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
The Edinburgh Building, Cambridge CB2 8RU, UK

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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Psychosis and schizophrenia

Psychosis is a difficult term to define and is frequently misused, not only in the media but unfortunately among mental health professionals as well. Stigma and fear surround the concept of psychosis, and sometimes the pejorative term “crazy” is used for psychosis. This chapter is not intended to list the diagnostic criteria for all the different mental disorders in which psychosis is either a defining feature or an associated feature. The reader is referred to standard reference sources such as the DSM (Diagnostic and Statistical Manual) of the American Psychiatric Association and the ICD (International Classification of Diseases) for that information. Although schizophrenia is emphasized here, we will approach psychosis as a syndrome associated with a variety of illnesses that are all targets for antipsychotic drug treatment.

Symptom dimensions in schizophrenia

Clinical description of psychosis

Psychosis is a syndrome – that is, a mixture of symptoms – that can be associated with many different psychiatric disorders, but is not a specific disorder itself in diagnostic schemes such as the DSM or ICD. At a minimum, psychosis means delusions and hallucinations. It generally also includes symptoms such as disorganized speech, disorganized behavior, and gross distortions of reality.

Therefore, psychosis can be considered to be a set of symptoms in which a person’s mental capacity, affective response, and capacity to recognize reality, communicate, and relate to others is impaired. Psychotic disorders have psychotic symptoms as their defining features; there are other disorders in which psychotic symptoms may be present, but are not necessary for the diagnosis.

Those disorders that require the presence of psychosis as a defining feature of the diagnosis include schizophrenia, substance-induced (i.e., drug-induced) psychotic disorders, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, and psychotic disorder due to a general medical condition (Table 4-1). Disorders that may or may not have psychotic symptoms as associated features include mania and depression as well as several cognitive disorders such as Alzheimer’s dementia (Table 4-2).

Psychosis itself can be paranoid, disorganized/excited, or depressive. Perceptual distortions and motor disturbances can be associated with any type of psychosis. Perceptual distortions include being distressed by hallucinatory voices; hearing voices that accuse, blame, or threaten punishment; seeing visions;

Table 4-1 Disorders in which psychosis is a defining feature

reporting hallucinations of touch, taste or odor; or reporting that familiar things and people seem changed. Motor disturbances are peculiar, rigid postures; overt signs of tension; inappropriate grins or giggles; peculiar repetitive gestures; talking, muttering, or mumbling to oneself; or glancing around as if hearing voices.

In paranoid psychosis, the patient has paranoid projections, hostile belligerence and grandiose expansiveness. Paranoid projection includes preoccupation with delusional beliefs; believing that people are talking about oneself; believing one is being persecuted or being conspired against; and believing people or external forces control one’s actions. Hostile belligerence is verbal expression of feelings of hostility; expressing an attitude of disdain; manifesting a hostile, sullen attitude; manifesting irritability and grouchiness; tending to blame others for problems; expressing feelings of resentment; complaining and finding fault; as well as expressing suspicion of people. Grandiose expansiveness is exhibiting an attitude of superiority; hearing voices that praise and extol; believing one has unusual powers or is a well-known personality, or that one has a divine mission.

In a disorganized/excited psychosis there is conceptual disorganization, disorientation, and excitement. Conceptual disorganization can be characterized by giving answers that are irrelevant or incoherent, drifting off the subject, using neologisms, or repeating certain words or phrases. Disorientation is not knowing where one is, the season of the year, the calendar year, or one’s own age. Excitement is expressing feelings without restraint; manifesting speech that is hurried; exhibiting an elevated mood; an attitude of superiority;

Table 4-2 Disorders in which psychosis is an associated feature

dramatizing oneself or one’s symptoms; manifesting loud and boisterous speech; exhibiting overactivity or restlessness; and exhibiting excess of speech.

Depressive psychosis is characterized by psychomotor retardation, apathy, and anxious self-punishment and blame. Psychomotor retardation and apathy are manifested by slowed speech; indifference to one’s future; fixed facial expression; slowed movements; deficiencies in recent memory; blocking in speech; apathy toward oneself or one’s problems; slovenly appearance; low or whispered speech; and failure to answer questions. Anxious self-punishment and blame is the tendency to blame or condemn oneself; anxiety about specific matters; apprehensiveness regarding vague future events; an attitude of self-deprecation, manifesting as a depressed mood; expressing feelings of guilt and remorse; preoccupation with suicidal thoughts, unwanted ideas, and specific fears; and feeling unworthy or sinful.

This discussion of clusters of psychotic symptoms does not constitute diagnostic criteria for any psychotic disorder. It is given merely as a description of several types of symptoms in psychosis to give the reader an overview of the nature of behavioral disturbances associated with the various psychotic illnesses.

Schizophrenia is more than a psychosis

Although schizophrenia is the commonest and best-known psychotic illness, it is not synonymous with psychosis, but is just one of many causes of psychosis. Schizophrenia affects 1% of the population, and in the US there are over 300 000 acute schizophrenic episodes annually. Between 25% and 50% of schizophrenia patients attempt suicide, and 10% eventually succeed, contributing to a mortality rate eight times greater than that of the general population. Life expectancy of a patient with schizophrenia may be 20–30 years shorter than the general population, not only due to suicide, but in particular due to premature cardiovascular disease. Accelerated mortality from premature cardiovascular disease in patients with schizophrenia is caused not only by genetic and lifestyle factors, such as smoking, unhealthy diet, and lack of exercise leading to obesity and diabetes, but also – sorrily – from treatment with some antipsychotic drugs which themselves cause an increased incidence of obesity and diabetes, and thus increase cardiac risk. In the US, over 20% of all social security benefits are used for the care of patients with schizophrenia. The direct and indirect costs of schizophrenia in the US alone are estimated to be in the tens of billions of dollars every year.

Schizophrenia by definition is a disturbance that must last for six months or longer, including at least one month of delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, or negative symptoms. Positive symptoms are listed in Table 4-3 and shown in Figure 4-1. These symptoms

Table 4-3 Positive symptoms of psychosis and schizophrenia

of schizophrenia are often emphasized, since they can be dramatic, can erupt suddenly when a patient decompensates into a psychotic episode (often called a psychotic “break,” as in break from reality), and are the symptoms most effectively treated by antipsychotic medications. Delusions are one type of positive symptom, and these usually involve a misinterpretation of perceptions or experiences. The most common content of a delusion in schizophrenia is persecutory, but it may include a variety of other themes including referential (i.e., erroneously thinking that something refers to oneself), somatic, religious, or grandiose. Hallucinations are also a type of positive symptom (Table 4-3) and may occur in any sensory modality (e.g., auditory, visual, olfactory, gustatory, and tactile), but auditory hallucinations are by far the most common and characteristic hallucinations in schizophrenia. Positive symptoms generally reflect an excess of normal functions, and in addition to delusions and hallucinations may also include distortions or exaggerations in language and communication (disorganized speech), as well as in behavioral monitoring (grossly disorganized or catatonic or agitated behavior). Positive symptoms are well known because they are dramatic, are often the cause of bringing a patient to the attention of medical professionals and law enforcement, and are the major target of antipsychotic drug treatments.

Negative symptoms are listed in Tables 4-4 and 4-5 and shown in Figure 4-1. Classically, there are at

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Figure 4-1. Positive and negative symptoms of schizophrenia. The syndrome of schizophrenia consists of a mixture of symptoms that are commonly divided into two major categories, positive and negative. Positive symptoms, such as delusions and hallucinations, reflect the development of the symptoms of psychosis; they can be dramatic and may reflect loss of touch with reality. Negative symptoms reflect the loss of normal functions and feelings, such as losing interest in things and not being able to experience pleasure.

least five types of negative symptoms all starting with the letter A (Table 4-5):

alogia – dysfunction of communication; restrictions in the fluency and productivity of thought and speech
affective blunting or flattening – restrictions in the range and intensity of emotional expression
asociality – reduced social drive and interaction
anhedonia – reduced ability to experience pleasure
avolition – reduced desire, motivation or persistence; restrictions in the initiation of goal-directed behavior

Table 4-4 Negative symptoms of schizophrenia

Negative symptoms in schizophrenia, such as blunted affect, emotional withdrawal, poor rapport, passivity and apathetic social withdrawal, difficulty in abstract thinking, stereotyped thinking and lack of spontaneity, commonly are considered a reduction in normal functions and are associated with long periods of hospitalization and poor social functioning. Although this reduction in normal functioning may not be as dramatic as positive symptoms, it is interesting to note that negative symptoms of schizophrenia determine whether a patient ultimately functions well or has a poor outcome. Certainly, patients will have disruptions in their ability to interact with others when their positive symptoms are out of control, but their degree of negative symptoms will largely determine whether patients with schizophrenia can live independently, maintain stable social relationships, or re-enter the workplace.

Although formal rating scales can be used to measure negative symptoms in research studies, in clinical practice it may be more practical to identify and monitor negative symptoms quickly by observation alone (Figure 4-2) or by some simple questioning (Figure 4-3). Negative symptoms are not just part of the syndrome of schizophrenia – they can also be part of a “prodrome” that begins with subsyndromal symptoms that do not meet the diagnostic criteria of schizophrenia and occur before the onset of the full syndrome of schizophrenia. Prodromal negative symptoms are important to detect and monitor over time in high-risk patients so that treatment can be initiated at the first signs of psychosis. Negative

Table 4-5 What are negative symptoms?

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Figure 4-2. Negative symptoms identified by observation. Some negative symptoms of schizophrenia – such as reduced speech, poor grooming, and limited eye contact – can be identified solely by observing the patient.

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Figure 4-3. Negative symptoms identified by questioning. Other negative symptoms of schizophrenia can be identified by simple questioning. For example, brief questioning can reveal the degree of emotional responsiveness, interest level in hobbies or pursuing life goals, and desire to initiate and maintain social contacts.

symptoms can also persist between psychotic episodes once schizophrenia has begun, and reduce social and occupational functioning in the absence of positive symptoms.

Current antipsychotic drug treatments are limited in their ability to treat negative symptoms, but psychosocial interventions along with antipsychotics can be helpful in reducing negative symptoms. There is even the possibility that instituting treatment for negative symptoms during the prodromal phase of schizophrenia may delay or prevent the onset of the illness, but this is still a matter of current research.

Beyond positive and negative symptoms of schizophrenia

Although not recognized formally as part of the diagnostic criteria for schizophrenia, numerous studies subcategorize the symptoms of this illness into five dimensions: not just positive and negative symptoms, but also cognitive symptoms, aggressive symptoms, and affective symptoms (Figure 4-4). This is perhaps a more sophisticated, if complicated, manner of describing the symptoms of schizophrenia.

Aggressive symptoms such as assaultiveness, verbally abusive behaviors, and frank violence can

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Figure 4-4. Localization of symptom domains. The different symptom domains of schizophrenia are hypothesized to be regulated by unique brain regions. Positive symptoms of schizophrenia are hypothetically modulated by malfunctioning mesolimbic circuits, while negative symptoms are hypothetically linked to malfunctioning mesocortical circuits and may also involve mesolimbic regions such as the nucleus accumbens, which is part of the brain’s reward circuitry and thus plays a role in motivation. The nucleus accumbens may also be involved in the increased rate of substance use and abuse seen in patients with schizophrenia. Affective symptoms are associated with the ventromedial prefrontal cortex, while aggressive symptoms (related to impulse control) are associated with abnormal information processing in the orbitofrontal cortex and amygdala. Cognitive symptoms are associated with problematic information processing in the dorsolateral prefrontal cortex. Although there is overlap in function among different brain regions, understanding which brain regions may be predominantly involved in specific symptoms can aid in customization of treatment to the particular symptom profile of each individual patient with schizophrenia.

occur with positive symptoms such as delusions and hallucinations, and be confused with positive symptoms. Behavioral interventions may be particularly helpful to prevent violence linked to poor impulsivity by reducing provocations from the environment. Certain antipsychotic drugs such as clozapine, or very high doses of standard antipsychotic drugs, or occasionally the use of two antipsychotic drugs simultaneously, may also be useful for aggressive symptoms and violence in some patients.

It can also be difficult to separate the symptoms of formal cognitive dysfunction from the symptoms of affective dysfunction and from negative symptoms, but research is attempting to localize the specific areas of brain dysfunction for each symptom domain in schizophrenia in the hope of developing better treatments for the often-neglected negative, cognitive, and affective symptoms of schizophrenia. In particular, neuropsychological assessment batteries are being developed to quantify cognitive symptoms, in order to detect cognitive improvement after treatment with a number of novel psychotropic drugs currently being tested. Cognitive symptoms of schizophrenia are impaired attention and impaired information processing manifested as impaired verbal fluency (ability to produce spontaneous speech), problems with serial learning (of a list of items or a sequence of events), and impairment in vigilance for executive functioning (problems with sustaining and focusing attention, concentrating, prioritizing, and modulating behavior based upon social cues).

Important cognitive symptoms of schizophrenia are listed in Table 4-6. These do not include symptoms of dementia and memory disturbance more characteristic of Alzheimer’s disease, but cognitive symptoms of schizophrenia emphasize “executive dysfunction,” which includes problems representing and maintaining goals, allocating attentional resources, evaluating and monitoring performance, and utilizing these skills to solve problems. Cognitive symptoms of schizophrenia are important to recognize and monitor because they are the single strongest correlate of real-world functioning, even stronger than negative symptoms.

Table 4-6 Cognitive symptoms of schizophrenia

Symptoms of schizophrenia are not necessarily unique to schizophrenia

It is important to recognize that several illnesses other than schizophrenia can share some of the same five symptom dimensions as described here for schizophrenia and shown in Figure 4-4. Thus, disorders in addition to schizophrenia that can have positive symptoms include bipolar disorder, schizoaffective disorder, psychotic depression, Alzheimer’s disease and other organic dementias, childhood psychotic illnesses, drug-induced psychoses, and others. Negative symptoms can also occur in other disorders and can also overlap with cognitive and affective symptoms that occur in these other disorders. However, as a primary deficit state, negative symptoms are fairly unique to schizophrenia. Schizophrenia is certainly not the only disorder with cognitive symptoms. Autism, post-stroke (vascular or multi-infarct) dementia, Alzheimer’s disease, and many other organic dementias (Parkinsonian/Lewy body dementia, frontotemporal/Pick’s dementia, etc.) can also be associated with cognitive dysfunctions similar to those seen in schizophrenia.

Affective symptoms are frequently associated with schizophrenia but this does not necessarily mean that they fulfill the diagnostic criteria for a comorbid anxiety or affective disorder. Nevertheless, depressed mood, anxious mood, guilt, tension, irritability, and worry frequently accompany schizophrenia. These various symptoms are also prominent features of major depressive disorder, psychotic depression, bipolar disorder, schizoaffective disorder, organic dementias, childhood psychotic disorders, and treatment-resistant cases of depression, bipolar disorder, and schizophrenia, among others. Finally, aggressive and hostile symptoms occur in numerous other disorders, especially those with problems of impulse control. Symptoms include overt hostility, such as verbal or physical abusiveness or assault, self-injurious behaviors including suicide, and arson or other property damage. Other types of impulsiveness such as sexual acting out are also in this category of aggressive and hostile symptoms. These same symptoms are frequently associated with bipolar disorder, childhood psychosis, borderline personality disorder, antisocial personality disorder, drug abuse, Alzheimer’s and other dementias, attention deficit hyperactivity disorder, conduct disorders in children, and many others.

Brain circuits and symptom dimensions in schizophrenia

The various symptoms of schizophrenia are hypothesized to be localized in unique brain regions (Figure 4-4). Specifically, the positive symptoms of schizophrenia have long been hypothesized to be localized to malfunctioning mesolimbic circuits, especially involving the nucleus accumbens. The nucleus accumbens is considered to be part of the brain’s reward circuitry, so it is not surprising that problems with reward and motivation in schizophrenia, symptoms that can overlap with negative symptoms and lead to smoking, drug and alcohol abuse, may be linked to this brain area as well. The prefrontal cortex is considered to be a key node in the nexus of malfunctioning cerebral circuitry responsible for each of the remaining symptoms of schizophrenia: specifically, the mesocortical and ventromedial prefrontal cortex with negative symptoms and affective symptoms, the dorsolateral prefrontal cortex with cognitive symptoms, and the orbitofrontal cortex and its connections to amygdala with aggressive, impulsive symptoms (Figure 4-4).

This model is obviously oversimplified and reductionistic, because every brain area has several functions, and every function is certainly distributed to more than one brain area. Nevertheless, allocating specific symptom dimensions to unique brain areas not only assists research studies, but has both heuristic and clinical value. Specifically, every patient has unique symptoms, and unique responses to medication. In order to optimize and individualize treatment, it can be useful to consider which specific symptoms any given patient is expressing, and therefore which areas of that particular patient’s brain are hypothetically malfunctioning (Figure 4-4). Each brain area has unique neurotransmitters, receptors, enzymes, and genes that regulate it, with some overlap, but also with some unique regional differences, and knowing this can assist the clinician in choosing medications and in monitoring the effectiveness of treatment.

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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:

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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

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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.

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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

Psychosis and schizophrenia

Symptom dimensions in schizophrenia

Clinical description of psychosis

Schizophrenia is more than a psychosis

Beyond positive and negative symptoms of schizophrenia

Symptoms of schizophrenia are not necessarily unique to schizophrenia

Brain circuits and symptom dimensions in schizophrenia

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