Psychiatry Bullets

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Author: Mimi W. Thein

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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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2

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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6

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×

9

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10

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

11

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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12

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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13

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)


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


First-degree relatives

50% genes shared


Second-degree relatives

25% genes shared

2% to 4% chance of transmission

Related genes (there is no major gene—all have 40″ Females >35″ Triglyceride levels >150 mg/dL HDL—C levels Males 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 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 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 160 mm Hg

Encompassing Major Side Effects

Lithium Valproate Carbemazepine ± Lamotrigine Clozapine Olanzapine Risperidone Ziprasidone Quetiapine Aripiprazole


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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Psychiatry Bullets

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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27

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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Psychiatry Bullets

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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29

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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Chapter 4 Depression

33

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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39

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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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 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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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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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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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 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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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 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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Psychiatry Bullets Childhood presentation Preadolescence (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 (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 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), 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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7

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 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 1 year maladaptive (Antisocial personality disorder: severe chronic CD and pattern of irresponsibility and as behavior 20% original body weight loss in 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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169

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


171

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Psychiatry Bullets

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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Psychiatry Bullets

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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177

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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Psychiatry Bullets

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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179

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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Psychiatry Bullets

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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181

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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Chapter

18

Geriatric Psychiatry

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


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 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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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 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 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

Child

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

12 hours

daily

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 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 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

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