP DISORDERS—PEDIATRIC POPULATION Pediatric insomnia Definitions DSM-IVR Primary insomnia Insomnia related to another mental health disorder Associated with general med condition or substance abuse ICSD II Behavioral insomnia of childhood Sleep onset association Falling asleep extended process with special conditions Sleep onset associations highly problematic or demanding Sleep onset significantly delayed or disrupted Nightline awakenings require parent to help the patient limit setting Difficulty initiating or maintaining steep

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Child stalls or refuses to go or return to bed Parent cannot set limits Psychophysiologic Associated with mental or medical disorders In general, “an age-appropriate, short-lived disturbance is less serious and requires less intervention than a disorder that appears earlier or persists beyond the usual age limits” Studies point out that kids do not necessarily “outgrow” developmental sleep problems Classification of sleep disorders ICSD-DCM Dyssomnia Night waking, DFA Limit-setting sleep disorder, sleep-onset association disorder, and food-allergy insomnia Parasomnia Sleep disorders associated with medical or psychiatric conditions DSM-IV TR Dyssomnia (insomnia, hypersonic, circadian rhythm sleep disorders) Protodysomnia (the child focused criteria for infants and toddlers) Parasomnia (REM and NREM persona) DC 0-3 Sleep behavior disorder Prevalence 20% to 25% of kids have some kind of sleep disturbance More 20% of 0 to 2 year olds have night waking 25% to 50% preschoolers have DFA night awakening 15% 4 to 10 year olds have bedtime resistance 10% of adolescents have primary insomnia High risk populations General numbers Developmental delays

70% to 80%

Autism PDD

70% to 80%

Psychiatric (depression anxiety)

75%

Disruptive (ADHD/ODD)

50%

Medical

50% to 60%

Specific populations Autism Especially younger kids Severe chronic intermittent Asperger syndrome differences Most common symptoms Irregular sleep-wake cycles Delayed sleep onset Prolonged night wakening Short sleep duration ?need Early morning wake times more common parasomnias Early onset depression 10% experience insomnia after treatment of depression Like adults, this may be predictive of treatment resistance 88% of depressed kids have insomnia Specifically find Delayed onset

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Decreased sleep efficiency Predicted prognosis Bipolar little data? decreased need for sleep certainly seen ADHD Measured objective findings show little difference with kids with or without ADHD Polysomnography (sleep lab) Actigraphy (more activity) But subjective findings (parents etc.) show bigger difference Delayed sleep onset Poor sleep quality Frequent night awakenings Daytime sleepiness Factors of Insomnia Environmental Circadian Medication and substances Psychiatric disorders Developmental factors (age) Primary sleep disorders Medical and neurological disorders Behavioral and conditioning factors This could explain the difference between the objective and subjective factors Impact Mood and affect Behavioral internalizing externalizing Neurocognitive especially executive function Performance––academic family social occupation driving Family disruption Health—more accidental injuries Differential diagnoses of sleep disorder Primary sleep disorders Dyssomnias Primary insomnia Primary hypersomnia Narcolepsy Circadian Breathing-related sleep disorder Circadian rhythm sleep disorder Parasomnia (Deep non-REM—stages III and IV) Nightmare disorder

Arousal disorder

Sleep terror disorder

Sleep-wake transition

Sleepwalking disorder

REM parasomnia

Sleep disorders related to a mental disorder Sleep disorders due to a general medical condition Substance-induced sleep disorders Differential diagnoses of sleep disorders according to developmental stage Infants Sleep disordered breathing SIDS Sleep-onset association disorder Children Failure to thrive Seizures

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Consider Visible tonic-clonic movements during sleep Enuresis beyond 16 years Night terrors from the ages of 5 to 9 years Treatments are not working Parasomnias Sleep disordered breathing Adolescents Circadian rhythm disorders Insomnia Sleep disordered breathing Excessive sleeping Evaluating the sleep disturbance in the pediatric population Taking a sleep history Age of onset of the problem Frequency (events/week) Course (stable, worsening, improving) Time of the night/day (clock time and time since falling asleep) Parasomnia related to sleep onset (90 to 120′) Phase delay related to clock time Nightmares occur later in the night when REM sleep predominates Recollection of dreams occurs Night terrors occur during the first 1/3 of the sleep period (4NREM) Dreams are not recalled Usual bedtime/rise time Regularity of sleep habits What are the sleeping arrangements? Room/bed mate? Do the symptoms disturb others? Bedtime rituals Common dreams and nightmares Common night waking and bedwetting Breathing during sleep/colds/labored breathing/pauses/snoring/mouth breathing Effects on daytime functioning (lethargic/bright) Sleep disorders in infants and toddlers (birth to 2 years old) Night waking problems → falling asleep problems → problems going to bed Falling asleep problems 15% to 20% of 6 months to 3 years old (rocking or holding at bedtime required) Night waking problems (assess what happens at the beginning of the night or naps) i.e. ask for symptoms of anxiety, specific phobias (dark, being alone) Treatment: night lights Signalers versus Self-soothers By 6 months, “all awaken once or twice during the night after 5-6 hours of sleep” Signalers Placed into the crib when already asleep No use of a sleep aid (pacifier) Awakens and begins to cry Self-soothers Placed into the crib and allowed to fall asleep using a sleep aid Awakens for 3 to 5 minutes, but falls asleep on own Separation issues (beyond 2years): battles, routines for transition Letting the infant cry five to seven nights Withdraw parental presence gradually by waiting for a longer time before intervening Shaping bedtime behaviors (getting ready for bed and sleep)

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Sleep disorders in preschool-aged children (3 to 5 years): usually limit-setting issues Enjoying daytime activities (?over stimulation, TV, working parents) Watch for longer bedtime routines Nightmares—after 2 a.m. (REM phenomenon) Sleep apnea syndromes (see lecture) CNS (voluntary cortical mechanisms versus involuntary subcortical systems) Voluntary: wakefulness and synchronizes breathing vocalization Involuntary: maintains oxygen saturation during sleep Mechanical/physical Enlarged tonsils/adenoids Structural narrowing of the airways Neurological/medical conditions Presentation may not be excessive, daytime sleepiness or fatigue/ Rather consider hyperactivity, inattention, or failure to thrive Growth hormone is secreted during 4NREM Awakenings can interfere with this stage Sleep disorders in school-aged children (6 to 13 years) Parasomnia episodes of nonwaking activity, interrupted sleep suddenly and intermittently) Occurring from 4NREM into REM—so they wake up during NREM Confused, disoriented, and cannot remember Occurs within 90 to 120 minutes of sleep onset Risk factors: males, family history , retrograde amnesia for the event the next day Treatment: sleep hygiene, after school nap, BNZP EEG, if this occurs in adolescence or if extends into adolescence Night terrors (not to be confused with nightmares where children can remember, are oriented, and occur later at night) Sleep talking (usually garbled and meaningless) Sleep walking (complex behaviors are not likely to occur) REM sleep behavior disorder (RARE) no inhibition of peripheral muscle tone during REM Sleep disorders in adolescents (puberty—18 years) Excessive somnolence Narcolepsy REM sleep hypersonic secondary to sleep-wake regulation dysfunction Prevalence 0.04% to 0.07% (4 to 7/10,000) Adolescents normally nap for 20 to 40 minutes, wake up refreshed then repeat Q2-3 hours (this is a treatment—regular naps) “Full blown” (the tetrad) Irresistible attacks of REM sleep during wakefulness Treatment: stimulants Cataplexy—sudden loss of muscle tone following strong effect Treatment: TCA, MAOIs Hypnagogic hallucinations—VH during sleep onset Treatment: MAOIs Sleep paralysis—limb immobility during sleep onset Phase delay syndromes Disordered sleep in medical and psychiatric conditions Consider in residences, mental retardation, autism ?Psychiatric conditions Adults: short initial REM latency Fragmented ultradian regulations with multiple arousals and EMA Blunting of early morning cortical levels ?Substances Decreased REM sleep Fragmented sleep Periods of prolonged “drugged states”

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SPECIFIC SLEEP DISORDERS Sleep disordered breathing (AKA obstructive sleep apnea) Signs and Symptoms Apnea/snoring Failure to thrive in toddlers Pulmonary hypertension Mood changes Depression/aggression/impulsivity/hyperactivity/decreased attention Memory /vocabulary/executive function––more so in adults (language and IQ same) Etiology: partial or complete air flow obstruction Large tonsils/adenoids Obesity Anatomical Micrognathia Macroglossa ?Reversibility in children Parasomnia Definition: A disorder of arousal Onset in the sleep cycle: typically within the first 3 hours of sleep Examine EEG: Symptoms of sleeping while awake and finding of 4NREM sleep Signs and symptoms Not sleeping during the day Does not remember (or if there is a memory, believes it was a nightmare) Confusion at the time of waking Types Sleep walking Sleep talking Night terrors Risk factors Male Family history Poor sleep hygiene Narcolepsy Features: Severe daytime sleepiness Episodes of cataplexy (found in over 2/3 of patients) Sleep paralysis Hypnagogic and hypnopompic solutions (especially during sleep attacks) Mechanism of action Loss of a function of HYPOCRETIN (Orexin) Found in patients with HLA DQB1*0602 and DQA1*0102 An autoimmune process suspected of causing degeneration of the hypothalamic neurons that produce hypocretin Circadian rhythm sleep disorder Etiology: “a different internal clock” The SCN in the hypothalamus is our “internal clock” Light is the most important stimulus to this brain region, although, the environment plays a role as well (activities, exercise) Examples Jet lag Shift work “Night owls” Delayed sleep phase (e.g., teenagers) “late to bed, late to rise” Worse in the summer

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Chapter 13 Sleep Signs: Sleepy Photophobic Depressed Family history Described as “willful or lazy” Advanced sleep phase (e.g. elderly) Early morning awakening Treatment Light

GENERAL TREATMENT OF SLEEP DISORDERS Steps: One: Rule out other conditions (depression) Two: Rule out other conditions’ contributory roles (obesity, medical illnesses, etc.) Three: Behavioral interventions Four: Pharmaceutical agents Treating sleep problems Insomnia TCAs

Histamine blockers anticholinergic

Benzodiazepines

GABA a/alpha (all subunits)

Zolpidem

GABA a/alpha1 subunit

Lunesta

GABA a/alpha1 subunit

Sonata

GABA a/alpha3 subunit

Trazodone

5-HT2 blocker/alpha1 blocker

Mirtazepine

5-HT2 blocker/histamine blocker

Diphenhydramine/hydroxyzine

Histamine blockers

Clonidine

Central alpha2 presynaptic agonist

Melatonin

Naturally secreted at night

Sleepiness Stimulants Mechanism of action Blocks DARI/NERI Enhances release of DA/NE ?release of histamine Caffeine Mechanism of action Blocks adenosine (during sleep, adenosine levels decrease) Increases ACh in the cortex Inhibits the VLPO, thus discouraging sleep Increases dopamine Modafanil Mechanism of action Releases histamine in the TMN Pharmacology No FDA-approved medications for children Behavioral intervention is the treatment of choice 80% get better Examples extinction, graduated extinction, preventative, scheduled awakenings Treatment studies Melatonin most studied in kids

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Findings Variable effects Well tolerated Some improvement daytime function No long-term data on efficacy safety Shortening of sleep onset Two essential roles Chronobiotic—circadian effects and to be given 5 to 6 hours before sleep Mild hypnotic effect—like diphenhydramine could its effects be more attributable to this? Premise—kids with circadian phase delay have later onset of melatonin secretion Darkness triggers melatonin secretion Lightness turns off melatonin secretion Diphenhydramine TIRED study (Mercer Stein et al. 2006) stopped due to lack of efficacy Clonidine Little empirical data No double-blind placebo controlled trials Comment of sudden death with stimulant high doses, structural heart defects Toxicity of rebound hypertension Adults benzodiazepine receptor agonists Less sleep onset delay Wake after sleep onset Total sleep time increase Better sleep quality with good safety profile Adults ramelteon Sleep onset latency and total sleep time effects Less side effect Medication and caffeine effects Psychotropic medications and sleep mechanisms Effects Effects on sleep architecture Stage 1 sleep, slow-wave sleep, REM sleep Effects on sleep onset latency Effects on sleep continuity arousals awakening Effects on subjective sleep quality freshness Effects on nocturnal sleep tenors nightmares Excessive daytime sleepiness Direct versus withdrawal effect Exacerbation of primary sleep disorder Some specific medication effects: TCA Anticholinergics decrease REM and increase REM latency Especially, clomipramine and amitriptyline CMI Histaminergic sedation (amitriptyline, doxepin, trazodone) Increase slow-wave sleep (doxepin) Rapid withdrawal leads to NM parasomnias (REM rebound), can exacerbate Restless leg syndrome SSRIs in general worsen periodic limb movement disorder Fluoxetine Paroxetine Sertraline Buproprion Venlafaxine Nefazodone/mirtazipine

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None SWS None SWS None SWS Reduces DFA less Daytime steepness

REM Less REM Less REM REM REM More REM

Wakeful Wakeful? no sedation Latency increases REM EDS

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Stimulants Wake Delayed steep onset Shorter sleep duration REM decrease Alcohol Faster sleep onset More disruption (REM rebound biphasic SWS) worse RLS SDB Nicotine Slower sleep onset—worse SDBRLS Caffeine Less total sleep SWS—REM Later sleep onset Fragmented sleep If intake is >300 mg, awake 3 hours after sleep Overall guidelines when using medications Optimize sleep hygiene Medications are rarely first choice or used alone Combine medications with behavioral Drugs should match symptoms (DFA → short half-life) Have treatment goals Short duration Screen for ETOH-drug use pregnancy OTC sleep agents Review side effects Follow-up frequently Avoid abrupt discontinuation Medication use contraindications Unrelated sleep disorder (OSA) Normal sleep behavior (ADH-D) Self-limited condition Drug-substance interactions Limited ability to monitor/follow-up Caffeinated beverages: Product

Serving size oz Caffeine mg

Coke

12

36 to 46

Diet

12

9 to 50

Mtn Dew

8

37

Orange soda

8

28

Red Bull

8.3

80

Tea

8

15 to 50

Brewed coffee 8

110 to 150

Filter drip

8

179

Decaf

8

3

Instant

8

76 to 106

Starbucks

8

380

NODOZ

1 tab

200

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Chapter

14

Gender Identity Disorders and Sexual Disorders

OVERVIEW OF GENDER IDENTITY DISORDER Gender Identity Sense of self as male or female established by age 2–3 years of age Aware of body’s genital difference between sexes by ages 3–6 years Gender roles seen in play Sexual orientation is not sexual identity disorder Children of gay and lesbian parents No different outcomes in Gender identity Gender role Sexual orientation A wish to be other or a discomfort critical in establishing a diagnosis

CLINICAL FINDINGS Phenomenology: stereotypes reversed (even color preferences) Age at onset (3–5) both boys and girls Associated psychopathology Varies Consider as the boy gets older Family factors can make it worse Biophysical markers: none, but consider genetic predispositions

DIFFERENTIAL DIAGNOSIS Diagnostic issues in children Diagnostic issues in adolescents Watch for continuation into adolescence and adulthood Watch for continued struggling with gender identity concerns Watch for distress over sexual orientation Watch for cross-dressing for sexual arousal

159

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ETIOLOGY Biological mechanisms Prenatal sex hormones—no consistent findings Physical appearance—cultural expectations of gender roles—no findings Handedness? Left Sibling sex ratio and birth order? Boys with more brothers and younger siblings Birth weight—no consistent findings Psychosocial Social reinforcements? Parental preference for sex of offspring? Mother-child and father-child relationships Maternal psychosexual development

TREATMENT Ethical issues Developmental considerations—understanding in kids Treatment of children—behavioral Treatment of adolescents—understand details Treatment in adults Psychotherapy Not to discourage sex reassignment (if applicable), but support regarding its irreversible nature Clarification of diagnosis Adjustment to the process of sex reassignment Sex reassignment

PROGNOSIS Homosexuality without gender dysphoria, most common outcome

SEXUAL DISORDERS Sexual dysfunctions Sexual aversion disorder Treatment goal—reduce fear and avoidance of sex via systematic desensitization Sexual arousal disorders Male erectile disorder Incidence 35% of males between 40 and 70 years 50% of males older than 70 years Treatment Behavioral therapy involving the partner Vasoactive injections Pharmacological medications External vacuum device Female sexual arousal disorder Treatment goal—reduce anxiety Behavioral—sensate focus Pharmacological

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Orgasmic disorders Female orgasmic disorder Treatment Directed masturbation followed by patient—partner instruction Systematic desensitization to reduce fear Male orgasmic disorder Treatment similar to female orgasmic disorder If secondary to medications, pharmacological Premature ejaculation Most prevalent male sexual disorder Treatment Behavioral “Start-stop” technique “Squeeze” technique Assess for biogenic causes Physical illness Medication side effects Pharmacologic SSRI’s Topical creams Sexual pain disorders Dyspareunia Assess for organic pathology Treatment Systematic desensitization Integrating medical and psychosexual factors Vaginismus Assessment Gynecological examination Other psychiatric conditions Somatization disorder Substance induced General medical conditions Treatment Systematic desensitization using dilators Paraphilias Assessment Differs from normal sexual behavior Often exclusive or preferred means of orgasm Nonconsensual Child involved Treatment Pharmacological Blocking or decreasing levels of androgens “chemical castration” agents SSRI’s Surgical castration (does not effectively eliminate deviant behavior) Behavioral Aversive conditioning Satiation (individual uses deviant fantasies post-orgasm repetitively to the point of boredom) Types Exhibitionism Frotteurism Pedophilia

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Psychiatry Bullets Sexual masochism Sexual sadism Transvestic fetishism Voyeurism Paraphilia NOS Sexual disorder NOS

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Chapter

15

PMDD, Pregnancy, Postpartum State, and Breast Feeding

PMDD: PREMENSTRUAL DYSPHORIC DISORDER Epidemiology Menstrual cycle related symptoms

85%

PMS

20%–40%

PMDD

2%–9%

Terminology DSM-IIIR: 1987 late luteal phase dysphoric disorder (LLPDD) DSM-IV: 1994 premenstrual dysphoric disorder (PMDD) Premenstrual dysphoria or premenstrual disorder Many women sought treatment despite not fulfilling criteria for PMDD PMS diagnostic criteria: ACOG Patient reports ≥1 of the following symptoms during 5 days before menses in each of three prior menstrual cycles Symptoms relieved within 4 days of menses onset without recurrence until at least cycle day 13 Symptoms present in absence of any pharmacologic therapy, hormone ingestion, or drug and alcohol use Symptoms occur reproducibly during two cycles in prospective recording Patient suffers from identifiable dysfunction in social or economic performance Affective Depression Angry outbursts Irritability Anxiety Confusion Social withdrawal Somatic Breast tenderness Abdominal bloating Headache Swelling of extremities Comorbidity MDD Dysthymia Anxiety disorders 163

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Increased prevalence in adolescents Risk factors Previous MDD Previous trauma? Suicidal ideation and attempts elevated DSM-IV diagnostic criteria for PMDD Five of the following symptoms (with at least one starred symptom) must occur during the week before menses and remit within days of menses Marked depression (mood, hopelessness) Marked anxiety, tension Marked affective lability or mood swings Marked anger or irritability Decreased interest in activities Difficulty in concentrating Lack of energy Change in appetite, e.g., food cravings Change in sleep Feeling out of control or overwhelmed Physical symptoms, e.g., breast tenderness, bloating Seriously interferes with work, social activities, relationships Not an exacerbation of another disorder Confirmed by prospective daily ratings for two consecutive symptomatic cycles Etiology Hypothalamic-pituitary-gonadal axis Hypothalamic-pituitary-adrenal axis Serotonin, norepinephrine, beta-endorphin Allopregnanolone/GABA a receptor insensitivity Renin-angiotensin-aldosterone system Calcium/bone metabolism regulation Altered genetic haplotypes Increased negative emotion processing Immune system Circadian Altered serotonin function Abnormal levels of serotonin Decreased plasma serotonin Decreased serotonin platelet uptake Increased binding to serotonin transporters Serotonin abnormalities, not menstrual cycle phase specific Symptom exacerbation during tryptophan depletion HPG axis GnRH is secreted by the hypothalamus Triggers the release and syntheses of LH and FSH by the anterior pituitary LH stimulates ovulation via a surge FSH stimulates ovaries to promote follicle growth, and these follicles secrete estradiol to negatively feedback the release of FSH During the luteal phase, progesterone inhibits GnRH secretion eventually by negative feedback mechanism. Abnormal allopregnanolone levels in PMDD Metabolite of progesterone: allopregnanolone GABA like PMDD sufferers demonstrate reduced luteal phase sensitivity of GABA-A receptors to benzodiazepines Suggestions of treatment efficacy: lowered allopregnanolone levels Associations Depression Anxiety

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Eating disorders Substance use disorders Allergies Asthma Seizures Herpes Headaches Rating scales DRSP—Daily Record of Severity of Problems 24 item scale 1–6 scales 31 day recording COPE—Calendar of Premenstrual Experiences PSST—Premenstrual Symptoms Screening tool VAS—Visual Analogue Scale Treatment Serotonin FDA-approved agents (continuous or intermittent) Fluoxetine Sertraline Paroxetine CR SNRI’s, clomipramine, busparone It appears that a greater dose may manage more physical symptoms Possible shortened cycle Ovulation suppression Estrogen Progesterone Oral contraceptives GnRH agonists (induce downregulation of pituitary GnRH receptors) Lupron Effective But, 90%: early menopause secondary to hypoestrogenism Luteal phase progesterone—not recommended Other Xanax Spirinolactone (for edema) Bromocriptine (for mastalgia) NSAIDS TAH/OOS Oral contraceptives FDA approved: Yaz 24 active days and 4 inactive days Combination of drospirenone and ethinyl estradiol Drospirenone A progestin not derived from 19-nortestosterone Analogue of 17 alpha spirinolactone—analogue of spirinolactone Increases K+ retention Increases Na+ excretion Increases water excretion Antiandrogenic activity Antimineralocorticoid activity Future directions Chastenberry—A dopamine agonist Anticonvulsants Levetiracetam (Keppra) Lamotrigine Calcium and vitamin D replacement

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Psychiatry Bullets Psychosocial support/therapy CBT

ISSUES RELATED TO PREGNANCY AND POSTPARTUM STATE AND BREAST FEEDING Demographics 15% miscarriage rate 2%–4% live births: major malformations sporadic 12% minor malformations (only diagnosed by specialist—thus, nonfunctional) 80% of pregnant women are on prescribed at least one medication Most women do not know that they are pregnant until >6 weeks gestational age Depression age of onset (first onset depression) (Weissman, 1996) Males—relatively equal risk of depression starting age 15–24 (1×) Females—risk increases 3.5× during puberty through menopause (mid-50s) and then, finally, has a decreased (compared to males) risk beginning in the mid-50s Depression in pregnancy Demographics 12.8% experience MDD in pregnancy (generally 10%–15%) 20% receive treatment at all A minority of them received “adequate” treatment Postpartum depression diagnosed antenatally (32 > 8WGA for depression scores) Asking how she sleeps in the first trimester versus third trimester—normal changes Ask about appetite changes—normal changes Ask about fatigue—normal changes Relapse is common Three groups Euthymic chose to discontinue antidepressants Euthymic chose to remain on antidepressants Nonpregnant euthymic women 68% of first group (euthymic choosing to discontinue antidepressants) relapsed within a few weeks (five times greater relapse) Treatment implications Most women do not receive treatment Possible effects of maternal depression on the fetus Preterm labor Small for gestational age neonates Associated with SSRI’s Later SSRI exposure Higher dose SSRI Poor maternal weight gain Smaller head circumference Lower Apgar scores Preeclampsia Poor self-care (nutrition, alcohol use, tobacco use, illicit drugs, and multiple prescribed medications) Maternal self-harm Be cautious—abrupt discontinuation of antidepressants may increase risk for serious relapse Neonatal neurobehavioral sequelae Poorer orienting skills (localizing sounds and tracking) Decreased motor tone Lower activity levels Lower vagal tone Right EEG asymmetry (left hypofrontality) Poorer orientation, reflex, excitability, and withdrawal clusters (Brazleton)

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Risk determination Goal of risk/benefit/alternative assessment is limit exposure to either illness or treatment, and help the patient decide which path exposure poses the least risk Individuals with similar illness histories make different decisions No medication is risk-free FDA categories A

Controlled studies

B

No evidence of risk in humans

C

Risk cannot be ruled out

D

Positive evidence of risk

X

Contraindicated in pregnancy

No risk

The medications and % of malformations—Prospective studies Agent

%

Fluoxetine

2.69

Sertraline

1.95

Citalopram

2.72

Paroxetine

3.5

Bupropion

2.20

Venlafaxine

1.82

Escitalopram

3.4

Swedish Medical Birth Registry Reanalysis of above No increased risk for malformations overall compared to general population But, increased risk for cardiovascular malformations for paroxetine FDA listing changed from C to D Try avoiding paroxetine—fetal heart formation occurs at 8 weeks gestational age Test—Test of neck thickness Structural cardiac ultrasound at week 18 Fetal echo at week 20 Poor neonatal adaptability—with third trimester exposure Lower birth weight Shorter mean gestational age (0.9 weeks) SSRI’s SSRI’s with later exposure, higher doses ?low maternal weight gain Lower Apgar score at 5 minutes (0.29 decrease) Transient perinatal adverse effects (usually disappears in hours; gone 2 weeks) Jitteriness Poor muscle tone Weak cry Respiratory distress Hypoglycemia Low Apgar scores Seizures (rare) No adverse impact on internalizing behaviors

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PPHN—Persistent Pulmonary Hypertension of the Newborn Newborn’s circulatory system does not fully adapt to breathing outside the womb—can be lethal Case controlled study (Chambers et al. 2006) Risk from 1/1000 → 1/100 if SSRI’s used after 20th WGA Rare Long-term neurodevelopmental studies: SSRI’s and TCA’s No differences at 16—81 months for IQ, language, behavioral But, exposure of maternal depression is correlated with lower IQ TCA’s No associated anomalies Same transient neonatal adaptability as SSRI’s Shorter duration of gestation? Other antidepressants Venlafaxine Too few cases to know No apparent increase FDA did extend late term use of SSRI and non-SSRI Bupropion No teratogenicity noted ?increased risk of spontaneous abortion (which could be the same as smokers)—more studies needed ACOG opinions Optimally work with obstetrician prior to pregnancy (N.B 50% are pregnancies are unplanned) Treatment with all SSRI’s and SNRI’s has to be individualized Mental health clinicians Obstetricians Mother’s values and informed consent Paroxetine should be avoided, if possible Monitor fetal echo Avoid abrupt discontinuation of antidepressants (to avoid relapse of depression as well as discontinuation syndrome) Recommendations Mild—(Moderate depression in pregnancy) Psychotherapy Conjoint counseling Stress-reduction strategies Mobilization of supports Light therapy Nonmild symptoms Switch medications Pregravid—to safest and most effective During—before switching explore history of responses Maintenance across labor and delivery compared to tapering close to due date Consider postpartum risk of psychiatric decompensation Benzodiazepines Data are unlimited Many mothers on benzodiazepines also abuse others agents Population risk for cleft palate is 1/10,000 and with benzodiazepines is 6–12/10,000 Lorazepam may not easily cross the placenta Clonazepam may have beneficial characteristics due to its long half-life SGA Lamotrigine can increase the risk of cleft palate

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Postpartum mood disorder General Numbers—risk for psychiatric admissions dramatically increases after delivery and falls each month (greatest risk within the first 2 months) Incidence Blues

80%

Depression

10%–22%

Psychosis

0.1%

Risk factors Depression in pregnancy—a strongest risk factor History of depression and bipolar illness History of postpartum depression (prophylactic use indication?) Family history of affective disorders Lack of partner support Unplanned pregnancy Comorbid medical illness (seizures, diabetes mellitus) Postpartum depression Characteristics Most cases recognized at ages 3–9 months 50% onset first postpartum week Symptoms of depression and obsessive preoccupation with baby’s health If untreated, increased risk maternal chronic/recurrent depression Maternal depression associated with adverse effects on infant, other children, marriage (recent studies say even more—medical conditions, depression, cardiovascular) Effects on infant development Poorer visual contact with mother More physiologically irritable Poorer vocalization Developmentally lagged at 1 year Increased risk for future depressive illness Treatment considerations Education, reassurance, support Psychotherapy for mild symptoms—individual and group Antidepressants and anxiolytics If severe, consider hospitalization Breastfeeding General information All psychotropics cross the placenta and enter breast milk; thus, the fetus is always exposed Fetal dose in pregnancy is greater than infant dose in lactation No controlled studies Long-term effects of medication exposure are unknown Increasing data As noted No evidence of adverse effects of antidepressant exposure during breast feeding Infant serum concentrations are usually below standard lab sensitivity, even more so for sertraline and paroxetine

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Chapter

16

Impulse Control Disorders

ESSENTIAL FEATURES Failure to resist an Impulse Drive, or Temptation to perform an act that is harmful to the person or others Before the act—the individual feels an increasing sense of tension or arousal At the time of the act—great pleasure and gratification After the fact—relief from the urge without regret, self-reproach, or guilt Comparing and contrasting Impulsivity and compulsivity Both—inability to refrain from repetitive behaviors Impulsivity is driven by an effort to obtain arousal and gratification Compulsivity—driven by an effort to reduce anxiety

COMORBIDITIES Adulthood

Substance use disorder Personality disorder

Childhood

PTSD Bipolar spectrum Obsessive compulsive spectrum ADHD PDD Conduct disorder

UNDERSTANDINGS Gender differences Males (Body dysmorphic disorder) (Sexual compulsion) Pyromania Pathological gambling Intermittent explosive disorder

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Women (Anorexia) (Binge eating) Kleptomania (Compulsive buying) Trichotillomania Brain regions Impulsivity

Decreased frontal lobe effectiveness Poor decision making

Compulsivity

Increased activity in the basal ganglia Increased repetitive activity

Nucleus accumbens

Decreased effectiveness in reward center Decreased activity in the setting of a potential reward However, money appears to increase NA firing

Neurotransmitters First stage—increased NE—arousal, detects novel/aversive stimuli Second stage—increased DA—reward and reinforcement Third stage—decreased 5HT—behavioral disinhibition and anxiety Models Addiction

Craving leads to impulse

Affect-driven

Mood leads to impulse

Compulsive

Anxiety leads to compulsive/impulse

PATHOLOGICAL GAMBLING Epidemiology in the US $85 billion/year 82% of US residents gamble 1%–3% meet criteria for pathological gambling Criteria Larger wagers than intended Restless and irritable when attempting to cut/stop Continuous, unsuccessful efforts to decrease gambling Gambling prevents usual and/or occupational activities Continuation of gambling in an attempt to reinstate losses Clinical presentation Winning phase Loss phase Desperation phase Highest risk of everything (legal, resistance) May be confused with bipolar disorder Individuals with bipolar disorder have less sleep and with no fatigue afterward Hopeless phase Medical consequences Hypertension Cardiovascular disease Peptic ulcer disease Exacerbation of baseline medical problems

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Psychiatric consequences Nicotine dependence Alcohol dependence Overeating and binge eating Sleep deprivation High levels of acute and chronic stress Screening tools SOGS: South Oaks Gambling Screen GOLD STANDARD 20 item test 10–20 minute self report EIGHT EARLY INTERVENTION GAMBLING HEALTH TEST Eight item 5 minute Cutoff A future yes/no question? Do you bet more than you like? Have you ever lied to a loved one for gambling? Alcohol Males: how frequently do you have >5 drinks in one night? Females: how frequently do you have >4? Nicotine—how many minutes till the moment you wake up and the first cigarette? Cognitive distortions Games—choices are based in irrational choices Superstitious beliefs Good like objects Behaviors Routines Interpretive biases Attributing wins to skills and losses to flukes Wrongly believing that a series of losses increases the chance to win Temporal telescoping—wins happen sooner rather than later Reference telescoping—the win will happen to me rather than others Selective memory remembering wins and not losses totaling wins without accounting for losses Treatments Social assistance Self-exclusion programs Financial counseling Gamblers Anonymous Psychotherapy CBT 24-hour crisis helplines Psychopharmacological: No FDA-approved treatments Addictive model Opioid antagonists Naltrexone studied at 200 mg daily reduces “reward cravings” Higher dose can induce hepatotoxicity/N Check LFT’s Nalmefene another opioid antagonist Lower dose better than higher dose Less or no hepatotoxicity Affect model Mood stabilizers Lithium (seems to also increase metabolic activity OFC, CG which project to NA, allowing better executive functions) Anticonvulsants Valproic acid Topiramate “riding the wave of excitement” for alcohol and cocaine

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Psychiatry Bullets Antidepressants SGA (blocking 5H2A receptors to affect mood) Compulsive model SSRI’s Treat any comorbidity NO → Use SSRI’s/Naltrexone YES → Bipolar → Mood stabilizer or add SSRI/Naltrexone if resistant Substance use disorder → Naltrexone Unipolar depression → SSRI ADHD → nonstimulants (bupropion) Stimulants (with caution)

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Chapter

17

Pain

www.painknowledge.org www.painedu.org DEA diversion website

Scales Complete opioid analgesics tool kit Signs of addiction

TYPES OF PAIN Nociceptive: Inflammation or mechanical damage Neuropathic: Peripheral nerve damage or entrapment Central: Brain disturbance in pain processing Hyperalgesia: Increased response to painful stimuli Allodynia: Painful response to typically nonpainful stimuli Sensory amplification: Greater painful response than normal

OPIOIDS Receptors Types Mu

Morphine

Kappa

Butorphanol

Delta

Enkephalin derivatives

Location Spinal column Cortex Ventral tegmental area Nucleus accumbens Sites of action “all over the body”—the finger has numerous nerve fibers Periphery, dorsal horn, descending inhibition to the brain Mu-receptor polymorphisms—explaining response variability Efficacy Osteoarthritis Neuropathic pain Back pain Cancer-related pain 175

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Randomized controlled trials with Codeine Tramadol Oxycodone is metabolized to oxymorphone via cytochrome P450 enzyme 2D6 Morphine Ropivacaine (Fentanyl) Levorphanol (best analgesic, but lasts 6 hours––multiple dosing required)

ALGORITHM FOR OPIOID TREATMENT OF CHRONIC PAIN Patient selection Five A’s of pain Analgesia Affect Activities of daily living Adverse effects Aberrant drug-taking behavior Aggressive complaining for need for greater doses Drug hoarding during periods of reduced symptoms Requesting specific drugs Prescriptions from other providers Dose escalation (unsanctioned) Stealing from another patient Obtaining medication from nonmedical individuals Selling prescription drugs Concurrent use with illicit drugs Repeatedly loses prescriptions Injecting oral forms Also Assessment Action (treatment plan) Persistent pain or severe pain or other medication use—nonideal Initial assessment Document risk/benefit assessment Pain syndrome Previous treatments and results Past medical history Did patient identify the drugs of choice? Document quantity, frequency, duration Suspect substance use disorder if Hepatitis C positive HIV positive History of tuberculosis History of cellulites History of sexually transmitted diseases Abnormal liver function test results Family history Substance use disorders Psychiatric disorders Social history and substance history Suspect substance use disorder if History of motor vehicle accidents History of legal issues Operating under the influence

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Domestic violence Other legal issues Fire or property loss Psychiatric history Suspect if The individual has been assessed and diagnosed History of outpatient or inpatient treatment History of psychotropic medications Patient’s perspectives on opioid therapy Pain assessment Why? Document characteristics Intensity, onset, location, duration, quality Associated features Treatment response (including misuse of med) Positive and negative factors Variability of pain Bottom line Documentation of rationale Documentation of previous treatments Documentation of risks to the patient Documentation of benefits How Pain diary Pain scales Pain intensity Verbal Pain Intensity Scale (none–worst) 010 numeric scale (0–10) Visual analog scale (0–10) Pain faces (0–5) Activities impaired by pain severity (enjoyable activities, work, mood, sleep, etc.) Medical history finding associated with substance use disorder Does the person identify drugs of choice for emotional symptoms? (document quantity, frequency, duration of each drug) Has the person received formal treatment for the substance use disorder? Conditions Hepatitis C HIV Tuberculosis Cellulites Sexually transmitted diseases Liver function abnormalities Social history Motor vehicle accident Legal (OUI, domestic violence, etc.) Loss of property in fire Psychiatric history CAGE questionnaire Making the diagnosis Define medical diagnosis and primary treatments Comprehensive pain management plan When to refer? Previous failure with opioids or other pain meds Psychosocial issues Legal

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Current use of illicit drugs Regular contact with high-risk groups History of substance use disorders Bio/psycho/social Bio—meds Psycho—mood changes, coping skills, sleep disturb Social—family/social supports, work, PT/OT/exercise Document realistic goals Patient education Helps with adherence Brochures Set realistic goals Reach agreement on the shared goal (30% reduce) Complete pain relief rarely achieved Common goals examples Pain reduction Improvement in selective areas of functioning Improved mood Improved work Treatment agreement and informed consent forms Detailed outline Limitations on scripts Emergency issues Refill and dose adjustment procedures Exit strategies Continue or discontinue Aberrant drug behavior Physical dependence Tolerance Pseudotolerance Addiction Pseudoaddiction Behaviors Exit strategy Discuss intervention options Helpful if clinician is Consistent Supportive Informative Nonjudgmental Firm Nonpunitive Gather resources for support Discuss options for detoxification Opioid therapy Start with short-acting agents Types Morphine Codeine Hydrocodone Oxycodone Hydromorphone Oxymorphone Fentanyl Long acting Types

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Methadone Considerations Possibly opioid and nonopioid MOA Cheap Liquid form Metabolite with long half-life Complex pharmacokinetics No known active metabolites Cardiac toxicity At high doses 3A4 inhibitors TCAs Drug interactions 3A4 2C8/9 2C19 2D6 Enzyme inducers: Barbiturates Carbamazepine Phenytoin Primidone Rifampin Thus, decreased methadone levels Thus, watch for withdrawal Food/herbal interactions 3A4 inhibitors Cardiovascular medications Erythromycin—HIV meds Somatostatin—decreased efficacy Compounds QTc prolongation Alcohol—sedation Herbs St. John’s wort Decrease methadone levels Increase CNS depressant Valeria, kavakava, gotu kol Increase CNS depressant Grapefruit juice—3A4 in gut Increase methadone levels Increase CNS depressant Types of long-acting opioid forms, continued MS Contin Oxycontin Fentanyl patch Levorphanol Partial opioid agonists Buprenorphine Short acting Onset 10–30 minutes Peaks 3 hours Duration 6–8 hours Dosing 0.3–0.6 mg q6–8h (parenterally) Ceiling analgesia is 1.5–5 mg Analgesic effect is 30× that of morphine SL form not FDA-approved for analgesia Opiates (including tramadol) contraindicated Prepare patients for emergencies (medication lists, info cards) If anticipating surgeries or procedures

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Stop buprenorphine in advance Change to methadone or longer acting opiate Parenteral buprenorphine (similar side effect profile as others) Surgical use More effective than morphine More effective than meperidine with longer duration of activity Alternatives to opioid therapy Pharmacology (There is no FDA-approved opioid agent for pain) NSAIDs/Acetominophen/Cox-2 inhibitors Corticosteroids Stimulants Mechanism Role in reversing opioid sedation Examples Methylphenidate Topical agents/local anesthetics Topical lidocaine NNT 4 Antidepressants Mechanism 5-HT has inhibitory and excitatory effect on pain NE has inhibitory effect on pain Examples TCA NNT 2-4 Amytriptyline Desipramine Imipramine Doxepin Bupropion SSRIs—not appearing to be helpful for pain SNRIs NNT 5 Venlafaxine/Desvenlafaxine (Pristiq) Duloxetine (Cymbalta) Milnacipran (Savella) MAOis Anxiolytics Mechanism No specific role in pain itself Usefulness Muscle relaxants Sedative/hypnotic agent Examples Benzodiazepines Nonbenzodiazepines Anticonvulsants Mechanism Sodium channel modulator Calcium channel modulator GABAergic Glutamate antagonism Examples Gabapentin—NNT 4 Topiramate Carbamazepine Oxcarbemazepine Pregabalin Valproic acid

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Muscle relaxants Lioresal Methocarbamol Avoid soma (metabolizes to meprobamate) Reduces anxiety but Extremely habit forming Antipsychotics Mechanism FGA not found to be as helpful SGA may be more helpful due to serotonergic activity Nonpharmacologic Behavioral Reduction of positive rewards Reduction of pain awareness Increasing self control of pain CBT Exercise Yoga Physical therapy and conditioning Therapeutic massage Muscle relaxation Acupuncture TENS

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ESSENTIALS OF MEMORY Types Declarative (explicit)

Facts Events

Nondeclarative (implicit) Definition

Skills/habits

Memory + one other in cognition Early < 65 late > 65

Memory impairment 1—immediate

RAS

2—recent

Limbic

3—remote

Assoc cortex

Cognitive Aphasia

Language

Agnosia

Recognition

Apraxia Executive functioning

COGNITIVE DISORDERS Term

Delirium

Amnestic disorder

Dementia

Definition

Short term confusion, cognitive changes

Memory impairment, forgetfulness

Severe memory impairment

Types of delirium: General medical condition Hypoxia Alzheimer’s dementia exacerbation Polysubstance abuse Toxin or medication effect Vascular effects 183

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Korsakoff—charaterzied by: Confusion Opthalmic findings Ataxia Depression like symptoms Recent memory difficulties Alcohol disorder Status post head injury Left temporal and parietal–temporal areas Hypertension Migraines Multiple etiologies Not otherwïse specified Other medical issues HIV Pick’s disease Creutzfeld-Jacob Prevalence of delirium 0.4%: >18years 1.1%: >55years Reasons for delirium >55 years of age SICU s/p Surgery Post coma

30% 40%–50% 90%

Burns AIDS >65 years old and hospitalized Nursing home

20% 30%–40% 30%–40% 60%

Prognosis of delirium 3 months 1 year If hospitalized After discharge 1 month 6 months

23%–33% 50% 20%–75% 15% 25%

Core features of delirium Change consciousness: cannot learn new information Change attention: cannot recall recent information Other confusion time/space Tests Multiple EEG—diffuse slowing

DEMENTIA Alzheimer’s Alzheimer’s Association 2007 Statistics 1/8 people older than 65 years (8.1 million with Alzheimer's Disease in the United States and 30 million worldwide)

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Most common cause of dementia 500,000 individuals with early onset dementia Increased awareness Capturing it earlier New case every 72 seconds $100 billion Medicare costs annually Factors Neuropathology Neuritic plaques Extracelluloid spheroid elements 10–120 mm in diameter Structure Amyloid fibrils and dystrophic neurite inner layer Microglia and reactive astrocyte outer layer Amyloid B-peptide core (from amyloid precursor protein) Regions—temporal and parietal lobes Neurofibrillary tangles (NFTs tau protein) NFTs especially in the entorhinal cortex is an early sign Regions—temporal and parietal Neuronal loss (hippocampus, entorhinal cortex, cortex, forebrain cholinergic nuclei—Meynert and Broca) Neurochemical deficits Acetylcholine (ACh) Loss of cortical cholinergic markers Choline acetyltransferase (ChAT) Acetylcholinesterase (AChE) Corticotropin: loss of CRF Somatostatin: loss of somatostatin immunoreactivity NE: decrease in NE, 5-HT, glutamate Inflammatory—controversial—but yes Genetic factors—controversial—but yes APOE: having one gene—three times the risk; having two genes—eight times the risk Found in 25% of Caucasians Presence overall (in individuals who are asymptomatic) Indicates reduced brain metabolism Indicates more dyslipidemia or diabetes metabolism 40% associated with family history Monozygotic > Dizygotic twin studies Autosomal dominant Chromosomes 1, 14, 21 B amyloid precursor protein Cardiovascular disease Familial type: chromosome 17 (40–50 years old onset; death after 11 years) Brain MRI findings Reduced metabolism in temporal and parietal lobes Reduced glucose uptake Lewy bodies Risk factors ApoE4 genes ?Anasthesia/surgery a risk factor ¼ of patients status post cardiac bypass did not fully return to cognitive baseline ?Complications of surgery ?Certain anesthetic agents ?Depression as a risk factor for Alzheimer’s Common finding in individuals with Alzheimer’s (approximately 75%)

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Greater mortality associated with depressed patients with Alzheimer’s Mid life major depression may lead to earlier onset Alzheimer’s ?Greater tangles and plaques in depression Issue of overlapping symptoms between the two conditions Common symptoms Decreased positive affect/spontaneity Social isolation and withdrawal Disturbances in appetite/weight Sleep disturbance Psychomotor changes Irritability Differentiating between depression and Alzheimer’s Depression—more sadness rather than apathy Treatment of Alzheimer’s disease (AD) Nonpharmacological The diagnosis matters (who/how/when/change/prior response) Something can be done at ALL stages Expect residual strengths Evaluate patient’s needs and feelings Stimulation Maintain daily activities and lifestyle when possible Optimize physical and social stimulation Avoid isolation Maintain mobility as long as possible Pneumonia Decubeti Urinary tract infections Monitor safety (wandering, driving, use of tools) Assess psychiatric status Assess medical status (comorbidities, nutrition, polypharmacy) Treatment Can slow decline in cognition and function Reduction of caregiver burden Behavioral impact (reduced symptoms and delayed emergence) Pharmacological FDA approved Cholinesterase inhibitors (mild/moderate AD) Tacrine Donepezil Galantamine Rivastigmine NMDA receptor antagonist (moderate/severe Alzheimer’s disease) Memantine (adding with Donepezil appropriate and helpful) Mild/moderate symptoms—cholinesterase inhibitors Hypothesis Acetylcholine is a neurotransmitter important for memory Safety profile—overall safe (?except galantamine death) Gastrointestinal side effects Nausea Vomiting Diarrhea Abdominal pain Can lead to anorexia and weight loss Cardiovascular side effects Bradycardia Tremor Dizziness Can lead to asthenia and fever

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Neuromuscular side effects Muscle cramps Weakness Can lead to falls Neurologic side effects Insomnia Nightmares Agitation Panic-like state Drug–drug interactions Vitamin E––Negative finding Moderate/severe symptoms—NMDA antagonists (Memantine) Hypothesis Impaired cognition and memory due to increased glutamatergic activity and persistent activation of NMDA receptors Studies Effective as monotherapy for cognition and functioning Adding donepezil may be helpful Side effects Agitation Fall/injury Dizziness Confusion Headaches Constipation Drug interactions Avoid other NMDA antagonists (amantadine, ketamine, “DMX”) Pharmocokinetics Renal tubular secretion clearance (careful when used with hydrochlorothiazide) Low plasma binding (warfarin use is safe) No change with metformin and glyburide Renal impairment if creatinine clearance CrCl < 30 (a level indicating severe renal insufficiency) Lower dose to 5 mg BID Consider pharmacodynamics and pharmacokinetics Pharmacodynamics Digoxin and beta-blockers Cholinesterase inhibitors exert vagotonic effects on the cardiovascular system Anasthesia—exaggerates succinylcholine muscle relaxant Anticholinergic or cholinergic meds Pharmacokinetics (Cytochrome 2D6 and 3A4) Rivastigmine: None Donepezil: Moderate Galantamine: Moderate Renal impairment: Galantamine clearance decreases Tangible benefits of AD treatment Addresses noncognitive behavioral symptoms Mood Activity Delusions/hallucinations Sleep issues Appetite issues Delay of nursing home placement or institutionalization Improved quality of life

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Psychiatry Bullets Reduction of caregiver burden Costs Future treatments Dimebon: Cholinesterase inhibitor and NMDA receptor antagonist AlzheMed: Taurine derivative (per oral amino acid) Antioxidants: No pending trials Anti-inflammatories TNF-alpha blocker: One negative trial Immunoglobulin Hormones: Discouraging results Statins: Three trials (one positive trial) Antiamyloid agents Active/passive immunization Secretase inhibitors—specifically gamma secretase Gamma-secretase modulator (R-Flurbipropen) Increase alpha-secretase activity (MoA of statins?) Antifibrillation (clioquinol, homotaurine) Enhance clearance from CNS (LRP) Block entrance to CNS (RAGE) Gamma secretase modulator Flurizan Anti-tau agents ADCS valproate lithium Growth factor strategies B vitamins Insulin: Inhaled straight to the hippocampus Fish oil and alpha-lipoic acid Metal protein chelators: Extracting zinc and copper from the brain Brain games: Crossword puzzle, museums, etc.

OTHER DEMENTIAS Vascular Formerly known as multiinfarct dementia Commonly comorbid with Alzheimer’s dementia Binswanger’s aka subcortical ateriorsclerotic encephalopathy Areas affected: White matter infarcts and spares cortex or gray matter Strokes Left sided Aphasia

Right sided Visual spatial deficits

Right-Left disorientation Finger agnosia Dysgraphia/aphasia Dyscalculia (#alexia) Constructional apraxia––details Limb apraxia

Decreased visual perception Neglect Dysgraphia (spatial neglect) Dyscalculia (spatial) Constructional apraxia––gestalt Dressing apraxia Anasognosia

Picks Areas affected Frontal temporal regions Sclerosis Atrophy

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Neuropathology Neuronal loss Gliosis Neuronal Pick’s bodies Masses of cytoskeletal elements Not necessary to be present for a diagnosis to occur Clinical findings Comprise 5% of all dementias Difficult to distinguish from Alzheimer’s dementia Less visual-spatial issues as in Alzheimer’s Stages Early—more personality and behavioral changes Later—progression to more cognitive symptoms Typically begins before 75 years of age If positive for family history, watch for earlier onset Males more affected Kluver-Bucy syndrome (suggesting temporal lobe involvement) Hypersexuality Placidity Hyperorality Lewy body disease Areas affected Cerebral cortex Neuropathology Lewy bodies Weakly eosinophilic spherical cytoplasmic inclusions Clinical findings Hallucinations Parkinsonian features Other extrapyramidal signs Antipsychotic medications may cause adverse effects Treatment Symptomatic Huntington’s Areas affected Subcortical (basal ganglia) Neuropathology Destruction of Caudate Putamen Frontal Autosomal dominant inheritance (chromosome 4) Clinical findings Onset typically between 35 and 45 years Juvenile type in 3% of cases More dystonia, akinesia, and rigidity Psychomotor slowing Depression Psychosis Choreoathetoid movements Frequent body-jerking movements Not as noticeable in early stages Fewer cognitive issues Especially in early and middle stages of the disease Due to cognitive awareness, watch for Suicide Substance abuse

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Treatment Symptomatic Parkinson’s Areas affected Subcortical (basal ganglia) Neuropathology Depigmentation of the pigmented nuclei Locus coeruleus Substantia nigra Lewy bodies Plaques Neurofibrillary tangles Neuronal loss Reduced choline acetyltransferase in cortex and substantia nigra Clinical findings Triad Tremor Rigidity Bradykinesia (slow movement) Dementia in 40% Depression Bradyphrenia (slow thinking) Micrographia Festinating gait Delusions paranoid-type Hallucinations Treatment Remove medications, which may exacerbate Parkinson’s symptoms SGA (to avoid exacerbation of extrapyramidal symptoms) Selegiline (selective MAO inhibitor) Dopamine agonists Levodopa Pramipexole Bromocriptine Pergolide mesylate Amantadine Infectious causes of dementia Subacute sclerosing panencephalitis (SSPE) Clinical findings Childhood onset (average age 10 years) Male Dementia Myoclonus Diagnosis Elevated measles titer in CSF EEG findings—periodic complexes Head CT Cerebral atrophy Dilated ventricles Creutzfeld-Jacob disease (CJ disease) Prion-containing protein transmission via: Transplant EEG electrodes Ingesting meat infected with the disease (Mad Cow) Kuru disease (transmitted by cannibalism) Clinical findings Dementia

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Dysfunction of the basal ganglia Dysfunction of the cerebellum Myoclonus Progression to Stupor Coma Death (in months) HIV dementia Neuropathology Toxoplasma gondii Found via head CT Increased toxoplasmosis antibody titers Fungal infection lesions Candida Aspergillus Mycobacterium tuberculosis Virus Cytomegalovirus Papovavirus Tertiary syphilis Cancer Kaposi’s sarcoma Gliomas Clinical findings Cognitive impairment Memory Confusion and poor concentration Behavioral impairment Apathy Anhedonia/depression Delusions/hallucinations Motor system impairment Incoordination Lower extremity paresis Difficulty with fine motor movements Parkinsonism Myoclonus Treatment—look toward causative agent Neurosyphilis Clinical findings Late stage syphilis Asymptomatic Meningovascular Parenchymal General paresis (20 years after infection) Cognitive impairment Myoclonus Dysarthria Personality changes Irritability Psychosis Grandiosity/mania Tabes dorsalis (25–30 years after infection) Loss of position and vibratory sense Aflexia (lower extremities) Chronic pain Ataxia

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Incontinence Dementia Dysarthria Babinski’s reflex Tremor Argyll Robertson pupils Myelitis Optic atrophy Treatment Penicillin to improve cognitive deficits (full recovery is rare) Head trauma-related dementia aka dementia pugilistica Clinical findings Sports related injuries involved with repetitive head injuries Boxers Emotional lability Dysarthria Impulsivity Substance-inducing persisting dementia DSM-IV TR substances Alcohol: Alcohol-induced dementia Clinical findings Increasing memory loss Personality change Worsening cognitive processing Cannot diagnose if Early abstinence Amnestic episodes Wernicke-Korsakoff syndrome Inhalant Sedative, hypnotic, or anxiolytic Other (or unknown) Normal pressure hydrocephalus Neuropathology—impedance of CSF flow Subarachnoid hemorrhage Meningitis Trauma Clinical findings Triad Dementia Urinary incontinence Gait apraxia Psychomotor retardation Head CT Ventricular dilation Intact cerebrum Treatment Shunting of CSF from lateral ventricle to chest/abdominal cavity Treat underlying conditions Wilson’s disease Neuropathology Hepatolenticular degeneration (copper deposits in liver, brain, and cornea) Clinical findings Adolescence and early adulthood Personality changes Mood disorder

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Thought disorder Wing-beating tremor Rigidity Akinesia Dystonia Kayser-Fleischer ring around the cornea (pathognomonic) Treatment Assure diagnostic confirmation (rule out other conditions) Chelating agents (penicillamine)

DEPRESSION IN THE GERIATRIC POPULATION Prevalence Epidemiology Common Often undiagnosed and undertreated Different presentation than in younger patients Different pathophysiology than in younger patients Prevalence General: 2%–8% Nursing home population: 6%–25% Dementia: 3%–21% Epidemiology and treatment Racial differences (blacks less likely than whites to receive antidepressant treatment when insomnia present) antidepressants, sedative hypnotics, neuroleptics. “A second metabolic syndrome” (various abnormalities of protein signaling) Evidence of a "second metabolic syndrome" Elevated proinflammatory cytokines Elevated acute phase proteins C-reactive proteins Elevated circulating adhesion molecules Relative insulin resistance Hypothalamo-pituitary disturbance Suppressed neurogenesis Stemcell–like cell in the medial temporal lobe Other neuromedical syndromes with depression Multiple sclerosis Depression as a modulator of multiple sclerosis Cardiovascular disease Impact of depression on treatment outcomes Neurodegenerative disease Diagnosis Consider this as a comorbidity Consider bereavement If bereavement is present ?History of depression ?Already treated for depression Presence of suicidal ideation Criteria met for more than 4–6 weeks “misery symptoms” Consider other types of losses Role loss/transition; retirement Normal aging/functional decline Medical illness and functional impairment Neurobiology of geriatric depression Vascular hypothesis Vascular changes

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Subcortical white matter lesions “UBOs” (deep white matter and periventricular) Subcortical gray matter lesions “UBOs” are correlated with vascular changes Cardiovascular disease may predispose, precipitate, or perpetuate some depression Disruption of the prefrontal systems by lesion(s) Drugs for cardiovascular disease may improve depression Treatment options Clinical management Clarify diagnosis Check TSH and B12 levels Obtain an MRI if Focal neurological deficits found (“UBOs” present) Severe cognitive impairment Severe treatment-refractory melancholic depression Basics of management of depression in the elderly Nonpharmacological Supportive for mild depression Behavioral activation Religious involvement Family activities Scheduling pleasant activities Previous hobbies/talents New hobbies Exercise for mild-moderate depression Therapeutic modalities Problem solving therapy (PST) For executive function issues Initiating conversation Perseveration Ideal if medications are problematic Interpersonal therapy ECT No negative studies Effective Generally safe TMS In a few case reports, there has been some improvement ?deeper structures targeted ?good alternative to ECT Pharmacological management General guidelines “Start low, go slow, but go” Duration If effective, remain for at least 2 years 30% will relapse even after effective maintenance Treatment Consider depression as lifelong at this point Consider Several trials Combination treatments ECT Specific agents TCAs Imipramine > pbo Nortriptyline > pbo SSRIs Sertraline antidepressant heart attack randomized trial (SADHART)

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Conclusion: Treatment with sertraline in patients with MDD after an myocardial infarction is well tolerated SNRIs Venlafaxine versus citalopram––both good versus fluoxetine––both good Duloxetine Bupropion Mirtazapine Psychotherapy and others Cognitive impairment and depression Co-occur Depression is a risk factor for dementia—and is an independent risk factor Mild cognitive impairment (MCI)––dementia Depression is a prodromal state Depression is the tip of the Dementia Iceberg Consequences of memory impairment in depression NCODE Study MCI-dementia predicts persistence of MCI Protective factors Female gender Education Number of impaired ADL Not risk factors Age Race Baseline MADRS Baseline MiniMSE Depression increases risk of dementia five times Optimal duration The classic curve also applies and maybe even more for >70 years old Go for 1 year and possibly 2 years of maintenance Consider comorbities of all kinds—especially anxiety and pain (studies) Psychosocial factors Role transitions Bereavement Increasing dependency Interpersonal conflicts Progressive depletion of psychosocial and economic resources Chronic sleep disturbance Neurodegenerative disorders Limited access to adequate treatment Medical burdens Timing of combination or switching strategies If the depression is not alleviated Study of rescue with duloxetine Principles GO FOR REMISSION (not response) If partially responding at 6 weeks, stay the course and go to 12 weeks If partially responding at 12 weeks, switch Switching = augmenting (and better: adverse effects more limited, less costly, better adherence) Risks and benefits of switching Predictors of response—see above Indications of maintenance treatment Predictors/moderators of variability during maintenance Coexistence of anxiety and medical burden “The dose that gets you well, keeps you well”

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PSYCHOSIS IN THE GERIATRIC POPULATION Diagnosis Differential diagnoses Delirium Characteristics of geriatric delirium Abrupt onset Physical symptoms are prominent Disorientation Memory impairment Other recent med changes Metabolic Hepatic impairment Renal failure Hyponatremia Thyroid CHF Alcohol withdrawal B12 deficiency Poor nutrition Medication induced Sedatives in standard doses (zolpidem—5% hallucinations) TCA Carbidopa-levodopa Anticholinergics Taper off all anticholinergic medications (TCA, some SGA) Use nonanticholinergic antipsychotics Haloperidol Risperidone Ziprasidone Aripiprazole Use trazodone to decrease agitation Benzodiazepine Amantadine Schizophrenia Typical Onset

Late Onset

Very Late Onset

Ages 18–39 years

Ages 40–60 years

Ages >65 years

Positive family history

Positive family history

Rarely family history

Few visual hallucinations (VH)

Few VH

Greater VH

Cognitive course as typified

Cognitive course as typified

Cognitive course more progressive

Dose of SGA recommended

¼–½ of SGA dose

1/10–1/5 of SGA dose

Bipolar disorder Major depression Dementia Behavioral abnormalities Prevalence of psychotic symptoms Psychosis: 33% Depression: 40% Aggression: 40% Agitation: 80% Agitation Common in late-life psychosis

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Not diagnostic of any type of psychosis Most common if psychosis is associated with dementia Worse at night Worse in unfamiliar surroundings (like hospitalizations) Worse when confronted Worse when restrained Worse when frightened Types Aggressive: Hitting, kicking, pushing, scratching, tearing, grabbing, biting, splitting Nonaggressive: Pacing, disrobing, escape attempts (rule-out akathisia) Inappropriate verbal: Crying, cursing, screaming (especially at night) Nonpharmacologic treatment Before adding meds Stop medications that contribute Provide orienting stimuli (board with information, clock etc) Provide supportive interaction Simple well-lit environments Do not challenge or provoke Stop offending behaviors Use patient’s own pets or pet therapy dogs Play familiar music from adolescence Gentle touching and/or massage Factors to consider Elderly more sensitive to all side effects Decreased adherence Impaired ability to self medicate accurately Polypharmacy Multiple dosing schedules Drug interactions (average veteran on 9 medications) Pharmacologic treatment Summary of early evidence—antipsychotics are first-choice treatment for psychosis and agitation Meta-analysis for antipsychotic agents Varies with techniques 1/3 will experience adverse events More rapid cognitive decline with medications than without 33 randomized clinical trials (only 17 placebo controlled) Doses Risperidone: 0.5–1 mg/day Olanzapine: 2.5–5 mg/day Quetiapine: 25–100 mg/day Ziprasidone: 40–80 mg/day Aripiprazole: 5–10 mg/day What we do not know (and did not since 1997)? Types and diagnosis of patients who benefit from antipsychotic agents Which works best? What dose works best? How much time till response? Optimal duration Seriousness of side effects SGA Safety Tardive dyskinesia developed within 3 years: 64% Metabolic concerns Obesity Diabetes mellitus

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Psychiatry Bullets Hyperlipidemia Hyperprolactinemia Strokes Mortality FDA warnings/guidelines NO FDA approval for treatment of psychosis in dementia (only schizophrenia and bipolar geriatric patients) All age groups Weight gain Diabetes mellitus Hyperlipidemia Dementia Strokes Death We still have to document eye exams for SGA—even though not standard for elderly patients Class warning for SGA (strokes, QTc issues, diabetes/death) Recommended doses Initial Dose (m/d) Typical Range (m/d) Risperidone

0.25–0.5

0.5–2

Olanzapine

2.5–5

5–10

Quetiapine

12.5–25

50–100

Aripiprazole

2–5

10–12

Ziprasidone

20–40

40–80

Consequences of not treating psychosis and agitation Psychosis of Alzheimer’s dementia tends to be recurrent/persistent Agitation and aggression associated with psychosis of Alzheimer’s dementia leads to hospitalization Pharmacotherapy needed in severe, dangerous cases Other meds Cholinesterase inhibitors best long-term safety data Memantine 5 mg → 10 mg Donepezil showed efficacy in treating behavioral symptoms (except elation) in patients with moderate Alzheimer’s dementia agitation, anxiety, apathy delusions, depression disinhibition hallucinations, irritability, motor activity Rivastigmine on behavior in patients with Alzheimer’s dementia––yes Galantamine Combo Divalproex ER 500–1,000 mg/day Five studies (4/5 showed improvement) reach for levels >45 ng/ml pbo controlled (agitation/aggression were examined) Psychosis (also helped the psychotic pt’s psychosis) ER causes less weight gain than non-ER forms Trazodone 25–100 mg/day Summary Behavioral and pharmacotherapy should be utilized Treatment depends on type of psychosis and presenting symptoms Remove the cause(s) rather than add medication to treat symptoms Controlling psychosis with medication may reduce agitation, but control of agitation does not reduce psychosis

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Risks/benefits/alternatives informed consent conversations with the patient and family—and document Monitor frequently Cholinesterase inhibitors have the best long-term safety data and donepezil (Aricept) has the best efficacy data (FDA-approved for all phases of dementia)

ANXIETY DISORDERS IN THE GERIATRIC POPULATION Fear and worry are different conditions (and thus pathways) of anxiety Fear danger → amygdala → DLPFC Worry/avoidance (no amygdale involvement) → right to the FC Features of anxiety disorders Fear Avoidance Arousal Antic worry Panic attacks PD x x x x x SAD x x x x* OCD x +/− ********************************************************************** GAD +/− x PTSD x x x Prevalence in older adults Any anxiety disorder (GAD > phobia > panic > OCD) more prevalent than MDD Why does it seem rare? Panic disorder/OCD/Social phobia—unlikely to appear later in life Arousal/panic is less intense GAD harder to detect—unlikely to be reported as a chief complaint (even in mental health clinics) Seeks treatment? GAD—there is a focus on this particular anxiety disorder Prevalence, does not remit with age Risk factors Changes in brain (aging, cerebral blood flow) leading to less effective problem solving Life stressors as more anxiogenic Chronic medical issues Finances What is it? Do you worry a lot (just the beginner) anxious/nervous/concerned? Patients may not want to admit to these worries; thus, open with gentle questions How do you feel in times of stress? What makes you feel that way? How often do you feel that way? If greater than ½ the week, then likely GAD Associated symptoms Sleep disturbance Irritability Muscle tension (clinical measurement not well studied) but individuals may experience it as pain Higher index of suspicion around head and neck Difficulty with concentration (aka memory) Late-onset characteristics Cognition Associated with poorer memory/attention and, older people will become more anxious about changes Does treatment improve cognition? Tests of cognitive decline Research oriented—psychological batteries, etc. Clinically—ask the family member! Overactive frontal lobe inhibits the amygdala

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Comorbidity with depression In general, ½ of adults with MDD have at least one anxiety disorder ¼–1/3 of adults with anxiety disorder have MDD Most common anxiety disorder → MDD Would treatment of anxiety prevent MDD? unknown Prognosis is more severe more suicidal ideation more cognitive decline more diff to treat more likely to remit (Steffens. Am J Psychol, 2005) Medications for GAD treatment in healthy young adults FDA-approved Escitalopram Paroxetine Venlafaxine XR Duloxetine Busparone Efficacious Other SSRI/SNRI Benzodiazepines Antihistamines Pregabalin Limitations of medications Possible risks Suicide in an FDA meta-analysis: SSRI use in those older than 65 is protective against increased suicidal ideation Falls: several association studies link SSRI with falls not known if individual effects v. med itself Bleeding: older age or history of gastrointestinal bleed, use caution antiplatelet effect Hyponatremia occurs in as much as 10% on SSRI’s Risk factors: history of low sodium, diuretics Conservatively: check sodium after 2 weeks Pharmacology SSRI as first-line choice High risk of side effect leads to drop out Start low, go slow—but not too slow Many will respond, few will remit (1/3 will remit) Frequent discontinuation also occurs (15% in one study) Medication adherence issues Not thought to have “durable” benefits unlike CBT Phobias are unlikely to respond to medication and can even impair response to therapy CBT Relaxation therapy Slow, deep breathing Progressive muscle relaxation Imagery Changing negative automatic thoughts Overestimation of risk Catastrophization Exposure to anxiety-provoking situations (systemic desensitization) Age impact on effectiveness—why CBT does not work so well Anxiety is too strong to allow CBT to work

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Impairment of cognition Exposure does not work well for GAD since there is no specific Combined pharmacology and CBT theory SSRI improves anxiety acutely CBT then teaches the skills (address durability) Thus SSRI → CBT when feeling better → discontinue SSRI Psychotherapy Managing anxiety Consider differential diagnoses Mood disorders Anxiety disorders Endocrinological conditions Delirium Dementia Cardiovascular disorders Infection Pain Gastrointestinal disorders Medications Antidepressant/depressant agents Antipsychotic agents Corticosteroids Bronchodilators Decongestants Thyroid replacement agents Stimulants Nicotine Abrupt withdrawal of (especially when hospitalized) Alcohol Barbiturates Benzodiazepines SSRIs Consider high medication self-discontinuation Anxious symptoms misperceived as side effects Increased anxiety Gastrointestinal symptoms Sedation Restlessness “Medication phobia” “Start low, go slow––but, not too slow and don’t stay low” Frequent visits and support Weekly or biweekly Phone availability 24 hours/day Counsel in advance about adverse effects Likely to be temporary Unlikely to be incapacitating Continue to counsel about side effects “Let’s keep going” 1/7 do drop out (by week 4) Unanswered questions Second line-combo treatment Maintenance treatment Optimal treatment of anxious depression

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SPECIAL FACTORS IN GERIATRIC PSYCHIATRY Pharmacokinetics and pharmacodynamics Pharmacokinetics Renal Clearance

Cause Effect

Plasma Protein Binding Hepatic Metabolism

Cause Effect Cause

Distribution

Effect Cause

Effect Absorption

Cause

Effect

Decreased renal blood flow Decreased GFR Longer elimination t ½ Higher steady state plasma levels Decreased albumin Increased drug potency (drugs that bind to albumin) Decreased actual liver volume Decreased hepatic blood flow Decreased oxidative metabolism Decreased N-demethylation Reduced activity of cytochrome P450 enzymes (modest) Reduced lean body mass Reduced total body water Increased body fat Longer elimination t ½ Slower steady state arrival Decreased gastric emptying time Increased gastric pH Reduced area for absorption (surface area) Reduced mesenteric blood flow Delayed onset of drug action Reduced clinical effect of drug

Pharmacodynamic GABAergic drugs Serotonergic drugs Noradrenergic drugs

Anticholinergic drugs

Antidopaminergic

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Not age dependent Blunted response (likely due to receptor loss) Blunted response Reduced noradrenergic drugs in locus coeruleus Receptor loss of NE Increased effects Reduced cholinergic neurons in basal forebrain Decreased choline uptake Decreased acetylcholine synthesis Increased acetylcholine breakdown Increased effects Decreased dopamine synthesis Increased dopamine breakdown

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CATIE-AD Design: Method:

Multicentered Double-blind, randomized, placebo controlled 36 week Flexible dosing N=421 outpatients with AD with anxiety and/or psychosis Olanzapine, risperidone, quetiapine, placebo CGIC Conclusions: No significant difference among treatments in time to cause discontinuation No significant difference in rates of response Side effects EPS Olanzapine = risperidone > quetiapine Sedation All drugs > placebo Confusion Olanzapine = risperidone > placebo Cognition No worsening in any group Body weight All medications increased Prolactin Increased with risperidone Falls All drugs = placebo CVA All drugs = placebo FDA black box warning (all neuroleptics including haloperidol) Causes of death Cardiac related Heart failure QTc prolongation leading to fatal arrhythmias Metabolic Hyperglycemia, diabetes, ketoacidosis Infections Pneumonia

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Chapter

19

Mental Disorders Due to a General Medical Condition

INTRODUCTION Review history, physical exam, and diagnostic tests Consider temporal correlation; consider if the symptoms are better accounted with psychiatric symptoms Consider differential diagnoses: psychosis, mood, anxiety, personality change Should treatment be emergent, treat underlying causes (if possible), tolerability

DELIRIUM Definition Impaired consciousness (thus, a disorder of arousal) Involves reticular activating syndrome (RAS) Consider all different levels of arousal Hyperactive Hypoactive Mixed Impaired cognition Memory deficit Language disturbance Perceptual disturbance Usually tactile hallucinations Delusions are often transitory Fluctuating course All symptoms can fluctuate Assess over 24 hours Caused by an underlying condition/agent Epidemiology Hospitalized patients: 15%–30% Advanced disease patients/palliative care patients: 40%–80% Associated with morbidity and distress Patient Family Hospital staff Course Untreated delirium can progress to dementia/worsen to cognitive disorder Can be irreversible 60% of hospitalized elderly patients die within the year 205

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Pathophysiology Common final pathway of dopamine excess Suggestive of neuroleptics’ effectiveness Risk factors Elderly Hospitalized individuals AIDS Advanced disease Advanced cancer Causes of delirium Primary tumor/metastatic effects Hypoxia Metabolic encephalopathy (organ failure) Electrolyte imbalance Withdrawal states Treatment side effects Infections Hematologic abnormalities Nutritional deficiencies Paraneoplastic syndromes Causes Hypoxia Metabolic encephalopathy (usually secondary to organ failure) Electrolyte imbalance Withdrawal states Treatment side effects Chemotherapy Steroids Radiation Opioids Anticholinergics Antiemetics Biological response markers Hematologic abnormalities Disseminated intravascular coagulation (DIC) Nutritional deficiencies Paraneoplastic syndromes Assessment DSM-IV TR criteria Delirium rating scale (DRS) Confusion rating scale (CRS) Memorial delirium assessment scale (MDAS): 10-item severity and diagnostic scale (Cognitive screening scales assess only cognition, not other criteria) Mini mental status examination (MMSE) Clinically Asterixis: suggesting hepatoencephalopathy EEG: diffuse slowing is a classic pattern but is only one type of pattern in delirium Frontal release signs Palmar release Subtypes (based upon the type of arousal disturbance) Hyperactive Approximately 25% of cases Hypoactive Approximately 50% of cases Often underrecognized and untreated due to presentation Equally distressing as hyperactive and mixed delirium

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Neuroleptics not as effective Hypoactive type still experiences delusions and hallucinations However, rates of delusions and hallucinations may be less Mixed Approximately 35% of cases Treatment Nonpharmacologic Reduce environmental overstimulation Orientation aids (wall clock, calendar) and frequent reorientation Minimize use of catheters, intravenous lines, physical restraints Monitor Dehydration Fluid and electrolyte balance Nutrition And control pain Sleep hygiene Treat underlying conditions/address symptoms if irreversible Preventative measures Hydration Optimize all bodily systems Eliminate anticholinergic agents where possible (prophylactic neuroleptics vary in effectiveness) ?Choice of anesthesia to avoid prolonged effect Pharmacologic (with a focus on reducing side effects from agents used) Address possible drug toxicity or withdrawal Neuroleptics (may exacerbate delirium secondary to side effects) FGA Examples Haloperidol

0.5–5 mg q2–12h

po/iv/sc/im

Thioridazine

10–75 mg q4–8h

po/im

Chlorpromazine

12.5–50 mg q4–12h

po/iv/im

Droperidol

0.5–5 mg q12h

im/iv

SGA Examples Risperidone

1–3 mg q12h

po

Olanzapine

2.5–5 mg q12h

po/im

Quetiapine

25–150 mg q12h

po

Ziprasidone

20–80 mg q12h

po/im

Aripiprazole

10–15 mg qd

po

Specific agent and subtype Aripiprazole: Hypoactive type in elderly Olanzapine: Hyperactive type Black box warnings All antipsychotics included in FDA warning However, there are no other agents available for effective treatment of delirium

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PSYCHOTIC DISORDER Definition: hallucinations, delusions, clear sensorium, IQ intact Etiology and pathophysiology Secondary to precipitants Neuroleptics Dopaminergic agents Disulfiram Sympathomimetics Bupropion Fluoxetine Baclofen (upon discontinuation) Postencephalitic Post head trauma Secondary to diseases with distinctive features Associated with epilepsy Interictal (complex partial seizures and exquisitely paroxysmal) Postictal (preceded by a “flurry” of seizures; time lapse can be hours or days) forced normalization (after medications stop the seizure), chronic interictal (in uncontrollable or long-standing seizures, delusions of persecution, auditory hallucinations, over weeks to months) Encephalitic onset: (consider headache, lethargy, fever)—Herpes simplex virus (treatable), infectious mononucleosis With other specific features: Huntington (chorea) Sydenham Chorea gravidarum Manganism (parkinsonism) Cruetzfeldt-Jacob (myoclonus) Hashimoto (myoclonus) Wilson’s (various abnormal involuntary movements) AIDS (thrush, pneumocystis pneumonia) SLE (arthralgia, rash, pericarditis, pleurisy) Hyperthyroid (tremor, tachycardia) Hypothyroid (cold intolerance, voice change, constipation, hair loss, myxedema) Cushing syndrome (cushinoid, moon face) Adrenocorticoid insufficiency (GI, dizzy) Porphyria (GI pain) Alzheimer’s cerebellar ataxia Prader-Willi syndrome (massive obesity) Dentatorubropallidoluysian atrophy Secondary to miscellaneous causes Brain tumors/strokes Multiple sclerosis Syphilis B12 deficiency Subacute sclerosing panencephalitis Metachromatic deficiency Fahr syndrome Thalamic degeneration VCFS VeloCardioFacial Syndrome (genetic disorder––cleft palate, cardiovascular malformation, micrognathia, large nose, mental retardation) Lyme disease Assessment and differential diagnoses Labs Blood/urine toxicology Testosterone levels (anabolic steroid users)

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CBC with differentiation (MCV large in alcohol and B12 deficiency) Liver function tests (alcohol) HIV FTA (Syphilis) B12 ANA Antithyroid antibodies (Hashimoto’s) TSH Cortisol and ACTH and 24-hour urine for free cortisol Copper and ceruloplasm levels MRI EEG Lumbar puncture Epidemiology and comorbidity: usually psychotic condition if Axis I present Course: determined by underlying cause Treatment: determined by underlying cause

MOOD DISORDER With depressive features Definition: depressed mood or lack of interest PLUS evidence of medical condition (depressive symptoms themselves are not necessary for the diagnosis) Etiology and pathophysiology Secondary to precipitants Medications Propanolol Interferon ACTH Prednisone Alpha-methyldopa Nifedipine Ranitidine Bismuth subsalicylate Pimozide Subdermal estrogen/progestin Anticholinergic withdrawal (cholinergic rebound) Poststroke depression Head trauma Coup-contrecoup head injury (“whiplash”) Secondary to diseases with distinctive features Hypothyroidism (hair loss, dry skin, voice changes) Hyperthyroidism (weight loss with increased appetite, tachycardia, atrial fibrillation/CHF [elderly]) Cushing (moon face, hirsute, acne, buffalo hump, abdominal striae) COPD (snoring when sleeping) Multiple sclerosis (various local findings) Down syndrome Epilepsy Ictal depression Chronic interictal depression Occurring as part of a certain degenerating/dementing disorder Alzheimer Vascular dementia Diffuse Lewy body

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Parkinson Fahr Tertiary neurosyphilis Limbic encephalitis Miscellaneous/rare Brain tumors Hydrocephalus Pancreatic cancer New variant Creutzfeldt-Jakob disease Systemic lupus erythematosus Pernicious anemia Pellagra Lead encephalopathy Hyperaldosteronism Assessment and differential diagnoses Underlying cause(s) Course Medications: days to weeks after discontinuation Steroids: days to weeks Anticholinergics: days Poststroke depression: remits within a year Head injuries can be sustaining Multiple sclerosis: waxing and waning With manic features Definition Etiology and pathophysiology Secondary to precipitants Corticosteroids Most likely Dose related ACTH hormone Levodopa induces hypomania in patients with a history of mania Anabolic steroids Physical evidence Look for gynecomastia and testicular atrophy Oral contraceptive Isoniazid Busparone Procyclidine Procarbazine Propafenone Baclofen (upon discontinuation after long-term use) Reserpine (upon discontinuation after long-term use) Methyldopa (upon discontinuation after long-term use) Closed head injuries Hemodialysis Encephalitis Aspartame Metrizamide Secondary to diseases with distinctive features Hyperthyroidism (proptosis, tremor, tachycardia) Cushing (moon face, hirsute, acne, buffalo hum, abdominal striae)

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Multiple sclerosis (various local findings) Cerebral infarct (sudden onset with localizing findings) Syndenham chorea Chorea gravidarum Hepatic encephalopathy (asterixis, delirium) Uremia (asterixis, delirium) Epilepsy Ictal mania Postictal mania Part of certain neurodegenerative or dementing disease Alzheimer dementia Neurosyphilis Huntington Creutzfeldt-Jacob Miscellaneous or rare Brain tumors Systemic lupus erythematosus B12 deficiency Metachromatic leukodystrophy Adrenoleukodystrophy Tuberous sclerosis Assessment and differential diagnoses Evaluating for underlying condition Epidemiology and comorbidity Variable Course Variable

ANXIETY DISORDER Definition Etiology and pathophysiology generally associated with acute anxiety Partial seizures Paroxysmal atrial tachycardia (Valsalva manuver does stop the attack) Hypoglycemia (Whipple’s triad: blood sugar <45, typical symptoms associated with hypoglycemia, symptom relief with glucose) Acute myocardial infarct or angina Pulmonary embolus Acute asthma Pheochromocytoma Parkinson disease Drugs Etiology of potential longer term anxiety Sympathomimetics Theophylline Alzheimer dementia Hyperthyroidism Cushing disease Hypocalcemia Chronic obstructive sleep disorder Congestive heart failure Poststroke Post head trauma

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CATATONIC DISORDER Definition Etiology and pathophysiology Stuporous catatonia Seizure association Ictal Postictal Psychosis of forced normalization Chronic interictal Medication Neuroleptics Disulfiram Benzodiazepine withdrawal Viral encephalitis Herpes simplex virus Encephalitis lethargica Focal (especially frontal lobe) lesions Miscellaneous Hepatic encephalopathy Limbic encephalitis Systemic lupus encephalitis Lyme (stage III) Subacute scerosing panencephalitis Tay-Sachs Thrombotic thrombocytic purpura Excited catatonia: viral encephalitis

SPECIFIC CONDITIONS Pseudobulbar palsy Definition Emotional lability (pathological laughing and crying) Dysarthria Dysphagia (gag, inability to protrude one’s tongue) Etiology and pathophysiology (bilateral interruption of the corticobulbar fibers) Vascular (most common) Internal capsule Corona radiata Binswanger (vascular dementia affecting brain’s white matter) Neurodegenerative (amyotrophic lateral sclerosis) Miscellaneous (tumors) Assessment and differential diagnoses Emotions are mood dystonic MRI testing can be helpful Course determined by the etiology Treatment: SSRIs for mood symptoms Kluver-Bucy syndrome: bilateral temporal lobectomy Definition Hypersexual Hyperoral Agnosis Emotional placidity Etiology and pathophysiology Pick Frontotemporal dementia

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Alzheimer late stages Seizures Adrenoleukodystrophy

HIV/AIDS Introduction 12/02: affecting 42 million Treatment of affected pregnant woman before labor, during delivery, and breast-feeding can reduce it 47% Global HIV/AIDS in children and adolescents Sub-Saharan––1/3 of pregnant women have HIV (overall number decreasing) West Africa—HIV Type 2 South and South-East Asia 2.7% of pregnant women (usually secondary to prostitution) Latin America and the Caribbean—homosexual men; IVDA Western Europe—risk-taking heterosexuals Eastern Europe—poor socioeconomic status, prostitution East Asia and Pacific Region—prostitution North Africa and Middle East—not well known Worldwide: AIDS Orphans HIV/AIDS in US children Overall Numbers declining due to timely medications Risk factors: IVDA, infected partners, black ethnicity, urban areas (notably; NYC, Miami, Newark) Transmission Mother with or at risk for HIV infection Average transmission rate is 25% (8% if given medications) Breast milk can double the transmission rate Blood transfusions and hemophilia/coagulation disorders Started in 1985 (chances are 1/100k—1/1 mL per unit of blood) 4% of HIV secondary to hemophilia/coagulation disorder Sexual transmission Detection and classification Test at 2 days, 1–2 months, 3–6 months via DNAPCR assay with seroconversion at 15–18 months Developmental delays The classic infections associated with AIDS Cancers Neurological symptoms including loss of milestones/cognitive functions/apathy/motor retardation Antiretroviral and supportive therapy HIV RNA correlates with risk for disease progression CD4 counts drop, AIDS Aggressive therapy with at least three drugs for initial treatment for kids 2NRTIs+ protease inhibitors HIV/AIDS in US adolescents Overview Increasing Heterosexual contact Females > males in 13–19 (males 2:1 otherwise) Transmission: disenfranchised inner city youth who engage in sex/IVDA Comorbidity Poor concentration, sensory and motor deficits Suicide (especially males ages 15–19 years) Psychological and developmental aspects Neurodevelopmental delays and persistent neuropsychological deficits 75% Anxiety, sadness, nightmares, irritability, “battle fatigue”

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Rejection, avoidance, estrangement Attachment (critical during the first 15 months) AIDS as a chronic illness Psychiatric treatment guidelines Psychological issues in uninfected children AIDS orphans Multidisciplinary and family-centered care Provider support Prevention Risk behaviors Education and prevention programs

DEVELOPMENTAL APPLICATION Consideration of stages of psychosomatic involvement Phases of illness Vulnerability to disease Symptom onset Recurrence Chronicity of the disease state Adaptation/reaction to illness Psychological aspects of chronic disease and their impact on development Chronic disease: (seizures, diabetes, cystic fibrosis, cancer, irritable bowel) Illness at developmental levels Preschool Verbal/motor delays Egocentrism: illness seen as punishment Misbehavior versus overcontrolled behaviors Latency Concrete interpretations of tests Self-esteem (time of mastery) (Tutoring and sports involvement may be helpful) Adolescence Affects autonomy, psychosocial development, peer relationships, focus on normal sexual development Adulthood Marital strain Occupational strain Family Guilt by siblings General treatment approaches Education: sessions, brochures, chat rooms Consultation: no diagnosis, focus on history, focus on dysfunction (not diagnosis), patience Referral to child psychologist (refusal is part of the process) Referral to agencies if necessary Outpatient psychosomatic intervention Individual behavioral techniques School Peers Family Inpatient focus: Psychosomatic intervention

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Chapter

20

Child and Adolescent Psychiatry

DEVELOPMENT General theories Life cycle theory Development occurs in “successive clearly defined” stages Epigenetic principle—each stage has characteristic issues/crises that must be successfully resolved Each phase is distinct from another by the characteristic issues/crises Theodore Litz Physical maturation Cognitive development Society seeks rules Children internalize parental characteristics Time changes around Contemporary theorists Daniel Levinson Psychosocial theory of development Stages are marked by transition—usually conflictual Bernice Neugarten “Psychological importance of increased awareness of aging and personalization of death” Time to live (not lived) Sense of competence Increased introspection Increased inferiority Calvin Colarusso and Robert Nemeroff—“lifelong dynamic process”; childhood processes continue but finiteness of death is a major organizer George Valliant Study of males over a 50-year time span Happy childhood (marked by decreased oral traits and pathology, a capacity to play, good object relations) leads to positive traits in middle life Hierarchy of ego mechanisms ranging from immature psychopathology to mature objective adaptation (altruism, anticipation realistic planning, asceticism, humor, sublimation, suppression) Factors in child development Family stability Death of loved ones and or acquaintances Day care centers Parenting styles Authoritarian Indulgent-permissive 215

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Indulgent-neglectful Authoritative-reciprocal Divorce effects Infant to toddler: changes in eating/sleeping 3–6 years old: does not understand/blames 7–12 years old: decrease in school performance >12 years old Blended families Therapists Take 3–5 years to recover 1/3 have psychological effects Attachment theorists Harry Harlow: terry cloth covered wire meshed adult-sized “monkeys” were preferred over a bottle with food by the infant monkeys Infant attachment is not just a result of feeding Bowlby: maintenance of physical contact between mom and child Hunger: fear depression Ainsworth: secured base effect—child can move away from attachment figure Winnicott: transitional object Spitz: institutional neglect (mental retardation secondary to neglect) Developmental observations throughout the lifetime Embryo: conception to 8 weeks gestational age (WGA)—apoptosis (programmed cell death) Fetus: 8WGA––birth Behavior (Amniocentesis: performed at 14–16WGA) Movement detected: 16–20WGA Grasp reflex: 17WGA Hears: 18WGA Bright light stimulation: 20WGA Moro startle: 25WGA Sucking: 28WGA Opens eyelids: 7 months Central nervous system Beginning of neural tube/crest neural plate: 16 days Beginning of cortex hemispheres: 6WGA Cortical development: 10WGA Layers of brain cortex: 24WGA Prior, sensitive to hypoxia: 32WGA Prenatal exposures: alcohol, tobacco, other environmental, radiation Infancy birth: 15 months Margaret Mahler Birth to 2 months: Normal autism 2–5 months: Symbiosis 5–10 months: Differentiation 10–18 months: Practicing moving autonomously to explore 18–2 years: Rapprochement moves away but returns 2–5 years: Object constancy: reassured that mom is present even when not physically there Chess and Thomas—Temperament difference Activity level Distractibility Adaptability Attention span Intensity Threshold of responsiveness (intensity is required for response) Quality of mood Rhythmicity: Regulation of functions

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Approach/Withdrawal: Response to new situations Goodness of fit (10% difficult, 40% easy, 50% mixed) Toddler: 15 months–2½ years Preschool: 2½–6 years Middle: 6–12 years Adolescence: 12–20 years Sexual Maturity Rating (SMR) or Tanner Stages Stage

Male

I

Female Elevation of papillae

II

Pubic hair; ejaculation

Pubic hair; breast bud

III

Penis enlargement starts

IV

Glans development

Increased breast size

V

Mature genitals

Mature breasts

VI Sexual activity Decreased teen pregnancy (especially in the black population) Risk of abuse/neglect Prematurity Prenatal exposures Poor follow-up Abortion <20 years old United States 30/1,000; France 10/1,000; Germany 6–8/1,000 Risk factors Alcohol: 30% 12th graders consume >5 drinks/one sitting Age of first drink Males 11 years of age or younger Females 13 years of age or younger Increased binge drinking in 18–25 years olds Tobacco: decreasing in United States but increasing in teens Cannabis: most popular illicit drug Cocaine: slight decrease but still high Opioids: especially prescription forms and heroin Violence Bullying: 30% Gangs: consider girls as well Weapons: 10 children die daily (due to easy access at home) School violence (risk factor: witnessing violence) Sexual offense (look for history of abuse) Prostitution: girls and gateway drugs Tattoos and piercings Phase of adolescence—75% no significant difficulties, but 25% problematic; 60% some distress Young adulthood (20–40 years) Transitions: 1st individuation → 2nd individuation (adolescence) → 3rd individuation Developmental tasks: “real and intrapsychic separation from family of origin” Work identity Female increasing presence Unemployment—monitor for Alcohol use Suicide Homicide Violence

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Psychiatry Bullets Developing adult friendships Parent → peers → spouse → community (order of primary connections) Sexuality and marriage “Experience of intimacy increases the desire for marriage” Older individuals getting married Lower divorce rates Interracial—a small % but increasing Single status—increased frequency Middle adulthood (40–60 years) Developmental tasks Erikson helping others/creative/contributes to society Valliant past predicts future Overall sense of stability in childhood Close sibling relationship(s) during college years Developing midlife friendships no sense of urgency or need for frequent contact Reappraising relationships, especially marriage “goodness of fit” Sexuality: accepting physical changes Climacterium: female (menopause 40–50’s); male (50’s) Transition/crisis “it’s going to happen” The therapist helps with the fallout Empty nest—especially depressed women Divorce/separation Psychological impact Legal 75%–80% remarry within 3 years Economic Community Coparental—joint/single/split Reasons Maturity—a mental state Late adulthood (“old age”) Demographics 1900: 4% 2003: 12.4% 2030: 20% Biology of aging Longevity Best indicator—Family history Males: 73.5 years Females: 80.4 years Individuals older than 85 increasing in the United States Death CVA Cancer Stroke Psychosocial Erikson: integrity versus despair and giving up authority Social activity: good health; social contract Ageism Transference: parental/peer-sibling/son-daughter Countertransference topics: False assumptions: individuals are near death and sexual activity is not present Retirement Sexual activity Long-term care (can cost $20,000–50,000 yearly or more) Death and dying Definitions

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Death versus dying Good death versus bad death Legal aspects Stages Denial Anger Bargaining Depression Acceptance Near death “unio mystica” oceanic feeling of mystical unity with an infinite power” Bereavement Stages Protest Search Despair Detach Reorganize Signs and symptoms to watch for Duration—varies Anticipatory—watch for premature separation and withdrawal Mourning Bereavement (noncomplicated or complicated bereavement) Chronic bitterness and idealization of lost one Hypertrophic Intense grief usually after unexpected loss Delayed Traumatic Medical/psychiatric illness Bereavement and depression Bereavement and PTSD (co-occurs more with traumatic events) Childhood/adolescent presentations Minimal grief at time of loss Cyclical thoughts of loss—especially death Milestones/anniversaries Loss of developmental function 2 year olds—speech 5 year olds—eating Adolescents: mood symptoms/behavioral symptoms/somatic symptoms Decreased sleep

CLINICAL CONDITIONS EARLY-ONSET SCHIZOPHRENIA Epidemiology General population 1%, childhood 0.01% (childhood onset defined as onset prior to 13 years of age) Differential diagnoses Affective disorders Schizo-affective disorders PTSD OCD Pervasive developmental disorder associated with Abnormal language

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Repetitive/ritualistic behaviors Abnormal “prodromal” stage Earlier onset Lack of hallucinations or delusions Substance use Medical etiologies Brain cancer Head injury Meningitis Porphyria Wilson disease Strokes AIDS Electrolyte imbalance Endrocrinological issues Medications (prescribed and over-the-counter) Velocardiofacial syndrome (VCFS) DiGeorge syndrome Environmental exposure (e.g., lead toxicity) Etiology Genetics—no consistencies Brain abnormalities—decrease in gray matter volume (with parietal to frontal pattern) during adolescence Assessment AACAP Practice Parameters Utilize DSM-IV-TR criteria for adult onset schizophrenia Watch for more of what follows than complex delusions and catatonia found in adults Hallucinations Thought disorder Loose associations Illogical thinking Affective flattening Chronic onset Chronic impairment Treatment AACAP Practice Parameters FDA approved (10–17 year olds) Olanzapine Risperidone Quetiapine Aripiprazole TEOSS Study: Treatment of Early-Onset Schizophrenia Design Multicentered, randomized, controlled Three-arm comparison: Risperidone, Olanzapine, Molindone 8-week, then 44-week double-blind maintenance for responders Conclusions Response to standard treatment is poorer in EOSS than first episode Differences in tolerability Olanzapine most associated with weight gain/metabolic Other findings Children are at greater risk for weight gain (compared to adults) Rank order similar to findings in CATIE trials but greater magnitude Greater likelihood of aripiprazole and ziprasidone not to be weight neutral Combined treatment With stimulants does not attenuate weight gain With mood stabilizers increases weight gain

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PEDIATRIC ANXIETY Epidemiology Prevalence Simple phobia: 1%–9% Social phobia: 1.4%–60% Panic disorder: 0.6% Selective mutism: 0.03%–2% Age at onset Simple phobia: 12.8 years Social phobia: 16.6 years Agoraphobia: 24.5 years Panic—before puberty/or adolescence/young adulthood Selective mutism: 2.7–4.13 years Etiology Family history Chemical agents (lactate, caffeine, CCK, carbon monoxide) panic disorders Hyporesponsive hypothalamic gonadotropin hypothalamic axis Learned response Behavioral inhibition Specific conditions Specific phobia Types Animals, insects Thunder, water, heights Blood injection painful event Tunnels, bridges, elevators High comorbidity with another disorder (70%) Obsessive compulsive disorder Epidemiology Course Treatments Studies Paroxetine study POTS I POTS II Strategies Augmentation Lithium Clomipramine Clonazepam Switching Treatment resistant Clomipramine + low-dose fluvoxamine Adding second SSRI iv clomipramine Separation anxiety disorder/generalized anxiety disorder/social phobia Separation anxiety disorder Characteristics Excessive concern regarding any separation from home and “bad things” happening to parent Cannot be alone Avoidance Difficulty falling asleep or sleeping with parents after waking up Physical aches and pains Generalized anxiety disorder––these three maybe the same

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Characteristics Restless, “edgy”, “keyed up” Fatigued at end of school day Poor test performance Sleep—DFA especially Tenses, irritable Social phobia––specific or generalized Treatment studies Fluvoxamine Fluoxetine Paroxetine Fluoxetine and social effectiveness therapy CAMS Other anxiety disorders Selective mutism Characteristics Able to speak Not speaking in social situations Make sure to rule out being a part of another disorder Acute stress disorder Characteristics Exposure to true event Reexperiences the event Avoidance numbing or hyperarousal present Time limited to 1 month PTSD Characteristics True life-threatening event Reexperiences avoidance numbing hyperarousal Risk factors Preexisting psychiatric disorder Proximity Posttraumatic environment Loss of a parent Move to another home location Financial stability Treatment Address comorbidity Depression Anxiety/panic Symptomatic treatment Sleep issues Hyperarousal Avoidance Prevention: b blockers Panic disorder Characteristics Physical symptoms Increased heart rate, “pounding” heart sensation, palpitations, hyperventilation, shortness of breath, choking sensation, chest discomfort or pain, abdominal pain, some psychological pain Worry about the next panic attack Avoidance behaviors related to the attacks Agoraphobia Assessment of anxiety disorders MASC broad-based screening

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Chapter 20 Child and Adolescent Psychiatry SCARED closely tied to DSM (available at no cost at www.aacap.org) CBCL also uncovers mood and anxiety BASC separates mood and anxiety Complications of treatment with SSRIs (“A through I” John T. Walkup, MD) “Activation” Response to diphenhydramine may be predictive Typically 1–3 days after initiation Teenagers experience more of a mental activation Other medications which may cause activation Stimulants Benzodiazepines Antihistamines TCAs Common as 15%–20% become activated on placebo Can occur at low doses, but is generally dose related No long-term prognostic implications—reversible Differential diagnoses an issue when activation becomes disinhibition How about younger kids with “minimal brain dysfunction”? Still unknown relationship with suicidal ideation/suicidal behavior “Bipolar switching” Rare 1% Look for classic euphoria, grandiosity, decreased need for sleep, and increased goal-directed activities—not just irritability Individually related Duration (not dose) 2–4 weeks Not so reversible with discontinuation “Celebration” Anxious all their life—finally get better No euphoria or grandiosity Will go away in 3–4 weeks “Dimensional other comorbidities surface” ADHD (poor self-control, conduct disorder, characteristic pathology) Parenting style (assertive children with high-IQ kids may be at risk) “Evolving psychopathology” Anxiety (SAD, OCD, GAD, social phobia) Mood Mixed “Frontal lobe symptoms (apathy, tachyphylaxis)” Neither depression nor sedation Serotonin syndrome? Lower the dose But if suicidal ideations were treated with SSRIs, maybe increase the dose of the SSRI’s Stimulants may be helpful “Gastrointestinal symptoms” “Hey” Sex life Hematological (bruising, bloody nose—rare) “Inhibited growth? Few case reports” Also consider genomic variants 2D6 poor metabolizers Careful use with Fluoxetine Paroxetine TCA (not an SSRI) Less care required with Bupropion (not an SSRI)

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Citalopram Escitalopram Mirtazapine Sertraline 2C19 poor metabolizers Careful use with Citalopram Escitalopram Sertraline TCA (not an SSRI) Less care required with Bupropion (not an SSRI) Fluvoxamine Mirtazapine Paroxetine Tic disorders Types Transient Chronic motor/vocal Tourette Tic disorder NOS Tourette syndrome Diagnosis Motor and vocal tics 1 year Impairment not necessary (removed in DSMIV) (two thirds are selfdiagnosed) Differential diagnosis Neurological—fairly easy to distinguish from the motor/vocal tics Sydenham chorea Myoclonus Tremor Dystonia Athetosis Spasms Dyskinesias Psychiatric—more difficulty to distinguish from motor/vocal tics Compulsions Sterotypies Perseverative behaviors Self-injurious behaviors Addictive behaviors (cannabis) Habits Mannerisms (trichotillomania, skin picking) History (A Cursing Brain? catalogs this history) Childhood chorea (Sydenham chorea) Charcot, Freud, and Tourette Psychology (Charcot and Freud were talking) Neurology (clomipramine and haloperidol as treatments for tics) Epidemiology (mid-1960s <100 case in the literature) Tourette syndrome found in roughly 1%–3% of the population Tics found in 25% of school-aged children Course Starts in young kids Motor → vocal Rostral to Caudal direction (head/face → body) Simple → complex

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Peaks in early to mid teens (versus latency for tic disorders) Most remit by adulthood Comorbidity OCD ADHD Anxiety Depression Disruptive behavior disorders Genetics Monozygotic twins > dyzogotic twins Family studies tics, OCD, ADHD Other findings Inconclusive linkage studies Genome wide association screening underway Rare variants? Treatment Mild Wait for remission Alpha2 adrenergic agonists Clonidine: short acting Guanfacine: longer acting Moderate/severe FDA-approved agents Pimozide Fluphenazine POTS study POTS II CBIT study Other agents Risperidone Aripiprazole Riluzole Behavioral Awareness training Aware of your tics (unlike in the past) Identify the first indication of the tic (usually not the disruptive action) Competing response Replace diaphragmatic breathing instead of the disruptive tic for 1–2 minutes to avoid the disruptive action Can be curative while in the session The competing response can be variable Exposure-based treatment Tics are similar to OCD symptoms Similar behavioral techniques Functional behavioral interventions Family members may be inadvertently reinforcing the tic (hugs after a run of tics) Behavioral interventions to extinguish the tics Clean room Do homework Other behavioral treatments effect Parent behavior management training Behavioral treatment for aggression School interventions for children Rehabilitation approaches for disabled adults

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ADHD Prevalence Internationally 6%–9% (adult prevalence 4.4%) Historical nomenclature Mental defect of moral control Minimal brain dysfunction Hyperactive child syndrome Hyperkinetic reaction of childhood (DSM II) Attention deficit disorder with or without hyperactivity (DSM III) Attention deficit hyperactivity disorder (DSM IV) Pending in 2013 (DSM V) Etiology Genetic One of the most highly inheritable of all psychiatric disorders Family, twin, and adoption studies support heritability Those at risk Parents Kids Siblings Concordance rates—convergence 0.6/7–0.9 (0.75–0.8) comparable to height and IQ Environmental—collectively explains only a small proportion of the variance of the disorder Perinatal complications Hemorrhage Prolonged labor Low Apgar scores Maternal smoking Prenatal maternal substance use—smoking in particular Increases risk for ADHD or other disruptive behavioral disorders Difficult to differentiate mothers who smoke as they may have ADHD themselves ?in utero exposure (a small Wisconsin study) Maternal depression Negative parenting styles Lead and environmental exposure Structural/anatomic MRI studies Structurally Significantly smaller brain size and cortical thinning Cerebellum and subcortical areas (DLPFC) associated with executive functioning Structural abnormalities are associated with behavioral ratings and other aspects of functioning Looking at CAUDATE and CEREBELLAR volumes Castellanos JAMA 2002 At least till age 15 there are differences in volume of the caudate Cerebellar volume diverges significantly in the 20s Extent of size reduction correlates with symptom severity Functional—fMRI studies Problems with response inhibition and task-switching in frontostriatal regions Problems with divided-attention tasks in the basal ganglia Tamm 2006 study—response inhibition Press a button at a stimulus and NOT press a button at another stimulus ADHD patients do not have brain activation Health kids have bilateral parietal lobe activation Pliszka 2006 study—errors of commission ADHD patients have less left VLPFC Healthy kids have more left VLPFC Shafritz, 2004 study—even children with ADHD on medications, the brain activation was still the same as those on no medications

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Effects of medication on brain function Different brain activation Inefficient brain function Subtypes Predominantly inattentive (IN) 30% Increases with age Predominantly hyperactive/impulsive (H/I) 9% Decreases with age Combined type 61% Most common form in children and adolescents Assessment DSM-IV-TR (created to diagnose male children with ADHD) Significant age-inappropriate symptoms of IN or H/I Onset before age 7 (the age of 7 was arbitrary not empiric) Causes significant impairment in two or more settings Causes significant impairment in social/academic/occupational functioning Are not better accounted for by another mental/medical disorder Diagnostic assessment technique Prior to visit Clarify chief complaint Obtain school records Placement Achievement—no evidence of helpfulness IQ tests—no evidence of helpfulness for diagnosis Obtain behavior reports Teacher rating scales Parent rating scales Obtain previous medical and psychological or psychiatric evaluations Interview and history Past medical history Developmental history Family history Psychiatric history Academic/occupational performance impairment Social relationships impairment Family and home environment impairment Individual functioning impairment Mood Self-esteem Standardized assessment measures Rating scales ADHD-RS-IV: ADHD rating scale Based upon DSM-IV criteria Useful, easy to administer Available for parent/teacher/self Quantifies how behavior deviates from norm Not to be used alone or rule out diagnosis Helpful in assessing and monitoring treatment Identifies areas of impairment ?Daily life problems Targets of treatment Consider the parents Highly heritable Difficulties

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Time management Organization Memory Impulse control Overall consistency Other psychopathology Potential for serious negative impact on any treatment used Untreated parents may lead to poorer treatment outcomes Neuropsychological tests (research settings use; not diagnostic tests) Types: CPT Wisconsin Card Sorting Stroop Word-Color Association Test Test of Working Memory DICA—parents; SCID—kids Observation Physical examination Age-related issues ADHD behaviors Preschool Busy: running, climbing excessively, impulsive Failure to learn Aggressive/cannot share Must be watched constantly Wandering touching everything Trouble with quiet time and passive activities Difficulty with self-soothing School-aged Impulsive Hyperactive Inattention (during an interesting task) Social skill impairment Underachievement in school tasks Low self-esteem Disruptive behaviors in classrooms Adolescents Decrease in motor activity but an increase in internal restlessness Poor frustration tolerance Bored, intolerant of inactivity Novelty seeking School underachievement Overly sensitive to peer approval Antisocial behavior, mood swings, and/or demoralizations Adulthood Persistence into adulthood shown Less overt hyperactivity and more subjective restlessness Impulsivity (romantic, finances, decision making, driving) Continued difficulty with focused attention Inability to complete tasks Difficulty with planning Stress intolerance, affective instability, temper Balanced gender presentation in adulthood Impairment across settings Interview with patient Review of previous medical/educational records Ask another adult (parent, spouse, employer) Physical examination Rating scales (CAARS, WURS)

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Overall management Medications Options Stimulants 70%–75% can benefit; 90% will respond TCAs—imipramine, desipramine, nortriptyline Alpha 2a agonists Specific types Clonidine and guanfacine Adjunct for aggression, insomnia, tics Rebound hypertension from sudden discontinuation Guanfacine extended release Other antidepressants Bupropion 1995 (increases tics) Fluoxetine (studies lacking) MAO inhibitors (side effects) Caffeine—some symptoms are reduced Antipsychotics (side effects) FDA-approved agents Ages 6–12

Ages 12–18

>18

Guanfacine ER

Child

Adolescent

Atomoxetine

Child

Adolescent

Adult

Methylphenidate OROS

Child

Adolescent

Adult

Methylphenidate LA/SR/ER/CD

Child

Methylphenidate

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Adolescent

Adult

Dexmethylphenidate

Child

Adolescent

Dexmethylphenidate XR

Child

Adolescent

Adult

Methylphenidate transdermal

Child

Dextroamphetamine

Child (>3 years) Adolescent

Adult

Nonstimulants

Stimulants

Dexedrine spansule

Child (>3 years) Adolescent

Adult

l-lysine dexamphetamine

Child

Adult

Mixed amphetamine salt XR

Child

Adolescent

Adult

Effect sizes with stimulants Preschoolers: 0.5–0.6 (PAT studies) School age: 0.8–1.2 depending on the rater Adolescents: 0.94 across studies Adults: 0.9 across 16 studies Psychosocial interventions Behavioral therapy Initial treatment If mild symptoms Uncertain diagnoses Parents/guardians prefer to avoid medications Disagreement amongst providers Family preference

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Examples Increased structure Positive reinforcement Time out Response cost Token economy Communication/negotiation/adolescents Adjunct psychosocial management School/vocational assistance—learning disability/test accommodations Psychosocial treatments Family therapy—parent management Individual—CBT, academic support Treat comorbid disorders Identify and address learning disabilities Depression—CBT, SSRIs Anxiety—behavioral therapy, SSRIs Substance use disorder—specific treatment ADHD coaching Identifies specific goals Implements specific strategies Prompts Monitors outcome/modification Reinforcement Increased structure Management of attention problems Environmental modifications/supports Attention process/training Self-regulatory strategies Use of external aids Psychosocial supports Little empiric support Attention process training Use a treatment model grounded in attention theory Use activities that are hierarchically organized Provide sufficient repetition Decisions are based on client performance Facilitate generalization Closer look at stimulants Developmental lines Preschoolers PAT study Design N = 303 3–5.5 year old kids with ADHD; 8 phases; 70 weeks Findings PAT optimal daily dose 14.2 mg/day ‘i-8.1 MPH All doses reduced ADHD 2.5, 5, and 7.5 mg significantly better than placebo Largest effect size was 7.5 mg TID Adverse effects correlated with dose Difficulty falling asleep Decreased appetite Emotional outbursts Adverse outbursts not correlated with dose GI discomfort Irritability Adverse effects Emotional outbursts DFA

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Repetitive behaviors/thoughts Appetite decrease Irritability Slower MPH clearance in preschoolers compared to school-aged 5- and 6-year-olds had significant responses to atomoxetine School age Effect sizes were higher in MTA studies MTA study Design minimum of 24 months Findings Teachers had larger effect 77% responded MPH (first given) 27% responded amphetamine (second given) Combinations of therapy and medications and medications alone are better than behavioral intervention and community counseling All treatments improved symptoms of the patients Medications alone were just as good as the combination and better than behavioral interventions and community counseling alone Side effects Appetite Insomnia But, irritability better with increased dose (therefore, treated this as a symptom) Adolescents Typical concerns How can the medicine help me? Are medications safe? Will medications change my personality? Will medications affect my grade? Do I need to take it/them at school? Will I be a drug user if I take the meds? Will I have to take it forever? Concerns about medication diversion ADHD adolescents treated with stimulants have less substance use disorders (SUD) Per oral MPH does not induce euphoria Concerta has minimal potential for abuse and diversion (cannot crush, snort, or inject this form) Study Wilens 2006; N=220, 13–18 year olds Concerta Design 1 week washout period; open-label titration; double blind placebo; open follow-up Results 52% on Concerta 34% placebo improved Effect size 0.9 (parents did the ratings) Dose of 72 mg were helpful Study Adderall XR; N = 287; 13–17year olds Results 70% (at 30 mg/day) versus 26.9% placebo Side effects decreased appetite, insomnia, weight loss Adults effect size 0.9 Study Spencer Fordone 2004 MPH meta-analysis; N=253; PET study Effect size 0.9 Concerta occupied DAT more and longer Same CMAX Longer T-max Times to DAT-occupancy Lower likeability scores Study Biederman et al. 2006; N =141; Concerta 66% versus 39% placebo

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Increase blood pressure and pulse but not clinically significant Treatment for adults target ADHD symptoms Impairment (vocational counseling) Comorbid impairments (mood CBT usage) Identify strengths and focus on positive (sports, social skills) General findings with stimulants The most Studied (200 studies) Commonly used Effective First-line agent Effect sizes Stimulants 1 Nonstimulants 0.6–0.7 Improves Core symptoms Inattention Impulsivity Hyperactivity And Compliance Impulsive aggression Social interactions Academic efficiency Academic accuracy Preparations Methylphenidate forms MPH OROS (Concerta) Metadate CD Ritalin LA dMPH (Focalin XR) MPH IR MPH transdermanl (Daytrana) Amphetamine forms MAS XR (Adderall XR) MAS (Adderall) D-AMP (Dexedrine) Dexedrine spansule Lisdexamfetamine(Vyvanse)

Osmotically released Bead (and biphasic) polymer 30% IR 70% DR Beads 50% IR 50% DR 8 hours 5/12 hours 4 hours 12 hours (on 9 hours) 10–12 hours 6–8 hours 4–6 hours 6–8 hours 12 hours

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8–10 hours

daily daily

2–3× day/daily 2–3× daily daily daily 2–3×/daily 2–3×/daily 1–2×/daily daily

Prescribing stimulants Initial Informed consent Parent/patient education regarding value Treatment program that recognizes it as chronic >50% of individuals do continue to manifest symptoms into adulthood Obtain baseline vital signs Determine target symptoms—what do you expect to change?

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Determine titration schedule (weekly versus monthly) Decide upon method of assessing drug response Evaluate target ADHD symptoms Parent/teacher/other informant rating scales Self/ratings: adolescent/adults Monthly until stable, then quarterly Consider severity and concurrent treatment Manage side effects—ask the specific questions On-going Try one to two stimulants before alternatives Titrate up dose to control the target symptoms To at least FDA dose limits Maximize improvement/doses as tolerated Consider long-acting forms Use adjunct behavioral therapies (non-core symptoms) Monitor adherence Consider comorbidity 15% develop tolerance—?switch quickly (weekly) Issues with stimulants Cardiovascular sudden death General population risk 1/100,000 Methylphenidate, amphetamines, and atomoxetine 0.2–0.05/100,000 patient-years <18 years of age 1.3–8.5/100,000 patient-years No evidence for need of routine EKG before starting treatment in healthy individuals Risk factors for severe cardiovascular events Preexisting heart disease History of severe palpitations Fainting Exercise intolerance not secondary to obesity Family history of sudden death prior to age of 55 Structural abnormalities Post-operative tetralogy of Fallot corrections Coronary artery abnormalities Subaortic stenosis Chest pain, arrhythmias, hypertension, syncope (Hypertrophic cardiomyopathy signs) American Heart Association guidelines Medical history History of congenital/acquired cardiac disease Palpitations/chest pain/syncope/seizures/postexercise symptoms Family history or premature cardiac disease <30 year old Other medications (including over the counter) Routine exam Vital signs—blood pressure/heart rate Pediatric patients—no EKG, Holter monitoring, or stress test needed (if asymptomatic) Adults—as indicated (like symptoms) Suspicion of cardiovascular defect (idiopathic hypertropic subaortic stenosis)—work-up Monitor above during treatment Informed consent An EKG detects arrhythmias 80%–90% of the time Stimulants and atomoxetine can increase heart rate and blood pressure, but does not appear to be clinically relevant

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Aggression, mood lability, and suicidal ideation Overall aggressive acts and antisocial behavior decline when patients with ADHD are treated Growth Growth hormone secretion is normal Slowing of growth height velocity slows down for first year of treatment 10% may demonstrate slower growth Onset of puberty is normal Mechanism decreased food intake—watch for nausea and vomiting Risk factors Prepubertal children greater than adolescents Males greater than females If tall and overweight at baseline ?Usage of sustained release forms and higher doses Association with reduction in expected height gain in first 1–3 years of treatment No published data regarding final adult height Atomoxetine Slowing of growth seen in first 1–2 years of treatment At 3–5 years of treatment initiation, “catch-up” in growth noted ?study effect Recommendations Check baseline height and weight Check every 6–12 months If greater than 1 standard deviation in Velocity of growth Contact pediatrician Consult pediatric endocrinologist Use lowest dose possible Use short-acting agents immediately prior to meals Usage of high-energy snacks/meals Drug holidays Tics Stimulants (relative to placebo) do not increase the rate of tics Children with comorbid ADHD and tics have fewer tics when treated with stimulants If tics do emerge during treatment, try another stimulant or nonstimulant If stimulants are the best choice, and the child has tics, consider adding clonidine or guanfacine forms Closer look at ADHD and substance use Overview SUD Carries significant individual dangers Mortality MVA Suicidal ideation Violence Sexually transmitted diseases/pregnancy Poor academic performance Social difficulties Criminal behavior or victimization from a crime ADHD as an independent risk for SUD Associated with three times the likelihood if one did not have ADHD Earlier onset of SUD Longer duration of SUD (an average of 20 years longer) Tobacco: gateway to SUDs If smoking starts <18 years old, it is considered a critical marker for SUD risk Tobacco use is highly comorbid with SUD ADHD itself is a risk factor for smoking

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Predicts earlier onset of tobacco use (by 2–3 years) Higher risk for use of other agents which then leads to SUD Predictors of progression from tobacco to other substances Early-onset smoking Higher smoking frequency Alcohol use and ADHD Early exposure increases alcohol risk especially Kids with ADHD Parents with alcohol use disorder or SUD Conduct disorder and ADHD are associated with repeated drunkenness Use of cannabis and other illicit drugs Daily cigarette smoking ADHD in adolescence predicts Earlier age of onset of alcohol use disorders Greater severity of alcohol use disorders Risk factors Increasing age ADHD comorbidity (ADHD + CD or bipolar even worse) Depression Low self-esteem Poor coping skills Family history of SUD Environmental influences Family Peers School Community/cultural environment Assessment General guidelines Assess level of risk Inquire about history of past substance use Established period of abstinence Ongoing substance use treatment Inquire about history of stimulant abuse How much needed to complete work How much needed to “get high” Precautions Limit and track pills Urine toxicology screen regularly Frequent patient visits Use nonstimulants or long-acting Emphasize prn use Discuss safe storage Talk with pharmacist Factors influencing abuse liability Reinforcing effects—rate at which active drug enters brain Mechanisms of delivery Delivery systems Formulations Routes of administration CRAFFT (³2 positive responses identifies potential problems) Car, Relax Alone Friends Forget Trouble FRAMES (John Knight, M.D. et al) How to discuss alcohol and drug use with the adolescent Feedback

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Psychiatry Bullets Risks Impairments Responsibility on the patient Self efficacy promoted Advice is clear (for change) Menu of alternatives Empathy as a counseling style self-efficacy Treatment Stabilize active addictions Consider inpatient setting Self-help groups Psychosocial therapies Treat ADHD—monotherapy, if possible with fewest adverse effects Once-daily dosage Monitor frequently Adherence with SUD + ADHD treatment Random toxicology screens Monitor motivation for treatment, target symptom response, behavioral change, and psychosocial function Coordinate care with addiction counselors and other caregivers Issues of diversion; 7%–15% diverted especially if comorbid with CD Use extended length formulations Ideally work with drug counselors Psychosocial therapy to improve daily living and coping skills Motivational interviewing Empathy, understand their perspectives Open-ended questions Affirmations of strengths Summarize Elicit motivation to change Articulate and resolve ambivalence Quiet and eliciting style (www.motivationalinterview.org) CBT Drug counselors

PEDIATRIC DEPRESSION Epidemiology of major depression Children 2% Male/female 1:1 Double depression (MDD + dysthymia) 0.6%–1.7% Adolescents 4%–8% Male/female 1:2 Puberty increases rate Double depression 1.6%–8% Course MDD 8-month duration (clinic sample) 1–2 month (community sample) Recurrence 20%–60% in 1–2 years 70% after 5 years Progression to adult MDD

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Chapter 20 Child and Adolescent Psychiatry Poor prognostic signs Severity Chronicity Multiple episodes Comorbidity Hopelessness Residual symptoms Negative cognitive style Family strain Low socioeconomic status Stressful life events Findings that may indicate a potential progression into bipolar disorder Psychosis Family history of depression/bipolar disorder Response to antidepressants Switch Subclinical response to three or greater optimized antidepressant trials Adolescents Sadness; tearfulness; crying Hopelessness Anhedonic Persistent boredom; lack of motivation Decreased energy Social isolation; poor communication Low self-esteem Guilt Extreme sensitivity to rejection/failure Increased irritability; anger; hostility Difficulty with relationships; loss of friendships Frequent physical complaints Headaches Dizziness Nausea Light-headedness Back pain Vomiting Stomach discomfort Menstrual problems Truancy Poor school performance Major eating/sleeping changes Thoughts of running away Suicide obsession Self-destructive behaviors/self-injury Alcohol and other drug abuse Children Old theory—children show little expression of depression Currently—typical symptoms starting at greater than 6 years old Preschoolers Typical symptoms Vegetative symptoms Anhedonia most specific Sadness and irritability most sensitive Somatic mostly atypical but neither sensitive or specific Treatment essential since developmental changes are robust and critical and can have long-term effects

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Dysthymia 3–4 year duration Increased MDD Substance Suicide risk factors History of previous attempts Comorbid psychiatric disorders/conditions Disruptive disorders Substance use Impulsivity/aggression Lethal means available Exposure to stressful/negative events Family history of suicidal behavior Comorbidity 40%–90% with other psychiatric disorders 50% youths with depression have ≥2 comorbid conditions in following order Anxiety Disruptive disorders ADHD Typically follows anxiety or ADHD Increases risks for Conduct disorder Substance abuse Risk factors for MDD Family history of MDD Increased reaction to stress and life events Family history of anxiety disorders Family history of substance abuse Other psychiatric diagnoses Limited cognitive capacity, family support, socioeconomic stress Prevention—address risk factors Assessment: AACAP Practice Parameters Assessment tools Journal Clinician Rated Children’s Depression Rating Scale (CDRS) Parent and Child Self-Reports Clinical Global Impression Scale (CGI) Global Assessment of Function (GAF) Children’s Global Assessment Scale (CGAS) Treatment Education Psychosocial supports (responsible for such high placebo response rates?) School Family Psychotherapy (CBT and IPT)—miscellaneous findings Evidence of efficacy based upon random controlled trials Effective with comorbidity and suicidal ideation Overall findings when used alone or in combination with medications No difference between CBT and placebo in adolescents with MDD Usefulness of CBT in younger children? Combination CBT with fluoxetine led to more rapid rate of improvement, but no difference at the endpoint Combination CBT with fluoxetine helpful in mild MDD For moderate and severe MDD, SSRI alone was best Combination CBT treatment increases rate of remission IPT efficacious in moderate and severe MDD in adolescents

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Pharmacotherapy FDA-approved agents for MDD in children and adolescents Fluoxetine ages 8–18 years for the maintenance phase of MDD Escitalopram ages 12–17 years for the maintenance phase of MDD Overall response rate of SSRIs appears to be approximately 55%–60% Number Needed to Treat (NNT) 10 Number Needed to Harm (NNH) 112 Higher placebo response rates Number of study sites strongly predicted placebo response Lower baseline severity of symptoms Younger age Shorter study periods (lasting 8 weeks) Psychosocial intervention of the studies Multiple appointments Accommodated to the family’s convenience Longer duration of appointments Specific studies Treatment of Adolescent Depression Study (TADS) Design: 13 sites Ages 12–17 years CDRS and CGI scores Flexible dosing of fluoxetine CBT Results No suicides Fluoxetine did not increase suicidality Risk of suicide was twice in nonmedicated group Treatment of SSRI Resistant Depression in Adolescents, 2008 (TORDIA) Design N = 386 Randomized SSRI (paroxetine, citalopram, fluoxetine) SNRI: Venlafaxine SSRI + CBT Venlafaxine + CBT Results No difference amongst the SSRIs SSRI switch with CBT better than just switch SSRI Switch SSRIs if no response or side effects prevent optimization Optimize dose or augment if partial response noted Extend duration of treatment Add lithium or triiodothyronine Venlafaxine was associated with more adverse events Treatment of Adolescent Suicide Attempter (TASA) Design N = 124 Ages 12–19 Depressive disorders MDD Dysthymia Depressive disorder NOS Double depression (MDD + dysthymia) Results High levels of suicide prior to entry into study Majority were female, highly impaired, mid-teen 19% of sample endorsed previous sexual abuse Four weeks after treatment Specific medication considerations Doses equivalent to adult dosing

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Psychiatry Bullets Shorter half-lives in children (consider discontinuation symptoms if prescribed once daily) Sertraline Citalopram Paroxetine Bupropion Remission by 12 weeks remains the goal Weekly visits ideal Maintenance treatment considerations Black box warning comments

PEDIATRIC BIPOLAR DISORDER Epidemiology lifetime findings BPI (Bipolar I) 0.8–1.6% (adolescents 0.1%) BPII (Bipolar II) 1.1% (adolescents 0.85%) BPOS (Bipolar Not Otherwise Specified) Subthreshold manic symptoms (adolescents—6%) Etiology Genetic Twin studies 60%–93% variance in bipolar disorder Shared environmental factors account for 30%–40% variance Unique environmental factors account for 10%–21% variance Family study—increased rates of affective disorder (depression), anxiety, and behavioral disorders (ADHD) in offspring Environmental factors Physical and sexual abuse Poor social supports Prenatal alcohol exposure Parenting style (irritable and negative) Brain structures MRI studies Abnormalities (white matter hyperintensities) in cortical and subcortical brain regions of emotional regulation Decreased amygdala volume fMRI studies Prefrontal limbic circuitry changes Greater hostility to emotionally neutral stimuli (facial expressions) Increased fear when viewing emotionally neutral facial expressions Increased activation of amygdala-striatal-ventral-prefrontal circuitry (when rating hostility) Assessment Parent/guardian as the primary historian (important) Evaluation of the child DIGFAST Distractibility Indiscretion Grandiosity Flight of ideas Activity increase Sleep deficit Talkativeness (pressured speech) HIPERS (Gabrielle Carlson, M.D.) Hyper Irritability/volatility

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Psychosis Elevated-expansive mood Racing thoughts/rapid speech Sleep—does not want or need Consider bipolar disorder if Family history is present Early onset of symptoms (<25 years of age) with high episode rates Psychotic symptoms Seasonal “Antidepressant misadventures” Hypomania/agitation Erratic/uneven antidepressant response Multiple failures Pediatric symptoms Chronic irritability Temper outbursts Aggression Mixed Insidious No clear episodes (ultraradian) Comorbidity with ADHD—ADHD is not as associated with Elevated mood Grandiosity Flight of ideas Decreased sleep Hypersexuality Other sources School Other family members Primary care provider Assessment tools Child Behavioral Checklist (CBCL) Child Symptom Inventory 4th Edition (CSI-4) Parent completed version of General Behavioral Inventory (P-GBI) Parent-Child Mania Rating Scale (P-CMRS) Parent-Young Mania Rating Scale (P-YMRS) Children’s Depression Rating Scale-Revised (CDRS-R) Mood Disorder Questionnaire-Adolescent version (MDQ-A) Rule out other causes Thyroid Steroid/drugs Marijuana associated with an increase in melatonin—thus, no sleep Bupropion can increase irritability when kids are coming off marijuana Current neurological conditions Trauma Stimulants Mixed results in findings Consider ADHD symptoms may precede bipolar symptoms Treat symptomatically in accordance to severity Specific conditions Acute mania Adults Typical onset between late adolescence and early adulthood Acute onset Duration of Mania 3 months

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Mixed 6 months Complete remission in 40%–50% of affected individuals Treatment “50% get 50% better” Lithium Divalproex Second generation antipsychotic Children Mean age of onset between 7 years Mean duration: 3.5 years Clinically Mixed or rapid cycling Grandiosity ADHD Suicidal ideation Recovery rates are slower if more classically manic Interference with developmental learning/tasks Symptoms more unique to mania Grandiosity (although may be age appropriate) Racing thoughts Decreased need for sleep Increase in goal-directed activity Recurrence likely in a year for BPI Conversion rates roughly 20%–25% from BPNOS → BP I/II → BP I Suggesting that bipolar disorder NOS is prodromal? High relapse rates within 2 years Not typically associated with acute onset Complete remission in less than 20% Treatment Poor response to lithium Poor response to divalproex ER Possibly due to ER form being less potent than IR Study utilized doses with plasma levels <75 ng/dL FDA-approved agents (ages 10–17 years) (similar to adults) Olanzapine (ages 13–17years)—NNT 4 NNH 3 Risperidone—NNT 3 NNH 11 Quetiapine—NNT 4 NNH 10 Aripiprazole—NNT 3 NNH 16 Synergistic studies? Divalproex and Seroquel Mood stabilizers and SGA Lithium and divalproex Divalproex and mixed amphetamine salts Divalproex/lithium and risperidone Lithium and Methylphenidate Bipolar depression studies pending Phenotypes of bipolarity in children and adolescents Liebenluft et al. Narrow phenotype Clear episodes of euphoria and grandiosity Severe mood dysregulation if no euphoria or grandiosity Geller et al. Wash U-K-SADS criteria Euphoria and grandiosity also required Biederman et al. Euphoria and grandiosity are not required Severe explosive irritability Differential diagnoses (as well as possible comorbidities!)

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Depression Disruptive behavioral disorders ADHD ODD CD Austism spectrum disorders Anxiety disorders PTSD Substance use Psychotic disorders Temperament Sleep disorders Treatment implications Monitor efficacy utilizing Young Mania Rating Scale (YMRS) Response >50% reduction of score Remission YMRS score ≤12 Bipolar depression Adults Quetiapine: FDA approves doses 300–600 mg Olanzapine plus fluoxetine: FDA approved Lamictal: Preventive/maintenance Teenagers Lithium Open-ended study: Not favorable 8-week trial: Not favorable Lamotrigine: Associated with 60% remission Seroquel: Not favorable Suggestions If presentation is equivalent to classic adult mania Utilize mood stabilizers Lithium Divalproex (please note a recent study indicated that divalproex ER did not fare better than placebo in a 4 week study) Carbemazepine Utilize SGA (and FGA although no data are available on these) If presentation is not equivalent to classic adult mania Mixed rapid cycling—use adult strategies If ADHD symptoms present Add stimulants Add stimulants and SGA Add stimulants and Lithium If severe mood dysregulation Treat ADHD symptoms Consider SGA for aggression Single mood stabilizer agents do not appear to be adequate Treatment of offspring of bipolar adults is nonconclusive Divalproex One positive finding One negative finding Lithium Family history of positive lithium response predicts offspring positive response to lithium Family history of negative lithium response predicts offspring positive response to SGA If comorbidities are present ADHD

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Stabilize bipolar symptoms first Add stimulants Add SGA Anxiety One study implied childhood presence of anxiety leads to bipolar disorder in adulthood Implication of avoidance of current symptoms in order to prevent later onset Anxiety is treatable FDA approved agents Adult Adult Adult Child/Adolescent Bipolar Mania Bipolar Depression Bipolar Maintenance Mania Lithium Lithium Divalproex Carbamaxepine Olanzapine Combination Olanzapine + fluoxetine Risperidone Risperidone Quetiapine XR Quetiapine XR Quetiapine XR Ziprasidone Aripiprazole Aripiprazole Lithium to prevent mania Lamotrigine to prevent depression Safety issues Weight gain Diabetes mellitus Metabolic Cognitive Hyperprolactinemia Polycystic ovarian syndrome (PCOS) Hypothyroidism Pancreatitis Movement disorders/NMS Risk factors First-onset depression Subthreshold studies Full-scale depression leads to bipolar in 18/1505 of cases Subthreshold bipolar disorder leads to Depression Anxiety Full-scale depression leads to bipolar disorder Anxiety disorder Alcohol or substance use disorder Conduct disorder or antisocial Personality disorder Full-scale ADHD leads to Depression Substance use disorder Subthreshold ADHD: leads to conduct disorder or antisocial personality disorder Predictors of suicide attempts Mixed episodes Psychosis Hospitalization Self-injurious behaviors Panic disorder SUD

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American Academy of Child and Adolescent Psychiatry Practice Parameter Recommendations: Recommendation #1 Psychiatric assessments for children and adolescents should include screening questions for bipolar disorder (minimal standard) Recommendation #2 The DSM-IV TR criteria, including duration critera, should be followed when making a diagnosis of mania and hypomania in children and adolescents (Minimal Standard) Recommendation #3 Bipolar NOS should be used to describe youths with manic symptoms lasting hours to less than 4 days or those with chronic manic-like symptoms representing their baseline level of functioning (clinical guideline) Recommendation #4 Youths with suspected bipolar disorder must also be carefully evaluated for other associated problems, including sucidality, comorbid disorders (including substance abuse), psychosocial stressors, and medical problems (minimal standard) Recommendation #5 The diagnostic validity of bipolar disorder has yet to be established. Caution must be taken before applying this diagnosis in preschool children (minimal standard) Recommendation #6 For mania in well-defined DSM-IV TR bipolar I disorder, pharmacotherapy is the primary treatment (minimal standard) Recommendation #7 Most youths with bipolar I disorder will require ongoing medication therapy to prevent relapse; some individuals will need lifelong treatment (clinical guideline) Recommendation #8 Psychopharmacological interventions require baseline and follow-up symptoms, side-effects (including patient’s weight, laboratory monitoring) as indicated (minimal standard) Recommendation #9 For severely impaired adolescents with manic or depressive episodes in bipolar I disorder, ECT may be used if medications either are not helpful or cannot be tolerated (options) Recommendation #10 Psychotherapeutic interventions are an important component of a comprehensive treatment plan for early-onset bipolar disorder (minimal standard) Recommendation #11 The treatment of bipolar disorder NOS generally involves the combination of psychopharmacology with behavior/psychosocial interventions (clinical guidelines)

Websites and other resources www.bpkids.org www.dbsalliance.org www.schoolpsychiatry.org www.manicdepressive.org Family Resource Centers (CHADD) Manic Depressive Disorder Association www.daniellesteel.com

PSYCHOTROPIC DRUG EFFECTS SSRI effects Brain effects

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SSRIs In theory, three main brain changes with function Presynaptic autoreceptors will slowdown 5HT production leading to low 5-HT Body adapts by lowering autoreceptor sensitivity thus increasing serotonin Postsynaptic 5-HT2A receptors are downregulated In reality Inconsistent 5-HT2A receptor effect Fluvoxamine no receptor effect and paroxetine decreased or no receptor effect; others vary Some effects 5-HT is found in nonadult regions 5-HT is an organizer of glial cell and neuronal growth Decrease in 5-HT turnover in nucleus accumbens during prepubertal stages Implications Immature brain cannot upregulate 5HT receptors SSRIs can persistently increase serotonin transport density Wilens 2001 children had 2× more of SSRI in plasma compared to adolescents Teicher 1987 agitation greater in younger children on SSRIs than adolescents Newborn Untreated depressed mothers Earlier gestational age Altered neurobehavioral function Poorer quality of movement Increased hypotonia Elevated fetal hormones Role in fetus Circadian rhythms arousal Regulation of respiratory and cardiovascular functions Vasoconstrictor → increased pulmonary vascular resistance Development of pulmonary smooth muscle 5HT cross placenta ? inhibit reuptake in fetus Lung is a reservoir for SSRI SSRI ? inhibits synthesis of nitrous oxide (a vasodilator) PPHN (persistent pulmonary hypertension of the newborn) SSRI after 29 WGA leading to PPHN But Oberlander et al. 2006 Problems in depressed mothers Whether treated or not SSRIs and depression can affect the fetus in an additive manner Gestational age Birth weight Feeding difficulties Jaundice But especially distress due to SSRIs occurred even when severity of illness was accounted for Aghajanian et al. 2006 Do SSRIs really cause suicidality? In 2004, the FDA issued a black box warning due to increased risks of suicidal thoughts or behaviors in children and adolescents treated with SSRIs. In 2006, the FDA recommended to extend the warning to individuals up to the age of 25 years. Whittington’s 2004 meta-analysis: fluoxetine benefits outweighed the risk TADS: fluoxetine along with CBT reduces suicidal ideation in adolescents Alderman et al. 2006 sertraline safe and effective Cheung, Emslie, and Mayes 2005—”Clinicians, use your judgment!” Problems Inconsistent ways to study adverse effects

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Definitions of adverse effects Unknown history of suicide Findings—suicidal behavior highest in first 9 days Population rate of suicide declined with use of antidepressants Risks of suicide Suicide history Conduct disorder Impaired function Long-term psychiatric issues SUD Age The younger the child, there is increased vocalization of suicidal ideation The older the individual, the more likely attempts Serotonin syndrome Definition : life threatening condition in which symptoms are caused be excessive serotonin Causes: excessive serotonin Increased doses of one agent Mixing of 2 or more agents Sometimes inadvertently since serotonin is found in agents other than SSRIs Triptans (migraine medications) Ecstasy LSD Signs and symptoms Subjective and or observed Agitation Irritability Restlessness Vital signs Tachycardia Elevated body temperature Blood pressure fluctuations Neurological signs Ataxia Hyperreflexia Myoclonus Gastrointestinal signs Nausea Vomiting Diarrhea Diagnosis Rule out other etiologies Intoxications/Drug withdrawals Infections Metabolic conditions Must have at least 3 of the above symptoms Treatment Withdraw medication(s) that caused the symptoms (if applicable) Intravenous fluids to address potential rhabdomyolysis Medication Cyproheptadine (serotonin production blocker) Benzodiazepines to treat muscle stiffness Discontinuation symptoms

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Definition: symptoms (no particular diagnostic criteria) caused by a lessened level of serotonin in the body Causes Discontinued serotonergic agents Decreased dosing of serotonergic agents Interruption of serotonergic agents use Signs and symptoms Diaphoresis Nightmares Neurological “Shocks” often perceived in the head region Dizziness Confusion Vertigo Sexual symptoms Treatment Prevention Readding serotonergic agent(s) Same agent or other long acting similar agent Slowly tapering of the agent Doses Same as initial Lower than initial Other psychotropic drug effects Thyroid function The feedback loop Hypothalamus TRH cold can induce its release Anterior pituitary TSH Thyroid gland Thyroid hormones Target cells throughout body (remember negative feedback loops) Lithium’s effects At therapeutic levels lithium inhibits release of thyroid hormone from gland T4 and T3 levels fall TSH increased to normalize T4 and T3 Damaged thyroid (radiation Hashimoto’s) cannot fully compensate low thyroid Reversible when lithium is stopped Females > males develop hypothyroidism 20% versus 3% after10 years Conditions Hypothyroidism Found in 10%–30% of patients Typically asymptomatic Goiter Autoimmune thyroiditis (especially if patient has anti-thyroid antibodies) Hyperthyroidism Much less common Graves presentation most common No association with Thyroid nodules Thyroid carcinoma Other VPA TSH rise ?mild thyroid hormone suppression Quetiapine Normal TSH but, low T3 and/or T4 (careful when using with lithium) Child’s effects of lithium on thyroid Minor transient changes TSH Lithium plus VPA 24% had high TSH (considered >10) Quetiapine + VPA also likely to be high TSH by 20 weeks

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Recommendations Check baseline TSH before starting Lithium Recheck at 1 month 6 months 12 months then a year If hypothyroid start thyroxine or get a consult If Lithium plus VPA or quetiapine check TSH every 3 months Prolactin Overall Hypothalamus dopamine exerts inhibitory effects on pituitary to inhibit prolactin release Antipsychotic agents exerting D2 receptor blockade affect pituitary to release more prolactin Estrogen affects pituitary to release more prolactin Antipsychotics Dopamine antagonists → thus raise prolactin Serum prolactin can spontaneously decrease Estrogens can enhance the release of prolactin (prepubertal girls are at greater risk Relative potency (risperidone > haloperidol > olanzapine > quetiapine > clozapine > aripirazole) Aripiprazole partial D2 agonist (thus, suppresses prolactin) Prolactin levels spontaneously decrease over time despite continued use of SGA starting around 4–7 weeks after initiation Effects of hyperprolactinemia Hypothalamus—suppress GNRH thus suppress LH FSH leading to Hypogonadism Osteoporosis ?Increased weight Breast—stimulate lactation CNS—inhibit penile erection Adrenals—androgen increase androgens (DHEA and androstenediol) → Hirsutism Acne Signs and symptoms Amenorrhea or oligomenorrhea Breast enlargement and galactorrhea Decreased libido and erectile dysfunction Osteoporosis Hirsutism Failure to enter or progress into puberty Variable effects: not all with high prolactin have symptoms because Low bioactivity prolactin Maybe macroprolactinemia or subthreshold hypothyroidism (look for TSH levels >10µ per L) Recommendations Ask about Menstrual cycles Nipple discharge Sexual function Pubertal development: if asymptomatic no need to check levels, but if symptomatic Check serum prolactin If elevated check HCG to rule out pregnancy TSH to rule out hypothyroidism Serum creatinine to rule out renal insufficiency Liver function tests to rule out hepatic disease Prolactin levels

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if <200ng/mL and symptoms reduce or switch SGA if >200ng/mL or remains after reducing/switching Check MRI sella turcica to rule out pituitary adenoma or parasellar tumor If MRI is within normal limits: treat with estrogen and testosterone and treat osteoporosis Treat with dopamine agonists (amantadine or cabergoline) and watch for psychosis If cannot stop/switch the SGA add aripiprazole Pituitary tumors Szarfmann 2006 77 patients taking risperidone had tumors since 1968 (prior to risperidone initiation) 10% of normal adults may have incidental pituitary tumors Polycystic ovarian syndrome (PCOS) Defined by Chronic anovulation Hyperandrogenism Loss of menses Acne Hirsutism 90% polycystic ovaries 50% are obese Insulin resistance Dyslipidemia Adding VPA Increases risk of PCOS 10 times Typically in younger females within the first year of treatment VPA directly stimulates androgen synthesis? Recommendation If on VPA check Menstrual cycle Hirsutism Provide diet and exercise counseling to avoid weight gain Endocrine referral or OB-GYN referral Address oligomenorrhea Address hirsutism Address dyslipidemia Address hyperglycemia Treatment with oral contraceptives Other medication considerations To treat PCOS symptoms To prevent PCOS symptoms? Weight, metabolic syndrome Negative effects of weight gain Medically Dyslipidemia Diabetes mellitus PCOS HTN Sleep onset Osteoarthritis Social stigma and withdrawal Nonadherence Body mass index Weight (kg) ÷ height (in meters squared) Age and gender specific

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Greater risk for weight gain in the younger population Waist circumference is possibly more closely associated with metabolic syndrome 5–11 years > 12–17 years > 33–44 years > 71 years Metabolic syndrome Defined Abdominal obesity Dyslipidemia (high triglycerides and low HDL) Glucose intolerance Hypertension Risk for cardiovascular disease and diabetes mellitus and their complications Now in the United States 25% adults and 5–10/adolescents meet criteria Mechanism is thought to be high insulin due to insulin resistance Children or adolescents need ≥3 of the following Waist circumference ≥ 90th% or BMI ≥ 95th% Triglycerides ≥ 110 ng/dL HDL < 40 ng/dL Blood pressure ≥ 90th% for sex and age Fasting blood sugar ≥ 110 ng/dL Rates: clozapine=olanzapine>risperidone=quetiapine>aripiprazole=ziprasidone Watch especially if valproate or lithium is also present New FDA warning for diabetes mellitus Increased glucoses are seen with SGAs Risks include hyperosmolar coma, DKA, or death Monitor blood sugar if polyuria or polydipsia or risk factors of diabetes mellitus are present Weight gain and effects on insulin secretion and action are likely to cause diabetes mellitus Clozapine findings—Koller 2001 risk of diabetes mellitus increases by the month Treatment Counseling on diet and exercise—structured Avoid treatments associated with weight gain If greater than 5% weight increase, change agents Specific agents Orlistat (oily diarrhea) Sibutramine (stroke, suicidal ideation) Metformin Topiramate (metabolic acidosis, sedation, cognitive) Amantadine (nausea, headache, psychosis) Diabetes monitoring and recommendations Check FBS baseline 3 and 6 months Check every 3 months if risk factors present (obesity, rapid weight gain, family history, nonwhite ethnicity, or on clozapine or olanzapine) Choose others agents for high-risk patients or those already with diabetes (and diabetes mellitus may remit if done) Lipid monitoring and treatment Check fasting lipid baseline 3 and 6 months Check every 3 months if positive family history, positive personal history, or high lipid values Treatment Diet Fibrates Fish oil Statins Niacin or SWITCH

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INFANCY AND EARLY CHILDHOOD Classification Diagnostic Classification in Infancy and Early Childhood DC:0-3 Functional-emotional Individual differences in Sensory Modulation Processing Motor planning Relationships and interactions Functional development profile Axes I: Primary diagnosis 100 Traumatic stress disorder 200 Affect disorder 300 Adjustment disorder 400 Regulatory disorder 500 Sleep behavior disorder 600 Eating disorder 700 Relating and communicating disorder II: Relationship disorder classification 901 Overinvolved 902 Underinvolved 903 Anxious-Tense 904 Angry-Hostile 905 Mixed 906 Abusive III: Physical, neurological, developmental, mental health disorders IV: Psychosocial stressors Mild Moderate Severe V: Functional, emotional, developmental level Mental Retardation Prevalence 1–3% Mild at 0.37%–0.59% Moderate/severe/profound 0.3–0.4% Definition Adaptive functioning difficulties and at least two standard deviations below population means (70) Score: level 129+: Exceedingly superior 120–129: Very superior 110–119: High average 90–109: Average 80–89: Low average 70–79: Borderline 50–69: Mild mental retardation 40–49: Moderate mental retardation 20–39: Severe mental retardation <20: Profound mental retardation Assessment Intelligence (assessing for overall IQ)

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Stanford Binet (ages 2–89 years) Wechsler Preschool (WPPSI) (ages 2–7 years) Wechsler Intelligence Scale (WISC) (ages 6–16 years) McCarthy Scale Peabody Picture Vocabulary Test Academic achievement (assessing for learning disabilities) Woodcock Johnson Psychoeducational Battery (ages 2–90 years) Wide Ranging Achievement Test (WRAT) (ages 5–94 years) Adaptive behavior Adaptive Behavior Assessment System (ages 0–89 years) Vineland (ages 0–90 years) Projective tests Children’s Apperception test (CAT) (ages 3–12 years) Draw a Person Test (ages 5–17 years) Kinetic Family Drawing (ages 5–20 years) Rorschach Inkblot Tests (ages 5–adulthood) Thematic Apperception Test (TAT) (ages 6–adulthood) Developmental assessment Brazelton Infant Evaluation (ages 37–44 weeks) Denver Developmental Screening Test (ages 0–72 months) Bayley (ages 1–42 months) Personality tests Minnesota Multiphasic Personality Inventory (MMPI) Milion Adolescent Personality Inventory (ages 14–18 years) Etiology Genetic Down syndrome Fragile X syndrome: second most common cause of single cause of mental retardation Prader-Willi syndrome Cri-du-chat syndrome Phenylketonuria Rett disorder Neurofibromatosis Tuberous sclerosis Lesch-Nyhan syndrome Adrenoleukodystrophy Maple syrup urine disease Acquired and developmental factors Prenatal Rubella (German measles) maternal infection Cytomegalic inclusion disease Syphilis Toxoplasmosis Herpes simplex HIV/AIDS Fetal alcohol syndrome Clinical features Facial dysmorphia Hypertelorism Microcephaly Short palpebral fissures Inner epicanthal folds Upturned, short nose Learning disabilities ADHD Cardiac defects

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Drug exposure Complications of pregnancy Perinatal Head trauma Infection Measles encephalitis Meningitis Environmental Significant neglect and malnutrition Assessment Obtain family history History Physical examination Laboratory examination Chromosome studies Urine and blood analyses EEG Neuroimaging Auditory evaluation Speech evaluation Psychological testing Treatment—based upon the etiology

PERVASIVE DEVELOPMENTAL DISORDERS (AUTISM SPECTRUM DISORDERS) Definition

A neurodevelopmental disorder with an onset prior to age 3 A group of neurodevelopmental syndromes with characteristic Social interactions Empathy Eye gaze Nonverbal communications Fusiform gyrus—area of brain involved in reading facial expressions Reciprocal interactions Language and communications Stereotyped/repetitive behaviors and interests Obsessional subfactor Anxiety Large volume basal ganglia (caudate) Compulsion subfactor Rituals/routines Self-stimulation subfactors (arousal issue) Hand-flapping Rocking Echolalia Hoarding subfactor Associated symptom domains Social phobia ADHD symptoms Expressive/receptive language disorders EEG abnormalities OCD Impulsivity/aggression/irritability Asperger syndrome Schizoid and/or schizotypal personality disorders

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Types Autistic disorder Rett disorder Childhood disintegrative disorder Asperger disorder Pervasive developmental disorder NOS Epidemiology Dramatic increase Increase in prevalence of autism Or, improved Screening Broader diagnostic spectrums Environmental factors Vaccine controversy No consistent findings Retracted findings ? Fetal testosterone ?Pitocin (synthetic oxytocin) Course Early intervention (before age 2 years) Higher intelligence associated with better prognosis Etiology Mostly unknown Genetic factors Twin studies: monozygotic 90% concordance and dizygotic 30% concordance Multiple genes implicated Possibly different genes coding for different symptoms Copy number variations (CNV) Older fathers (greater than 40 years of age) have greater number of CNVs—and associated with increased autistic offspring Family history Repetitive behavior associated with family history Other factors Advanced parental age (see CNV) Serotonin deficiency 5-HT1D receptor sensitivity (repetitive behaviors) increase 5-HT2A receptor increase Clinical subtypes Autistic disorder Delay in social interactions, language, or play by age or abnormal functioning by 3 years At least two social interaction impairments Nonverbal behaviors Developmentally appropriate peer relationships Spontaneous seeking of sharing enjoyment with others Social or emotional reciprocity At least one communication impairment Initiating or sustaining a conversation with others Or inadequate speech Stereotyped and repetitive use of language Or idiosyncratic language Lack of varied, spontaneous, pretend play At least one behavior impairment Preoccupied with one or more stereotyped/restrictive patterns or interests Nonfunctional rules or rituals Stereotyped and repetitive motor mannerisms Persistent preoccupations with parts of objects

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Rett disorder Normal prenatal development Normal motor development for first 5 months Deceleration of head growth between ages of 5 and 48 months Social interactions: Loss during course Communication Severely repetitive language development retardation Severely impaired expressive psychomotor retardation Behavior Loss of previously acquired purposeful hand movements Poor coordinated gait or trunk movements Childhood disintegrative disorder Normal development for the first 2 years Loss of previously acquired skills before 10 years of age Social interactions Same as Autistic disorder but loss of communications Same as Autistic disorder but loss of (expressive, receptive, and language) behaviors Same as Autistic disorder but loss of and bowel and bladder continence Cannot be due to other PDD or schizophrenia Asperger disorder Normal development Social interactions Same as Autistic disorder Communications No delays Behavior Same as Autistic disorder Cannot be due to other PDD or schizophrenia Pervasive developmental disorder NOS above criteria not met Testing Genomic considerations 15q11 (Angelman or Prader-Willi) Trinucleotide repeat (Fragile X) 22q11 (VCFS) MECP2 mutations (Rett): females Large head Circumference NF-1 (Neurofibromatosis) ADOS ADINA Treatment Identification Evaluation History Physical exam Laboratory findings Measures of intelligence, functioning According to core and associated domains Academic Interventions meeting the level of the child Speech therapy as applicable Occupational therapy as applicable Physical therapy as applicable Behavioral Interventions Social skills Communication skills Vocational skills

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Psychopharmacology addressing core and associated domains Anxiety symptoms SSRIs Ritualistic obsessive symptoms SSRIs More effective with obsessive-repetitive behaviors But, not necessarily, the self-stimulatory repetitive type Oxytocin (Vasopressin) Hyperactivity/attention/impulsivity Stimulants can be helpful for decreased attention Caution required as increased adverse events found in this population Aggression/irritability Divalproex Risperidone—FDA-approved in ages 6–17 years (for aggression/irritability) Aripiprazole—FDA-approved in ages 6–17 years (for aggression/irritability) Alpha adrenergic agents Social deficits Oxytocin (vasopressin) Oxytocin receptors found throughout the brain Frontal lobe: Executive functioning Nucleus accumbens: Reward Limbic system: Interpreting emotional cues ?Helpful Social deficits Also in repetitive self-stimulatory behaviors Repetitive self-stimulatory behaviors ?Oxytocin Future approaches Immunological approaches Addressing associated domains of EEG abnormalities Divalproex Address comorbidities

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Unit

III General Diagnostic Approaches Chapter

21

Laboratory and Diagnostic ic Testing

GENERAL IMPORTANCE Identify unrecognized medical conditions Determine baseline values of physiological parameters that may be affected by the meds Identify any medical condition that may be complicated by the meds

LAB TESTING IN INITIAL ASSESSMENT Baseline Is there a positive medical history or physical finding(s)? Possibly: CBC with differential Urinalysis Electrolytes Kidney functions Liver functions Lead levels (<7) Hematologic Anemia (asthenia, depression, psychosis) in iron deficiency toddlers, adolescent girls/women CBC Prior to initiation of clozapine, lithium, carbamazepine Treatment monitoring (obtain CBC with differential) for infectious diseases and leukemias Biochemistry markers for low sodium, low potassium (also check EKG) Kidney BUN (lithium effects) Other medical conditions Liver High amylase in bipolar patients, prior to initializing an anticonvulsant (first several weeks and then every 6–12 months) Atomoxetine—if clinically germaine Neuroendocrine Thyroid (anxiety, depression, panic, restlessness, concerns of mental retardation, psychosis, ADHD) Others as clinically necessary 259

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Baseline drug screening—new-onset psychosis, behavioral changes, severe anxiety, substance use disorders Baseline EKG family history of Sudden death or cardiac arrhythmia Hypertension Cardiac disease Syncope On antipsychotics (particularly thioridazine) QTc prolongation Clonidine (?baseline EKG and monitor)

SPECIAL POPULATIONS Symptoms of suicide Unexplained weight loss Eating disorders: CBC with differential Electrolytes Kidney functions Amylase Urinalysis EKG TSH Bone scan (with bulimia nervosa, high cholesterol, low T4, high leptin, high neuropeptide Y urine Na/Cl predict bulimic behavior) Neurodevelopmental disorders Fragile X—FMR1 gene via cytogenetic testing Karyotype: Turner, Klinefelter FISH and polymerase chain reaction: Prader-WIli Serum ceruloplasmin, serum/urine copper—Wilson’s

NEUROIMAGING AND ELECTROENCEPHALOGRAPHY EVALUATION MRI: rapid onset of severe psychopathology MRS: structural MRI—measures metabolism and reflects change over weeks and months fMRI: measures O2 consumption of brain regions and reflects changes PET: need for use of isotopes (potentially dangerous in children) SPECT—less radioactive isotope used—no use EEG—monitoring for epileptiform activity Magneto-EEG—deeper limbic structures (not yet used in pediatric populations)

LABS IN TREATMENT MANAGEMENT TCAs: vital signs (blood pressure, pulse), EKG, drug levels SSRIs, MAO inhibitors, neuroleptics, and stimulants Lithium Anticonvulsants SGA

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GENOMIC TESTING Polymorphisms associated with complex psychiatric illnesses Cytochrome P-450 (2D6) On long arm of the 22nd chromosome 22g14 70 variables Caucasians: 7% have a polymorphism that are poor metabolizers Asians: 2% Other ethnic groups: 1% Metabolizes codeine and dextromethorphan Dopamine transporter and dopamine receptor genes DA1T Located on short arm of the 5th chromosome 5p15.3 “ten repeat polymorphism” association with Tourette’s and ETOH Stimulants do not work as well DR2: 11q23 ?polymorphism associated with alcohol DR3: 3q13.3 glycine polymorphism–allele2 assoc with schizophrenia and tardive dyskinesia (allele-1 is normal serine) DR4: 11p15.5 2R (2 repeat): 11R (11 repeat) are the polymorphisms 4R is most popular 7R associated with ADHD: less sensitive to endogenous dopamine Polymorphisms of the 5-HT transporter and 5-HT receptor gene 5HTT 17q12 Short allele s; long allele l ll polymorphism associated with OCD Suicide and depressed ?autism Positive response to paroxetine ss polymorphism associated with Suicide and violence Repetitive suicidal behavior Fear and anxiety symptoms 5HT receptor genes 5HT2a 13qX:T position Mood Schizophrenia Promoter region linked to OCD and eating disorders Tryptophan hydroxylase gene (rate-limiting step for serotonin synthesis) U versus L allele (L ETOH) Introns 7, 8, 9 polymorphism SI Bipolar polymorphisms Initiation of smoking COMT gene 22q11.2 metabolism of DA in PFC and metabolism of 5-HT and NE throughout the brain SNP: single nucleotide (point) polymorphism Valine: high activity; serine—low activity (VisAD?) VCFS: lack an entire copy of one gene; therefore, low activity and psychotic High: ?psychosis Low activity VCFS Schizophrenia Alcohol use disorders

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Chapter

22

Psychological Assessments

THREE DIFFERENT FORMATS Psychological tests Rating scales Semistructured interviews

DIFFERENT AREAS OF ASSESSMENT Overview of a wide variety of symptoms Minnesota Multiphasic Personality Inventory-2 (MMPI-2) Revised (1989) version of MMPI (1967) 566-item checklist (true/false) 2 hours to complete Self-report Scoring can be calculated manually or by computer Personality Assessment Inventory (PAI) 344-item checklist (4-point Likert system) Self-report Symptom Checklist 90-revised (SCL-90-R) 90-item checklist (5-point Intensity scale) 30 minutes to complete Self-report Computer-scored Brief Psychiatric Rating Scale (BPRS) 16-item checklist (7-point severity) Clinician interview Million Clinical Multiaxial Inventory (MCMI-III) 175-item checklist (True/False) Self-report Specific symptoms or characteristics Intelligence Wechsler Adult Intelligence Scale (WAIS) Third Edition Factual questions Scored by trained neuropsychologists Anxiety State-Trait Inventory (STAI) 20-item scales (4 point) Self-report

263

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S-R Inventory of Anxiousness 14-item response (5-point scale) to 11 situations Self-report Liebowitz Social Anxiety Scale (LSAS) Clinician administered semistructured interview Yale-Brown Obsessive Compulsive Scale (YBOCS) Semistructured clinician administered interview Children’s YBOCS (CYBOCS) Posttraumatic Stress Diagnostic Scale (PDS) Depression Beck Depression Inventory (BDI) 21-item (4-point intensity) Self-report Hamilton Rating Scale for Depression (HRSD) 26-items (3–5 point intensity score) Clinical interview Mania Manic-State Rating Scale (MSRS) 26-item (frequency and intensity scores) Observer rating Suicide Suicide Intent Scale (SIS) 15-item (3-point category) Self-report Index of Potential Suicide 50-items (5-point severity) Self-report or semistructured Reasons for Living Inventory (RFL) 6 factors Self-report Personality disorders Personality Diagnostic Questionnaire-4 (PDQ-4) Structured Clinical Interview for DSM-IV TR (SCID) Personality Disorder Examination (PDE) Structured Interview for DSM-IV Personality (SIDP-IV) Psychodynamics and patient enabling factors Rorshach Projective tests (unstructured) 10 inkblots Scored by trained psychologist using statistical methods Thematic Apperception Test (TAT) Projective tests (unstructured) 30 scenes Scored by trained neuropsychologists Schizophrenia Positive and Negative Symptom Scale (PANSS) 30-item scale 16 general psychopathology symptom questions 7-point severity scale Potential score of 30–210 Patient with schizophrenia typically scores 91 Clinician scored

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PSYCHOLOGICAL TESTS Intelligence Wechsler Adult Intelligence Scale (WAIS III) Third Edition Personality Assessment Minnesota Multiphasic Personality Inventory-2 (MMPI-2) Rorschach I

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Chapter

23

Biometrics

STUDY DESIGNS Exploratory studies What? Small-scale study Short duration Applications useful when little information is known on the subject Features may include Descriptive elements Comparative elements Descriptive studies What? Describes characteristics of a particular situation, event, or case Basic categories based upon scale Small scale: a case study Large scale: a cross-sectional study Comparative studies (aka analytical studies) What? Goals are to find causal factors or risk factors between/among two or more groups Basic categories Cross-sectional comparative Subjects are described and compared Case-control studies Subjects are selected on whether they have a particular disease or not The control group represents subjects from the same source of the above population but with/without the disease being investigated Cohort studies Subjects (in groups) are selected on whether they may have (or not) suspected risk factors for a disease or not

VALIDITY VERSUS RELIABILITY Validity Definition: The scientific measurements actually measure what it intends to measure Threats to validity Confounding factors Definition: A factor which is an extraneous variable, which will correlate with both dependent and independent factors. An error in a study would also be known as: False-positive error 267

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Type I error Alpha error The error of rejecting a null hypothesis “Rejecting the null hypothesis when it is true” Calculation of false-positive rates FPR = # of false negatives Total # of actual negatives Bayes theorem: an equation that calculates the probability in which an observed positive result is actually a false-positive result Solution to minimize this threat: include placebo group History Differential subject loss in various groups Selectivity (bias) Reliability Definition: Another investigator using the same scientific measurement will obtain the same results

SENSITIVITY AND SPECIFICITY Sensitivity Specificity

The test identifies the true-positive cases The test identifies the true-negative cases

DATA Nominal Data in which there is no ordering Mean and standard deviation cannot be calculated Statistical tests used Chi-square test Interval Data are measured in scales of equal intervals Allows comparison, thus mean and standard deviation can be calculated Statistical tests used Pearson’s coefficient correlation (linear association determination) Regression analysis (nonlinear determination)

STATISTICAL TESTS T-test Assesses if two groups are statistically different from each other p-value Probability of obtaining the result by chance alone 5% appears to be a common “cutoff” for significance (meaning 1/20 would obtain the result by chance) Also referred to as the alpha level Chi-square test Tests the null hypothesis (no difference between the observed and expected result) ANOVA Assesses if two or more groups are statistically different from each other Pearson’s coefficient correlation Measures linear association determination Regression Measures nonlinear determinations

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CONFIDENCE INTERVAL Measurement of how stable an estimate is Range of values of a parameter estimate such that the parameter lies within the range of a particular value (alpha) or confidence level Alpha is often 95%

NUMBER NEEDED TO TREAT AND NUMBER NEEDED TO HARM Number needed to treat or NNT Defined: Number of patients who must be given a treatment for one to benefit Calculation = 1 – {(c/d) – (a/b)} Outcome Present Not Present Treatment

Given

a

b

Not given

c

d

Number needed to harm or NNH Defined: Number of patients who must be given a treatment for one to develop untoward effects Calculation = 1 –{(y/y+z) – (w/w+x)} Untoward Effect Present Not present Treatment Given Not given

w

x

y

z

INCIDENCE AND PREVALENCE Incidence: The proportion of individuals developing new disease during a period of time Prevalence: The proportion of individuals with existing disease at a point in time

TYPE OF PREVENTION Primary: Prevention of a disease (reduces incidence) Secondary: Early identification and treatment of an illness (reduces prevalence) Tertiary: Reducing the residual sequelae caused by the illness

EFFECT SIZES Describes the relative magnitude of the experimental treatment Understanding the scores 0.2 Small 0.4 Medium 0.8 Large SSRIs are 0.5 for OCD

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EPIDEMIOLOGICAL METHODS Measures of disease frequency Incidence Cumulative number of new cases total population at risk Incidence rate number of new cases person-years Prevalence Prevalence rate number of cases total population at risk Measure of association Studies Experimental studies Quasi-experimental studies Nonexperimental studies Cross sectional Longitudinal Case control Cohort: following a pt over time Threats to validity Selection bias: minimize by placebo Information (Observation Bias): minimize by blinding Confounding bias: minimize by placebo The Epidemiological Catchment Area (ECA) Study sampled community and institutionalized individuals in the US surveying adult psychiatric disorders using structured diagnostic interviews of the time. Lifetime prevalence rates: Anxiety disorder 15.5% Affective disorder 7.9% Psychosis 1.7% Substance use disorders 16.7% Any disorder 52.6% The National Comorbidity Survey: 1994 by Kessler et al. Adults and structured interviews Findings Prevalence of mental health conditions Lifetime: 48.7% 1 year: 27% Comorbidity with other mental health conditions 21% with one disorder 14% with greater than 3 disorders Risk factors and correlates Confirmation of gender as a risk factor Use of mental health services: only 40% received care Ongoing research programs

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Unit

IV Therapeutic Modalities Chapter

24

Hypnosis

OVERVIEW Activating one’s trance capacity to effect change

DEFINITION Absorption: attentive, receptive, focal concentration Dissociation: unaware of surroundings—relatively Suggestibility Transference: different from analysis

ASSESSING HYPNOTIZABILITY Use scales: Stanford hypnotic clinical scale, hypnotic induction profile (HIP)

SPECIAL CONSIDERATIONS WITH CHILDREN AND ADOLESCENTS 70% of the adult population is hypnotizable; children/teens are even more likely to be Concrete thinkers More open-minded Study: genetics, same-sex similarities

INDICATIONS AND APPLICATIONS Pain: helpful, appropriate imagery Psychosocial factors affecting medical condition—at least promotes relaxation to control psychogenic factors Seizures, pseudoseizures GI issues 271

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Addressing cancer chemotherapy Headaches Asthma Somatoform: multimodal treatment Dissociative Anxiety: as an adjunct Habit: trichotillomania

NEUROPSYCHOLOGICAL CONSIDERATIONS PET scans

PRECAUTIONS AND LIMITATIONS Not recommended for patients with schizophrenia

FORENSIC Excluded in some courts

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Chapter

25

Cognitive Behavioral Therapy

OVERVIEW SCOPE OF BEHAVIOR MODIFICATION Conceptual views Mediational forces (cognitive schemas) Nonmediational forces (operant conditioning) Intervention techniques: contingency management

CHARACTERISTICS OF BEHAVIOR MODIFICATION Focus on behavior Focus on current determinants of behavior Focus on learning experiences to promote change Overview Assessment and evaluation Application in everyday life Comment

TREATMENT: ILLUSTRATIONS OF SELECTIVE INTERVENTIONS Cognitive behavioral therapy for anxiety Background and rationale Looking at cognitive content, products, distortions Looking for adaptive skills Characteristics of treatments 15–20 sessions First half to manage anxiety Second half to use new skills Evidence and overall evaluation: good Adolescent coping with depression course Background and rationale: look at negative constructs/behaviors Coping with depression: A is the name of this approach Characteristics of treatment: group treatment Group activities Role playing Homework assignments Parent component Evidence and overall evaluation: very good 273

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Cognitive problem-solving skills training (PSST) Background and rationale: examining cognitive processing Characteristics of treatment Skills Alternative solution Means-end thinking (looking at the middle steps) Causal thinking Sensitivity to interpersonal problems Emphasis How kids approach treatment? Engage in step-step process Structured tasks Therapists play an active role Several procedures required Self-statements What am I supposed to do? I have to look at all my possibilities I have to concentrate and focus I need to make a choice and select a solution I need to find out how I did Evidence and overall evaluation: very good Parent management training Background and rationale—alter the interactions between the parents and child/ren Characteristics of treatment Defining and observing Positive reinforcement Time out from reinforcement Shaping Review and problem solving Attending and ignoring School reprimands Family meetings Review of skills Negotiating and contracting Problem solving Practicing Evidence and rationale—widely studied Operant conditioning techniques—think in terms of the general principle Background and rationale Characteristics of treatment Evidence and overall education

SALIENT ISSUES IN CURRENT TREATMENT RESEARCH Magnitude of therapeutic change Maintenance of change

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Chapter

26

Family Therapy

DEFINITION Family is interpersonal Nonlinear components Complex interlocking feedback mechanisms and patterns of interaction Goals Explore the interactional dynamics of the family relative to the problem Mobilize the family’s strengths Restructure maladaptive styles Strengthen the family’s problem-solving behavior

HISTORY 1909 1920s 1940s 1943 1946 1948 1949

Child Guidance Movement Marriage counseling Origins of family therapy Levy “maternal overprotection” Whitaker family therapy using fantasy, countertrans @Emory Fromm-Reichmann “schizophrenogenic mother” Bolwby bonding Boszormenyi-Nagy Zuk Sullivan “interpersonal psychoanalytic school”—interactions and relationships Erikson’s epigenetic theory of human development as interrelationship 1954 Ackerman shared unconscious conflicts/defenses; symbiosis; metaphor use 1960s Bowen differentiation (anxiety, triangulation, marital/family fusion, family projective system)––intergenerational 1959 Wynne pseudomutuality and pseudohostility; communication deviance Bell Bateson+Satir communication patterns, cybernetics, systems theory, 1959 Jackson MRI a major Family Therapy center 1956 Lidz schismatic/eschewed family related to schizophrenia (overt hostility versus enabling) Flick 1960’s Milan (Palazzoli) school Anorexia Nervosa family work 1965 Minuchin Structural School of Family Therapy 1962 Treatment: Multiple Impact Therapy Group, 2 intense days of multi family therapy 1982 Patterson Family therapy with children delinquency 1986 Zilback systemic way to include children 1984 Boszormenyi-Nagy intergenerational; good for long-standing issues 1987 Scharff2 formulations and recommendations 1987 Finnish Adoptive Family Study of schizophrenia––genetic transmission 275

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INDICATIONS AND CONTRAINDICATIONS Indications—overt/covert conflicts, major psychological disorder, personality disorders (narcissistic and borderline) Contraindications—relative not absolute: dormant, explosive, severe decompensation

MODELS Intergenerational Family system Bowen Family triangulation Differentiation versus undifferentiation (triangulation) and maturation Anxiety within family system Transmission of illness across generations Genogram creation Usage of the therapist as the “funnel” Contextual (bulimia nervosa) Pathological loyalty/indebtedness/entitlement/ethical basis of relationship Communicational/Systems Models: rigid families keep status quo at all costs Structural (Minuchin) Enmeshed (intrusive) disengaged (unavailable) Therapist “joins” the family via homework and “shifts” to abolish dysfunction Use in anorexia nervosa, psychosomatic, and behavioral problems Strategic: the therapist comes up with strategies to effect change Paradoxical intervention: discourage the change Prescribing the symptoms Haley and Madanes—strengthen the parents Milan school—history taking of family uncovers stuff MRI (Mental Research School) uses this technique Shift the focus from the problem to the solution Narrative—empower the family to restore the situation Triadic-based family therapy Force the conflict between family members Resist incorporating the therapist into the situation Psychodynamic—good for dealing with personality disorders—focus on “unconscious” life Of the family looking at unconscious conflicts, dyads/triads, transferences, projective ident Ackerman Shapiro, Zinner, Framo, Scharrf Experiential—expression of feelings, c/prec fantasies, transferences, clear communication, role flexibility, exploration, spontaneity, Whitaker and Satir Behavioral—parent management training (encourage communication, problem solving; discourage punishment, avoidance, power play) Psychoeducational—schizophrenia, depression, alcohol, suicide (use with combo of others) Social network—dysfunction of family is related to dysfunction of social network

THE FAMILY LIFE CYCLE Duvall 1977: the family goes through life cycles Haley 1973: problems occur in moving from one cycle to another Zilbach 1989: marriage, child, school-age, teens, launching center, middle age, aging

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FAMILY THERAPY WITH CHILDREN AND ADOLESCENTS Theoretical concepts Separation/individuation to allow differentiation—an issue Projective identification: child’s roles, parentification, Stierlin 1974 ways to overcome prolonged fusion Binding: child is psychotic or suicidal ideation to escape the family Delegating: “long leash” Expulsion: rejected and extruded by the family Techniques Open-ended play (paper, crayons) not conversations Phases First—(10–20s) improve child’s behavior (school, peers, sports) Second—improve marriage (note this is second—Montalvo and Haley suggested this to promote child-centered) Third—one of the parents wants productivity, maturity, creativity Family therapy and child and adolescent psychiatry (the war?) not really individual versus group ADHD—MTA study Conduct disorder Overview Patterson looked at coercive family processes: punitive then in the face of child aggression, release of punitive measures Alexander and Barton looked at function of aggression and change from defensive to supportive measures Reiss: weakness of cooperation, coordination, cohesiveness Functional: good for runaways, conduct disorder on younger siblings, and depression in parents Parent management training (Patterson) Preventative effects on younger siblings Interact more productively with their children Multisystemic therapy—good for kids really in trouble Empower parents/empower youth Home-based Intense—several hours per week Hospitalizations—? come to a compromise Residences Available families: no issue Potentially available: recognize limitations Partially available: maintain connection with realistic strategies Unavailable: locate family, if possible (negates fantasies) Psychosomatic disorders Minuchin in eating disorder, psychosomatic; Sholevar and Bahnson Substance abuse—functional as well as multisystemic therapy

VARIABLES IN SCHIZOPHRENIA EE Brown 1962—Hooley and Vaughn 1970s high EE is bad Communication deviance: families of schizophrenia have issues in communication Affective style not studied much

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FAMILY INTERVENTION AND DEPRESSION Characteristics Aversive to others; feel victimized; verbalize negative feelings; silence Spouses are at risk; also increases stress Treatment—everything

PSYCHOEDUCATIONAL To cope with illness

ALCOHOL Alcohol issues become the central and defining characteristic of the family Phases Early: bright-eyed, bushy-tailed optimism of family is gone Middle: recycling between intoxication and sobriety Late: losses and gains revolved around alcohol Treatment: multimodal

PSYCHODYNAMIC Look for: Projective identification Unresolved grief Clarity of ego boundaries and capacity for intimacy/separateness Think about: Internal processes within individual family members shape family interactions Family members’ motivations/conflicts/defenses/relationships from past/current relationship Therapeutic change occurs through family members gaining conscious insight into previously unconscious processes Do: Opening emotional expression in family relationships Clarifying communications Encouraging family members to speak from the “Indication” position Interpretation of unconscious conflicts to resolve projective processes/cutoff relationships and modulating closeness and distance in family relationships Psychodramatic techniques Doubling Role reversal Therapeutic rituals to facilitate developmental transitions and grief over losses Family genograms

STRUCTURAL FAMILY THERAPY Look for: Organization (structure) Rules (sequence of action) Roles that shape family members’ actions Boundaries

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Hierarchy of power Alliances Coalitions Verbal and nonverbal behavioral sequences Think about presenting problem results from a structural misalignment with the culture and development stage of the family Do: Actively shift the structure In-session enactments Out-of-session homework assignments

STRATEGIC FAMILY THERAPY Look for: Here and now context of the problem Who, what, when, where, and how people are involved in trying to solve the problem Think about The solution to the problem is the solution Different life transitions lead to problems when old coping styles are used (no changes) Do: Psychoeducation Direct behavioral assignments to adopt new coping styles Defiance-based/paradoxical interventions

COGNITIVE-BEHAVIORAL THERAPY Look for: Each member of the family is doing their best to cope with the problem Lack of clearly-defined family roles Problems in emotional communication from little positive and lots of negative expressions Relational skills need improvement Relational conflicts due to errors in interpretation Think about: Each member is doing the best s/he can Family members need to learn CBT points Skills necessary: Reinforce desired behaviors Eliminate reinforcement of undesired behaviors Modify faulty assumps and interpretations about family members’ actions Learn to communicate clearly and effectively Do: Psychoeducate around current problem Develop empathic listening, expressing positive feelings, respectful negative comm. Training in problem-solving and conflict-resolution Operant conditioning for behavioral training in children Teach contingency contracting (to replace coercion and blaming) Use behavioral observation and through diaries as homework

POST-MODERN FAMILY THERAPY Look for: Exact use of language in metaphors, stories, and beliefs First-person narratives with abstract important works Note exceptions when bad outcomes could have occurred but did not note what is happening when there are no problems

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Think about: Limits of a person’s language that may limit a person’s experiential world Narratives are basic units of human experience These narratives in collection define the individual and family Conflicts occur: When lack of narrative skills make the experience unintelligible to others When available narratives overshadow/do not allow conflictual others When specific words hold different meanings for individuals When family members have fixed ways of hearing others Do: Create dialogues where important narratives can be safely expressed Ask questions regarding forgotten/unnoticed narratives—especially if they can be problem solving Engage family to ask about: What is happening in family interactions when problems are being solved or nothing is happening Skills, practical knowledge, competencies, resources of the family that can contribute to problem solving

FAMILY PSYCHOEDUCATION THERAPIES FAMILY RESILIENCE THERAPIES

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Chapter

27

Adult Psychodynamic Therapy

PSYCHODYNAMIC THERAPY Developmental concerns Psychosexual Psychosocial Principles Conflicts Unconscious Intrapsychic Id Ego Superego Defense mechanisms developed to avoid harm Psychopathology is develops from childhood experiences and relationship to drives and conflicts Issues emerge in therapy Transference Countertransference Free association is the methodology to explore conflicts Key figures Alfred Adler Equality as a prevention of psychopathology “Inferiority complex” Feminism Michael Balint Focal Psychotherapy Erik Erikson Focus on ego development Eight stages of psychosocial development across the lifetime Trust versus Mistrust Autonomy versus Shame Initiative versus Guilt Industry versus Inferiority Identity versus Confusion Intimacy versus Isolation Generativity versus Stagnation Integrity versus Despair Anna Freud Child psychoanalysis

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Sigmund Freud Psychoanalysis Erich Fromm Personality from its economic and cultural roots Karen Horney Neurosis as “internal control and coping” Carl Jung Psyche Ego Individual unconscious Collective unconscious Archetypes Mother Father Child Story Hero Wise Old Man Maiden Mana The Shadow The Persona Anima/Animus Melanie Klein Child psychoanalysis Object Relations Hans Kohut Self Psychology Margaret Mahler Separation-Individuation in child development Henry Stack Sullivan Interpersonal theory D.W. Winnicott Object relations Mother-child “Holding environment” and the “transitional object” “Good enough”

CHILD PSYCHODYNAMIC THERAPY Kleinian child psychoanalysis Three principles Play is the child’s free association Kids have transference Analyst solely interprets unconscious source of anxiety Freudian psychoanalysis Principles Kids are not motivated for therapy Kids tend to deny problems and try to externalize their causes Kids will run away from discomfort Kids will prefer acting to talking Kids are not able to free-associate Kids are not capable of transference except in overt actions

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Psychodynamic psychotherapy Play Projection Content and interaction with the therapist Allow corrective emotional experience Games themselves Squiggle (Winnicott in 1971) House-Tree-Person

COMMENT Effectiveness of psychotherapy Development is a moving target Children can get better Reliance on parents Strong reactivity to changes at home Measuring effectiveness is difficult

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Chapter

28

Group Therapy

OVERVIEW Age differentiation School age 4–6: mixed Latency 6–10: mixed Preadolescent and adolescent 10–14: single-sex Mid-late adolescent 14–19: mixed Young adult 18–21: mixed Psychoanalytic group treatment Concepts Dynamic unconsciousness exists in thoughts and behaviors Anxiety is a result of unconsciousness coming into conscious awareness Ego defense mechanisms operate outside of one’s conscious awareness Transference Goal: restructure patient’s character and personality system Free association/“go-round technique or free-floating” Interpretation of underlying verbalizations and meanings To allow for insight and modes for change Therapeutic groups—(T groups) six to eight participants lasting 90′ sessions Modification for children Play/art/music Activity observation—play interpreted by the therapist CBT Consider developmental stages if cognitive restructuring is a goal Preschool—here and now—behavior skill teaching Latency (concrete)—trouble focusing on the task Teens (formal)—can cognitively restructure Leaders Model behaviors Provide reinforcement (praise, approval, support, attention) Contigency contracts Group play therapy Psychoanalytic—play is interpreted as noted above Structured—a specific toy reflection, reexperiencing Therapeutic relationship—corrective emotional experience Expressive and art therapies—used to allow children to process 9/11 event Psychodrama Stages: warmup, action, sharing/wrap-up Protagonist, alter egos, auxiliaries (shyer kids who can become protagonists)

285

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Self-help and 12-step groups—school age and teens Special populations Chronic medical illnesses—they are not alone Abused children—learn appropriate punishment Divorced parents—supportive—they are not alone

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Chapter

29

Milieu Therapy

INPATIENT, PARTIAL, RESIDENTIAL OVERVIEW COMMON ISSUES Parent or sponsoring body Administrative issues Clinical issues The milieu Child or adolescent requiring milieu treatment The family

RESIDENTIAL TREATMENT CENTERS History Residential care Role in system of care Outcome and quality assurance

INPATIENT History Inpatient care Outcome and quality assurance

PARTIAL AND DAY History Partial and day care Outcome and quality assurance

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Chapter

30

Couples Therapy

GOALS Promote positive feelings between partners More reasonable behavior

SUBSET OF FAMILY THERAPY Issues Power Intimacy Personal growth Couples and dysfunction Couples development Expansion WE: committed, interconnected Contraction I: trapped, lonely, different places Resolution: “working on it” Sexuality of couples 50% of couples psychological or physical difficulties versus dysfunction Diagnosis/systems issues Approaches to treatment Marital discord → sexual problems—treat the marriage Marital discord + sexual problems—treat marriage first, then sexual Sexual problems → marital discord—treat sexual problems Sexual problems + marriage is okay—treat individual first then marital couple Frequency 1/3 2× week 1/3 few × month 1/3 0–few × year Differential diagnoses Ignorance of anatomy Negative attitude Self-defeating behavior Anger Power/intimacy issues Medical/physical issues Medicines Secrets and confidentiality Avoid secrecy as it is connected to fear/anxiety/shame Disclose when safe 289

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Evaluation of the couple General topics Communication Problem solving Roles Affective expression Involvement Behavioral expression (sex and aggression) Gender roles Cultural/racial/power inequities (gender, class, age, money) Alcohol/illicit substance use, health issues, reproductive issues, violence Genograms for evaluation Assessment for concomitant psychiatric illness Evaluation—sexual disorders Indications for couples versus individual therapy Address acute conditions first in the setting in which it occurs Separate therapist preferable (couples therapist and individual therapist) Individual/couple: sex therapy for sex problems Contraindications Health (psychiatric and medical) illness Physical danger If individual therapy is the first priority Treatment Specify the problem Increase communication skills balance of power Recognize mutual contributions Decrease coercion and blame Clear communication Clarify marital boundaries Increase diff and resolution Transfer of distribution Clarify each spouses needs/desires Increase intimacy Resolution of conflict Strategies and techniques of intervention Interrupt the process between husband and wife Link individual experience to the past Have each one change themselves Treatment of sexual function Dropouts High Usually secondary to lack of activity of the therapist Ethical issues First—do no harm Second—“sorter outer” Conflicting interests of family members

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Unit

V Law and Ethics and Economics Chapter

31

Law and Ethics

LAW Rights and responsibilities Right to treatment Rouse versus Cameron 1966: bonafide effort to try to treat (not cure/improve) Wyatt versus Stickney 1972: right to humane treatment; beginning of patient’s rights Youngberg versus Romeo 1982: right to reasonably safe conditions to confinement, freedom from unreasonable bodily restraints, and minimally adequate training to do so (protection) Right to refuse treatment “Rights-driven”—driven by the rights of the patient—least restrictive environment “Treatment-driven”—driven by the necessity of the treatment Rogers versus Commissioner of Department of Mental Health (Commonwealth of MA)—refusal of medications Patient’s previously expressed preference Patient’s religious convictions Family’s preference Side effects Prognosis with treatment Prognosis without treatment Liberty and civil commitment O’Connor versus Donaldson 1975—state cannot confine without treatment, if patients are not dangerous and capable of living on their own Addington versus Texas 1979—clear and convincing burden of proof for commitment Spectrums Parens patriae—unable to protect from danger from self Police power—protect from danger to others Outpatient commitment Confidentiality Confidentiality and privilege The circle of confidentiality “Within the circle”—no permission needed (staff supervision, nursing/support, patient) “Outside the circle”—permission required (family, lawyer, output, police)

291

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Exceptions Consent Duty to protect Obliged reporting (infectious disease, abuse) Emergencies When breaching confidentiality Warn the patient Ally with the patient (breach confidentiality together) Breach to select individuals Psychiatrist-patient privilege: it is the patient’s privilege for confidentiality Informed consent General Natanson versus Kline 1960—reasonable medical practitioner Canterbery versus Spence 1972—alternative treatments must be included Truman versus Thomas 1980—amount of information significant for a reasonable person Exceptions Emergencies Incompetent patient Therapeutic privilege (should be rare—since no information is shared) Wavering of the information by the patient Consent to the treatment of minors Obtain guardian consent Some state exceptions Ideal informed consent contains Comment on the capacity of the individual to make decisions Contains information that a reasonable person would require Serious side effects Common side effects Specific to the individual Specifies risks/benefits/alternatives Including lack of intervention risks/benefits Contains Off label safety and efficacy information Black box warnings Documentation of previous intolerance Medicolegal aspects—malpractice and risk management Definition “the failure of the physician … to use the reasonable care, skill, or knowledge ordinarily used under similar circumstances” “Four D’s” of malpractice law Dereliction of Duty (once relationship established) Directly (or proximately) causing Damages Third party payers Wilson versus State of CA—1987 insurance denial does not obviate the psychiatrist’s duties Wilson versus BC of CA—1990 insurance companies share in the liability Liability for supervising other professionals Supervisory Psychiatrist has treatment responsibility Psychiatrist may hire or fire Psychiatrist has final authority Collaborative Responsibility shared between parties Delineation of responsibilities required Consultative Consultee may/may not take advice

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Consultant is not responsible for supervision Consultant has no hire or fire authority Risk management techniques Obtain consultants Informed consent Documentation—“think for the record” Criminal law As expert witness Special knowledge Financially compensated Offers opinions Calm Clear Concise Competence to stand trial evals Dusky versus US 1960—ability to consult with his lawyer McGarry criteria 1973—assessment of 13 different functions Jackson versus Indiana 1972—if incompetent to stand trial, hospitalize for legitimate purposes or be discharged Insanity defense Actus Reus—defendant is guilty of COMMITTING a crime Mens Reus—defendant is guilty of INTENDING to commit a crime M’Naughten rule 1843—conclusive that at the time insanity occurred Did not know what s/he was doing Did not know that it was wrong Irresistible impulse 1922 The person was compelled by mental illness to commit a crime Not guilty by reason of insanity Model Penal Code 1955—extended M’Naughten’s rule to include that the individual lacks substantial capacity to appreciate the wrongfulness of the action Civil litigation Tort liability compensation potential as the injuries occurred by the acts of others Disability—different for each state Physical trauma causing mental injury Mental injury causing physical effects Mental stress causing mental injury Competence, capacity, and guardianship Competence—a legal term Capacity—based upon an evaluation Guardianship Child abuse reporting Elder/disabled abuse reporting Child custody evaluations Wishes of the parents’ as to custody Wishes of the child Interaction of the parent and child ADA and the Olmstead case 1990 ADA with four parts Title I: no discrimination in employment Title II: by government entities (like state hospitals) Title III: private entities Title IV: telecommunications Tarasoff I—the physician has the duty to warn others of potentially violent patients Tarasoff II—duty to protect others from potentially violent patients

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ETHICS Sources Law Religion Professional associations Competence, compassion, and respect for human dignity Honesty Best interest of the patient Rights of others Continued study Free to choose whom to serve Improvement to community Potential consequences of diagnostic labels Boundaries Research—Institutional Review Boards Suicide Health system changes

RESPECT FOR AUTONOMY Beneficence: Heeds patient’s wishes Nonmaleficence: Educate, encouraging of second opinions, no harm by actions (or inactions)

JUSTICE Managed care: Responsibility to disclose, appeal, treat, cooperate with utilization review

CHILD FOCUSED OVERVIEW Practice parameters available

CHANGING STATUS OF CHILDREN’S RIGHTS Children as property Twentieth century—Child labor laws 1909—White House Conference on Children and Youth 1970—WHCCY outlined specific rights 1999—Mental Health: A Report of the Surgeon General—highlights awareness of children’s mental health Parens patriae: empowers the state to protect citizens who are unable to protect themselves Best Interest of the Child: started in 1881 to take care of kids before others

OVERVIEW OF THE LEGAL SYSTEM Two main categories State courts Trial (lower) Family: divorce and child custody

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Juvenile: delinquency, abuse, neglect Surrogate: civil commitment, guardianship, adoption, trusts/estates/wills Appellate (higher) Supreme Federal courts (civil and criminal) Trial courts Courts of appeal Proof Standard of proof—preponderance of proof for judicial decision Clear and convincing evidence—required for cases of deprivation of rights Beyond a reasonable doubt—required for criminal cases Evidence Legal fact—what the court accepts Expert opinion—Frye rule: an opinion that has gained general acceptance Rule 702: the judge can determine if the witness is an expert

FORENSIC EVALUATION Report How one was referred or became involved? Purpose of the evaluation What procedures were performed? What observations were made? What conclusions? If subpoena’d a deposition—may require release of records If the courts are asking for expert opinions; ask for stipulations: Statement of the appointment of the expert to proceed with the work The purpose of the evaluation (including the persons to be evaluated) and the scope of the evaluator’s authority regarding collateral information Specification of the person to whom the report is to be made Method of payment of fees for professional services rendered Use the latest DSM (IV-TR)

ETHICAL ISSUES IN THE CLINICIAN’S PRACTICE The child is a minor and parental involvement is necessary to some degree Child’s developmental maturation expands capacity for understanding and judgment and responsibility for behavior. The child is involved with school and other organizations which require collaboration.

LEGAL ISSUES IN THE CLINICIAN’S PRACTICE Confidentiality, privilege, and duty Confidentiality—even minors have the right to this Duty to protect/warn Privilege—disclosure of info in judicial, quasi and admin proceedings Informed consent and competency Civil commitment Professional liability Duty—duty of care was owed to the patient by the physician Dereliction—duty of care was breached

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Damages—the patient experienced actual damage due to breach of duty Direct causation—the dereliction was the direct cause of damages Child custody and divorce Child abuse and neglect Child as a witness Youth violence Dependency, delinquency, and the juvenile court School related legal issues

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Chapter

32

Economic Issues

GOVERNMENT FUNDED PROGRAMS Public Federal: Medicare, Medicaid, Veteran, Indian Health Care State: Medicaid, public hospitals, grants Local Costs Federal: 28% State/local: 28% Private/insurers: 44% Historical understanding: In 1965, the federal government was the major funding source for mental health (Medicare/Medicaid, community mental health centers) Medicare: universal health coverage for citizens older than 65 years are eligible for social security A: hospital insurance B: supplemental Medicaid: need Community mental health centers Federal Health Care Law Passed March 23, 2010 Legislation that will change the United State’s health care system affecting, among others Affordable health insurance Preventative services Shrinking of the Part D “doughnut hole” Changes to subsidies to private plans Coverage despite pre-existing conditions Medicare payroll tax changes for high income earners Small businesses employing less than 50 employees will not be required to provide health insurance Private insurers will not be able to cancel coverage secondary to illness Extending eligibility for Medicaid Children 26 years of age and younger can remain on parent’s insurance Inpatient Outpatient

EMPLOYER SPONSORED INSURANCE Managed care HMO fixed payment = capitation Social Services Title XX of the Social Securities Act: federal funds to states with children who need this for protection from abuse Juvenile justice 297

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Education SSDI Consumers, employers, government, insurers, physicians, uninsured Solutions Single payer Define: contribution health plan Medical savings account Subcapitation for selected population Clinical care redesign Continuum of care Treatment guidelines Disease management Case management Disease prevention and wellness Structural and systems changes Integration of services Specialized medical offices Outcomes data research Continuous quality improvement Creating fair allocation of services

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References

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Index

A Acamprosate (Campral) clinical trial findings, 98 contraindications, 98 pharmacology, 97–98 side effects, 98 ACOG, 163, 168 ADA, 25, 293 Addiction, 3 ADHD (see Attention deficit hyperactivity disorder) Adolescents ADHD, 228 alcohol, 90–91 developmental observations, 217 HIV/AIDS, mental disorders, 213 sleep disorders in, 153 substance use disorders preventative measures for, 88 risk factors in, 87 Adrenergic inhibitors, PTSD, 78 Adulthood ADHD, 228 developmental observations late, 218 middle, 218 young, 217–218 Adults excessive daytime sleepiness, 149 insomnia differential diagnoses, 146–147 hierarchical levels of arousal, 147 management of, 147 nonpharmacological approaches for, 147 pharmacological approaches for, 147–148 mania, acute, 241–242 psychodynamic therapy, 281–282 sleep disorders, epidemiology, 145 Afferents and effects, in limbic system, 34 Age differentiation, group therapy, 285 Age-related issues, in ADHD, 228 Aging, biology of, 218

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Agoraphobia, 65, 67 Alcohol comorbidity diagnostic categories, 92 ETOH dependence and mood and anxiety, 92 genetic predisposition, 92 prevalence, 92 epidemiology adolescence, 90–91 definitions, 91–92 gender, 90 prevalence, 90 sexual dysfunction, 91 type A and B, 92 metabolism, 94 pathophysiology assessment, 93–94 metabolism, 94 treatment acamprosate (Campral), 97–98 acamprosate + naltrexone combo, 98–99 disulfiram (Antabuse), 96 FDA-approved meds, 96 naltrexone (Revia), 96–97 neurotransmitters, 94–95 nonpharmacological approaches, 99–100 withdrawl, 95 Alzheimer’s disease factors genetic factors, 185 neurochemical deficits, 185 neuropathology, 185 risk factors, 185–186 statistics, 184–185 treatment of antiamyloid agents, 188 nonpharmacological, 186 pharmacological, 186–188 American Academy of Child and Adolescent Psychiatry Practice Parameter Recommendations, 245 309

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310

Index

Amnesia, dissociative disorders assessment, 131 treatment, 131 Amphetamine intoxication, 107–108 withdrawal, 108 Amygdala, 33–34 Anabolic steroids disorders, 108 side effects/toxicity, 108 withdrawal symptoms, 108–109 Anatomical construct, depression frontal lobe systems, 33 hippocampus, 34 limbic system, 33–34 Anatomy, brain arousal and attention, 1 emotion (depression and anxiety), 2 motor and behaviors, 1–2 perception, 2–3 Anorexia nervosa clinical features cardiovascular complications, 136 endocrine complications, 136 gastrointestinal complications, 136 skeletal complications, 136 course, 136 diagnostic criteria, 135 differential diagnosis, 137 epidemiology, 135 etiology, high-risk populations, 137 pathogenesis, 137 prognosis, 139 psychological assessment, 136 starvation effects physical, 137 psychological, 136–137 treatment cognitive behavioral therapy, 138 coping styles, 139 family, 138 pharmacology, 138–139 practice guidelines, 137 resistance to, 139 setting of, 137–138 Antiamyloid agents, in Alzheimer’s disease, 188 Anticonvulsants, 180–181 Antidepressants, 168, 180 anxiety, 67–68 bulimia nervosa, 141 PTSD, 77 reparation and growth construct in depression hippocampus, 35 mediators role, 35

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Antipsychotics, 249 obesity and diabetes, 25 PTSD, 77–78 Antisocial personality disorder, 127 Anxiety age of onset, comorbidity with depression, 66 CBT for, 273 considerations for, 70 and depression DSM-IV classification, 65 panic attacks and disorder, and agoraphobia, 65 prevalence, 65 WHO findings, 65 disorder caffeine, 102 etiology, 211 in geriatric psychiatry, 199–201 and fatigue, 71 generalized anxiety disorder (GAD), 79–81 heritability, 66–67 and insomnia, 72 MDD and, 71 medications, 70–71 obsessive-compulsive disorder, 84–86 panic disorder, 82–84 pathophysiology of brain regions, 73 neurotransmitters, 73 PTSD assessment, 74–78 comorbidity, 74 developmental considerations, 74 diagnostic criteria and clinical findings, 73–74 etiology, 74 history of, 73 neurobiology, 73 risk factors, 74 sleep disturbances, 78 treatment considerations for, 78–79 and pulmonary disease, 72 residual symptoms, 69–70 separation, 82 social, 81–82 treatment antidepressants, 67–68 benzodiazepines, 68 gabapentin, 68 guidelines, 69 pregabalin, 68–69 Anxiolytics, 180 APOE, 185 Aripiprazole, 60–61

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Index Arousal and attention CNS areas, 1 memory categories, 1 types, 1 Asperger disorder, 256 Asthma, 72 Astrocytes, 5 Attention, 257 Attention deficit hyperactivity disorder (ADHD), 151 and bipolar disorder, 54 in infancy and early childhood adjunct psychosocial management, 230 age-related issues, 228 assessment, 227–228 attention process training, 230 coaching, 230 comorbid disorders, 230 etiology, 226–227 management, 229 prevalence, 226 psychosocial interventions, 229–230 stimulants, 230–233 and substance use, 234–236 subtypes, 227 Atypical antipsychotics, bipolar disorder aripiprazole, 60–61 BP depression, 62–63 maintenance, 63 rapid cycling, 63 FDA-approved medications, 62 olanzapine, 60 quetiapine, 61 recurrence, 63 risperidone, 61 side effects profiles, 62 ziprasidone, 61 Atypical depression, 39–41 Auditory perception, 2 Autistic disorder, 255 Avoidant personality disorder, 127 B Benzodiazepines, 168 anxiety, 68 generalized anxiety disorder (GAD), 80 PTSD, 77 receptor agonists, 148 Biochemistry markers, for low sodium, low potassium, 259 Biogenic neurotransmitters DA, 6 histamine, 7

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311

5-HT, 7 norepinephrine (NE) and epinephrine (E), 6–7 Biometrics confidence interval, 269 data, 268 effect sizes, 269 epidemiological methods association, 270 disease frequency, 270 epidemiological catchment area (ECA) study, 270 threats to validity, 270 incidence and prevalence, 269 number needed to harm (NNH), 269 number needed to treat (NNT), 269 prevention type, 269 reliability, 268 sensitivity and specificity, 268 statistical tests, 268 study designs, 267 validity confounding factors, 267–268 definition, 267 false-positive rates (FPR), 268 Bipolar disorder, 241 assessment diagnosis, validators of, 56 scales, 55–56 course childhood presentation, 54 clinical course, 53 phenomenological issues, 53 prognosis, 53 statistics, 53 definitions of, 57 diagnosis cardinal symptoms, 57 duration, 56 mania, 56 mood elevation, 56 subtypes, 56 differential diagnoses, 57–58 etiology genetic, 51 mitochondria, 52 monoamine hypothesis, 51–52 neuroimaging, 52 neuronal circuits, alteration of, 52 neuropeptides/hormones, 52 sensitization, kindling model, 52 stress diathesis model (genes and environment), 52–53 misdiagnosis clinician factors, 54 disease factors, 54–55

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312

Index

Bipolar disorder (Continued) nonpharmacologic, 58 overview, 51 pediatric acute mania, 241–242 assessment, 240–241 in children and adolescents, phenotypes of, 242 differential diagnoses, 242–243 epidemiology, 240 etiology, 240 risk factors, 244 treatment implications, 243–244 pharmacotherapy atypical antipsychotics, 60–63 mood stabilizers, 59–60 treatment, 58 Blood pressure (BP) atypical antipsychotics depression, 62–63 maintenance, 63 rapid cycling, 63 in schizophrenia, 23 Body dysmorphic disorder assessment, 130 treatment, 130 Brain anatomy, 1–3 areas, in sleep, 143–144 physiology, 5–7 regions (see Brain regions) structures, in depression fMRI studies, 240 MRI studies, 240 substance use disorders addiction, 87 seeking and craving, 87 Brain regions anxiety disorders, 73 impulse control disorders, 172 in schizophrenia microstructure, 12 neuroanatomic abnormalities, 11–12 neurodegenerative disorder, 11 neurodevelopmental abnormality, 10–11 physiology, 12 Brain-derived neurotrophic factor (BDNF), 35 Breastfeeding, 169 Breathing, sleep disordered, 154 Bulimia nervosa definition and diagnostic criteria, 140 developmental features, 140 differential diagnosis, 141 etiology biological, 140 psychological and family, 140

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labs, 141 prevalence and epidemiology, 139 psychological symptoms, 141 risk factors, 139–140 signs, 140 treatment antidepressants, 141 binge eating agents, 142 Buprenorphine, 179–180 Buspirone, in generalized anxiety disorder, 81 C Caffeine anxiety disorder, 102 beverages, sleep, 157 dependence, DSM-IV TR, 102 disorders, 100 etiology, 102 intoxication assessment, 101 definition, 100–101 pathophysiology, 101 sleep disorder, 103 sleepiness, 155 withdrawal, DSM-IV TR assessment, 102 definition, 101 differential diagnosis, 102 Campral (see Acamprosate (Campral)) Cannabis disorders, 103 etiology and pathophysiology, 104–106 Carbamazepine, bipolar disorder, 59 Carbohydrate deficient transferrin (CDT), 94 Cardinal symptoms, bipolar disorder, 57 Cardiovascular disease risk factors, in schizophrenia, 20–21 Catatonic disorder, 212 CBT (see Cognitive behavioral therapy) Child abuse, reporting, 293 Child and adolescent psychiatry ADHD adjunct psychosocial management, 230 age-related issues, 228 assessment, 227–228 attention process training, 230 coaching, 230 comorbid disorders, 230 etiology, 226–227 management, 229 prevalence, 226 psychosocial interventions, 229–230 stimulants, 229–233 and substance use, 234–236 subtypes, 227

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Index early-onset schizophrenia assessment, 220 differential diagnoses, 219–220 medical etiologies, 220 treatment, 220 pediatric anxiety acute stress disorder, 222 assessment, 222–224 epidemiology, 221 etiology, 221 generalized anxiety disorder, 221–222 obsessive compulsive disorder, 221 panic disorder, 222 phobia, 221 PTSD, 222 separation anxiety disorder, 221–222 tic disorders, 224–225 pervasive developmental disorders, 254–257 psychotropic drug effects brain effects, 245–246 hyperprolactinemia, 249 polycystic ovarian syndrome (PCOS), 250 prolactin, 249–250 recommendations, 249–250 signs and symptoms, 249 SSRI effects, 245–246 thyroid function, 248–249 theories attachment theorists, 216 contemporary theorists, 215 divorce effects, 216 factors in, 215–216 life cycle theory, 215 lifetime, developmental observations, 216–219 Litz, Theodore, 215 websites and other resources, 245 Childhood disintegrative disorder, 256 Children HIV/AIDS, mental disorders, 213 rights, in law and ethics, 294 Cholinesterase inhibitors, 186–187 Chromium picolinate, 41 Circadian rhythm sleep disorder, 154–155 Civil litigation, 293 Clinical instrument withdrawal assessment scale (CIWA), 95 Clonidine, 156 Clozapine, 19, 25 CNS areas addiction, 3 arousal and attention, 1 auditory and gustatory, 3 emotion (depression and anxiety), 2 gustatory, 3

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313

motor and behaviors, 1 obsessions and compulsions, 3 olfactory, 3 somatosensory, 2 visual, 2 in fetus, 216 Cocaine complications, 107 disorders, 106 epidemiology, 106 erythrooxylon coca, 106 gender differences, 106 psychiatric disorders, 107 treatment, 107 Cognitive behavioral therapy (CBT), 279 anorexia nervosa, 138 anxiety, 69, 81 behavior modification, 273 for geriatric psychiatry, 200–201 group therapy, 285 treatment adolescent, depression course, 273 for anxiety, 273 operant conditioning techniques, 274 parent management training, 274 problem-solving skills training (PSST), 274 research, salient issues in, 274 Cognitive disorders, in geriatric psychiatry Korsakoff, 184 prevalence, 184 prognosis, 184 types, 183 Cognitive impairment and depression, in geriatric psychiatry, 195 Cognitive processing therapy (CPT), 75 Conversion disorder assessment, 129–130 treatment, 130 COPD, 72 Cortisol and depression, 34–35 Cortisol releasing factor (CRF), 94 Couples therapy family therapy, subset of contraindications, 290 and dysfunction, 289 evaluation of, 290 intervention, strategies and techniques of, 290 issues, 289 secrets and confidentiality, 289 treatment, 290 goals, 289 Cranial electrotherapy stimulation, depression, 45

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314

Index

Creutzfeld–Jacob disease (CJ disease), 190–191 Criminal law, 293 Cytochrome P-450, 261 variants, 26 D Deep brain stimulation (DBS), 45 Delirium assessment, 206 causes, 206 course, 205 definition, 205 epidemiology, 205 geriatric characteristics of, 196 medication induced, 196 metabolic, 196 risk factors, 206 subtypes, 206–207 treatment nonpharmacologic, 207 pharmacologic, 207 Dementia, in geriatric psychiatry Alzheimer’s, 184–188 infectious causes of, 190–193 Parkinson’s, 190 vascular, 188 Depakote, bipolar disorder, 59–60 Dependent personality disorder, 128 Depersonalization disorder, 132 Depression Alzheimer’s disease, 185–186 anxiety and, 65, 66 bipolar disorder, BP, 62–63 differential diagnoses, 41–42 emotions, 31–32 etiology of anatomical construct, 33–34 antidepressants, reparation and growth construct, 35 genetics construct, 36 metabolic syndrome construct, 36–37 neuroendocrinological construct, 34–35 neurotransmitter construct, 32–33 family intervention and, 278 geriatric psychiatry, 193–195 pediatric assessment, 238 comorbidity, 238 course, 236–238 epidemiology of, 236 risk factors, for MDD, 238 treatment, 238–240 postpartum mood disorder, 169 in pregnancy, 166 risk factors for, 37 SSRI effects, 246

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subtypes atypical, 39–41 severe, 38–39 suicide comorbidity, 38 differential diagnoses, 38 risk factors, 37–38 treatment, 38 treatment adverse events, 45 approach, 42 coordinated care, 42 cranial electrotherapy stimulation, 45–46 deep brain stimulation (DBS), 45 effectiveness, 44–45 electroconvulsive therapy (ECT), 43–44 electrode placement, 44 findings, 48–49 history of, 42 monitoring, 44 seizures, 44 side effects, 46 STAR*D trial, 46–47 transcranial magnetic stimulation (TMS), 45 Diabetes mellitus, 21–22 monitoring and recommendations, PCOS, 251 Diagnostic approaches biometrics, 267–270 laboratory and diagnostic testing, 259–261 psychological assessments, 263–275 Dissociative disorders amnesia, 131 depersonalization disorder, 132 fugue, 131 identity disorder, 131–132 trance disorder, 132 Disulfiram (Antabuse) adherence and abstinence, 96 mechanism of action, 96 Dopamine (DA), 12–13 critical formations, 6 depression, 33 metabolism, 6 receptors, 6 tracts, 6 transporter and receptor genes, 261 DPP-4 inhibitors, 22 Drospirenone, 165 Dyslipidemia, treatment, 21 Dyspareunia, 161 E Early-onset schizophrenia assessment, 220 differential diagnoses, 219–220

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Index medical etiologies, 220 treatment, 220 Eating disorders anorexia nervosa, 135–139 bulimia nervosa, 139–142 continuum of, 135 genetics and environment, 135 types, 135 Economic issues employer sponsored insurance solutions, 298 structural and systems changes, 298 government funded programs, 297 Electroconvulsive therapy (ECT), depression contraindications, 43 indications, 43 mechanism of action, 43 medication effects, 44 premedication, 44 preparation, 43 Electrophysiology, of brain, 12 Emotions, 2 components of behavioral expression, 31 conscious experience, 31 physiologic arousal, 31 involvement of, 32 neurobiologically based components of, 31 role of, 31 types of Ekman, 31 Plutchik, 31 Employer sponsored insurance, economic issues, 297–298 Epinephrine (E), 6–7, 35 Ethics, 294 ETOH, 92 Eye-movement desensitization and reprocessing (EMDR), 76 F Factitious disorders assessment, 133 treatment, 133 types Munchausen, 133 non-Munchausen, 133 Family therapy chidren and adolescents, 277 cognitive-behavioral therapy, 279 couples and dysfunction development, DYM 1993, 289 diagnosis/systems issues, 289 differential diagnoses, 289 sexuality of, 289

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315

definition, 275 history, 275 indications and contradictions, 276 intervention and depression, 278 life cycle, 276 models communicational/systems models, 276 experiential, 276 intergenerational, 276 psychodynamic, 276 post-modern therapy, 279–280 psychodynamic, 278 strategic therapy, 279 structural therapy, 278–279 subset of evaluation of, 290 issues, 289 treatment, 290 SZ, variables in, 277 Fatigue and anxiety, 71 FDA, 62, 198, 220, 251 ADHD, 229 anxiety indications, 67 and insomnia, 72 buprenorphine forms, 120 geriatric psychiatry, 186, 198 neonatal neurobehavioral sequelae, 167 yaz, 165 Fetus, 246 developmental observations, 216 FGA (see First-generation antipsychotics) Fibrates, 21 Fight-or-flight response, cortisol and depression, 34–35 First-generation antipsychotics (FGA), 25, 26, 207 Forensic evaluation, 295 Freudian psychoanalysis, 282–283 Frontal lobe, 2, 33 Functional fMRI studies, ADHD, 226–227 G GABA, 94 generalized anxiety disorder (GAD), 80–81 Gabapentin, in anxiety, 68 GAD (see Generalized anxiety disorder) Gender identity disorders clinical findings, 159 differential diagnosis, 159 etiology biological mechanisms, 160 psychosocial, 1600 overview of, 159 prognosis, 160 treatment, 160

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316

Index

Generalized anxiety disorder (GAD), 221–222 differential diagnoses, 80 epidemiology, 79–80 in geriatric psychiatry, 199 goal for, 80 pharmacotherapy benzodiazepines, 80 GABA, 80–81 prognosis, 81 psychotherapy, 81 risk factors, 80 symptoms, 79 Genetics construct, in depression, 36 Geriatric psychiatry anxiety disorders in CBT, 200–201 comorbidity with depression, 200 features of, 199 GAD, 199 prevalence in, 199 cognitive disorders, 183–184 dementia Alzheimer’s, 184–188 infectious causes of, 190–193 Parkinson’s, 190 vascular, 188 depression in clinical management, 194 cognitive impairment and, 195 diagnosis, 193 neurobiology of, 193–194 nonpharmacological, 194 pharmacological management, 194–195 prevalence, 193 factors in FDA black box warning, 203 pharmacokinetics and pharmacodynamics, 202–203 memory cognitive, 183 impairment, 183 types, 183 psychosis in behavioral abnormalities, 196–197 cholinesterase inhibitors, 198 diagnosis, 196 divalproex, 198 nonpharmacologic treatment, 197 pharmacologic treatment, 197–198 GLP-1 receptor agonists, 22 Glutamate, 13, 94–95 Glutamyl peptidase (GGT), 93 Government funded programs, economic issues, 297 Group therapy age differentiation, 285

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CBT, 285 play therapy, 285 populations in, 286 psychoanalytic group treatment, 285 psychodrama, 285 Gustatory perception, 2 H Hallucinogens acute intoxication, treatment for, 110 and MDMA-related disorders, 109–110 perception disorder and intoxication, 110 Head trauma-related dementia, 192 Hippocampus, in depression, 34, 35 Histamine receptors H1, 7 H2, 7 H3, 7 H4, 7 HIV and AIDS, mental disorders in adolescents, 213 antiretroviral and supportive therapy, 213 in children and adolescents, 213 detection and classification, 213 psychological and developmental aspects, 213 dementia, 191 HPG axis, 164 5-HT (see Serotonin) 5-HT transporter (5-HTT) promoter gene polymorphism (5-HTTLPR), 36 Huntington’s disease, 189–190 Hydrocephalus, normal pressure, 192–193 Hyperactivity/attention/impulsivity, 257 Hyperprolactinemia, 249 risperidone, 19 Hypertension, 23 Hypnosis children and adolescents, 271 definition, 271 hypnotizability, 271 indications and applications, 271–272 Hypnotics, 148 Hypochondriasis assessment, 130 treatment, 130 Hypothalamic-pituitary-adrenal (HPA) axis, cortisol and depression, 34 I Illness, phases of, 214 Impulse control disorders brain regions, 172 comorbidities, 171 features, 171

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Index gender differences, 171–172 models, 172 neurotransmitters, 172 pathological gambling cognitive distortions, 173 criteria, 172 epidemiology, 172 medical consequences, 172 psychiatric consequences, 173 screening tools, 173 treatments, 173–174 Impulsivity, 257 Infants development, postpartum depression, effects on, 169 and early childhood diagnostic classification in, 252 mental retardation, 252–254 and toddlers, sleep disorders, 152 Informed consent, 292 Insomnia and anxiety, 72 sleep, 144, 155 pediatric population, 149–150 K Kleinian child psychoanalysis, 282 Kluver–Bucy syndrome, bilateral temporal lobectomy definition, 212 etiology and pathophysiology, 212–213 L Laboratory and diagnostic testing genomic testing COMT gene, 261 polymorphisms, 261 SNP, 261 tryptophan hydroxylase gene, 261 importance of, 259 in initial assessment biochemistry markers for, 259 EKG family history of, 260 hematologic, 259 neuroimaging and EEG, 260 suicide, symptoms of eating disorders, 260 neurodevelopmental disorders, 260 in treatment management, 260 Lamotrigine, bipolar disorder BP depression, 62–63 dosing, 60 FDA, 60 profile, 60 Law child abuse reporting, 293

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317

civil litigation, 293 competence, capacity, and guardianship, 293 confidentiality, 291–292 criminal law, 293 and ethics autonomy, respect for, 294 children’s rights, status of, 294 in clinician’s practice, 295 forensic evaluation, 295 justice, 294 legal system, 294–295 informed consent, 292 liability for, 292–293 liberty and civil commitment, 291 medicolegal aspects, malpractice and risk management, 292 right to refuse treatment, 291 treatment, 291 risk management techniques, 293 third party payers, 292 Legal system, 294–295 Lewy body disease, 189 Lifetime, developmental observations adolescence risk factors, 217 sexual activity, 217 sexual maturity rating (SMR)/tanner stages, 217 adulthood late, 218 middle, 218 young, 217–218 death and dying, 218–219 fetus behavior, 216 CNS, 216 infancy birth Chess and Thomas, 216–217 Mahler, Margaret, 216 Limbic system in depression afferents and effects, 34 amygdala, 33–34 emotion, 2 Lipid monitoring and treatment, PCOS, 251 Lithium, bipolar disorderBP depression, 62 issues, 59 side effects, 59 usage for, 59 M Male erectile disorder, 160 Malingering assessment, 133 treatment, 133

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318

Index

Mania, acute, 241 MDD, 236–237 and anxiety, 71 risk factors for, 238 MDMA disorders and hallucinogens acute intoxication, diagnosis for, 110 epidemiology, 109 etiology and pathophysiology, 109–110 findings, 109 epidemiology, 110 physical consequences, 110–111 Medical illness and relationship, with depression, 36–37 Melatonin, 155–156 receptor agonist (ramelteon), 148 Memory arousal and attention, 1 in geriatric psychiatry, 183 Mental disorders anxiety disorder, 211 catatonic disorder, 212 delirium, 205–207 developmental application psychological aspects of, 214 psychosomatic involvement, stages of, 214 treatment approaches, 214 HIV/AIDS, 213–214 Kluver–Bucy syndrome, bilateral temporal lobectomy, 212–213 mood disorder, 209–211 pseudobulbar palsy, 212 psychotic disorder, 208–209 Mental retardation assessment, 254 academic achievement, 253 adaptive behavior, 253 developmental assessment, 253 intelligence, 252–253 personality tests, 253 projective tests, 253 definition, 252 etiology acquired and developmental factors, 253–254 genetic, 253 prevalence, 252 Metabolic syndrome, 250, 251 construct, depression, 36–37 in schizophrenia blood pressure, 23 cardiovascular disease risk factors, 20–21 definition, 20 diabetes mellitus, 21–22 time of occurrence, 20

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Methadone considerations, 179 drug interactions, 179 food/herbal interactions, 179 Milieu therapy inpatient, 287 issues, 287 partial and day, 287 residential treatment centers, 287 Monoamine hypothesis, bipolar disorder, 51–52 Monoamine oxidase inhibitors (MAOIs), 40 anxiety, 71 Mood disorder, 43 with depressive features course, 210 definition, 209 etiology and pathophysiology, 209–210 with manic features, 210–211 neurotransmitters in, 70 postpartum, 169 Mood stabilizers bipolar disorder carbamazepine, 59 depakote, 59–60 lamotrigine, 60 lithium, 59 PTSD, 77 Motor and behaviors autonomic motor system, 1–2 CNS areas, 1 Multiple personality disorder (see Dissociative disorders, identity disorder) Munchausen, 133 Muscle relaxants, 181 N Naltrexone (Revia) clinical trials, 96–97 contraindications, 97 pharmacology, 96 side effects, 97 Narcolepsy features, 154 mechanism of action, 154 Neonatal neurobehavioral sequelae, 166–167 Neuritic plaques, 185 Neurobiology anxiety disorders, 73 of geriatric depression, 193–194 Neurodegenerative disorder, 11 Neurodevelopmental abnormality, in schizophrenia, 10–11 Neuroendocrinological construct, depression, 34–35 Neurogenesis, in hippocampus, 35

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Index Neuroimaging and EEG, 260 Neuroleptics, 207 Neuropathology, in Alzheimer’s disease, 185 Neuropeptides/hormones, bipolar disorder, 52 Neurosyphilis, 191–192 Neurotransmitters, 94–95 anxiety disorders, 73 depression, construct monoamine (and receptor) hypothesis dopamine pathways (DA), 33 evidence and issues of, 32 noradrenergic pathway (NA), 32 serotonin pathway (5HT), 32–33 support of, 33 in schizophrenia dopamine, 12–13 glutamate, 13 sleep, 143 Newborn, 246 Nicotine definition, 114 etiology and pathophysiology, 115 gum, 116–117 inhaler, 117 nasal spray, 117 patch, 117 treatment, phases of, 116 Nmber needed to treat (NNT), in biometrics, 269 NMDA antagonists (Memantine), 187 Noradrenergic pathway (NA), in depression, 32 Norepinephrine (NE) and epinephrine (E) formation, 6 receptors alpha-adrenergic, 6 beta-adrenergic, 7 NREM, 143, 145 Number needed to harm (NNH), in biometrics, 269 O Obsessions and compulsions, 3 Obsessive compulsive disorder, 221 clinical findings, 84 differential diagnoses, 84 epidemiology, 84 etiology, 84 PANDAS, 86 subtypes, 84 treatment, 84–86 Olanzapine, 19 Olfactory perception, 2 Ondansetron (5-HT3 antagonist), 99 Opioids (opiates) agents, 118

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319

agonists, 120 algorithm for continue/discontinue, 178 initial assessment, 176–178 long acting, 178–180 patient selection, 176 short-acting agents, 178 antagonists, 120 comorbidity, 121 dependence, 119 disorders, 117–118 efficacy, 175 epidemiology of, 118 etiology and pathophysiology of, 118 intoxication, 118 laboratory values, 119 nonopioid, 120–121 physical exam, 119 psychosocial/behavioral therapies, 121 randomized controlled trials with, 176 receptors, 118, 173 use, 118 withdrawal, 118–119 Oral contraceptives, PMDD, 165 Orgasmic disorders, 161 Ovulation suppression, PMDD, 165 Oxytocin (vasopressin), 257 P Pain opioids chronic, algorithm for, 176–181 efficacy, 175 randomized controlled trials with, 176 receptors, 175 types of, 175 Panic disorder, 222 comorbidity, 82 differential diagnoses, 84 treatment, 82–83 Paranoid personality disorder, 126 Paraphilias, 161–162 Parasomnia, 154 Parkinson’s disease clinical findings, 190 neuropathology, 190 treatment, 190 PCOS (see Polycystic ovarian syndrome) PCP course and natural history, 112 forms, 111 ketamine/K/special K, 111–112 treatment, 112 Pediatric autoimmune neuropsychiatric disorders associated with strep (PANDAS), 84, 86

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320

Index

Pediatric OCD treatment study (POTS), 85 Pediatrics anxiety acute stress disorder, 222 assessment, 222–224 epidemiology, 221 etiology, 221 generalized anxiety disorder, 221 obsessive compulsive disorder, 221 panic disorder, 222 phobia, 221 PTSD, 222 separation anxiety disorder, 221 tic disorders, 224–225 bipolar disorder, 240–244 depression assessment, 238 comorbidity, 238 course, 236–238 epidemiology of, 236 risk factors, for MDD, 238 treatment, 238–240 sleep disorders autism, 150 classification of, 150 differential diagnoses of, 151 early onset depression, 150–151 impact, 151 insomnia, 149–150 prevalence, 150 Perception addiction, 3 obsessions and compulsions, 3 somatosensory CNS areas, 2 functions, 2 visual association fibers, development of, 2 auditory, 3 CNS areas, 2 functions, 2 gustatory, 3 olfactory, 3 Persistent pulmonary hypertension of newborn (PPHN), 246 Personality disorders assessment, 125 definition, 125 longititudinal studies, 125–126 personality development, 125 types antisocial personality disorder, 127 avoidant personality disorder, 127 borderline, 126–127 dependent personality disorder, 128 histrionic, 126

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narcissistic, 127 paranoid personality disorder, 126 schizoid personality disorder, 126 schizotypal personality disorder, 126 Pervasive developmental disorders clinical subtypes Asperger disorder, 256 Autistic disorder, 255 childhood disintegrative disorder, 256 Rett disorder, 256 course, 255 definition, 254–255 epidemiology, 255 etiology, 255 testing, 256 treatment behavioral interventions, 256–257 evaluation, 256 hyperactivity/attention/impulsivity, 257 types, 255 Pharmacodynamics, 187 Pharmacokinetics, 187 Phobia, 221 Physiology, of brain 1012 glial cells, 5 biogenic neurotransmitters, 6–7 neural formations, 5 types anandamides, 6 biogenic amines, 5 eicosanoids, 5 neurotrophic factors, 5 sigma receptors, 6 PMDD (see Premenstrual dysphoric disorder) Polycystic ovarian syndrome (PCOS) definition, 250 diabetes monitoring and recommendations, 251 lipid monitoring and treatment, 251 weight, metabolic syndrome, 250–251 Polymorphisms associated with complex psychiatric illnesses, 261 5-HT transporter and 5-HT receptor gene, 261 Positive and negative symptom scale (PANSS), 16, 264 Post-modern family therapy, 279–280 Postpartum mood disorder breastfeeding, 169 depression, 169 incidence, 169 Pregabalin, anxiety beta-blockers, 69 buspirone, 69 cognitive behavioral therapy (CBT), 69

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Index kava-kava, 69 SGA, 69 Pregnancy demographics, 166 depression in, 166 postpartum mood disorder breastfeeding, 169 depression, 169 incidence, 169 relapse ACOG, 168 antidepressants, 168 benzodiazepines, 168 neonatal neurobehavioral sequelae, 166–167 PPHN, 168 recommendations, 168 SSRI’s and TCA’s, 168 treatment implications, 166 Premenstrual dysphoric disorder (PMDD) associations of, 164–165 comorbidity, 163 DSM-IV diagnostic criteria for, 164 epidemiology, 163 etiology, 164 HPG axis, 164 luteal phase progesterone, 165 premenstrual dysphoria/premenstrual disorder, 163 rating scales, 165 serotonin function, 164 treatment ovulation suppression, 165 serotonin FDA-approved agents, 165 Premorbid personality, 17 Preschoolers depression, 237 sleep disorders in, 153 Problem-solving skills training (PSST), cognitive, 274 Prolactin, 249–250 Pseudobulbar palsy, 212 Psychoanalytic group treatment, 285 Psychodynamic therapy adult Adler, Alfred, 281 Balint, Michael, 281 Erikson, Erik, 281 Freud, Anna, 281 Freud, Sigmund, 282 Fromm, Erich, 282 Horney, Karen, 282 Jung, Carl, 282 Klein, Melanie, 282 Kohut, Hans, 282 Mahler, Margaret, 282

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321

principles, 281 Sullivan, Henry Stack, 282 Winnicott, D.W., 282 child Freudian psychoanalysis, 282 Kleinian child psychoanalysis, 282 psychotherapy, 283 Psychological assessments areas of anxiety, 263 Brief Psychiatric Rating Scale (BPRS), 263 depression, 264 intelligence, 263 mania, 264 Million Clinical Multiaxial Inventory (MCMI-III), 263 Minnesota Multiphasic Personality Inventory-2 (MMPI-2), 263 Personality Assessment Inventory (PAI), 263 personality disorders, 264 psychodynamics and patient enabling factors, 264 suicide, 264 symptom checklist 90-revised (SCL-90-R), 263 tests, 265 Psychosis, in geriatrics, 196–199 Psychotherapy, 283 generalized anxiety disorder, 81 Psychotic disorder assessment and differential diagnoses, 208–209 etiology and pathophysiology, 208 PTSD assessment children, 76 EMDR, 76 history, 74–75 nonpharmacological treatment, 75–76 pharmacological, 76–78 psychodynamic, 76 resources, 76 characteristics, 222 comorbidity, 74 developmental considerations, 74 diagnostic criteria and clinical findings, 73–74 etiology, 74 history of, 73 neurobiology, 73 risk factors, 74 sleep disturbances, 78 treatment, 222 treatment considerations for, 78–79 Pulmonary disease and anxiety, 72

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322

Index

Q Quetiapine, 61 R REM, 143, 145 medication effects, 157 Restless legs (RLS) and periodic limb movement disorder, 146–147 Rett disorder, 256 Risperidone, 61 hyperprolactinemia, 19 S Schizoid personality disorder, 126 Schizophrenia, 196 affective impairment associated with depression, 17 individual outcome optimization, 18 substance abuse, 17–18 suicide, 17 course lifelong prognosis, 17 premorbid personality, 17 diagnosis differential diagnosis, 16 signs and symptoms, 15 subtypes, 16 epidemiology age of onset, 10 morbidity, 9 mortality, 9 prevalence, 9 prognosis, 10 etiology brain regions, 10–12 genetic, 14 historical theories, 10 infectious disease and immunological factors, 14–15 neurolinguistic factors, 14 neuropsychological factors, 14 obstetric complications, 14 nonpharmacologic treatment approaches, 29–30 assertive community treatment, 30 cognitive behavioral therapy, 30 cognitive rehabilitation, 30 family intervention, 30 practice recommendations, 26–27 SGA studies, 24–26 substance abuse in agents, 29 prevalence, 29 risk factors, 29 treatment, 29 treatment first-generation antipsychotics (FGA), 19

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medication selection, considerations of, 18–19 metabolic syndrome, 20–23 second-generation antipsychotics (SGA), 19–20 side effects, 23–24 treatment-resistant, pharmacological strategies for approaches, 28 extreme agitation, rapid treatment for, 27 long-acting forms, 28 medications, 28–29 p-glycoprotein, 28 polypharmacy strategy, 27 synergistic effects, 28 Schizotypal personality disorder, 126 School-aged children, sleep disorders, 153 Second-generation antipsychotics (SGA), 207 PTSD, 78 in schizophrenia clozapine, 19 cost utility of the latest antipsychotic drugs in schizophrenia study (CUtLASS), 26 genetic polymorphisms, 26 olanzapine, 19 risperidone, 19 side effects, 19–20 trial design, 24–25 Selegeline, 40 Separation anxiety disorder, 82, 221 Serotonin (5-HT), 7 bipolar disorder, 51 depression, 32–33 FDA-approved agents, 165 transporter and receptor gene, 261 Sertraline, 85 Sexual disorders paraphilias, 161–162 sexual arousal disorders male erectile disorder, 160 orgasmic disorders, 161 sexual pain disorders, 161 types, 161–162 Sexual dysfunction, alcohol-induced, 91 Sexual maturity rating (SMR)/tanner stages, 217 Sexual pain disorders, 161 SGA (see Second-generation antipsychotics) Single nucleotide (point) polymorphism (SNP), 261 Sleep apnea, 149 brain areas suprachiasmatic nucleus (SCN), 144 wakefulness, factors, 143–144

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323

Index depression, 144 disorders in adolescents, 153 adults, 145–149 breathing, 154 caffeine, 103 circadian rhythm, 154–155 in infants and toddlers, 152 in medical and psychiatric conditions, 153 narcolepsy, 154 parasomnia, 154 pediatric population, 149–153 in preschool-aged children, 153 in school-aged children, 153 disturbances, PTSD, 78 insomnia, 144 in medical and psychiatric conditions, 153 medication effects caffeinated beverages, 157 guidelines, 157 SSRIs, 156 TCA, 156 neurological understandings, 143–145 neurotransmitters NREM, 143 REM, 143 wake, 143 physiology of, 145 problems in, treatment of effects, 156 insomnia, 155 pharmacology, 155–156 sleepiness, 155 steps, 155 REM sleep, 144 requirements, 145 sleep-wake organization, 145 Social anxiety disorder clinical findings, 81 comorbidity, 82 treatment, 82 Somatization disorder assessment, 129 treatment, 129 Somatoform disorders body dysmorphic disorder, 130 conversion disorder, 129–130 hypochondriasis, 130 somatization disorder, 129 undifferentiated, 129 SSRIs, 40–41, 201, 246 panic disorder, 83 pediatric anxiety activation, 223 bipolar switching, 223

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in sleep, 156 and SNRIs, in generalized anxiety disorder, 81 Starvation effects, anorexia nervosa physical, 137 psychological, 136–137 Stimulants, 107–108 ADHD findings with, 232 issues with, 233 MTA study, 231 PAT study, 230–231 sleepiness, 155 Strategic family therapy, 279 Stress diathesis model, bipolar disorder, 52–53 disorder, acute, 222 Stress inoculation training (SIT), 75 Structural family therapy, 278–279 Subacute sclerosing panencephalitis (SSPE), 190 Substance abuse, in schizophrenia, 17–18, 29 Substance use and ADHD SUD, 234 tobacco, 234–236 disorders brain areas, 87 definition, 88 environment, 87–88 genetics, 87 Substance withdrawal alcohol, 90–100 (see also Alcohol) anabolic steroids, 108–109 assessment domains and stages, 89–90 standardized instruments, 90 caffeine, 100–103 cannabis, 103–106 cocaine, 106–107 course and natural history, 89 ecstasy, 113 etiology and pathophysiology biological factors, 88 psychological, 88–89 hallucinogens, 109–110 inhalants, 113–114 issues, in psychiatric exam, 89 MDMA, 110–111 nicotine, 114–117 opiates, 117–121 sedative, hypnotic, anxiolytics acute intoxication with, 122 assessment, 122 dependence, 122 detoxification, 123

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324

Index

Substance withdrawal (Continued) etiology, 121–122 ICD-10, 123 patterns of, 122 stimulants, 107–108 Substance-inducing persisting dementia, 190 Suicide, 37–38, 264 risk factors, 238 symptoms of, 260 Sulfonyureas, 22 Suprachiasmatic nucleus (SCN), 144 T TCA, in sleep, 156 Therapeutic modalities cognitive behavioral therapy, 273–274 couples therapy, 289–290 family therapy, 275–280 group therapy, 285–286 hypnosis, 271–272 milieu therapy, 287 Thiazolidinediones, 22 Thyroid function, 248–249 Tic disorders, 224–225 Tobacco, ADHD alcohol use and, 235 assessment, 235–236 psychosocial therapy, 236 risk factors, 235 treatment, 236 Tourette, tic disorders, 224–225 Transcranial magnetic stimulation (TMS), 45

Thein_Index.indd 324

Treatment of adolescent depression study (TADS), 239 Treatment of adolescent suicide attempter (TASA), 239 Treatment of early-onset schizophrenia (TEOSS) study, 220 Treatment of SSRI resistant depression in adolescents (TORDIA), 239 Tryptophan hydroxylase gene, 261 T-test, in biometrics, 268 Twin studies bipolar disorder, 51 neuroticism and internalizing disorder in, 66 V Vaginismus, 161 Vascular dementia, in geriatric psychiatry clinical findings, 189 Huntington’s, 189–190 Lewy body disease, 189 Vascular hypothesis, geriatric psychiatry, 193–194 Visual perception, 2 W Wilson’s disease, 192–193 Y Yaz, oral contraceptive, 165 Z Ziprasidone, 61

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