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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This chapter will explore antipsychotic drugs, with an emphasis on treatments for
schizophrenia. These treatments include not only conventional antipsychotic drugs,
but also the newer atypical antipsychotic drugs that have largely replaced the older
conventional agents. Atypical antipsychotics are really misnamed, since they are also
used as treatments for both the manic and depressed phases of bipolar disorder, as
augmenting agents for treatment-resistant depression, and “off-label” for various
other disorders, such as treatment-resistant anxiety disorders. The reader is referred
to standard reference manuals and textbooks for practical prescribing information,
such as drug doses, because this chapter on antipsychotic drugs will
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Figure 5-1.Qualitative and semi-quantitative representation of receptor binding properties. Throughout this chapter, the receptor binding properties of the atypical antipsychotics
are represented both graphically and semi-quantitatively. Each drug is represented
as a blue sphere, with its most potent binding properties depicted along the outer
edge of the sphere. Additionally, each drug has a series of colored boxes associated
with it. Each colored box represents a different binding property, and binding strength
is indicated by the size of the box and the number of plus signs. Within the colored
box series for any particular antipsychotic, larger boxes with more plus signs (positioned
to the left) indicate stronger binding affinity, while smaller boxes with fewer plus
signs (positioned to the right) represent weaker binding affinity. The series of boxes
associated with each drug are arranged such that the size and positioning of a box
reflect the binding potency for a particular receptor. The vertical dotted line cuts
through the dopamine 2 (D2) receptor binding box, with binding properties that are more potent than D2 on the left and those that are less potent than D2 on the right. All binding properties are based on the mean values of published Ki (binding affinity) data (http://pdsp.med.unc.edu). The semi-quantitative depiction used throughout this chapter provides a quick visual
reference of how strongly a particular drug binds to a particular receptor. It also
allows for easy comparison of a drug's binding properties with those of other atypical
antipsychotics.
emphasize basic pharmacologic concepts of mechanism of action and not practical issues
such as how to prescribe these drugs (for that information see for example Stahl's Essential Psychopharmacology: the Prescriber's Guide, which is a companion to this textbook).
Antipsychotic drugs exhibit possibly the most complex pharmacologic mechanisms of
any drug class within the field of clinical psychopharmacology. The pharmacologic
concepts developed here should help the reader understand the rationale for how to
use each of the different antipsychotic agents, based upon their interactions with
different neurotransmitter systems (Figure 5-1). Such interactions can often explain both the therapeutic actions and the side effects
of various antipsychotic medications and thus can be very helpful background information
for prescribers of these therapeutic agents.
Conventional antipsychotics
What makes an antipsychotic “conventional”?
In this section we will discuss the pharmacologic properties of the first drugs that
were proven to effectively treat schizophrenia. A list of many conventional antipsychotic
drugs is given in Table 5-1. These drugs are usually called conventional antipsychotics, but they are sometimes also called classical antipsychotics, or typical antipsychotics, or first-generation antipsychotics. The earliest effective treatments for schizophrenia and other psychotic illnesses
arose from serendipitous clinical observations more than
Table 5-1 Some conventional antipsychotics still in use
60 years ago, rather than from scientific knowledge of the neurobiological basis
of psychosis, or of the mechanism of action of effective antipsychotic agents. Thus, the first antipsychotic drugs were discovered by accident in the 1950s when
a drug with antihistamine properties (chlorpromazine) was serendipitously observed
to have antipsychotic effects when this putative antihistamine was tested in schizophrenia
patients. Chlorpromazine indeed has antihistaminic activity, but its therapeutic actions
in schizophrenia are not mediated by this property. Once chlorpromazine was observed
to be an effective antipsychotic agent, it was tested experimentally to uncover its
mechanism of antipsychotic action.
Early in the testing process, chlorpromazine and other antipsychotic agents were all
found to cause “neurolepsis,” known as an extreme form of slowness or absence of motor
movements as well as behavioral indifference in experimental animals. The original
antipsychotics were first discovered largely by their ability to produce this effect
in experimental animals, and are thus sometimes called “neuroleptics.” A human counterpart
of neurolepsis is also caused by these original (i.e., conventional) antipsychotic
drugs and is characterized by psychomotor slowing, emotional quieting, and affective
indifference.
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Figure 5-2.D2 antagonist. Conventional antipsychotics, also called first-generation antipsychotics or typical
antipsychotics, share the primary pharmacological property of D2 antagonism, which is responsible not only for their antipsychotic efficacy but also
for many of their side effects. Shown here is an icon representing this single pharmacological
action.
D2 receptor antagonism makes an antipsychotic conventional
By the 1970s it was widely recognized that the key pharmacologic property of all “neuroleptics”
with antipsychotic properties was their ability to block dopamine D2 receptors (Figure 5-2). This action has proven to be responsible not only for the antipsychotic efficacy
of conventional antipsychotic drugs, but also for most of their undesirable side effects,
including “neurolepsis.”
The therapeutic actions of conventional antipsychotic drugs are hypothetically due
to blockade of D2 receptors specifically in the mesolimbic dopamine pathway (Figure 5-3). This has the effect of reducing the hyperactivity in this pathway that is postulated
to cause the positive symptoms of psychosis, as discussed in Chapter 4 (Figures 4-12 and 4-13). All conventional antipsychotics reduce positive psychotic symptoms about equally
well in schizophrenia patients studied in large multicenter trials if they are dosed
to block a substantial number of D2 receptors there (Figure 5-4). Unfortunately, in order to block adequate numbers of D2 receptors in the mesolimbic dopamine pathway to
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Figure 5-3.Mesolimbic dopamine pathway and D2 antagonists. In untreated schizophrenia, the mesolimbic dopamine pathway is hypothesized to be
hyperactive, indicated here by the pathway appearing red as well as by the excess
dopamine in the synapse. This leads to positive symptoms such as delusions and hallucinations.
Administration of a D2 antagonist, such as a conventional antipsychotic, blocks dopamine from binding to
the D2 receptor, which reduces hyperactivity in this pathway and thereby reduces positive
symptoms as well.
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Figure 5-4.Hypothetical thresholds for conventional antipsychotic drug effects. All known antipsychotics bind to the dopamine 2 receptor, with the degree of binding
determining whether one experiences therapeutic and/or side effects. For most conventional
antipsychotics, the degree of D2 receptor binding in the mesolimbic pathway needed
for antipsychotic effects is close to 80%, while D2 receptor occupancy greater than
80% in the dorsal striatum is associated with extrapyramidal side effects (EPS) and
in the pituitary is associated with hyperprolactinemia. For conventional antipsychotics
(i.e,. pure D2 antagonists) it is assumed that the same number of D2 receptors is
blocked in all brain areas. Thus, there is a narrow window between the threshold for
antipsychotic efficacy and that for side effects in terms of D2 binding.
quell positive symptoms, one must simultaneously block the same number of D2 receptors throughout the brain, and this causes undesirable side effects as a “high
cost of doing business” with conventional antipsychotics (Figures 5-5 through 5-8). Although modern neuroimaging techniques are able to measure directly the blockade
of D2 receptors in the dorsal (motor) striatum of the nigrostriatal pathway, as shown in
Figure 5-4, for conventional antipsychotics it is assumed that the same number of D2 receptors is blocked in all brain areas, including the ventral limbic area of striatum
known as the nucleus accumbens of the mesolimbic dopamine pathway, the prefrontal
cortex of the mesocortical dopamine pathway, and the pituitary gland of the tuberoinfundibular
dopamine pathway.
Neurolepsis
D2 receptors in the mesolimbic dopamine system are postulated to mediate not only the
positive symptoms of psychosis, but also the normal reward system of the brain, and
the nucleus accumbens is widely considered to be the “pleasure center” of the brain.
It may be the final common pathway of all reward and reinforcement, including not
only normal reward (such as the pleasure of eating good food, orgasm, listening to
music) but also the artificial reward of substance abuse. If D2 receptors are stimulated in some parts of the mesolimbic pathway, this can lead to
the experience of pleasure. Thus, if D2 receptors in the mesolimbic system are blocked, this may not only reduce positive
symptoms of schizophrenia, but also block reward mechanisms, leaving patients apathetic,
anhedonic, lacking motivation, interest, and joy from social interactions, a state
very similar to that of negative symptoms of schizophrenia. The near shutdown of the
mesolimbic dopamine pathway necessary to improve the positive symptoms of psychosis
(Figure 5-4) may contribute to worsening of anhedonia, apathy, and negative symptoms, and this
may be a partial explanation for the high incidence of smoking and drug abuse in schizophrenia.
Antipsychotics also block D2 receptors in the mesocortical DA pathway (Figure 5-5), where DA may already be deficient in schizophrenia (see Figures 4-14 through 4-16). This can cause or worsen negative and cognitive symptoms even though there is only
a low density of D2 receptors in the cortex. An adverse behavioral state can be produced by conventional
antipsychotics, and is sometimes called the “neuroleptic-induced deficit syndrome”
because it looks so much like the negative symptoms produced by schizophrenia itself,
and is reminiscent of “neurolepsis” in animals.
Extrapyramidal symptoms and tardive dyskinesia
When a substantial number of D2 receptors are blocked in the nigrostriatal DA pathway, this will produce various
disorders of movement that can appear very much like those in Parkinson's disease;
this is why these movements are sometimes called drug-induced
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Figure 5-5.Mesocortical dopamine pathway and D2 antagonists. In untreated schizophrenia, the mesocortical dopamine pathways to dorsolateral prefrontal
cortex (DLPFC) and to ventromedial prefrontal cortex (VMPFC) are hypothesized to be
hypoactive, indicated here by the dotted outlines of the pathway. This hypoactivity
is related to cognitive symptoms (in the DLPFC), negative symptoms (in the DLPFC and
VMPFC), and affective symptoms of schizophrenia (in the VMPFC). Administration of
a D2 antagonist could further reduce activity in this pathway and thus not only not improve
such symptoms but actually potentially worsen them.
parkinsonism. Since the nigrostriatal pathway is part of the extrapyramidal nervous
system, these motor side effects associated with blocking D2 receptors in this part of the brain are sometimes also called extrapyramidal symptoms,
or EPS (Figures 5-4 and 5-6).
Worse yet, if these D2 receptors in the nigrostriatal DA pathway are blocked chronically (Figure 5-7), they can produce a hyperkinetic movement disorder known as tardive dyskinesia.
This movement disorder causes facial and tongue movements, such as constant chewing,
tongue protrusions, facial grimacing, and also limb movements that can be quick, jerky,
or choreiform (dancing). Tardive dyskinesia is thus caused by long-term administration
of conventional antipsychotics and is thought to be mediated by changes, sometimes
irreversible, in the D2 receptors of the nigrostriatal DA pathway. Specifically, these receptors are hypothesized
to become supersensitive or to “upregulate” (i.e., increase in number), perhaps in
a futile attempt to overcome drug-induced blockade of D2 receptors in the striatum (Figure 5-7).
About 5% of patients maintained on conventional antipsychotics will develop tardive
dyskinesia every year (i.e., about 25% of patients by 5 years), not a very encouraging
prospect for a lifelong illness starting in the early twenties. The risk of developing
tardive
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Figure 5-6.Nigrostriatal dopamine pathway and D2 antagonists. The nigrostriatal dopamine pathway is theoretically unaffected in untreated schizophrenia.
However, blockade of D2 receptors, as with a conventional antipsychotic, prevents dopamine from binding there
and can cause motor side effects that are often collectively termed extrapyramidal
symptoms (EPS).
dyskinesia in elderly subjects may be as high as 25% within the first year of exposure
to conventional antipsychotics. However, if D2 receptor blockade is removed early enough, tardive dyskinesia may reverse. This reversal
is theoretically due to a “resetting” of these D2 receptors by an appropriate decrease in the number or sensitivity of them in the
nigrostriatal pathway once the antipsychotic drug that had been blocking these receptors
is removed. However, after long-term treatment, the D2 receptors apparently cannot or do not reset back to normal, even when conventional
antipsychotic drugs are discontinued. This leads to tardive dyskinesia that is irreversible,
continuing whether conventional antipsychotic drugs are administered or not.
Is there any way to predict those who will be harmed with the development of tardive
dyskinesia after chronic treatment with conventional antipsychotics? Patients who
develop EPS early in treatment may be twice as likely to develop tardive dyskinesia
if treatment with a conventional antipsychotic is continued chronically. Also, specific
genotypes of dopamine receptors may confer important genetic risk factors for developing
tardive dyskinesia with chronic treatment using a conventional antipsychotic. Risk
of new cases of tardive
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Figure 5-7.Tardive dyskinesia. Long-term blockade of D2 receptors in the nigrostriatal dopamine pathway can cause upregulation of those receptors,
which may lead to a hyperkinetic motor condition known as tardive dyskinesia, characterized
by facial and tongue movements (e.g., tongue protrusions, facial grimaces, chewing)
as well as quick, jerky limb movements. This upregulation may be the consequence of
the neuron's futile attempt to overcome drug-induced blockade of its dopamine receptors.
dyskinesia, however, can diminish considerably after 15 years of treatment, presumably
because patients who have not developed tardive dyskinesia despite 15 years of treatment
with a conventional antipsychotic have lower genetic risk factors for it.
A rare but potentially fatal complication called the “neuroleptic malignant syndrome,”
associated with extreme muscular rigidity, high fevers, coma, and even death, and
possibly related in part to D2 receptor blockade in the nigrostriatal pathway, can also occur with conventional
antipsychotic agents.
Prolactin elevation
Dopamine D2 receptors in the tuberoinfundibular DA pathway are also blocked by conventional antipsychotics,
and this causes plasma prolactin concentrations to rise, a condition called hyperprolactinemia
(Figure 5-8). This is associated with conditions called galactorrhea (i.e., breast secretions)
and amenorrhea (i.e., irregular or lack of menstrual periods). Hyperprolactinemia
may thus interfere with fertility, especially in women. Hyperprolactinemia might lead
to more rapid demineralization of bones, especially in postmenopausal women who are
not taking estrogen replacement therapy. Other possible problems associated with elevated
prolactin levels may include sexual dysfunction and weight gain, although the role
of prolactin in causing such problems is not clear.
The dilemma of blocking D2 dopamine receptors in all dopamine pathways
It should now be obvious that the use of conventional antipsychotic drugs presents
a powerful dilemma. That is, there is no doubt that conventional antipsychotic medications
exert dramatic therapeutic actions upon positive symptoms of schizophrenia by blocking
hyperactive dopamine neurons in the mesolimbic dopamine pathway. However, there are
several dopamine pathways in the brain, and it appears that blocking dopamine receptors in
only one of them is useful (Figure 5-3), whereas blocking dopamine receptors in the remaining pathways may be harmful (Figures 5-4 through 5-8). The pharmacologic
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Figure 5-8.Tuberoinfundibular dopamine pathway and D2 antagonists. The tuberoinfundibular dopamine pathway, which projects from the hypothalamus to
the pituitary gland, is theoretically “normal” in untreated schizophrenia. D2 antagonists reduce activity in this pathway by preventing dopamine from binding to
D2 receptors. This causes prolactin levels to rise, which is associated with side effects
such as galactorrhea (breast secretions) and amenorrhea (irregular menstrual periods).
quandary here is what to do if one wishes simultaneously to decrease dopamine in the mesolimbic dopamine pathway in order to treat positive psychotic
symptoms theoretically mediated by hyperactive mesolimbic dopamine neurons and yet
increase dopamine in the mesocortical dopamine pathway to treat negative and cognitive symptoms,
while leaving dopaminergic tone unchanged in both the nigrostriatal and tuberoinfundibular
dopamine pathways to avoid side effects. This dilemma may have been addressed in part
by the atypical antipsychotic drugs described in the following sections, and is one
of the reasons why the atypical antipsychotics have largely replaced conventional
antipsychotic agents in the treatment of schizophrenia and other psychotic disorders
throughout the world.
Muscarinic cholinergic blocking properties of conventional antipsychotics
In addition to blocking D2 receptors in all dopamine pathways (Figures 5-3 through 5-8), conventional antipsychotics have other important pharmacologic
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Figure 5-9.Conventional antipsychotic. Shown here is an icon representing a conventional antipsychotic drug. Conventional
antipsychotics have pharmacological properties in addition to dopamine D2 antagonism. The receptor profiles differ for each agent, contributing to divergent
side-effect profiles. However, some important characteristics that multiple agents
share are the ability to block muscarinic cholinergic receptors, histamine H1 receptors, and/or α1-adrenergic receptors.
properties (Figure 5-9). One particularly important pharmacologic action of some conventional antipsychotics
is their ability to block muscarinic M1-cholinergic receptors (Figures 5-9 through 5-11). This can cause undesirable side effects such as dry mouth, blurred vision, constipation,
and cognitive blunting (Figure 5-10). Differing degrees of muscarinic cholinergic blockade may also explain why some
conventional antipsychotics have a lesser propensity to produce extrapyramidal side
effects (EPS) than others. That is, those conventional antipsychotics that cause more
EPS are the agents that have only weak anticholinergic properties, whereas those conventional antipsychotics that cause
fewer EPS are the agents that have stronger anticholinergic properties.
How does muscarinic cholinergic receptor blockade reduce the EPS caused by dopamine
D2 receptor blockade in the nigrostriatal pathway? The reason seems to be based on the
fact that dopamine and acetylcholine have a reciprocal relationship with each other
in the nigrostriatal pathway (Figure 5-11).
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Figure 5-10.Side effects of muscarinic cholinergic receptor blockade. In this diagram, the icon of a conventional antipsychotic drug is shown with its
M1 anticholinergic/antimuscarinic portion inserted into acetylcholine receptors, causing
the side effects of constipation, blurred vision, dry mouth, and drowsiness.
Figure 5-11
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A.Reciprocal relationship of dopamine and acetylcholine. Dopamine and acetylcholine have a reciprocal relationship in the nigrostriatal dopamine
pathway. Dopamine neurons here make postsynaptic connections with the dendrite of
a cholinergic neuron. Normally, dopamine suppresses acetylcholine activity (no acetylcholine
being released from the cholinergic axon on the right).
B.Dopamine, acetylcholine, and D2 antagonism. This figure shows what happens to acetylcholine activity when dopamine receptors
are blocked. As dopamine normally suppresses acetylcholine activity, removal of dopamine
inhibition causes an increase in acetylcholine activity. Thus if dopamine receptors
are blocked at the D2 receptors on the cholinergic dendrite on the left, then acetylcholine becomes overly
active, with enhanced release of acetylcholine from the cholinergic axon on the right.
This is associated with the production of extrapyramidal symptoms (EPS). The pharmacological
mechanism of EPS therefore seems to be a relative dopamine deficiency and a relative
acetylcholine excess.
C.D2 antagonism and anticholinergic agents. One compensation for the overactivity that occurs when dopamine receptors are blocked
is to block the acetylcholine receptors with an anticholinergic agent (M1 receptors being blocked by an anticholinergic on the far right). Thus, anticholinergics
overcome excess acetylcholine activity caused by removal of dopamine inhibition when
dopamine receptors are blocked by conventional antipsychotics. This also means that
extrapyramidal symptoms (EPS) are reduced.
Dopamine neurons in the nigrostriatal dopamine pathway make postsynaptic connections
with cholinergic neurons (Figure 5-11A). Dopamine normally inhibits acetylcholine release from postsynaptic nigrostriatal cholinergic neurons, thus suppressing
acetylcholine activity there (Figure 5-11A). If dopamine can no longer suppress acetylcholine release because dopamine receptors
are being blocked by a conventional antipsychotic drug, then acetylcholine becomes overly active (Figure 5-11B).
One compensation for this overactivity of acetylcholine is to block it with an anticholinergic
agent (Figure 5-11C). Thus, drugs with anticholinergic actions will diminish the excess acetylcholine
activity caused by removal of dopamine inhibition when dopamine receptors are blocked
(Figures 5-10 and 5-11C). If anticholinergic properties are present in the same drug with D2 blocking properties, they will tend to mitigate the effects of D2 blockade in the nigrostriatal dopamine pathway. Thus, conventional antipsychotics
with potent anticholinergic properties have lower EPS than conventional antipsychotics
with weak anticholinergic properties. Furthermore, the effects of D2 blockade in the nigrostriatal system can be mitigated by co-administering an agent
with anticholinergic properties. This has led to the common strategy of giving anticholinergic
agents along with conventional antipsychotics in order to reduce EPS. Unfortunately,
this concomitant use of anticholinergic agents does not lessen the ability of the
conventional antipsychotics to cause tardive dyskinesia. It also causes the well-known
side effects associated with anticholinergic agents, such as dry mouth, blurred vision,
constipation, urinary retention, and cognitive dysfunction (Figure 5-10).
Other pharmacologic properties of conventional antipsychotic drugs
Still other pharmacologic actions are associated with the conventional antipsychotic
drugs. These include generally undesired blockade of histamine H1 receptors (Figure 5-9) causing weight gain and drowsiness, as well as blockade of α1-adrenergic receptors causing cardiovascular side effects such as orthostatic hypotension and drowsiness. Conventional
antipsychotic agents differ in terms of their ability to block these various receptors
represented in Figure 5-9. For example, the popular conventional antipsychotic haloperidol has relatively little anticholinergic or antihistaminic binding activity,
whereas the classic conventional antipsychotic chlorpromazine has potent anticholinergic and antihistaminic binding. Because of this,
conventional antipsychotics differ somewhat in their side-effect profiles, even if
they do not differ overall in their therapeutic profiles. That is, some conventional
antipsychotics are more sedating than others, some have more ability to cause cardiovascular
side effects than others, some have more ability to cause EPS than others.
A somewhat old-fashioned way to subclassify conventional antipsychotics is “low potency”
versus “high potency” (Table 5-1). In general, as the name implies, low-potency agents require higher doses than high-potency
agents, but, in addition, low-potency agents tend to have more of the additional properties
discussed here than do the so-called high-potency agents: namely, low-potency agents
have greater anticholinergic, antihistaminic, and α1 antagonist properties than high-potency agents, and thus are probably more sedating
in general. A number of conventional antipsychotics are available in long-acting depot
formulations (Table 5-1).
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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
5HT2C 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
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
5HT1A receptors
5HT2C 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
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:
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
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
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
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.
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