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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Antidepressants

In this chapter, we will review pharmacological concepts underlying the use of antidepressant drugs. There are many different classes of antidepressants and dozens of individual drugs. The goal of this chapter is to acquaint the reader with current ideas about how the various antidepressants work. We will explain the mechanisms of action of these drugs by building upon general pharmacological concepts introduced in earlier chapters. We will also discuss concepts about how to use these drugs in clinical practice, including strategies for what to do if initial treatments fail and how to rationally combine one antidepressant with another, or with a modulating agent. Finally, we will introduce the reader to several new antidepressants in clinical development.

Our discussion of antidepressants in this chapter is at the conceptual level, and not at the pragmatic level. The reader should consult standard drug handbooks (such as the companion Stahl’s Essential Psychopharmacology: the Prescriber’s Guide) for details of doses, side effects, drug interactions, and other issues relevant to the prescribing of these drugs in clinical practice. Here we will discuss putting together an antidepressant “portfolio” of two or more mechanisms of action, often requiring more than one drug, as a strategy for patients who have not responded to a single pharmacological mechanism. This treatment strategy for depression is very different than that for schizophrenia, where single antipsychotic drugs as treatments are the rule and the expected improvement in symptomatology may be only a 20–30% reduction of symptoms with few if any patients with schizophrenia becoming truly asymptomatic and in remission. Thus, the chance to reach a genuine state of sustained and asymptomatic remission in major depression is the challenge for those who treat this disorder; this is the reason for learning the mechanisms of action of so many drugs, the complex biological rationale for combining specific sets of drugs, and the practical tactics for tailoring a unique drug treatment portfolio to fit the needs of an individual patient.

General principles of antidepressant action

Patients who have a major depressive episode and who receive treatment with any antidepressant often experience improvement in their symptoms, and when this improvement reaches the level of 50% reduction of symptoms or more, it is called a response (Figure 7-1). This used to be the goal of treatment with antidepressants: namely, reduce symptoms substantially, and at least by 50%. However, the paradigm for antidepressant treatment has shifted dramatically in recent years so that now the goal of treatment is complete remission of symptoms (Figure 7-2), while maintaining that level of improvement so that the patient’s major depressive episode does not relapse shortly after remission, nor does the patient have a recurrent episode in the future (Figure 7-3). Given the known limits to the efficacy of available antidepressants, especially when multiple antidepressant treatment options are not deployed aggressively and early in the course of this illness, the goal of sustained remission can be difficult to reach. In fact, remission is usually not even reached with the first antidepressant treatment choice.

Do antidepressants work anymore in clinical trials?

Although remission (Figure 7-2) without relapse or recurrence (Figure 7-3) is the widely accepted goal of antidepressant treatment, it is becoming more and more difficult to prove that antidepressants – even well-established antidepressants – work any better than placebo in clinical trials. This is generally due to the fact that in modern clinical trials, the placebo effect has inflated so much over recent decades that placebo now seems to work as well as antidepressants in some trials and nearly as well as antidepressants in other trials. Why this is occurring is the subject of vigorous debate. Some experts propose that it is due to problems conducting clinical ratings in a clinical trial setting that is now unlike a clinical practice setting since patients are seen weekly, often for hours, whether they receive an antidepressant or not; other experts point out that subjects in trials may really be “symptomatic volunteers” who are less ill and less complicated than “real” patients. Critics of psychiatry and psychopharmacology proclaim from clinical trial evidence that antidepressants don’t even work and that their side effects and costs do not justify their use at all. This phenomenon of shrinking and erratic efficacy of long-established antidepressants as well as new antidepressants in clinical trials has also caused

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Figure 7-1. Response. When treatment of depression results in at least 50% improvement in symptoms, it is called a response. Such patients are better but not well. Previously, this was considered the goal of depression treatment.

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Figure 7-2. Remission. When treatment of depression results in removal of essentially all symptoms, it is called remission for the first several months and then recovery if it is sustained for longer than 6 months. Such patients are not just better – they are well. However, they are not cured, since depression can still recur. Remission and recovery are now the goals when treating patients with depression.

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Figure 7-3. Relapse and recurrence. When depression returns before there is a full remission of symptoms or within the first several months following remission of symptoms, it is called a relapse. When depression returns after a patient has recovered, it is called a recurrence.

the pharmaceutical industry to increasingly abandon the development of new antidepressants. Even patients seem to be affected by this debate, perhaps losing their confidence in the efficacy of antidepressants, since up to a third of patients in a real clinical practice setting never fill their first antidepressant prescription, and for those who do, perhaps less than half get a second month of treatment and maybe less than a quarter get an adequate trial of 3 months or longer. One thing is for sure about antidepressants, and that is that they don’t work if you don’t take them. Thus, the clinical effectiveness of antidepressants in clinical practice settings is reduced by this failure of “persistency” of treatment for a long enough period of time to give the drug a chance to work.

Whatever the cause of this controversy over the efficacy of antidepressants in clinical trials, one only needs to spend a short time in a clinical practice setting to be convinced that antidepressants are powerful therapeutic agents in many patients. Nevertheless, there have been some useful consequences of the debate on the efficacy of antidepressants, such as re-energizing the integration of psychotherapies with antidepressants, searching for new non-medication

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Figure 7-4. Remission rates in MDD. Approximately one-third of depressed patients will remit during treatment with any antidepressant initially. Unfortunately, for those who fail to remit, the likelihood of remission with another antidepressant monotherapy goes down with each successive trial. Thus, after a year of treatment with four sequential antidepressants taken for 12 weeks each, only two-thirds of patients will have achieved remission.

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Figure 7-5. Common residual symptoms. In patients who do not achieve remission, the most common residual symptoms are insomnia, fatigue, painful physical complaints, problems concentrating, and lack of interest. The least common residual symptoms are depressed mood, suicidal ideation, and psychomotor retardation.

neurostimulation therapeutics, and studying the combination of currently available antidepressants in order to gain better outcomes, all of which will be discussed in this chapter.

How well do antidepressants work in the real world?

“Real world” trials of antidepressants tested in clinical practice settings that include patients normally excluded from marketing trials, such as the STAR*D trial of antidepressants (Sequenced Treatment Alternatives to Relieve Depression), have recently provided sobering results. Only a third of such patients remit on their first antidepressant treatment, and even after a year of treatment with a sequence of four different antidepressants given for 12 weeks each, only about two-thirds of depressed patients achieve remission of their symptoms (Figure 7-4).

What are the most common symptoms that persist after antidepressant treatment, causing this disorder not to go into remission? The answer is shown in Figure 7-5, and the symptoms include insomnia, fatigue, multiple painful physical complaints (even though these are not part of the formal diagnostic criteria for depression), as well as problems concentrating, and lack of interest or motivation. Antidepressants appear to work fairly well in improving depressed mood, suicidal ideation, and psychomotor retardation (Figure 7-5).

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Figure 7-6. Relapse rates. The rate of relapse of major depression is significantly less for patients who achieve remission. However, there is still risk of relapse even in remitters, and the likelihood increases with the number of treatments it takes to get the patient to remit. Thus the relapse rate for patients who do not remit ranges from 60% at 12 months after one treatment to 70% at 6 months after four treatments; but for those who do remit, it ranges from only 33% at 12 months after one treatment all the way to 70% at 6 months after four treatments. In other words, the protective nature of remission virtually disappears once it takes four treatments to achieve remission.

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Figure 7-7. Antidepressants over the life cycle. The efficacy, tolerability, and safety of antidepressants have been studied mostly in individuals between the ages of 25 and 64. Existing data across all age groups suggest that the risk–benefit ratio is most favorable for adults between the ages of 25 and 64 and somewhat less so for adults between the ages of 19 and 24, due to a possibly increased risk of suicidality in younger adults. Limited data in children and adolescents also suggest increased risk of suicidality; this, coupled with a lack of data demonstrating clear antidepressant efficacy, gives children between the ages of 6 and 12 the worst risk–benefit ratio, with adolescents intermediate between young adults and children. Elderly patients, 65 years of age and older, may not respond as well or as quickly to antidepressants as other adults and may also experience more side effects than younger adults.

Why should we care whether a patient is in remission from major depression or has just a few persistent symptoms? The answer can be found in Figure 7-6, which shows both good news and bad news about antidepressant treatment over the long run. The good news is that if an antidepressant gets your patient into remission, that patient has a significantly lower relapse rate. The bad news is that there are still very frequent relapses in the remitters, and these relapse rates get worse the more treatments the patient needs to take in order to get into remission (Figure 7-6).

Data like these have galvanized researchers and clinicians alike to treat patients to the point of remission of all symptoms whenever possible, and to try to intervene as early as possible in this illness of major depression, not only to be merciful in trying to relieve current suffering from depressive symptoms, but also because of the possibility that aggressive treatment may prevent disease progression. The concept of disease progression in major depression is controversial, unproven, and provocative, but makes a good deal of sense intuitively for many clinicians and investigators (Figure 6-23). The idea is that chronicity of major depression, development of treatment resistance, and likelihood of relapse could all be reduced, with a better overall outcome, with aggressive treatment of major depressive episodes that leads to remission of all symptoms, thus potentially modifiying the course of this illness. This may pose an especially difficult challenge for treatment of younger patients, where risks versus benefits of antidepressants are currently debated (Figure 7-7).

Antidepressants over the life cycle

Adults between the ages of 25 and 64 might have the best chance of getting a good response and with the best tolerability to an antidepressant (Figure 7-7). Adults aged 65 or older may not respond as quickly or as robustly to antidepressants, especially if their first episode starts at this age, and especially when their presenting symptoms are lack of interest and cognitive dysfunction rather than depressed mood, but do not have increased suicidality from taking an antidepressant. At the other end of the adult age range, those younger than 25 may benefit from antidepressant efficacy but with a slightly but statistically greater risk of suicidality (but not completed suicide) (Figure 7-7). Age is thus an important consideration for whether, when, and how to treat a patient with antidepressants throughout the life cycle, and with what potential risk versus benefit.

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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

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Medical Disclaimer

Contents

Preface to the fourth edition

CME information

Suggested reading and selected references

Index

Antidepressants

General principles of antidepressant action

Do antidepressants work anymore in clinical trials?

How well do antidepressants work in the real world?

Antidepressants over the life cycle

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