Stahl's Essential Psychopharmacology

4th Edition - 9781107686465

This fully revised edition returns to the essential roots of what it means to become a neurobiologically empowered psychopharmacologist. This remains the essential text for all students and professionals in mental health seeking to understand and utilize current therapeutics.

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CAMBRIDGE UNIVERSITY PRESS
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Cambridge University Press
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Published in the United States of America by Cambridge University Press, New York

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Information on this title: www.cambridge.org/9781107025981

This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press.

First edition published 1996
Second edition published 2000
Third edition published 2008
Fourth edition published 2013

Printed and bound in the United Kingdom by the MPG Books Group

A catalog record for this publication is available from the British Library

Library of Congress Cataloging in Publication data

ISBN 978-1-107-02598-1 Hardback
ISBN 978-1-107-68646-5 Paperback

Cambridge University Press has no responsibility for the persistence or accuracy of URLs for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate.

Every effort has been made in preparing this book to provide accurate and up-to-date information which is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors, and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

Preface to the fourth edition

CME information

Chapter 1	Chapter 11
Chemical neurotransmission	Disorders of sleep and wakefulness and their treatment
Chapter 2	Chapter 12
Transporters, receptors, and enzymes as targets of psychopharmacological drug action	Attention deficit hyperactivity disorder and its treatment
Chapter 3	Chapter 13
Ion channels as targets of psychopharmacological drug action	Dementia and its treatment
Chapter 4	Chapter 14
Psychosis and schizophrenia	Impulsivity, compulsivity, and addiction
Chapter 5
Antipsychotic agents
Chapter 6
Mood disorders
Chapter 7
Antidepressants
Chapter 8
Mood stabilizers
Chapter 9
Anxiety disorders and anxiolytics
Chapter 10
Chronic pain and its treatment

Index

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Dementia and its treatment

This chapter will provide a brief overview of the various causes of dementias and their pathologies, including the most recent diagnostic criteria and the emerging integration of biomarkers into clinical practice for Alzheimer’s disease. Full clinical descriptions and formal criteria for how to diagnose the numerous known dementias should be obtained by consulting standard reference sources. The discussion here will emphasize the links between various pathological mechanisms, brain circuits, and neurotransmitters and the various symptoms of dementia, with an emphasis on Alzheimer’s disease. The goal of this chapter is to acquaint the reader with ideas about the clinical and biological aspects of dementia and its currently approved treatments as well as new treatments that are on the horizon. The emphasis here is on the biological basis of symptoms of dementia and of their relief by psychopharmacologic agents, as well as on the mechanism of action of drugs that treat these symptoms. For details of doses, side effects, drug interactions, and other issues relevant to the prescribing of these drugs in clinical practice, the reader should consult standard drug handbooks (such as Stahl’s Essential Psychopharmacology: the Prescriber’s Guide).

Causes, pathology, and clinical features of dementia

Dementia consists of memory impairment (amnesia) plus deficits in either language (aphasia), motor function (apraxia), recognition (agnosia), or executive function such as working memory and problem solving. Personality changes can also be present,

Table 13-1 Pathological features of selected degenerative dementias

Table 13-2 Not all memory disturbance is Alzheimer’s disease: clinical features of selected degenerative dementias

sometimes even before memory impairment begins. There are many causes of dementia (Tables 13-1 through 13-3), and the unique pathologies associated with some of the major dementias are listed in Table 13-1. Knowing the pathology does not mean that a treatment is available, as it is often not evident how to translate information about brain pathology into pharmacological treatments. The best hope currently is in the area of amyloid pathology, where new treatments under investigation are attempting to interfere with amyloid processing in Alzheimer’s disease, as will be discussed later in this chapter.

Just because a patient develops memory disturbance does not mean it is Alzheimer’s disease (Table 13-2). Alzheimer’s dementia is perhaps the best-known and commonest dementia, but it is often the other symptoms associated with memory loss that help make the diagnosis clinically (Table 13-2). Just to complicate things, many patients have mixed types of dementia, particularly Alzheimer’s dementia plus dementia with Lewy bodies, or Alzheimer’s dementia plus vascular dementia (Figure 13-1). Such cases

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Figure 13-1. Mixed dementia. There are several types of dementia, of which Alzheimer’s disease is the most common. They are distinguished by their underlying pathologies. It is possible to have more than one dementia, and in fact many patients have both Alzheimer’s disease and either dementia with Lewy bodies or vascular dementia.

are complicated to diagnose clinically, and definitive diagnosis sometimes must await autopsy. Most dementias are really pathological diagnoses, not clinical diagnoses.

Table 13-3 Nondegenerative dementias

A wide variety of dementias are considered nondegenerative, and these are listed in Table 13-3. Many of these are treatable upon discovering the underlying cause, but others are not. Extensive clinical evaluation and laboratory testing must rule out these causes prior to concluding that a case of dementia is due to Alzheimer’s disease.

Alzheimer’s disease: β-amyloid plaques and neurofibrillary tangles

Without the introduction of disease-modifying treatments, Alzheimer’s disease is poised for an exponential increase throughout the world, with projections that it will quadruple over the next 40 years to affect 1 in every 85 people on earth: over 100 million people by 2050. Fortunately, new treatments are being designed to interfere with various known pathological processes, particularly the formation of amyloid plaques, in an attempt to halt or slow disease progression in Alzheimer’s disease before neurons are irretrievably lost. To understand the current diagnostic criteria for Alzheimer’s disease, how and why biomarkers are being integrated into the diagnosis of this disorder, and the rationale behind the hot pursuit of new therapeutics, it is necessary to understand how the two hallmarks of this disorder, amyloid plaques and neurofibrillary tangles, are thought to be formed in the brain in Alzheimer’s disease.

The amyloid cascade hypothesis

The leading contemporary theory for the biological basis of Alzheimer’s disease centers around the formation of toxic amyloid plaques from peptides due to the abnormal processing of amyloid precursor protein (APP) into toxic forms of Abeta (Aβ) peptides (Figures 13-2 through 13-9). Why do we make Aβ in the first place? Although this is not fully understood, nontoxic Aβ peptides have antioxidant properties, can chelate metal ions, regulate cholesterol transport, and may be involved in blood vessel repair, as a sealant at sites of injury or leakage, possibly protecting from acute brain injury. Hypothetically, Alzheimer’s disease is a disorder in which toxic Aβ peptides are formed, leading to deposition of amyloid plaque in the brain, with the ultimate destruction of neurons diffusely throughout the brain, somewhat analogous to how the abnormal deposition of cholesterol in blood vessels causes atherosclerosis.

Thus, Alzheimer’s disease may be essentially a problem of too much formation of Aβ amyloid-forming peptides, or too little removal of them. One idea is that neurons in some patients destined to have Alzheimer’s disease have abnormalities either in genes that code for a protein called amyloid precursor protein (APP), or in the enzymes that cut this precursor into smaller peptides, or in the mechanisms of removal of these peptides from the brain and from the body. APP is a

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Figure 13-2. Processing of amyloid precursor protein into soluble peptides. The way in which amyloid precursor protein (APP) is processed may help determine whether an individual develops Alzheimer’s disease or not. A nontoxic pathway for APP processing is shown here. APP is a transmembrane protein with the C-terminal inside the neuron and the N-terminal outside the neuron. The enzyme α-secretase cuts APP close to where it comes out of the membrane to form two peptides: α-APP, which is soluble, and an 83-amino-acid peptide that remains in the membrane. A second enzyme, γ-secretase, cuts the embedded peptide into two smaller peptides, p7 and p3, which are not “amyloidogenic” and thus are not toxic.

transmembrane protein with the C-terminal inside the neuron and the N-terminal outside the neuron. One pathway for APP processing does not produce toxic peptides and involves the enzyme α-secretase (Figure 13-2). Alpha-secretase cuts APP close to the area where the protein comes out of the membrane, forming two peptides: a soluble fragment known as α-APP and a smaller 83-amino-acid peptide that remains embedded in the membrane until it is further cleaved by a second enzyme acting within the neuronal membrane, called γ-secretase (Figure 13-2). That enzyme produces two smaller peptides, p7 and p3, which are apparently not “amyloidogenic” and therefore not toxic (Figure 13-2).

Another pathway for APP processing can produce toxic peptides that form amyloid plaques (i.e., “amyloidogenic” peptides). In this case a different enzyme, β-secretase, cuts APP a little bit further away from the area where APP comes out of the membrane, forming two peptides: a soluble fragment known as β-APP and a smaller 91-amino-acid peptide that remains embedded in the membrane until it is further cleaved by γ-secretase within the membrane (Figure 13-3). This releases Aβ peptides of 40, 42 or 43 amino acids that are “amyloidogenic,” especially Aβ42 (Figure 13-3).

In Alzheimer’s disease, genetic abnormalities may produce an altered APP that, when processed by this second pathway involving β-secretase, produces smaller peptides that are especially toxic. Individuals who do not get Alzheimer’s disease may produce peptides that are not very toxic, or may have highly efficient removal mechanisms that prevent neuronal toxicity from developing. The amyloid cascade hypothesis of Alzheimer’s disease therefore begins with an APP that is hypothetically genetically abnormal, or genetically or environmentally abnormal in the way it is processed, so that when it is cut into smaller peptide fragments too many toxic peptides are made, accumulate, and form neuron-destroying amyloid plaques, i.e., amyloidosis, and neurofibrillary tangles. Hypothetically, this process triggers a lethal chemical cascade that ultimately results in Alzheimer’s disease (Figures 13-3 through 13-8).

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Figure 13-3. Processing of amyloid precursor protein into Aβ peptides. The way in which amyloid precursor protein (APP) is processed may help determine whether an individual develops Alzheimer’s disease or not. A toxic pathway for APP processing is shown here. APP is a transmembrane protein with the C-terminal inside the neuron and the N-terminal outside the neuron. The enzyme β-secretase cuts APP at a spot outside the membrane to form two peptides: β-APP, which is soluble, and a 91-amino-acid peptide that remains in the membrane. Gamma-secretase then cuts the embedded peptide; this releases Aβ peptides of 40, 42, or 43 amino acids. These toxic (amyloidogenic) peptides form amyloid plaques.

Specifically, abnormal genes or other influences cause the formation of an altered APP, or altered processing into too many toxic Aβ42 peptides (Figure 13-4). Next, the Aβ42 peptides form oligomers (a collection of a few copies of Aβ42 assembled together: Figure 13-5). These oligomers can interfere with synaptic functioning and neurotransmitter actions such as those of acetylcholine, but they are not necessarily lethal to the neurons at first. Eventually, Aβ42 oligomers form amyloid plaques, which are even larger clumps of Aβ42 peptides stuck together with a number of other molecules (Figure 13-6). A number of nasty biochemical events then occur, including inflammatory responses, activation of microglia and astrocytes, and release of toxic chemicals including cytokines and free radicals (Figure 13-6). These chemical events then hypothetically trigger the formation of neurofibrillary tangles within neurons by altering the activities of various kinases and phosphatases, causing hyperphosphorylation of tau proteins, and converting neuronal

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Figure 13-4. Amyloid cascade hypothesis, part 1: increased production of Aβ42. One theory for the pathophysiology of Alzheimer’s disease is that there are genetic abnormalities in amyloid precursor protein (APP), so that when it is processed by the pathway involving β-secretase, it produces smaller, toxic peptides (especially Aβ42, as shown here).

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Figure 13-5. Amyloid cascade hypothesis, part 2: Aβ42 oligomers form and interfere with synaptic function. Aβ42 peptides assemble together to form oligomers, which interfere with synaptic functioning and neurotransmitter actions but are not necessarily lethal to neurons.

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Figure 13-6. Amyloid cascade hypothesis, part 3: formation of amyloid plaques causing inflammation. Aβ42 oligomers clump together along with other molecules to form amyloid plaques. These plaques can cause inflammatory responses, activation of microglia and astrocytes, and release of toxic chemicals such as cytokines and free radicals.

microtubules into tangles (Figure 13-7). Finally, widespread synaptic dysfunction from Aβ42 oligomers, neuronal dysfunction and death from formation of amyloid plaques outside of neurons and neurofibrillary tangles within neurons leads to diffuse neuronal death (Figure 13-8) and regional expansion of neuronal destruction in the cortex, causing the relentless progression of Alzheimer’s symptoms of amnesia, aphasia, agnosia, apraxia, and executive dysfunction. Some investigators believe that Alzheimer’s disease may spread from neuron to neuron, with pathological phosphorylated tau transported down axons, released at synapses and then taken up by neighboring cells. Pathological tau possibly then latches onto normal tau in the connected neurons, triggering the formation of new pathological mis-folded tau, from one affected neuron to the next.

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Figure 13-7. Amyloid cascade hypothesis, part 4: amyloid plaque induces formation of tangles. Amyloid plaques and the chemical events they cause activate kinases, cause phosphorylation of tau proteins, and convert microtubules into tangles within neurons.

Support for the amyloid cascade hypothesis comes from genetic studies of those relatively rare inherited autosomal dominant forms of Alzheimer’s disease. Sporadic (i.e., noninherited) cases account for the vast majority of Alzheimer’s disease cases, but inherited cases can provide clues for what is wrong in the usual sporadic cases of Alzheimer’s disease. Rare familial cases of Alzheimer’s disease have an early onset (i.e., before age 65) and have been linked to mutations in at least three different chromosomes: 21, 14, and 1. The mutation on chromosome 21 codes for a defect in APP, leading to increased deposition of β-amyloid. Recall that Down’s syndrome is also a disorder of this same chromosome (i.e., trisomy 21), and virtually all such persons develop Alzheimer’s disease if they live past age 50. A different mutation on chromosome 14 codes for an altered form of a protein called presenilin 1, a component of the γ-secretase enzyme complex. A third mutation, on chromosome 1, codes for an altered form of presenilin 2, a component of a different form of γ-secretase. It is not yet clear what if anything these three mutations in the rare familial cases tell us about the pathophysiology of the usual sporadic, nonfamilial, and late-onset cases of Alzheimer’s disease. However, they all point to abnormal processing of APP into amyloidogenic β-amyloid peptides as a cause for the dementia, consistent with the amyloid cascade hypothesis. Theoretically, different abnormalities in amyloid processing may occur in sporadic Alzheimer’s disease from those identified in inherited cases, and there may even be multiple abnormalities that could be responsible for sporadic Alzheimer’s disease as a final common pathway, but the evidence nevertheless implicates something in the amyloid cascade that goes wrong in Alzheimer’s disease. If so, this implies that preventing the formation of amyloidogenic peptides could prevent Alzheimer’s disease.

ApoE and risk of Alzheimer’s disease

A corollary to the amyloid cascade hypothesis is the possibility that something may be wrong with a protein that binds to amyloid peptides in order to remove them (Figure 13-9). This protein is called apolipoprotein E (ApoE). In the case of “good” ApoE, it binds to β-amyloid peptides and removes them, hypothetically preventing the formation of Alzheimer’s disease and dementia (Figure 13-9A). In the case of “bad” ApoE, a genetic abnormality in the formation of ApoE causes it to be ineffective in how it binds to β-amyloid peptides. This causes amyloid plaques to be formed and deposited around neurons, which goes on to damage neurons and cause Alzheimer’s disease (Figure 13-9B).

Genes coding for ApoE are associated with different risks for Alzheimer’s disease. There are three alleles (or variants) of this gene coding for this apolipoprotein called E2, E3, and E4, and everyone has two alleles. The E4 variant on chromosome 19 (“bad” ApoE) is linked to many cases of late-onset Alzheimer’s disease, the usual form of this

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Figure 13-8. Amyloid cascade hypothesis, part 5: neuronal dysfunction and loss. The effects of amyloid plaques and the build-up of neurofibrillary tangles can ultimately lead to neuronal dysfunction and death.

illness. ApoE is associated with cholesterol transport and involved with other neuronal functions including repair, growth, and maintenance of myelin sheaths and cell membranes. Having one or two copies of E4 increases the risk of getting Alzheimer’s disease. In fact, some studies show that you have a 50–90% chance of developing Alzheimer’s disease by age 85 if you are an E4 homozygote (i.e., you have two copies of E4); a 45% chance if you are a heterozygote for E4, versus the risk in the general population at 20%. Alzheimer’s patients with the E4 gene also have more amyloid deposits and progress more rapidly to dementia than those without the E4 gene. The E2 variant may actually be somewhat protective.

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Preface to the fourth edition

For this fourth edition of Stahl’s Essential Psychopharmacology you will notice there is a new look and feel. With a new layout, displayed over two columns, and an increased page size we have eliminated redundancies across chapters, have added significant new material, and yet have decreased the overall size of the book.

Highlights of what has been added or changed since the 3rd edition include:

Integrating much of the basic neurosciences into the clinical chapters, thus reducing the number of introductory chapters solely covering basic neurosciences.
Major revision of the psychosis chapter, including much more detailed coverage of the neurocircuitry of schizophrenia, the role of glutamate, genomics, and neuroimaging.
One of the most extensively revised chapters is on antipsychotics, which now has:
- new discussion and illustrations on how the current atypical antipsychotics act upon serotonin, dopamine, and glutamate circuitry
- new discussion of the roles of neurotransmitter receptors in the mechanisms of actions of some but not all atypical antipsychotics
  - 5HT₇ receptors
  - 5HT_2C receptors
  - α₁-adrenergic receptors
- completely revamped visuals for displaying the relative binding properties of 17 individual antipsychotics agents, based upon log binding data made qualitative and visual with novel graphics
- reorganization of the known atypical antipsychotics as
  - the “pines” (peens)
  - the “dones”
  - two “pips”
  - and a “rip”
- inclusion of several new antipsychotics
  - iloperidone (Fanapt)
  - asenapine (Saphris)
  - lurasidone (Latuda)
- extensive coverage of switching from one antipsychotic to another
- new ideas about using high dosing and polypharmacy for treatment resistance and violence
- new antipsychotics in the pipeline
  - brexpiprazole
  - cariprazine
  - selective glycine reuptake inhibitors (SGRIs, e.g., bitopertin [RG1678], Org25935, SSR103800)

The mood chapter has expanded coverage of stress, neurocircuitry, and genetics.
The antidepressant and mood stabilizer chapters have:
- new discussion and illustrations on circadian rhythms
- discussion of the roles of neurotransmitter receptors in the mechanisms of actions of some antidepressants
  - melatonin receptors
  - 5HT_1A receptors
  - 5HT_2C receptors
  - 5HT₃ receptors
  - 5HT₇ receptors
  - NMDA glutamate receptors
- inclusion of several new antidepressants
  - agomelatine (Valdoxan)
  - vilazodone (Viibryd)
  - vortioxetine (LuAA21004)
  - ketamine (rapid onset for treatment resistance)

The anxiety chapter provides new coverage of the concepts of fear conditioning, fear extinction, and reconsolidation, with OCD moved to the impulsivity chapter.
The pain chapter updates neuropathic pain states.
The sleep/wake chapter provides expanded coverage of melatonin and new discussion of orexin pathways and orexin receptors, as well as new drugs targeting orexin receptors as antagonists, such as:
- suvorexant/MK-6096
- almorexant
- SB-649868

The ADHD chapter includes new discussion on how norepinephrine and dopamine tune pyramidal neurons in prefrontal cortex, and expanded discussion on new treatments such as:
- guanfacine ER (Intuniv)
- lisdexamfetamine (Vyvanse)

The dementia chapter has been extensively revamped to emphasize the new diagnostic criteria for Alzheimer’s disease, and the integration of biomarkers into diagnostic schemes including:
- Alzheimer’s diagnostics
  - CSF Aβ and tau levels
  - amyloid PET scans, FDG-PET scans, structural MRI scans
- multiple new drugs in the pipeline targeting amyloid plaques, tangles, and tau
  - vaccines/immunotherapy (e.g., bapineuzumab, solenezumab, crenezumab), intravenous immunoglobulin
  - γ-secretase inhibitors (GSIs, e.g., semagacestat)
  - β-secretase inhibitors (e.g., LY2886721, SCH 1381252, CTS21666, others)

The impulsivity–compulsivity and addiction chapter is another of the most extensively revised chapters in this fourth edition, significantly expanding the drug abuse chapter of the third edition to include now a large number of related “impulsive–compulsive” disorders that hypothetically share the same brain circuitry:
- neurocircuitry of impulsivity and reward involving the ventral striatum
- neurocircuitry of compulsivity and habits including drug addiction and behavioral addiction involving the dorsal striatum
- “bottom-up” striatal drives and “top-down” inhibitory controls from the prefrontal cortex
- update on the neurobiology and available treatments for the drug addictions (stimulants, nicotine, alcohol, opioids, hallucinogens, and others)
- behavioral addictions
  - major new section on obesity, eating disorders, and food addiction, including the role of hypothalamic circuits and new treatments for obesity
  - lorcaserin (Belviq)
  - phentermine/topiramate ER (Qsymia)
  - bupropion/naltrexone (Contrave)
  - zonisamide/naltrexone
  - obsessive–compulsive and spectrum disorders
  - gambling, impulsive violence, mania, ADHD and many others

One of the major themes emphasized in this new edition is the notion of symptom endophenotypes, or dimensions of psychopathology that cut across numerous syndromes. This is seen perhaps most dramatically in the organization of numerous disorders of impulsivity/compulsivity, where impulsivity and/or compulsivity are present in many psychiatric conditions and thus “travel” trans-diagnostically without respecting the DSM (Diagnostic and Statistical Manual) of the American Psychiatric Association or the ICD (International Classification of Diseases). This is the future of psychiatry – the matching of symptom endophenotypes to hypothetically malfunctioning brain circuits, regulated by genes, the environment, and neurotransmitters. Hypothetically, inefficiency of information processing in these brain circuits creates symptom expression in various psychiatric disorders that can be changed with psychopharmacologic agents. Even the DSM recognizes this concept and calls it Research Domain Criteria (or RDoC). Thus, impulsivity and compulsivity can be seen as domains of psychopathology; other domains include mood, cognition, anxiety, motivation, and many more. Each chapter in this fourth edition discusses “symptoms and circuits” and how to exploit domains of psychopathology both to become a neurobiologically empowered psychopharmacologist, and to select and combine treatments for individual patients in psychopharmacology practice.

What has not changed in this new edition is the didactic style of the first three editions. This text attempts to present the fundamentals of psychopharmacology in simplified and readily readable form. We emphasize current formulations of disease mechanisms and also drug mechanisms. As in previous editions, the text is not extensively referenced to original papers, but rather to textbooks and reviews and a few selected original papers, with only a limited reading list for each chapter, but preparing the reader to consult more sophisticated textbooks as well as the professional literature.

The organization of information continues to apply the principles of programmed learning for the reader, namely repetition and interaction, which has been shown to enhance retention. Therefore, it is suggested that novices first approach this text by going through it from beginning to end, reviewing only the color graphics and the legends for those graphics. Virtually everything covered in the text is also covered in the graphics and icons. Once having gone through all the color graphics in these chapters, it is recommended that the reader then go back to the beginning of the book, and read the entire text, reviewing the graphics at the same time. After the text has been read, the entire book can be rapidly reviewed again merely by referring to the various color graphics in the book. This mechanism of using the materials will create a certain amount of programmed learning by incorporating the elements of repetition, as well as interaction with visual learning through graphics. Hopefully, the visual concepts learned via graphics will reinforce abstract concepts learned from the written text, especially for those of you who are primarily “visual learners” (i.e., those who retain information better from visualizing concepts than from reading about them). For those of you who are already familiar with psychopharmacology, this book should provide easy reading from beginning to end. Going back and forth between the text and the graphics should provide interaction. Following review of the complete text, it should be simple to review the entire book by going through the graphics once again.

Expansion of Essential Psychopharmacology books

This fourth edition of Essential Psychopharmacology is the flagship, but not the entire fleet, as the Essential Psychopharmacology series has expanded now to an entire suite of products for the interested reader. For those of you interested in specific prescribing information, there are now three prescriber’s guides:

for psychotropic drugs, Stahl’s Essential Psychopharmacology: the Prescriber’s Guide
for neurology drugs, Essential Neuropharmacology: the Prescriber’s Guide
for pain drugs: Essential Pain Pharmacology: the Prescriber’s Guide

For those interested in how the textbook and prescriber’s guides get applied in clinical practice there is a book covering 40 cases from my own clinical practice:

Case Studies: Stahl’s Essential Psychopharmacology

For teachers and students wanting to assess objectively their state of expertise, to pursue maintenance of certification credits for board recertification in psychiatry in the US, and for background on instructional design and how to teach there are two books:

Stahl’s Self-Assessment Examination in Psychiatry: Multiple Choice Questions for Clinicians
Best Practices in Medical Teaching

For those interested in expanded visual coverage of specialty topics in psychopharmacology, there is the Stahl’s Illustrated series:

Antidepressants
Antipsychotics: Treating Psychosis, Mania and Depression, 2nd edition
Anxiety, Stress, and PTSD
Attention Deficit Hyperactivity Disorder
Chronic Pain and Fibromyalgia
Mood Stabilizers
Substance Use and Impulsive Disorders

Finally, there is an ever-growing edited series of subspecialty topics:

Next Generation Antidepressants
Essential Evidence-Based Psychopharmacology, 2nd edition
Essential CNS Drug Development

Essential Psychopharmacology Online

Now, you also have the option of accessing all these books plus additional features online by going to Essential Psychopharmacology Online at www.stahlonline.org. We are proud to announce the continuing update of this new website which allows you to search online within the entire Essential Psychopharmacology suite of products. With publication of the fourth edition, two new features will become available on the website:

downloadable slides of all the figures in the book
narrated animations of several figures in the textbook, hyperlinked to the online version of the book, playable with a click

In addition, www.stahlonline.org is now linked to:

our new journal CNS Spectrums (www.journals.cambridge.org/CNS), of which I am the new editor-in-chief, and which is now the official journal of the Neuroscience Education Institute (NEI), free online to NEI members. This journal now features readable and illustrated reviews of current topics in psychiatry, mental health, neurology, and the neurosciences as well as psychopharmacology
the NEI website, www.neiglobal.com:
- for CME credits for reading the books and the journal, and for completing numerous additional programs both online and live
- for access to the live course and playback encore features from the annual NEI Psychopharmacology Congress
- for access to the NEI Master Psychopharmacology Program, an online fellowship with certification
plans for expansion to a Cambridge University Health Partners co-accredited online Masterclass and Certificate in Psychopharmacology, based upon live programs held on campus in Cambridge and taught by University of Cambridge faculty, including myself, having joined the faculty there as an Honorary Visiting Senior Fellow

Hopefully the reader can appreciate that this is an incredibly exciting time for the fields of neuroscience and mental health, creating fascinating opportunities for clinicians to utilize current therapeutics and to anticipate future medications that are likely to transform the field of psychopharmacology. Best wishes for your first step on this fascinating journey.

Stephen M. Stahl, MD, PhD

CME information

Release/expiration dates

Originally released: February 1, 2013

Reviewed and re-released: February 1, 2016

CME credit expires: January 31, 2019

Target audience

This activity has been developed for prescribers specializing in psychiatry. All other health care providers interested in psychopharmacology are welcome for advanced study, especially primary care physicians, physician assistants, nurse practitioners, psychologists, and pharmacists.

Statement of need

Psychiatric illnesses have a neurobiological basis and are primarily treated by pharmacological agents; understanding each of these, as well as the relationship between them, is essential in order to select appropriate treatment for a patient. The field of psychopharmacology has experienced incredible growth; it has also experienced a major paradigm shift from a limited focus on neurotransmitters and receptors to an emphasis as well upon brain circuits, neuroimaging, genetics, and signal transduction cascades.

The following unmet needs and professional practice gaps regarding mental health were revealed following a critical analysis of activity feedback, expert faculty assessment, literature review, and through new medical knowledge:

Mental disorders are highly prevalent and carry substantial burden that can be alleviated through treatment; unfortunately, many patients with mental disorders do not receive treatment or receive suboptimal treatment.
There is a documented gap between evidence-based practice guidelines and actual care in clinical practice for patients with mental illnesses. This gap is due at least in part to lack of clinician confidence and knowledge in terms of appropriate usage of the therapeutic tools available to them.

To help address clinician performance gaps with respect to diagnosis and treatment of mental health disorders, quality improvement efforts need to provide education regarding (1) the fundamentals of neurobiology as it relates to the most recent research regarding the neurobiology of mental illnesses; (2) the mechanisms of action of treatment options for mental illnesses and the relationship to the pathophysiology of the disease states; and (3) new therapeutic tools and research that are likely to affect clinical practice.

Learning objectives

After completing this activity, you should be better able to:

Apply fundamental principles of neurobiology to the assessment of psychiatric disease states
Differentiate the neurobiological targets for psychotropic medications
Link the relationship of psychotropic drug mechanism of action to the pathophysiology of disease states
Identify novel research and treatment approaches that are expected to affect clinical practice

Accreditation and credit designation statements

The Neuroscience Education Institute is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The Neuroscience Education Institute designates this enduring material for a maximum of 67.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses:

for all of your CNE requirements for recertification, the ANCC will accept AMA PRA Category 1 Credits™ from organizations accredited by the ACCME. The content of this activity pertains to pharmacology and is worth 67.0 continuing education hours of pharmacotherapeutics.

Physician assistants:

the NCCPA accepts AMA PRA Category 1 Credits™ from organizations accredited by the AMA (providers accredited by the ACCME).

A certificate of participation for completing this activity will also be available.

Optional posttests and CME credit instructions

The estimated time for completion of this activity is 67 hours. Optional certificates of CME credit or participation are available for each topical section of the book (total of twelve sections). There is a fee for each posttest (varies per section) which is waived for NEI members.

Read the desired topical section, evaluating the content presented
Complete the related posttest, available only online at www.neiglobal.com/CME (under “Book”)
Print your certificate (if a score of 70% or more is achieved)

Questions? call 888-535-5600, or email CustomerService@NEIglobal.com

Peer review

The content was originally peer-reviewed in 2013 by 3 MDs and a PharmD to ensure the scientific accuracy and medical relevance of information presented and its independence from commercial bias. The content was reviewed again in 2016 to verify it is still up-to-date and accurate. The Neuroscience Education Institute takes responsibility for the content, quality, and scientific integrity of this CME activity.

Disclosures

Disclosed financial relationships with conflicts of interest have been reviewed by the NEI CME Advisory Board Chair and resolved.

Author

Stephen M. Stahl, MD, PhD

Adjunct Professor, Department of Psychiatry, University of California, San Diego School of Medicine, La Jolla, CA

Honorary Visiting Senior Fellow, University of Cambridge, UK Director of Psychopharmacology, California Department of State Hospitals, Sacramento, CA

Grant/Research: Alkermes, Clintara, Forest, Forum, Genomind, JayMac, Jazz, Lilly, Merck, Novartis, Otsuka America, Pamlab, Pfizer, Servier, Shire, Sprout, Sunovion, Sunovion UK, Takeda, Teva, Tonix

Consultant/Advisor: Acadia, BioMarin, Forum/EnVivo, Jazz, Orexigen, Otsuka America, Pamlab, Servier, Shire, Sprout, Taisho, Takeda, Trius

Speakers Bureau: Forum, Servier, Sunovion UK, Takeda Board Member: BioMarin, Forum/EnVivo, Genomind, Lundbeck, Otsuka America, RCT Logic, Shire

Content editors

Meghan Grady

Director, Content Development, Neuroscience Education Institute, Carlsbad, CA

No financial relationships to disclose

Debbi Ann Morrissette, PhD

Adjunct Professor, Biological Sciences, California State University, San Marcos

Medical Writer, Neuroscience Education Institute, Carlsbad, CA

No financial relationships to disclose

The 2013 Peer Reviewers and Design Staff had no financial relationships to disclose. The 2016 Peer Reviewer has no financial relationships to disclose.

Disclosure of Off-Label Use

This educational activity may include discussion of unlabeled and/or investigational uses of agents that are not currently labeled for such use by the FDA. Please consult the product prescribing information for full disclosure of labeled uses.

Disclaimer

Participants have an implied responsibility to use the newly acquired information from this activity to enhance patient outcomes and their own professional development. The information presented in this educational activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this educational activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. Primary references and full prescribing information should be consulted.

Cultural and linguistic competency

A variety of resources addressing cultural and linguistic competency can be found at http://cdn.neiglobal.com/content/cme/regulations/ca_ab_1195_handout_non-ca_2008.pdf.

Provider

This activity is sponsored by the Neuroscience Education Institute.

Support

This activity is supported solely by theNeuroscience Education Institute.

Optional posttests with CME credit are available for a fee (waived for NEI Members). For more information, visit www.neiglobal.com/CME.

Suggested reading and selected references

General references: textbooks

Brunton LL (ed) (2011) Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th edn. New York, NY: McGraw-Hill Medical. [Google Scholar]

Schatzberg AF, Nemeroff CB (eds.) (2009) Textbook of Psychopharmacology, 4th edn. Washington, DC: American Psychiatric Publishing. [Google Scholar]

Index

The -icon indicates content; the -icon indicates figures; the -icon indicates tables.

Abeta peptides
role in Alzheimer’s disease, , ,
ABT560,
acamprosate, , ,
acetaminophen,
acetylation of histones,
acetylcholine,
as brain’s own nicotine,
basis for cholinesterase treatment of dementia,
cholinergic pathways,
cholinergic receptors,
precursors,
acetylcholine transporters,
acetylcholine vesicular transporter,
acetylcholinesterase, ,
Adapin,
adenosine antagonist
caffeine,
adiponectin,
adolescents
bipolar disorder,
mania,
mood stabilizer selection,
affective disorders.. See mood disorders.
aggression
disorders associated with,
impulsive–compulsive behavior in psychiatric disorders,
in schizophrenia,
agomelatine, , ,
agonist action
G-protein-linked receptors,
ligand-gated ion channels,
agonist spectrum
G-protein-linked receptors,
ligand-gated ion channels,
agoraphobia
in children,
agouti-related peptide,
agouti-related protein,
akathisia, ,
Akiskal, Hagop,
AKT (kinase enzyme)
in schizophrenia,
alcohol dependence,
alcoholism treatment,
allodynia,
allosteric modulation
ligand-gated ion channels,
almorexant (SB649868),
alogia
in schizophrenia,
alpha 1 adrenergic antagonists
atypical antipsychotics,
alpha 2 antagonists,
alpha 2 delta ligands
as anxiolytics,
alpha 2A adrenergic agonists
ADHD treatment,
alpha-melanocyte stimulating hormone (alpha-MSH),
alprazolam, ,
Alzheimer’s dementia,
and psychosis,
Alzheimer’s disease
acetylcholine as target for current symptomatic treatment,
aggressive and hostile symptoms,
amyloid as target of disease- modifying treatment,
amyloid cascade hypothesis,
basis for cholinesterase treatments,
beta amyloid plaques,
beta secretase inhibitors,
biomarker-enhanced early detection,
biomarkers,
causes,
cholinergic deficiency hypothesis of amnesia in,
cholinesterase inhibitors,
clinical features,
cognitive symptoms,
diagnosis,
diagnostic categories for Alzheimer’s dementia,
donepezil,
galantamine,
gamma secretase inhibitors,
genetic studies,
glutamate hypothesis of cognitive deficiency,
immunotherapy research,
memantine,
neurofibrillary tangles,
neuroimaging biomarkers,
pathology,
positive symptoms,
possible Alzheimer’s dementia category,
possible benefits of lithium,
probable Alzheimer’s dementia category,
prodromal stage,
range of proposed targets,
risk factors for disease progression,
risk related to Apo-E,
rivastigmine,
role of Abeta peptides, , ,
role of amyloid precursor protein (APP), ,
role of pathological tau,
search for a vaccine,
targeting glutamate,
testing of potential treatments,
treatments for psychiatric and behavioral symptoms,
Alzheimer’s disease stages,
amyloidosis with neurodegeneration and cognitive decline,
amyloidosis with some neurodegeneration,
asymptomatic amyloidosis,
dementia stage,
distinction of MCI from normal aging,
first stage (preclinical),
mild cognitive impairment (MCI),
presymptomatic stage,
second stage,
symptomatic predementia stage,
third (final) stage,
amenorrhea,
amisulpride,
pharmacologic properties,
amitifidine (triple reuptake inhibitor),
amitriptyline, ,
amoxapine, ,
AMPA PAMs,
AMPA receptor modulators,
AMPA receptors,
AMPAkines, ,
amphetamine, , ,
ADHD treatment,
brain's own (dopamine),
wake-promoting agent,
amygdala,
fear response,
neurobiology of fear,
neuroimaging in schizophrenia,
role in fear conditioning,
amyloid precursor protein (APP)
role in Alzheimer’s disease, ,
amyotrophic lateral sclerosis (ALS),
Anafranil,
analgesics
interactions with MAOIs,
anandamide, , ,
anatomical basis of neurotransmission,
anatomically addressed nervous system,
anesthetics
interactions with MAOIs,
“angel dust”.. See phencyclidine (PCP)
anhedonia
in schizophrenia,
anorexia nervosa,
antagonist action
G-protein-linked receptors,
ligand-gated ion channels,
anticholinergics,
anticonvulsants,
as mood stabilizers,
antidepressant action,
atypical antipsychotics,
comparison with placebo in clinical trials,
debate over efficacy,
definition of a treatment response,
discovery of,
disease progression in major depression,
effects throughout the life cycle,
efficacy in clinical trials,
failure to achieve remission,
general principles,
goal of sustained remission,
importance of achieving remission,
in “real world” trials,
STAR-D trial of antidepressants,
antidepressant augmenting agents,
brain stimulation techniques,
buspirone,
deep brain stimulation (DBS),
electroconvulsive therapy (ECT),
l-methylfolate,
psychotherapy as an epigenetic “drug”,
SAMe (S-adenosyl-methionine),
thyroid hormones,
transcranial magnetic stimulation (TMS),
antidepressant classes
5HT2C antagonism,
alpha 2 antagonists,
circadian rhythm resynchronizer,
melatonergic action,
monoamine oxidase inhibitors (MAOIs),
monoamine transporter blockers,
norepinephrine–dopamine reuptake inhibitors (NDRIs),
selective norepinephrine reuptake inhibitors (NRIs),
serotonin antagonist/reuptake inhibitors (SARIs),
serotonin–norepinephrine reuptake inhibitors (SNRIs),
serotonin partial agonist-reuptake inhibitors (SPARIs),
serotonin selective reuptake inhibitors (SSRIs),
tricyclic antidepressants, ,
antidepressant-induced bipolar disorder,
antidepressant-induced mood disorders,
antidepressant “poop-out”,
antidepressant selection
arousal combos,
based on genetic testing,
based on weight of the evidence,
breastfeeding patient,
California rocket fuel (SNRI plus mirtazapine),
combination therapies for major depressive disorder,
combination therapies for treatment-resistant depression,
depression treatment strategy,
equipoise situation,
evidence-based selection,
for pregnant patients,
for women based on life-cycle stage,
for women of childbearing age,
postpartum patient,
symptom-based approach,
triple action combination (SSRI/SNRI/NDRI),
antidepressants in development
CRF1 (corticotrophin-releasing factor) antagonists,
future treatments for mood disorders,
glucocorticoid antagonists,
multimodal agents,
NMDA blockade,
serotonin–norepinephrine– dopamine reuptake inhibitors (SNDRIs),
triple reuptake inhibitors (TRIs),
vasopressin 1B antagonists,
antihistamines,
antimanic actions
atypical antipsychotics,
antipsychotics, ,
as mood stabilizers, . See also atypical antipsychotics conventional antipsychotics
antisocial personality disorder,
aggressive and hostile symptoms,
anxiety disorder treatments,
alpha 2 delta ligands,
atypical antipsychotics,
benzodiazepines, ,
buspirone,
generalized anxiety disorder (GAD),
panic disorder,
posttraumatic stress disorder (PTSD),
social anxiety disorder,
anxiety disorders, , , ,
blocking reconsolidation of fear memories,
COMT genotypes and vulnerability to worry,
cortico-striatal-thalamic-cortical (CSTC) feedback loops,
fear conditioning,
fear extinction,
fear response,
in children,
noradrenergic hyperactivity in anxiety,
overlapping symptoms of anxiety disorders,
pain associated with,
pain symptoms,
painful physical symptoms,
role of GABA,
role of the amygdala,
serotonin and anxiety,
symptom overlap with major depressive disorder,
symptoms,
worry circuits,
anxious self-punishment and blame
in depressive psychosis,
apathy
in depressive psychosis,
ApoE (apolipoprotein E)
and Alzheimer’s disease risk,
appetite regulation
neurobiological basis,
aripiprazole, , , , , , ,
metabolic risk,
pharmacologic properties,
armodafinil
in combinations of mood stabilizers,
mode of action,
mood-stabilizing properties,
aromatic amino acid decarboxylase (AAADC),
arousal spectrum,
arson,
asenapine, , , ,
metabolic risk,
pharmacologic properties,
Asendin,
asociality
in schizophrenia,
aspirin,
atomoxetine, ,
ADHD treatment,
atorvastatin,
ATPase (adenosine triphosphatase),
atropine,
attention deficit hyperactivity disorder (ADHD), , ,
age of onset diagnostic criterion,
aggressive and hostile symptoms,
and neurodevelopment,
as a disorder of the prefrontal cortex,
as inefficient “tuning” of the prefrontal cortex,
as norepinephrine and dopamine dysregulation in the prefrontal cortex,
circuits involved in the brain,
comorbidity in adults,
environmental factors,
executive dysfunction,
impulsive–compulsive dimension,
impulsivity symptom,
in adults,
in children and adolescents,
inability to focus,
inattention symptom,
late-onset type,
selective inattention symptom,
symptoms,
attention deficit hyperactivity disorder (ADHD) treatment
alpha 2A adrenergic agonists,
amphetamine,
atomoxetine,
DAT target for stimulant drugs,
differences in children, adolescents and adults,
future treatments,
general principles of stimulant treatment,
methylphenidate,
noradrenergic treatment,
slow-release vs fast-release stimulants,
stimulants,
which symptoms to treat first,
atypical antipsychotics, ,
5HT1A receptor partial agonism,
5HT2A receptor antagonism,
anticholinergic actions,
antidepressant actions in bipolar and unipolar depression,
antihistamine actions,
antimanic actions,
anxiolytic actions,
as mood stabilizers,
breastfeeding patient,
cardiometabolic risk,
characteristic properties,
classification by pharmacologic binding properties,
clinical profile,
dopamine D2 receptor partial agonism,
effects on 5HT1B/D receptors,
effects on 5HT2C receptors,
effects on 5HT3 receptors,
effects on 5HT6 receptors,
effects on 5HT7 receptors,
effects on dopamine D2 receptors,
effects on prolactin levels,
link between receptor-binding properties and clinical actions,
low extrapyramidal symptoms,
mechanisms of action,
metabolic disease risk,
mitigation of extrapyramidal symptoms,
pharmacologic properties of specific drugs,
pharmacologic properties of the “dones”,
pharmacologic properties of the “pines” (peens),
pharmacologic properties of “two pips and a rip”,
pharmacological profile,
relative actions on 5HT2A receptors,
relative actions on dopamine D2 receptors,
sedating actions,
sedative-hypnotic actions,
serotonin–dopamine antagonists,
therapeutic window,
atypical antipsychotics in clinical practice,
integration with psychotherapy,
issues related to switching antipsychotics,
treatment resistance,
violent and aggressive treatment-resistant patients,
atypical depression,
auditory hallucinations
in schizophrenia,
autism
cognitive symptoms,
autism spectrum disorders
impulsive–compulsive dimension,
autoreceptors
5HT1B/D receptors,
dopamine D2 receptors,
on monoamine neurons,
Aventyl,
avoidant personality disorder,
avolition
in schizophrenia,
axoaxonic synapses,
axodendritic synapses,
axosomatic synapses,

Stahl's Essential Psychopharmacology

4th Edition - 9781107686465

My Bookmarks

Medical Disclaimer

Contents

Preface to the fourth edition

CME information

Suggested reading and selected references

Index

Dementia and its treatment

Causes, pathology, and clinical features of dementia

Alzheimer’s disease: β-amyloid plaques and neurofibrillary tangles

The amyloid cascade hypothesis

ApoE and risk of Alzheimer’s disease

My Images

Preface to the fourth edition

Expansion of Essential Psychopharmacology books

Essential Psychopharmacology Online

CME information

Release/expiration dates

Target audience

Statement of need

Learning objectives

Accreditation and credit designation statements

Nurses:

Physician assistants:

Optional posttests and CME credit instructions

Peer review

Disclosures

Author

Stephen M. Stahl, MD, PhD

Content editors

Meghan Grady

Debbi Ann Morrissette, PhD

Disclosure of Off-Label Use

Disclaimer

Cultural and linguistic competency

Provider

Support

General references: textbooks

Index