1

ANTIPSYCHOTIC DRUGS

INTRODUCTION
Information about antipsychotic drugs and developments in
the treatment of psychosis is rapidly expanding. The advent of
newer second-generation antipsychotics in the wake of clozapine
represents the first significant advances in the pharmacologic
treatment of schizophrenia and related psychotic disorders,
and second-generation antipsychotics have become first-choice
agents for acute and maintenance therapy for these illnesses.
There is growing evidence that most of the new medi-
cations can offer advantages over conventional neuroleptics;
these include fewer extrapyramidal symptoms, lower risk of
tardive dyskinesia, reduced cognitive impairment, and possible
improvement in negative symptoms. Treatment successes have
contributed to the increased use of newer antipsychotic agents
and have also allowed psychiatrists to expand clinical expec-
tations. In addition, these second-generation drugs are being
used increasingly for various conditions beyond schizophrenia,
as happened with the conventional antipsychotics.

PHARMACOLOGY
The first-generation antipsychotic agents are equally effec-
tive in the treatment of psychotic symptoms of schizophrenia,
although they vary in potency and their propensity to induce
various side effects. All have a high affinity for dopamine

Handbook of Psychiatric Drugs Jeffrey A. Lieberman and Allan Tasman

© 2006 John Wiley & Sons, Ltd. ISBN: 0-470-02821-1
2 HANDBOOK OF PSYCHIATRIC DRUGS

D2 receptors. In addition, all produce extra-pyramidal symp-

toms (EPS), including parkinsonism, dystonia, akathisia, are
associated with a substantial risk of tardive dyskinesia (TD),
and increase serum prolactin concentration in the usual clin-
ical dose range. First-generation agents are usually classi-
fied into three groups: phenothiazines, butyrophenones (e.g.,
haloperidol), and others (e.g., thiothixene, molindone, and
loxapine), based on their structure.
Second-generation antipsychotic drugs are characterized by
the following criteria:
• few or no EPS; significant reduction in tardive dyskinesia
liability compared to first-generation antipsychotics
• expanded spectrum of therapeutic efficacy
• less prolactin elevation

There is a continuum of typical and atypical effects in atypical

drugs rather than several dichotomous groups.

Chemistry
Antipsychotic drugs bind to numerous neurotransmitter
receptor subtypes, including those of dopamine, norepinephrine,
epinephrine, acetylcholine, serotonin, and histamine. They act
to antagonize the endogenous ligands at these receptors. Both
therapeutic and extrapyramidal side effects can be attributed to
the antagonism of dopamine at D2 receptors, with actions at the
other neuroreceptors associated with various other side effects.
The typical antipsychotics have been described as being of
high (e.g., haloperidol), low (e.g., chlorpromazine), and mid
(e.g., loxapine) potency on the basis of their degree of
affinity for D2 receptors and their therapeutic dose range.
Atypical antipsychotics are characterized by generally lower
affinities for D2 receptors and relatively greater affinities
for serotonin (5-hydroxytryptamine) 5-HT2A receptors in
particular, but also for noradrenergic receptors (!1 and
!2 ", muscarinic acetylcholine receptors, histamine, and other
dopamine (DA) subtype receptors. Aripiprazole is currently
the only antipsychotic that acts as a partial agonist at D2 and
5-HT1A receptors as well as an antagonist at the 5-HT2A and
D2 receptors, and these properties are believed to account
for its therapeutic effects. It has no appreciable activity at
 ANTIPSYCHOTIC DRUGS 3

muscarinic receptors and modest affinity for alpha-1 adrenergic

and histamine H1 receptors.

Mechanism of Action
The therapeutic actions of antipsychotic drugs are generally
attributed to antagonism of DA receptors, particularly the D2
subtype. Atypical antipsychotics, with their lower D2 receptor
affinities and broader spectrum of pharmacologic properties,
also antagonize 5-HT2A receptors, giving possible therapeutic
advantages and a superior motor side effect profile. At this point
it is unclear what clinical effects 5-HT2A antagonism confers,
other than mitigating the adverse effect of striatal D2 antag-
onism, and propensity to cause EPS. The low EPS liability
of aripiprazole is at least in part related to its partial agonist
activity at the D2 receptor. Its D2 antagonist activity is broadly
comparable with that of haloperidol and chlorpromazine, but it
clearly has weaker cataleptogenic activity. Furthermore, chronic
treatment with aripiprazole is associated with much less upregu-
lation of striatal D2 receptors compared with haloperidol.
What has been established is that as a consequence of their
different pharmacologic profile, the atypical drugs have a much
wider separation of the dose-response curves of therapeutic
antipsychotic action and extrapyramidal side effects.

Pharmacokinetics
Antipsychotic agents are rapidly absorbed from the gastroin-
testinal tract and undergo extensive first pass metabolism.
They are highly lipophilic, which results in ready transport
across the blood-brain barrier. Antipsychotics are metabolized
by the cytochrome P450 enzyme system. The isozyme systems
predominantly involved are CYP2D6, CYP1A2, CYP3A4, and
CYP2C19, and medications that inhibit or compete for these
substrates can increase antipsychotic blood levels. After under-
going various degrees of metabolism, antipsychotic drugs and
their metabolites are glucuronidated in the liver and excreted
by the kidney in the urine or in feces.
The average plasma half-life of the antipsychotics as a
family is approximately 20 to 24 hours, allowing for once-
daily dosing. Aripiprazole and its active metabolite dehydro-
aripiprazole have exceptionally long half-lives of 75 and 94
4 HANDBOOK OF PSYCHIATRIC DRUGS

hours respectively and steady state concentrations are achieved

after 14 days. Some drugs have shorter half-lives (e.g., queti-
apine: 6 to 12 hours; ziprasidone: 4 to 10 hours), which suggests
twice-daily administration. However, with repeated dosing
the pharmacodynamic effects may extend beyond the period
suggested by pharmacokinetic parameters, allowing the consol-
idation of dosing to once daily.
Among the second-generation antipsychotics, olanzapine
(5–10 mg initial dose) and ziprasidone (10–20 mg initial dose)
are available in a parenteral form for acute use in agitated
patients, giving the benefits of a more rapid onset of action
and the ability to bypass the extensive first-pass metabolism
that these agents undergo.
Several of the antipsychotic drugs (three in the United
States: haloperidol and fluphenazine decanoate, and Risperi-
done – Risperdal Consta) are available in long-acting injectable
preparations for intramuscular administration. This allows for
less fluctuation in plasma level compared to oral formula-
tions, bypasses first-pass metabolism, and can improve patient
compliance.
Recommended dosages for second-generation antipsy-
chotic agents are shown in Table 1-1.

INDICATIONS FOR USE OF ANTIPSYCHOTIC DRUGS

Antipsychotic agents are effective for treating nearly every
medical and psychiatric condition where psychotic symptoms
or aggression are present. They are currently used routinely in
the management of psychosis and/or agitation associated with:
• Schizophrenia and Schizoaffective Disorder
• Acute manic and mixed episodes of bipolar disorder
• Major depression with psychosis
• Delusional disorder
• Delirium
• Dementia
• Mental retardation
• Developmental disorders (e.g., Autism)
• Huntington’s disease
• Tourette’s syndrome
• Substance-induced psychoses (psychostimulants, phencycli-
dine, levodopa, steroids)
! TABLE 1-1. Antipsychotic Drugs, Doses, Forms, and Costs

THERAPEUTIC DOSE RANGE: THERAPEUTIC

USUAL ORAL DAILY EQUIVALENT ORAL
DRUG CLASS DOSE (mg/d) DOSE (mg/d) FORMS HALF-LIFE (h)

First-generation
antipsychotics
Perphenazine 8–64 10 Tablets (2, 4, 8, 16 mg) 9
Concentrate (16 mg/5 ml)
Injectable solution (5 mg/ml)
Chlorpromazine 200–1,000 100 Tablets (10, 25, 50, 100, 200 mg) 23–37
Concentrate (30, 100 mg/ml)
Gel Caps (30 mg)
Spansules (30, 75, 150 mg)
Injectable solution (25 mg/ml)
Rectal suppositories (25 mg)
Haloperidol 2–20 2 Tablets (0.5, 1, 2, 5, 10, 20 mg) 24
Concentrate (2 mg/ml)
Injectable solution (5 mg/ml)
Second-generation
antipsychotics
Risperidone 2–8 1–2 Tablets (0.25, 0.5, 1, 2, 3, 4 mg) Parent 3
Concentrate (1 mg/ml) Metabolite 24
M-tabs (0.5, 1, 2 mg) rapidly
disintegrating tablets
Risperdal Consta long-acting injectable
(25, 37.5, 50 mg) q 2 wk)
! TABLE 1-1. (Continued)

THERAPEUTIC DOSE RANGE: THERAPEUTIC

USUAL ORAL DAILY EQUIVALENT ORAL
DRUG CLASS DOSE (mg/d) DOSE (mg/d) FORMS HALF-LIFE (h)

Ziprasidone 80–200 20 Capsules (20, 40, 60, 80 mg) 4–10

Injectable solution 20 mg/ml
Clozapine 25–600 50 Tablets (25, 100 mg) 8–12
Olanzapine 5–30 2.5–5 Tablets (2.5, 5, 7.5, 10, 15, 20 mg) 27
Zydis (5, 10, 15, 20 mg) rapidly
disintegrating tablets
Injectable solution 5 mg/ml
Quetiapine 150–800 50–100 Tablets (25, 50, 100, 200, 300, 400 mg) 7
Aripiprazole 10–30 5–10 Tablets (5, 10, 15, 20, 30 mg) 75–96
Oral solution 1 mg/ml
Long-acting preparations
Fluphenazine 12.5–50 q 2–4 wk 12.5–50 Injectable solution (25 mg/ml) 2–3 wk
decanoate
Haloperidol decanoate 50–300 q 3–4 wk 50–300 Injectable solution (100 mg/ml) 3 wk
Risperdal Consta 25–50 mg q 2 wk 25, 37.5, 50 mg Microspheres in fixed dose vials; 2 ml 3–6 days

Adapted and reprinted from Lieberman JA and Mendelowitz AJ (2000). Antipsychotic Drugs, Doses, Forms, and Costs. In Psychiatric
Drugs, Lieberman JA and Tasman A (eds.) WB Saunders, pp. 1–43. © 2000, with permission from Elsevier.
 ANTIPSYCHOTIC DRUGS 7

The development of second-generation antipsychotics has been

a major clinical advance for the treatment of schizophrenia.
At present, these drugs are used as the first-line treatment
for schizophrenia, and are being used increasingly for various
conditions beyond schizophrenia. The low incidence of EPS
and TD associated with second-generation agents is highly
beneficial in several neuropsychiatric conditions.

DRUG SELECTION AND INITIATION OF TREATMENT

Drug Selection for the Treatment of Schizophrenia
In choosing an antipsychotic agent for the treatment of an
episode of schizophrenia, the clinician should be guided by the
patient’s history. The following tests should be performed:

• a complete physical examination including weight

• a review of symptoms
• routine blood chemistry including fasting blood glucose and
lipid profile
• complete blood cell count
• electrocardiogram

Once any medical or neurologic causes of the symptoms have

been ruled out, the clinician should consider the following
questions:

• Is this a psychotic episode consistent with schizophrenia?

• Have affective syndromes such as mania and depression with
psychotic features been ruled out?
• Is this the patient’s first episode?
• Is there a history of prior antipsychotic treatment response?
• How well was the antipsychotic tolerated?
• Were there prominent side effects?
• Did the patient ever previously have EPS or TD?
• Does the patient have a history of neuroleptic malignant
syndrome?
• What symptoms (positive or negative) are predominant in
the episode?
8 HANDBOOK OF PSYCHIATRIC DRUGS

• Is there a history of non-compliance, and, if so, has the

patient had a trial of depot preparations?
• If there have been antipsychotic trials that have failed, were
the trials of an adequate dose and of an adequate duration?
• Does the patient meet the criteria for treatment resistance?
• Does the patient have a history of cardiac conduction delay?
• Does the patient have any prior history of blood dyscrasias?
• Does the patient have normal hepatic and renal functions?
• Is the patient medically debilitated?

TREATMENT INITIATION AND DOSE TITRATION

Once the questions above are answered, the clinician should
select an antipsychotic medication and initiate the treat-
ment trial. The algorithm from the practice guidelines for
schizophrenia developed by the American Psychiatric Associ-
ation may be useful for drug selection (Figure 1-1).
Selection of an agent in emergency settings for the manage-
ment of the gross agitation, excitement, and violent behavior
associated with psychosis might be based on clinical symptoms,
differences in efficacy or side effects of candidate drugs, or,
more pragmatically, the formulation of a drug as it affects route
of administration, onset, and duration.
There is now a considerable amount of clinical experience
with atypical antipsychotics in acute emergency situations, and
they have come to replace first-generation antipsychotics as
the agents of choice when treatment is initiated. Olanzapine
and ziprasidone are available in short-acting formulations for
intramuscular administration; risperidone and aripiprazole are
available as oral solutions; and olanzapine and risperidone are
available as rapidly disintegrating oral tablets. These various
formulations provide tremendous flexibility to the clinician in
choosing the optimal medication and method of administration
based on clinical considerations.
The use of oral second-generation antipsychotics and
benzodiazepines in combination is the most common medica-
tion strategy in psychiatric emergency settings. It is best to
avoid combining antipsychotics in favor of sequential trials
of monotherapy with different antipsychotics. Because most
patients with schizophrenia will require long-term treatment
with antipsychotics it is imperative that, in addition to short-
term treatment goals of control of behavioral dysregulation
 ANTIPSYCHOTIC DRUGS 9

Group 1: First-generation agents

Acute Phase Choose medication based
Group 2: Risperidone, olanzapine, quetiapine,
on clinical circumstances
ziprasidone, aripiprazole
from following (refer to
Group 3: Clozapine
Tables 3 and 4):
Group 4: Long-acting injectable antipsychotic agents

Yes Good response No

without intolerable
side effects?
For intolerable side effects: For inadequate therapeutic
choose a different medication response: choose a different
from Group 1 or 2 (refer to medication from Group 1, 2,
Tables 2 and 3). or 3 (refer to Table 3).

Good response
Yes without intolerable No
side effects?
For intolerable side effects:
For inadequate therapeutic
choose a different medication
response: choose a different
from Group 1 or 2 (refer to
medication from Group 1, 2, or 3.
Tables 2 and 3).
For persistent psychotic symptons,
clozapine should be given strong
consideration. Consider ECT for
patients with persistent severe
Good response psychosis, catatonia, and/or suicidal
Yes No ideation or behavior for whom prior
without intolerable
side effects? treatments including clozapine have
failed.

Stabilization or Continue acute-phase medication treatment. Consider maintenance ECT for

Maintenance Phase patients who have responded to an acute course of ECT and whose symptoms
cannot be controlled with medication maintenance therapy alone.

For intolerable side effects: For residual or intercurrent For treatment nonadherence:
choose a different medication positive, negative, cognitive, consider a different medication
from Group 1 or 2 (refer to or mood symptoms: from Group 4.
Tables 2 and 3). consider a different medication
from Group 2 or 3 or appropri-
ate adjunctive medication.

FIGURE 1-1. Somatic Treatment of Schizophrenia. Also refer to

Table 1-1 and the following: First episode–Group(G) 2; Persis-
tent suicidal ideation or behavior–G3; Persistent hostility and
aggressive behavior–G3; Tardive dyskinesia–G2 all group 2 drugs
may not be equal in their lower or no tardive dyskinesia
liability and G3; History of sensitivity to extrapyramidal side
effects–G2 except higher doses of risperidone; History of sensi-
tivity to prolactin elevation–G2 except risperidone; History of
sensitivity to weight gain, hyperglycemia, or hyperlipidemia–G2
ziprasidone or aripiprazole; Repeated nonadherence to phar-
macological treatment–G4 (taken from the Practice Guidelines
for the Treatment of Patients with Bipolar Disorder, Second
Edition from the American Psychiatric Association Practice Guide-
lines for the Treatment of Psychiatric Disorders Compendium,
Copyright 2004).
10 HANDBOOK OF PSYCHIATRIC DRUGS

and psychotic symptom resolution, clinicians consider long-

term side effect profiles of the available treatment options with
the goal of minimizing long-term side effect burden. Ziprasi-
done and aripiprazole may be specifically indicated in patients
who are intolerant of the side effects that can occur in greater
frequency with some of the second-generation drugs, such as
weight gain and alterations in glucose and lipid metabolism, as
they do not produce these effects to any significant degree.
One can safely escalate the dose of second-generation
antipsychotics more rapidly than is usual in outpatient settings
to achieve target doses typically utilized for the treatment of
schizophrenia. Once behavioral control is achieved, benzo-
diazepines should be discontinued and the patient should
be maintained on the atypical antipsychotic alone. The dose
recommendations for second-generation antipsychotic drugs
are summarized in Table 1-2.
The anti-aggressive characteristics of clozapine are well
established in chronically psychotic patients; however cloza-
pine initiation is contraindicated in the psychiatric emergency
setting because of its serious potential side effects, including
seizures and agranulocytosis.
On the rare occasion that a physician elects to use a first-
generation antipsychotic during the first few days of treat-
ment, “rapid neuroleptization” should be avoided as there is no
evidence for increased efficacy and risk of side effects is greater
at higher doses. If a low-potency agent is chosen, the recom-
mendation is to begin with a low dose such as chlorpromazine,
50 mg twice a day, and to titrate slowly so that the difficulties
associated with orthostatic hypotension can be reduced. If a
high-potency agent such as haloperidol is chosen, the recom-
mendation is also to begin a course of prophylactic antiparkin-
sonism medication such as benztropine, 1 mg twice a day, to
decrease the incidence of EPS side effects. The initial dose of
antipsychotic should be titrated to between 5 and 10 haloperidol
equivalents or 200 to 400 chlorpromazine equivalents. At this
time, the only groups of patients in which the first-generation
antipsychotics are clearly preferable are those who have a history
of good response to these agents with minimal side effects.
After initiating treatment and titrating to a standard dose
of antipsychotic, the clinician, patient, and family must wait for
the antipsychotic to take effect. Because patients are acutely
! TABLE 1-2. Recommended Dosages for Second-Generation Antipsychotic Agents

AVERAGE DOSE RANGE (mg/day) AVERAGE

HALF-LIFE STARTING DOSE MAINTENANCE DOSE ROUTES OF
(hr) (MEAN) (TOTAL mg/day) FIRST EPISODE RECURRENT EPISODE (mg/day) ADMINISTRATION

Clozapine 10–105 (16) 25–50 150–300 400–600 400 Oral

Risperidone 3–24 (15) 1–2 2–4 3–6 3–6 Oral, depot
Olanzapine 20–70 (30) 5–10 10–20 15–30 10–20 Oral, IM
Quetiapine 4–10 (7) 50–100 300–600 500–800 400–800 Oral
Ziprasidone 4–10 40–80 80–120 120–200 120–160 Oral, IM
Zotepine 12–30 (15) 50–100 75–150 150–450 75–300 Oral
Amisulpride 8–20 (12) 50–100 50–300 400–800 400–800 Oral
Aripiprazole (75–96) 10–15 10–30 15–30 15–30 Oral

Source: Adapted from McEvoy JP, Scheifler PL, Frances A (1999) The expert consensus guideline series: Treatment of schizophrenia. J Clin
Psychiatr 60, 1–80; Burns MJ (2001) The pharmacology and toxicology of atypical antipsychotic agents. J Clin Toxicol 39, 1–14; Worrel JA,
Marken PA, Beckman SE, et al. (2000) Atypical antipsychotic agents: A critical review. Am J Health Syst Pharm 57, 238–255.
12 HANDBOOK OF PSYCHIATRIC DRUGS

ill, there is often a tremendous temptation and external pres-

sure to increase the dose of the antipsychotic in the hope that
the patient’s condition will improve more rapidly. Despite this
hope, there is little, if any, clinical evidence that a higher dose
of antipsychotic is in any way advantageous; in fact, it will only
increase the likelihood of side effects. During this difficult time
it may be necessary to add sedating medications such as short-
acting benzodiazepines (e.g., lorazepam) to help the patient
maintain control until the antipsychotic has started to work.

TREATMENT EVALUATION AND DRUG SWITCHING

If the first-episode patient has failed to respond to a 6-week
trial of an antipsychotic, the clinician should evaluate possible
non-compliance with medication, the likelihood of a partial
response or a complete nonresponse to treatment. If there was no
response, a change to a second antipsychotic from a new family is
recommended. If one of the newer agents was not the clinician’s
first choice, it should be used at this point in the decision tree.
If a patient has already discontinued use of a medication,
then the new treatment is selected and initiated as described
above. However, if the patient is undergoing maintenance drug
treatment and drugs are to be electively switched in the hope
of achieving a better therapeutic response or alleviating drug
side effects, then the goal is to switch medications without
destabilizing the patient.
Medication changes should be performed by a concurrent
slow tapering of the initial antipsychotic while the second
antipsychotic is being slowly titrated. The specific rate of cross-
titration depends on the dose of the old medication and the
relative stability of the patient. In general, the higher the dose
and the more unstable the patient, the longer and more gradual
the cross-titration schedule. Although this varies, a rule of
thumb is to cross-titrate by yoked increments and decrements
of 25% every 2 to 5 days. Adjunctive medications should be
adjusted or tapered accordingly.
If the patient is judged to be a partial responder to the
antipsychotic trial, then the clinician may consider the addition
of an agent for augmentation. At this point, it is again impor-
tant for the clinician to re-evaluate the presence of affective
symptoms. If there is significant depressive symtomatology in
 ANTIPSYCHOTIC DRUGS 13

the clinical presentation, then the addition of an antidepressant

may be warranted. If the presence of mood symptoms is consis-
tent with a manic episode, the addition of a mood stabilizer such
as lithium as an augmentation strategy may be clinically useful.

Treatment During the Resolving Phase If a particular

antipsychotic medication has improved the acute symptoms it
should be continued at the same dose for the next six months
before a lower maintenance dose is considered for continued
treatment. Rapid dose reduction or discontinuation of the
medications during the resolving phase may result in relatively
rapid relapse. It is essential to continue to assess side effects
present in the acute phase and modify treatment to minimize
their negative impact, and to re-evaluate the necessity of any
adjunctive therapies used in the acute phase.
If the decision has been made to switch to a long-acting
depot antipsychotic agent, this can often be achieved during this
phase. This is also a good time to educate the patient and family
regarding the course and outcome of schizophrenia, as well
as factors that influence the outcome such as drug compliance.

MAINTENANCE TREATMENT
The goals of treatment during the stable or maintenance
phase are to maintain symptom remission, to prevent psychotic
relapse, to implement a plan for rehabilitation, and to improve
the patient’s quality of life.
Current guidelines recommend that first-episode patients
should be treated for one to two years; however, 75% of
patients will experience relapses after their treatment is discon-
tinued. Patients who have had multiple episodes should receive
at least five years of maintenance therapy. Patients with severe
or dangerous episodes should probably be treated indefinitely.
Gradual dose reduction to identify the minimum effective
dose for the patient can be attempted in this phase, although
relapse rates are excessively high when doses are reduced to
about 10% of the acute dose.
Antipsychotics have been proven to be effective in reducing
the risk of psychotic relapse in maintenance therapy for
schizophrenia. In the stable phase of illness, antipsychotics
can reduce the risk of relapse to less than 30% per year.
14 HANDBOOK OF PSYCHIATRIC DRUGS

Without maintenance treatment, 60–70% of patients relapse

within one year and almost 90% relapse within two years.
These results indicate that antipsychotic medications are effec-
tive in preventing relapse in most stabilized patients. There
is also strong evidence that patients who relapsed while on
antipsychotic medications had episodes that were less severe
than patients not on antipsychotic drugs.
As atypical drugs have fewer EPS side effects, patients on
these compounds may be less likely to be non-compliant with
treatment and may thereby decrease their risk of relapse. It
has also been suggested that in addition to fewer side effects,
atypical drugs may have inherently greater prophylactic effi-
cacy than typical drugs and therefore be better for patients
with an increased risk of relapse.

TREATING TREATMENT RESISTANCE

Treatment resistance is generally defined as a failure of two
prior drug trials of 4–6 weeks duration. Although most defini-
tions of treatment resistance focus on the persistence of posi-
tive symptoms, there is growing awareness of the problems
of persistent negative symptoms and cognitive impairments,
which may have an important impact on level of functioning,
psychosocial integration, and quality of life.
Approximately 10 to 15% of patients with first-episode
schizophrenia are resistant to drug treatment, and between
25% and 50% of long-term patients will have severe, persistent
symptoms including psychosis.
Only clozapine has consistently demonstrated efficacy
for psychotic symptoms in well-defined treatment refractory
patients; the mechanism responsible for this therapeutic advan-
tage remains uncertain. Serum levels of 350 #g/mL or greater
have been associated with maximal likelihood of response.
Depending on the type of residual symptom, augmentation
strategies include adding another antipsychotic, anticonvulsants,
benzodiazepines, and cholinergic agonists may prove useful.
Since the approval of clozapine, attention has shifted to
a greater focus on the use of other second-generation antipsy-
chotics for managing treatment resistance in schizophrenia.
Both olanzapine (15–25 mg/day) and clozapine (200–600
mg/day) were shown to be similarly effective in reducing
 ANTIPSYCHOTIC DRUGS 15

overall psychotic symptoms in treatment-resistant patients clin-

ically eligible for treatment with clozapine. Some preliminary
reports suggest that higher doses of olanzapine may be more
effective; however, dosage issues of olanzapine have not yet
been adequately addressed in more controlled conditions. There
are also several recent reports of beneficial effects of quetiapine
in treatment-resistant patients with schizophrenia.
Given the risk of agranulocytosis, the burden of side
effects, and the requirement of white blood cell monitoring,
the second-generation agents (risperidone, olanzapine, queti-
apine, ziprasidone, and aripiprazole) should be tried in almost
all patients before proceeding to clozapine. Many clinicians
express the impression that certain patients do respond pref-
erentially to a single agent of this class.

SCHIZOAFFECTIVE DISORDER AND VIOLENT PATIENTS

Among the specific therapeutic effects claimed for atypical
drugs is their ability to alleviate mood symptoms associated
with the psychotic disorder. Although this has not been defini-
tively proved, preliminary results indicate that mood symp-
toms may selectively abate with atypical drugs. This evidence
suggests that patients with schizoaffective disorder, residual
mood symptoms (e.g., postpsychotic depression), a history of,
or current, suicidal behavior, and violent behavior may benefit
most from treatment with an atypical drug as compared to a
conventional antipsychotic agent.

ADJUNCTIVE TREATMENTS
For patients who are unresponsive to antipsychotic agents,
including clozapine, and for patients who are responsive but
have substantial residual symptoms, the question is what further
options exist. Adjunctive medications as indicated in the algo-
rithm (other than electroconvulsive therapy) have been used
extensively but without any empiric data to demonstrate their
efficacy. These adjuncts include anticonvulsants, lithium, antide-
pressants, benzodiazepines, and cholinesterase inhibitors.

Effects of Antipsychotic Agents on Symptoms of

Schizophrenia
The clinical profile of second-generation antipsychotic agents on
the symptoms of schizophrenia are summarized in Table 1-3.
! TABLE 1-3. Clinical Profile of Second-Generation Antipsychotic Drug Efficacy

DRUG CLOZAPINE RISPERIDONE OLANZAPINE QUETIAPINE ZIPRASIDONE SERTINDOLE AMISULPRIDE ARIPIPRAZOLE ILOPERIDONE

Clinical effect
Psychotic +++ +++ +++ ++ ++ +++ +++ +++ +++
symptoms
Negative + + + + + ++ ++ ++ ++
symptoms
Cognitive ++ ++ ++ + ? ? ? ++ ?
symptoms
Mood +++ ++ +++ +++ ++ ++ ++ ++ ?
symptoms
Refractory +++ ++ ++ ++ ? ? ++ ? ?
symptoms

+ to +++, weakly to strongly active; ?, questionable to unknown activity.

Source: Adapted from Dawkins K, Lieberman JA, Lebowitz BD, et al. (1999) Antipsychotics: Past and future. National Institute of Mental
Health Division of Services and Intervention Research Workshop (July 14, 1998). Schizophr Bull 25, 395–404, with permission from Oxford
University Press.
 ANTIPSYCHOTIC DRUGS 17

Positive Symptoms Antipsychotic agents have a specific

effect on positive symptoms of schizophrenia including halluci-
nations, delusions, and thought disorder. Approximately 30%
of patients with acutely exacerbated psychotic symptoms have
little or no response to conventional antipsychotics, and up
to 50% of patients have only a partial response to medica-
tion. Although the proportion of patients who improve and
the magnitude of therapeutic effects vary greatly, second-
generation antipsychotics appear to be at least as effective for
psychotic symptoms as conventional drugs.

Negative Symptoms Studies of the early course of illness

have shown that about 70% of schizophrenics develop primary
negative symptoms such as affective blunting, emotional with-
drawal, poverty of speech, anhedonia, and apathy, before the
onset of positive symptoms. Negative symptoms may represent
core features of the illness, and may be associated with poor
outcome and prolonged hospitalization for patients.
Negative symptoms can be divided into three components
that are usually difficult to distinguish:

• primary or deficit – enduring negative symptoms

• primary – non-enduring negative symptoms
• secondary negative symptoms that may be associated with
psychotic symptoms, EPS, depression, and environmental
deprivation

Conventional antipsychotics are generally less effective against

negative than positive symptoms of schizophrenia; thus, the
efficacy of second-generation antipsychotics on negative symp-
toms compared with that of first-generation drugs has received
much attention. Second-generation agents such as cloza-
pine, olanzapine and risperidone demonstrate significantly
greater efficacy than conventional agents in reducing negative
symptoms.
However, there is a continuing debate as to whether these
effects are related to a reduction in EPS or to a direct effect
on primary negative symptoms. Moreover, the effect sizes
of improvement on negative symptoms for second-generation
agents are usually moderate to small in comparison with
18 HANDBOOK OF PSYCHIATRIC DRUGS

placebo or conventional agents. Path analyses have suggested

that both risperidone and olanzapine exert direct effects on
(primary) negative symptoms independent of differences in
psychotic, depressive, or extrapyramidal symptoms. A collabo-
rative working group concluded that second-generation drugs
are superior in terms of the “totality” of negative symptoms,
but their impact on specific components is still under investi-
gation. This and other clinical questions will become clear as
the new agents are tested in clinical trials.

Cognitive Symptoms Cognitive impairment appears to be an

integral characteristic of schizophrenia and may be evident in
up to 60% of patients. Measurable deficits are prominent in
tasks involving attention, verbal fluency, memory, and exec-
utive function. A wide range of cognitive deficits are usually
present at the time of the first psychotic episode and remain
relatively stable or only slowly progressive during the course
of the illness, independent of psychotic symptoms. Cognitive
deficits are particularly prominent in patients meeting criteria
for the deficit syndrome and in patients with TD. They are
more strongly related to social and vocational functioning than
psychotic symptoms and may influence the quality of life of
patients. Thus, targeting cognitive impairments appears to be
a major focus of the treatment of schizophrenia.
Conventional neuroleptics produce small and inconsistent
effects on cognitive functioning. In general, clozapine, risperi-
done, and olanzapine have demonstrated superior efficacy
compared to first-generation antipsychotics on tests of verbal
fluency, digit–symbol substitution, fine motor function, and
executive function. Measures of learning and memory were
least affected by second-generation agents. Because these tests
all measure performance during a timed trial, enhanced perfor-
mance with second-generation drugs could result, in part,
from reduced parkinsonian side effects. Preliminary evidence
suggests that risperidone may be more effective for visual and
working memory than clozapine.

Mood Symptoms and Suicidal Behavior Depressive symp-

toms frequently occur in the context of psychotic symptoms
or intercurrently between psychotic episodes. Antidepressant
 ANTIPSYCHOTIC DRUGS 19

medication used adjunctively to antipsychotic drugs is gener-

ally indicated and effective. Atypical antipsychotics have been
reported to have selective benefits against mood symptoms in
schizophrenia, both manic and depressive.
Suicidal behavior presents a particular problem in patients
with schizophrenia. Clozapine is approved for use in suicidal
patients with schizophrenia on the basis of results in the
InterSePT study. This study found that clozapine treatment
produced a lower rate of suicidal behavior than the compar-
ison treatment of olanzapine in patients with active or histories
of suicidal behavior.

Drug Selection for the Treatment of Bipolar

Disorder
Antipsychotic agents are effective in treating acute manic
episodes; these agents are believed to possess antimanic qual-
ities in addition to their antipsychotic properties. One benefit
is their rapid onset compared to mood stabilizers; as a result,
these agents are often used preferentially or combined until
the mood stabilizer has reached its therapeutic effectiveness.
All the second-generation antipsychotics (except clozapine)
are now approved for the treatment of acute manic episode
in the United States, as well as the acute treatment of mixed
episodes (except clozapine and quetiapine). Olanzapine and
aripiprazole are also approved for maintenance treatment.
A concern with the use of antipsychotics in this popula-
tion is the potential for TD. As a result, it is recommended
that atypical antipsychotics be used with this population
when clinically indicated but that attempts be made to treat
this population with mood-stabilizing agents by themselves if
possible.

Drug Selection for the Treatment of Major

Depression With Psychotic Features
Clear psychotic symptoms, such as delusions or hallucinations,
are observed in approximately 25% of patients with major
depressive disorder. These symptoms often respond poorly to
antidepressants when they are administered alone, and usually
require the use of adjunctive antipsychotic agents.
20 HANDBOOK OF PSYCHIATRIC DRUGS

Treatment can be initiated simultaneously, though many

clinicians prefer to start the antipsychotic dose first and then
add the antidepressant to the regimen. Though there are
limited data on the adequate dose of antipsychotic for this
group, most clinicians would recommend 5 to 10 haloperidol
equivalents. This group of unipolar depressed patients may be
at the highest risk of TD; thus the antipsychotic dosage should
be tapered and then discontinued when the patient’s psychotic
symptoms remit.

Drug Selection for the Treatment of Delusional

Disorder
Delusional disorder differs from other psychotic disorders in
terms of family history and age distribution. In addition, it
has displayed a difference in treatment response; as a general
rule, patients with delusional disorder do not respond well
to antipsychotic agents. Some uncontrolled clinical data have
suggested that these patients may do better with drugs from
the diphenylbutylpiperidine class (e.g., pimozide). However,
the majority of this group of patients are untreated and do not
seek psychiatric help. There is only very limited experience
with atypical drugs in this population.

Drug Selection for the Treatment of Delirium

Antipsychotics are effective in treating the psychotic symp-
toms and agitation associated with deliria of various etiologies.
In treating a delirium, high-potency agents are preferable to
low-potency agents because low-potency agents usually have
more anticholinergic properties and cardiovascular side effects,
which can adversely affect a delirious patient. Antipsychotic
drugs are commonly given parenterally when used for this
indication, including by intravenous routes.
Risperidone is also relatively free from anticholinergic side
effects and has a favorable side-effect profile in relation to
the production of EPS. The newer agents olanzapine and
quetiapine are now being utilized for these conditions. The
parenteral forms of the atypical drugs should be particularly
useful for this indication.
 ANTIPSYCHOTIC DRUGS 21

Drug Selection for the Treatment of Psychosis and

Agitation Associated with Dementia
Antipsychotics are effective in treating the psychotic symptoms
that are often associated with dementias. Additionally, they
have been demonstrated to have anti-aggressive and calming
effects against dysregulated behavior and affect. Although
many patients with dementia have agitation and behavioral
disturbances that clearly require the use of antipsychotic drugs,
these drugs should be used judiciously.
The atypical drugs offer several potential advantages over
typical drugs in treating dementia. They produce fewer EPS
and less TD, side effects to which elderly patients are highly
susceptible. They also may have broader efficacy against the
constellation of pathologic symptoms and behaviors (e.g.,
mood symptoms, hostility) that occur in dementia. To date,
extensive placebo-controlled trials have been conducted with
risperidone, olanzapine and aripiprazole. Other atypical drugs
must be systematically evaluated to determine their efficacy for
this disorder and to determine how well their antiadrenergic
and anticholinergic properties are tolerated.
Elderly patients with dementia who are treated with an
antipsychotic agent are at increased risk of death. Analyses of
clinical trials with a modal duration of 10 weeks suggest that
the excess risk is 1.6–1.7 compared with placebo. Most of the
deaths appear to be due to cardiovascular events (including
heart failure and sudden death) or infection. Because these
events have been associated with antipsychotics regardless of
their chemical structure, this is probably a class effect associ-
ated with their pharmacological activity and the risk applies
also to both atypical and older antipsychotics and to drugs
that were not included in these trials. The FDA has reminded
prescribers that these agents are not approved for the treat-
ment of dementia in older people.

Drug Selection for the Treatment of Mental

Retardation and Developmental Disorders
Patients with mental retardation are another patient popu-
lation with psychotic symptoms and behavioral disturbances
22 HANDBOOK OF PSYCHIATRIC DRUGS

about whom there has been controversy. As with patients

with dementia, a number of these patients have documented
psychosis, and for these patients the use of antipsychotics is
clearly indicated. There are other patients, however, whose
primary symptoms are those of behavioral dyscontrol. In
this group it is possible that the risks of antipsychotics may
outweigh their benefits, especially in long-term treatment.
Again, atypical drugs may be advantageous because of their
lower EPS and TD liabilities, to which these patients are highly
susceptible.

Drug Selection for Huntington’s Disease and

Tourette’s Disorder
Antipsychotics have been shown to be effective in the manage-
ment of Huntington’s disease and Tourette’s disorder. In
Huntington’s, various antipsychotics have been used to help
control the agitation and chorea as well as the psychotic
symptoms associated with the disorder. In Tourette’s disorder,
the antipsychotics used most extensively to manage patients’
vocalizations and tics include haloperidol and pimozide. Most
recently, risperidone has shown promise in this patient popula-
tion. Beyond risperidone, there is little experience with atypical
drugs in these disorders. The exception to this is clozapine,
which was found to have little therapeutic benefit in either
condition.
On the basis of this evidence, the typical drugs might be
the preferred therapeutic option in these disorders; nonstriatal
weak D2 agents would be less likely to be effective.

Substance-induced Psychoses
PSYCHOSTIMULANT- AND PHENCYCLIDINE-INDUCED PSYCOSES
Substance intoxication resulting in psychotic symptoms may
be treated effectively with antipsychotic drugs. This is partic-
ularly the case with intoxication from psychostimulants such
as amphetamine, methamphetamine, and cocaine and from
phencyclidine. Previously the clinical approach was not to use
typical neuroleptics for fear of exacerbating the patient’s condi-
tion with side effects but, rather, to employ benzodiazepines
 ANTIPSYCHOTIC DRUGS 23

and a calm low-stimulus environment, unless the condition

persisted for days or well beyond the period of the toxin’s
elimination. With the availability of the atypical drugs and
their ability to alter the effects of NMDA receptor antagonists
as well as psychostimulants, the use of these agents should
be evaluated. At present, however, only limited data on their
efficacy in these conditions are available.

LEVODOPA-INDUCED AND STEROID-INDUCED PSYCHOSIS

Antipsychotics are an integral part of the treatment
of medication-induced psychotic syndromes. The psychosis
induced by levodopa in the treatment of Parkinson’s disease
presents unique clinical dilemmas. Treatment of the symp-
toms with first-generation antipsychotic agents will by defini-
tion worsen the Parkinson’s symptoms. The clinician is often
caught between attempts to reduce the patient’s severe para-
noid state and attempts to keep the patient from becoming
more immobile from worsening rigidity and akinesia. Recently,
case reports utilizing clozapine and risperidone in this popula-
tion have shown encouraging results.
Steroid-induced psychotic symptoms have proved to
be somewhat more complicated: psychotic symptoms may be
prolonged, requiring the use of antipsychotics, and at the
same time, despite the emergence of psychosis, some patients
may still require steroid treatment for their medical condition.
There have been a few case reports in which patients known
to become psychotic during a steroid course were pretreated
with antipsychotics or with a mood stabilizer, with good
results.

ADVERSE EFFECTS OF ANTIPSYCHOTICS

Antipsychotics as a group have a wide range of potential side
effects corresponding to their pharmacologic properties. Atyp-
ical and typical drugs vary markedly in their side-effect profiles;
clozapine has the most complicated and potentially serious side
effects. The side effects for representative high-, mid-, and low-
potency typical drugs and individual atypical drugs are shown
in Table 1-4.
! TABLE 1-4. Side-Effect Profile of Second-Generation Antipsychotic Drugs

CONVENTIONAL
DRUG AGENTS CLOZAPINE RISPERIDONE OLANZAPINE QUETIAPINE ZIPRASIDONE SERTINDOLE AMISULPRIDE ARIPIPRAZOLE ILOPERIDONE

Side effect
EPSa +++ 0 ++ + 0 + 0 ++ + +
TD +++ 0 ++ + 0 + 0 to + + + +
NMS ++ + + + ? + + + ? ?
Prolactin elevation +++ 0 +++ 0 to + 0 0 to + 0 to + ++ 0 0 to +
Weight gain + to ++ +++ + +++ + 0 + + 0 ?
Prolonged QTa + to +++ 0 + 0 + ++ +++ + 0 0
Hypotensiona + to ++ +++ + ++ ++ + + 0 + +
Sinus + to +++ +++ + ++ ++ + + 0 0 +
tachycardiaa
Anticholinergic + to +++ +++ 0 ++ + 0 0 0 0 0
effectsa
Hepatic + to ++ ++ + ++ + + + + 0 +
transaminitis
Agranulo-cytosis 0 to + ++ 0 0 0 0 0 0 0 0
Sedation + to +++ +++ + ++ +++ + + + + +
Seizuresa 0 to + +++ 0 0 to + 0 to + 0 to + 0 to + 0 to + 0 to + 0 to +

EPS, extrapyramidal side effects; TD, tardive dyskinesia; NMS, neuroleptic malignant syndrome.
+ to +++, active to strongly active; 0, minimal to none; ?, questionable to unknown activity.
a
Dose dependent.
Adapted and modified with permission from Dawkins K, Lieberman JA, Lebowitz BD, et al. (1999) Antipsychotics: Past and future. National Institute of Mental
Health Division of Services and Intervention Research Workshop (July 14, 1998). Schizophr Bull 25, 395–404; Burns MJ (2001) The pharmacology and toxicology
of atypical antipsychotic agents. J Clin Toxicol 39, 1–14.
 ANTIPSYCHOTIC DRUGS 25

Acute Extrapyramidal Side Effects (Dystonia,

Parkinsonism, Akathisia)
Antipsychotic-induced EPS occur both acutely and after
chronic treatment. All antipsychotic medications are capable
of producing EPS. In general, first-generation antipsychotics
are more likely to cause EPS than second-generation antipsy-
chotics when the drugs are used at usual therapeutic doses.
Among second-generation drugs, clozapine and quetiapine
have been shown to carry minimal to no risk for EPS within
the therapeutic dosage range. Risperidone can produce dose-
related EPS $≥ 6 mg/day". With the exception of akathisia, the
incidence of EPS with olanzapine, aripiprazole, and ziprasi-
done is not appreciably different from that with placebo. The
relative liability of the individual second-generation agents to
produce EPS will become apparent only when they have been
directly compared with each other in prospective clinical trials.
Commonly occurring acute EPS include akathisia, dystonia,
and parkinsonism, with each having a characteristic time of
onset. This group of acute EPS develops relatively soon after
the initiation of antipsychotic medications and remits soon
after the drugs are discontinued. These movement disorders
are dose-dependent and reversible.
Dystonias tend to be sudden in onset, the most dramatic
form of acute EPS, and extremely distressing to patients.
They present as sustained muscle contraction with contorting,
twisting, or abnormal postures affecting mainly the muscula-
ture of the head and neck but sometimes the trunk and lower
extremities. Dystonic reactions usually occur within the first
few days of therapy. Laryngeal dystonias are the most serious,
and are potentially fatal. Risk factors for acute dystonias
include a history of prior dystonias, young age, male gender,
use of high-potency neuroleptic agents such as haloperidol
or fluphenazine, high dose of medication, and parenteral
administration.
Medication-induced parkinsonism is characterized by the
symptoms of idiopathic parkinsonism, including rigidity,
tremor, akinesia, and bradykinesia. Risk factors include older
age, higher dose, a history of parkinsonism, and underlying
damage in the basal ganglia.
26 HANDBOOK OF PSYCHIATRIC DRUGS

Patients with akinesia or bradykinesia suffer from slow

movement, apathy, and with difficulty with spontaneity of
speech and initiating movement. These symptoms need to
be distinguished from negative symptoms of schizophrenia,
depressive symptoms, and catatonia.
Akathisia, the most common EPS of conventional antipsy-
chotics agents, is characterized by both the subjective and
objective somatic restlessness. Patients with akathisia may
usually experience an inner tension, discomfort, irritation,
anxiety, or irresistible urge to move various parts of their
bodies. Akathisia appears objectively as psychomotor agita-
tion, such as continuous pacing, rocking from foot to foot, or
the inability to sit still. Akathisia is typically witnessed in a
few hours to days after medication administration. This side
effect can be seen in up to 20 to 25% of patients treated with
conventional agents. Akathisia is frequently cited as a reason
for poor drug compliance, since it is often extremely distressing
to patients. It can also result in dysphoria and aggressive or
suicidal behavior.
The treatment of acute EPS depends on the specific
side effect. Dystonia can be quickly and successfully treated
with an intramuscular injection of an anticholinergic (i.e.,
benztropine, diphenhydramine). The initial treatment of
parkinsonian side effects is lowering the dose of antipsy-
chotic. If an adequate response is not achieved, adding an
anticholinergic, or amantadine (a weak dopamine agonist),
may be efficacious. If symptoms persist, switching to an
second-generation antipsychotic or a low-potency conventional
antipsychotic should be considered. Akathisia is less respon-
sive to treatment than are other acute EPS. The first step of
the treatment of akathisia is lowering the antipsychotic dose.
The next step is individual trials of beta-adrenergic blockers
(i.e., propranolol), and benzodiazepines (i.e., lorazepam and
clonazepam).

Tardive Dyskinesia and Other Tardive Syndromes

TD is a repetitive, involuntary, hyperkinetic movement
disorder caused by sustained exposure to antipsychotic
medication. TD is characterized by choreiform movements,
 ANTIPSYCHOTIC DRUGS 27

tics and grimaces of the oro-facial muscles, and dyskinesia

of distal limbs, often the paraspinal muscles, and occasion-
ally the diaphragm. Younger patients with TD tend to exhibit
slower athetoid movements of the trunk, extremities, and
neck. In addition to the more frequently observed oro-facial
and choreoathetoid signs of TD, tardive dystonias (sustained
abnormal postures or positions) and tardive akathisia (persis-
tent subjective and/or objective signs of restlessness) have
been described. The abnormal movements of TD are usually
increased with emotional arousal and are absent when the indi-
vidual is asleep. According to the diagnostic criteria proposed
by Schooler and Kane, the movements should be present for at
least four weeks, and exposure to antipsychotic drugs should
have totaled at least three months. The onset of the abnormal
movements should occur either while the patient is receiving
an antipsychotic agent or within a few weeks of discontinuing
the offending agent.
Prevalence surveys indicate that mild forms of TD occur in
approximately 20% of patients who receive chronic treatment
with conventional antipsychotic medication. A major prospec-
tive research demonstrates that the cumulative incidence of
TD is 5% in the first year, 10% the second year, 15% the
third year, and 19% the fourth year in a patient who receives
a typical neuroleptic. Prevalence rates of TD may exceed 50%
in high-risk groups, such as the elderly. The reported preva-
lence of tardive dystonia is around 1.5 to 4%. Among the most
significant predictors of TD are older age, female gender, pres-
ence of EPS, diabetes mellitus, affective disorders, and certain
parameters of neuroleptic exposure such as dose and duration
of therapy.
All first-generation antipsychotic agents are associated
with a risk of TD. Studies of newer antipsychotics suggest
that TD liability is much lower with the second-generation
agents, and clozapine is associated with a substantially lower
risk for development of TD than other antipsychotic medi-
cations. A double-blind, random assignment study of 1,714
patients found a 0.52% long-term risk of TD with olanza-
pine treatment, as compared to a 7.45% risk with haloperidol.
Another published double-blind randomized study showed a
28 HANDBOOK OF PSYCHIATRIC DRUGS

significantly lower risk of TD in olanzapine-treated patients

(1%) than haloperidol-treated schizophrenic patients (4.6%).
In a double-blind, randomized 1-year study comparing risperi-
done to haloperidol, the rate of TD was 0.6% in the risperidone
group and 2.7% in the haloperidol group. Among a sample of
geriatric patients, a lower incidence of TD in patients treated
with risperidone than in those treated with haloperidol, at least
over a 9-month period, has been reported. The rate of TD
with risperidone has been reported to be low (0.6%) for doses
currently used (2–8 mg/day). The incidence of TD with queti-
apine is preliminarily reportedly low or virtually non-existent,
although this remains to be demonstrated prospectively. The
risk of TD with ziprasidone and aripiprazole is not known but
is expected to be similarly low.
For most patients, TD does not appear to be progressive
or irreversible. The onset of TD often tends to be insidious
with a fluctuating course. With time, TD will either stabilize
or improve even if the antipsychotic medication is continued,
although there are reports of TD worsening during continued
drug therapy. After discontinuation of antipsychotic medica-
tion, a significant proportion of patients with TD will have
remission of symptoms, especially if the TD is of recent onset
or the patient is young. Unfortunately, withdrawal of antipsy-
chotic agents is seldom an option for patients with serious
psychosis.
The American Psychiatric Association Task Force on TD
has issued a report in which a number of recommendations
were made for preventing and managing TD. These include
(1) establishing objective evidence that antipsychotic medica-
tions are effective for an individual; (2) using the lowest effec-
tive dose of antipsychotic drugs; (3) prescribing cautiously for
children, elderly patients, and patients with mood disorders;
(4) examining patients on a regular basis for evidence of TD;
(5) considering alternatives to antipsychotic drugs, obtaining
informed consent, and also considering a reduction in dosage
when TD is diagnosed; and (6) considering a number of options
if the TD worsens, including discontinuing the antipsychotic
medication, switching to a different drug, or considering a trial
of clozapine.
 ANTIPSYCHOTIC DRUGS 29

Although a large number of agents have been studied for

their therapeutic effects on TD, there is no definitive drug
treatment for it. Second-generation antipsychotics, in partic-
ular clozapine, have been used in clinical practice to treat TD,
but there have been no adequately controlled trials to date
to support this practice. It has been suggested that second-
generation antipsychotics should be used as first-line treatment
for patients who have TD or are at risk for TD. Guidelines for
treating TD recommend using second-generation agents for
mild TD symptoms, and clozapine or a newer agent for more
severe symptoms.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is characterized by
the triad of rigidity, hyperthermia, and autonomic instability in
association with the use of an antipsychotic medication. NMS
is often associated with elevation of creatine kinase (greater
than 300 U/mL), leukocytosis (greater than 15,000 mm3 ), and
change in level of consciousness. NMS can be of sudden and
unpredictable onset, usually occurring early in the course of
antipsychotic treatment, and can be fatal in 5 to 20% of
untreated cases.
The incidence of NMS varies from 0.02 to 3.23%, reflecting
differences in criteria. Prevalence rates are unknown, but
are estimated to vary from 1 to 2% of patients treated
with antipsychotic medication. The relative risk of second-
generation antipsychotics for NMS is likely to be lower,
but conclusive data are not yet available. NMS has been
reported with clozapine, risperidone, olanzapine, and queti-
apine. Proposed risk factors include prior episode of NMS,
younger age, male gender, physical illness, dehydration, use
of high-potency antipsychotics, rapid dose titration, use of
parenteral (IM) preparations, and pre-existing neurological
disability.
If NMS is suspected, the offending antipsychotic agent
should be discontinued and supportive and symptomatic treat-
ment started. Both dantrolene and dopamine agonists such
as bromocriptine have also been used in the treatment of
NMS. These agents, however, have not shown greater efficacy
compared to supportive treatment.
30 HANDBOOK OF PSYCHIATRIC DRUGS

The usual course of treatment is between 5 and 10 days.

Long acting depot preparations will prolong recovery time.
After several weeks of recovery, treatment may be cautiously
resumed with a different antipsychotic medication with gradu-
ally increased doses.

Endocrine and Sexual Effects

All standard antipsychotic drugs elevate serum prolactin levels
by blocking the tonic inhibitory actions of dopamine on
lactotrophic cells in the pituitary. Among second-generation
antipsychotics, risperidone and amisulpride can produce dose-
dependent hyperprolactinemia to a greater extent than first-
generation antipsychotics, whereas clozapine, olanzapine,
ziprasidone, and quetiapine do not cause a sustained eleva-
tion of prolactin above normal levels. Aripiprazole, being a
partial DA agonist, produces no elevation of prolactin and
even suppresses prolactin levels slightly. Hyperprolactinemia
in women can lead to menstrual disturbances, including anovu-
latory cycles and infertility, menses with abnormal luteal
phases, or frank amenorrhea and hypoestrogenemia. Women
have also reported decreased libido and anorgasmia, and
there are reports of increased long-term risk of osteoporosis
although this is controversial. Antipsychotic-induced gyneco-
mastia has been reported in 3% of women and 6% of men.
Galactorrhea occurs in 2.7% of men and 10 to 50% of women.
The major effects of hyperprolactinemia in men are loss of
libido, impotence, hypospermatogenesis, and erectile or ejac-
ulatory disturbances. Although amisulpride and risperidone
cause significant elevations of prolactin levels, a number of
studies have found only a small incidence of sexual dysfunc-
tions in patients treated with these drugs. This may be due to
the fact that these reports have relied on spontaneous reporting
of sexual side effects. In a drug monitoring study, in which side
effects profiles of haloperidol and clozapine were investigated,
a significantly higher frequency of sexual disturbances have
been found. Using a side effect rating scale, it was shown that
the prevalence of these adverse events was high during the
first weeks of the study. However, side effects usually remitted
spontaneously despite continuous treatment in the majority of
patients.
 ANTIPSYCHOTIC DRUGS 31

Metabolic Effects
Various degrees of weight gain have been recognized as a
common problem with conventional antipsychotic medica-
tions. Weight gain is an important issue in the management
of patients, because this adverse effect may be associated
with non-compliance and certain medical illnesses, such as
diabetes mellitus, cardiovascular disease, certain cancers, and
osteoarthritis.
Differences have been discovered among second-
generation antipsychotics with respect to their ability to induce
weight gain (Table 1-4). A recent meta-analysis, which esti-
mates the weight change after 10 weeks of treatment at a
standard dose, demonstrated that mean increases were 4.45 kg
for clozapine, 4.15 kg for olanzapine, 2.10 kg for risperidone,
and 0.04 kg for ziprasidone. The long-term risk of weight gain
with quetiapine appears to be less than that with olanzapine
and clozapine. Short-term weight gain (2.16 kg over 10 weeks)
with quetiapine appears comparable to risperidone. Ziprasi-
done has been associated with minimal weight gain, which
could distinguish it among other second-generation antipsy-
chotics. Similarly, aripiprazole appears to cause little or no
weight gain. During long-term treatment, clozapine and olan-
zapine have the largest effects on weight gain; risperidone
produces intermediate weight gain; quetiapine and ziprasidone
produce the least weight gain. Weight gain does not appear to
be dose-dependent, tends to plateau between 6 and 12 months
after initiation of treatment, and is mainly due to an increase in
body fat. The mechanism by which weight gain occurs during
treatment with antipsychotics is poorly understood, but the
broader receptor affinities of the agents and their antagonism
of histamine H1 and serotonin 5-HT2C receptors have been
implicated. There is currently no standard approach to the
management of weight gain induced by antipsychotic medi-
cation. Patient education prior to initiating treatment should
be provided, and regular exercise should be encouraged in all
patients receiving antipsychotic medication. Switching to other
second-generation antipsychotics with fewer propensities for
producing weight gain may be the most efficient way to deal
with antipsychotic-induced weight gain.
32 HANDBOOK OF PSYCHIATRIC DRUGS

Abnormalities in peripheral glucose regulation and

diabetes mellitus (DM) occur more commonly in schizophrenic
patients compared with the general population. There is
growing concern with metabolic disturbances associated with
antipsychotic use, including hyperglycemia, hyperlipidemia,
exacerbation of existing type 1 and 2 DM, new-onset type 2
DM, and diabetic ketoacidosis. A number of case reports have
implicated both clozapine and olanzapine in the emergence of
non-insulin-dependent (type 2) DM and diabetic ketoacidosis.
There are fewer reports describing an association between DM
and quetiapine or risperidone, but these drugs do appear to
have this side effect potential albeit to a lesser degree. In
contrast there are many fewer reports for ziprasidone and arip-
iprazole which suggests they may have less or no metabolic side
effect liability. The limited reporting for ziprasidone may be
related to the relatively limited use of the agent at the present
time. Although no clear mechanism of action of the second-
generation agents has been established, significant weight
gain or antagonism of specific serotonin receptor subtypes
may contribute to the development of these abnormali-
ties. Physicians employing second-generation agents should
routinely monitor weight, fasting blood glucose, and lipid
profiles.

Cardiovascular Effects
Orthostatic hypotension is usually seen with low-potency
conventional antipsychotic agents (e.g., chlorpromazine or
thioridazine) and clozapine through alpha-l-adrenergic antag-
onism. Among the first-line second-generation antipsychotics,
quetiapine has the greatest potential for inducing orthostasis
although all agents have this potential. Orthostasis is most
likely to occur during the first few days after initiation of
treatment, or when increasing the dose of medications; most
patients develop tolerance to it in the following four to six
weeks. Elderly patients are particularly vulnerable to this side
effect and it may predispose them to falls and increase the
incidence of serious injuries or fractures. A gradual upward
titration of dosage may help to reduce the risk of hypotension,
and patients should be advised to change posture slowly.
 ANTIPSYCHOTIC DRUGS 33

Tachycardia may occur as a result of the anticholinergic

effects of antipsychotic medications on vagal inhibition, or
secondary to orthostatic hypotension. Clozapine produces the
most pronounced tachycardia; approximately 25% of patients
will have a sinus tachycardia with an increase of about 10 to 15
beats per minute. Although quetiapine has virtually no cholin-
ergic activity, tachycardia is a possible side effect, perhaps
secondary to its adrenergic effects on blood pressure. Most
patients will develop tolerance to this side effect over time.
If tachycardia is sustained or becomes symptomatic, an elec-
trocardiogram (ECG) should be obtained. Low doses of a
peripherally acting beta-blocker such as atenolol can be useful
to treat medication-induced tachycardia without hypotension.
ECG changes are observed with many antipsychotic agents.
Chlorpromazine may cause prolongation of the QT and PR
intervals, ST depression, and T-wave flattening or inversion,
and thioridazine may cause QT and T-wave changes. These
effects rarely cause clinically relevant symptoms within thera-
peutic dose ranges.
Ziprasidone has very specific recommendations in the
package insert as to the types of patients it should not be
used in. Needless to say, antipsychotics that lead to QTc-
prolongation must not be combined with other drugs that
have similar effects. The effect of many but not all antipsy-
chotic drugs on the QT interval appears to be dose-related.
Several antipsychotic drugs have infrequently been associated
with malignant arrhythmias such as torsade de pointes. To date,
torsade de pointes has not been reported following therapeutic
doses or overdose with ziprasidone or other second-generation
antipsychotics.
Sudden unexplained deaths have been rarely reported with
therapeutic doses of antipsychotic drugs, and such deaths could
result from cardiac arrhythmias in the absence of another
explanation. There is, however, currently no evidence that
antipsychotic drugs are associated with an increased prevalence
of sudden deaths due to cardiac events, although a number
of case reports and case series concerning death following
cardiomyopathy, potentially induced by clozapine are a matter
of concern.
34 HANDBOOK OF PSYCHIATRIC DRUGS

Gastrointestinal Effects
The anticholinergic effects of antipsychotic medications can
induce dry mouth and constipation as well as tachycardia,
urinary retention, and blurring of vision. These adverse effects
are relatively commonly encountered with low-potency first-
generation antipsychotics and may be dose related. In cases of
more serious gastrointestinal adverse events, such as paralytic
ileus, which has been reported following treatment with cloza-
pine, medication must be discontinued immediately and rele-
vant medical or surgical interventions may become necessary.
Anticholinergic manifestations are common with poisoning
from clozapine and olanzapine.

Hepatic Effects
Asymptomatic mild, transient, and reversible elevations of
liver enzyme levels occur infrequently with both first-
and second-generation antipsychotic drugs. These abnor-
malities usually occur during the first three months of
treatment, are idiosyncratic, and seldom a serious concern.
Rarely, symptomatic hepatotoxicity (cholestatic or hepatitic)
may be associated with second-generation antipsychotics; in
these cases, the offending medication should be discon-
tinued. Recovery occurs in up to 75% of patients within
two months; 90% recover within one year. Patients
taking antipsychotics who have nausea, fever, abdom-
inal pain, and rash should have their liver function
evaluated to exclude hepatotoxicity. Since antipsychotic-
induced jaundice is infrequent, other etiologies should be
ruled out before the cause is judged to be antipsychotic
treatment.

Hematological Effects
Antipsychotic medications may cause blood dyscrasias,
including neutropenia, leukopenia, leukocytosis, throm-
bopenia, and agranulocytosis. Leukopenia, usually transient,
commonly occurs early in treatment, and resolves sponta-
neously. Chlorpromazine has been associated with benign
leukopenia, which occurs in up to 10% of patients. This
 ANTIPSYCHOTIC DRUGS 35

phenomenon is even more common following clozapine

administration.
Agranulocytosis (granulocyte count less than 500/mm3 )
is a fatal side effect of antipsychotic drugs. The risk of
agranulocytosis with clozapine is 1% and is greatest early in
treatment, usually within the first 8 to 12 weeks of treatment.
It tends to occur slightly more often in women, the elderly,
and young patients (less than 21 years old). Agranulocy-
tosis from clozapine is usually reversible if the drug is with-
drawn immediately. Olanzapine is not associated with severe
agranulocytosis. Despite these encouraging studies, there are
a number of case studies reporting agranulocytosis during
treatment with olanzapine (and quetiapine) in patients who
had suffered this adverse event during previous clozapine
exposure.
Before initiating treatment with clozapine, patients in the
USA must be registered in a program that ensures that they
receive weekly monitoring of their white blood cell (WBC)
count during the first six months of treatment. Current guide-
lines require weekly monitoring for one month after the termi-
nation of clozapine treatment. Guidelines on the use of cloza-
pine vary between different countries.

Other Side Effects

Sedation is the single most common side effect among low-
potency conventional antipsychotics, as well as clozapine,
zotepine, and quetiapine. Although sedation is often benefi-
cial at the beginning of treatment to calm down an anxious or
aggressive patient, it usually impairs functioning during long-
term treatment. Most patients usually develop tolerance over
time, or it may be possible to minimize sedation by dose reduc-
tion or by shifting most of the medication to night to reduce
daytime sleepiness.
Antipsychotic medications can lower the seizure threshold
to some degree. Seizure is more common with low-potency
first-generation antipsychotics and clozapine. Clozapine is
associated with dose-related increase in seizures. For example,
doses of clozapine below 300 mg/day have been found to have
a seizure rate of about 1%, doses between 300 and 600 mg/day
36 HANDBOOK OF PSYCHIATRIC DRUGS

have a seizure rate of 2.7%, and doses above 600 mg/day have
a rate of 4.4%. Strategies to reduce the risk for seizures include
slower dose titration, a lower dose, and the addition of an
anticonvulsant agent (i.e., valproic acid).

DRUG INTERACTIONS AND ANTIPSYCHOTIC

AGENTS
Most antipsychotics are metabolized by hepatic microsomal
oxidases (cytochrome P450 system); the major isoenzyme
systems involved are CYP1A2, CYP2C19, CYP2D6, and
CYP3A4. Induction or inhibition of these enzymes by other
drugs may occasionally produce clinically important drug
interactions. Table 1-5 summarizes clinically significant phar-
macokinetic drug interactions involving second-generation
antipsychotic drugs. SSRI’s, particularly fluoxetine and parox-
etine, can increase plasma concentrations of antipsychotic
medications by inhibiting CYP2D6 and decreasing the clear-
ance of antipsychotics, possibly leading to toxicity. Conven-
tional antipsychotic drug clearance can be decreased by 50%
with concurrent administration of certain heterocyclic antide-
pressants, beta-blockers, some antibiotic/antifungal agents,
and cimetidine. Clozapine toxicity has occurred following
co-administration with the CYP1A2 inhibitors cimetidine,
erythromycin, and fluvoxamine.
Quetiapine, ziprasidone, and aripiprazole toxicity can be
caused by inhibitors of CYP3A4 such as erythromycin, fluox-
etine, nefazadone, and protease inhibitors.
In contrast, drugs such as carbamazepine, phenobarbital,
and phenytoin can reduce plasma concentrations of antipsy-
chotic drugs by increasing the metabolism of the antipsychotic
agent. For example, carbamazepine, commonly combined with
antipsychotic medications, can reduce the plasma concentra-
tion of haloperidol by 50%. Anticonvulsants, however, may
not have a significant effect on the metabolic clearance of olan-
zapine or risperidone as they are not substantially metabolized
through CYP3A4. Cigarette smoking increases drug clearance
for many antipsychotic drugs, including clozapine and olan-
zapine. The clearance rate of clozapine and olanzapine are
increased by 20 to 50%.
 ANTIPSYCHOTIC DRUGS 37
! TABLE 1-5. Pharmacokinetic Drug Interactions Involving Second-
Generation Antipsychotic Agents
DRUG AND CYTOCHROME
P-450 ISOENZYME(S) INHIBITORS INDUCERS

Clozapine
1A2 Fluoroquinolones, Smoking, PAHsa
fluvoxamine
3A4 Erythromycin, Rifampin,
ketoconazole, ritonavir, carbamazepine,
sertraline,b cimetidine phenytoin,
barbiturates
2D6 Ritonavir, quinidine, None
risperidone,b
fluoxetine,b sertralineb
Risperidone
2D6 Paroxetine, fluoxetine Rifampin,
carbamazepine,
phenytoin,
barbiturates
Olanzapine
1A2 Fluvoxamine Smoking, PAHs,
carbamazepine
2D6 None Phenytoin
Quetiapine
3A4 Ketoconazole, Rifampin,
erythromycin carbamazepine,
phenytoin,
barbiturates
Ziprasidone
3A4 Ketoconazole, Rifampin,
erythromycin carbamazepine,
phenytoin,
barbiturates
None None
Aripiprazole
3A4 Ketoconazole, Rifampin,
erythromycin carbamazepine,
phenytoin,
barbiturates
2D6 Paroxetine, fluoxetine None

a
PAHs, polycyclic aromatic hydrocarbons.
b
Case reports of mild to moderate elevations in serum concentration.
Adapted from Worrel JA, Marken PA, Beckman SE, et al. (2000) Atypical antipsy-
chotic agents: A critical review. Am J Health Syst Pharm 57, 238–255.
38 HANDBOOK OF PSYCHIATRIC DRUGS

Other common interactions are:

• Antacids: can decrease the absorption of the antipsychotic
agent from the gut.
• Antipsychotics: can antagonize the effects of dopamine
agonists or levodopa when these drugs are used to treat
parkinsonism
• Antipsychotic agents: may also enhance the effects of CNS
depressants such as analgesics, anxiolytics, and hypnotics.
• Doses of pre-anesthetic medication or general anesthetics
may need to be reduced.

Antipsychotic Medications and Pregnancy

Most antipsychotic agents readily cross the placenta and are
secreted in breast milk to some degree. There is little data to
demonstrate whether prenatal exposure to antipsychotic agents
is linked to spontaneous abortion, congenital malformations,
carcinogenesis, intrauterine growth retardation, or behavioral
teratogenicity.
Fetal exposure over the course of pregnancy may affect
development of the dopamine system; the benefits of control-
ling psychotic symptoms during pregnancy versus the possible
risks to the mother and the fetus of withdrawing treatment
and the risks to the fetus of continuing treatment must be
considered.
There is no evidence that second-generation antipsychotics
are teratogenic in humans. However, if possible, use of antipsy-
chotic medication should be avoided during the first trimester,
especially between weeks six and ten, unless the patient’s
psychosis places the mother and/or her fetus at significant risk.
Antipsychotic medications may be relatively safe during the
second and third trimesters of pregnancy.
If a first-generation antipsychotic is used, high-potency
agents appear to be preferable for first-line management, due
to a lower propensity to cause orthostasis. Low doses should
be given, administration of antipsychotic medication should be
as brief as possible, and the medication should be discontinued
five to ten days before delivery to minimize the chances of
the newborn experiencing EPS. This notion, however, has
been re-evaluated, since discontinuation of medication before
 ANTIPSYCHOTIC DRUGS 39

delivery may put the mother at risk for decompensation. Anti-

cholinergic agents should also be avoided during pregnancy,
especially for the first trimester. Since antipsychotics are also
secreted into breast milk, the infants should not be breast-fed
if the mother resumes antipsychotic medication postpartum.

ADDITIONAL READING
1. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck
RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD,
Severe J, Hsiao JK: Effectiveness of antipsychotic drugs in patients
with chronic schizophrenia. New England Journal of Medicine 2005;
353(12):1209–1223
2. Miyamoto S, Duncan GE, Marx CE, Lieberman JA: Treatments
for schizophrenia: a critical review of pharmacology and mecha-
nisms of action of antipsychotic drugs. Molecular Psychiatry 2005;
10(1):79–104
3. Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller
AL, Perkins DO, Kreyenbuhl J; American Psychiatric Associa-
tion; Steering Committee on Practice Guidelines: Practice guideline
for the treatment of patients with schizophrenia, second edition.
American Journal of Psychiatry 2004; 161(2 Suppl):1–56
4. Miyamoto S, Aoba A, Duncan GE, Lieberman JA: Acute Pharma-
cological Treatment of Schizophrenia. In: Schizophrenia, Second
Edition. Blackwell Publishing, Oxford, 2002
5. Miyamoto S, Duncan GE, Goff DC, Lieberman JA: Therapeutics of
Schizophrenia. In: Neuropsychopharmacology The Fifth Generation
of Progress. Lippincott Williams & Wilkins, Philadelphia, pp. 775–
807, 2002
6. Schooler NR, Kane JM: Research diagnosis for tardive dyskinesia.
Arch. Gen. Psychiat. 1982; 39:486–487.