34

THE NEW ENGLAND JOURNAL OF MEDICINE

DRUG THERAPY
ALASTAIR J. J. WOOD, M.D., Editor

Jan. 4, 1996

peutic or adverse effects of specic drugs; however, all

effective antipsychotic drugs block some type of dopamine receptor.4
DRUGS USED

TO

TREAT SCHIZOPHRENIA

Antipsychotic Drugs

SCHIZOPHRENIA
JOHN MICHAEL KANE, M.D.

CHIZOPHRENIA is an often severe and disabling

disorder that usually begins in late adolescence or
early adulthood. The essential features of this illness
are a variable array of symptoms, such as delusions,
hallucinations, disorganized or impoverished speech or
behavior, attened affect, and avolition. The onset may
be abrupt or insidious; in most instances, however,
there is a prodromal phase characterized by gradual social withdrawal, diminished interest in or functioning at
school or work, changes in appearance and hygiene, or
behavior that is odd or unusual for the person. Although a diagnosis of schizophrenia cannot be made on
the basis of these prodromal symptoms, such changes
in behavior and functioning should be evaluated by a
mental health professional. The disorder is associated
with marked social or occupational dysfunction, and its
course and outcome vary greatly. In some patients the
disorder is persistent. Others have remissions and exacerbations, but full recovery occurs only in a small minority.
Although the pathophysiology of schizophrenia has
not been delineated,1,2 drug development has been heavily inuenced by the hypothesis that certain dopamine
pathways are overactive.3 The recent cloning of the
genes for several dopamine receptors has added a new
dimension to research in this area.4
Evidence for dopamine overactivity in patients with
schizophrenia includes the capacity of antipsychotic
drugs to block dopamine receptors in vivo5 and in vitro6
and the fact that the clinical efcacy of antipsychotic
drugs is, in general, highly correlated with their ability
to block dopamine D2 receptors.6,7 (Clozapine is an exception, but its relatively high afnity for other dopamine receptors may contribute to its clinical efcacy.)
Other evidence includes the ability of dopamine agonists to exacerbate the symptoms and signs of schizophrenia,8 as well as several reports of elevated densities
of dopamine D2 receptors in tissue obtained at autopsy
from patients with schizophrenia.3 Some studies using
positron-emission tomography (PET) have shown increased dopamine D2receptor density in untreated
patients,9 but others have not.10
Other receptors may also be involved in the theraFrom the Department of Psychiatry, Hillside Hospital, Long Island Jewish
Medical Center, Glen Oaks, N.Y., and the Department of Psychiatry, Albert Einstein College of Medicine, Bronx, N.Y. Address reprint requests to Dr. Kane at
the Department of Psychiatry, Hillside Hospital, Long Island Jewish Medical
Center, 75-59 263rd St., Glen Oaks, NY 11004.
1996, Massachusetts Medical Society.

Antipsychotic (neuroleptic) drugs are by far the most

effective medications for the treatment of schizophrenia. Table 1 lists the antipsychotic drugs currently available in the United States.
Until the superiority of clozapine in patients who had
not responded adequately to other drugs was demonstrated,11 antipsychotic drugs were generally thought to
be interchangeable in terms of efcacy. Among 100
studies comparing the effectiveness of chlorpromazine,
thioridazine, and triuoperazine with that of the other
drugs listed in Table 1 (excluding clozapine and risperidone), only 1 study reported a signicant difference.12,13
Antipsychotic drugs are often described as having
high potency, meaning that the daily dose is a few milligrams, or low potency, indicating a high daily dose.
Low-potency drugs tend to have considerably stronger
sedative effects. Many clinicians think that agitated patients respond best to the more sedating drugs and that
withdrawn patients respond better to the less sedating
drugs, but these views are not supported by the results
of controlled trials.14,15 High-potency drugs (e.g., haloperidol and uphenazine) have more extrapyramidal effects and cause less sedation and less postural hypotension, whereas low-potency drugs (e.g., chlorpromazine
and thioridazine) cause more sedation and hypotension
and have fewer extrapyramidal effects. High-potency
drugs are better suited for intramuscular injection and
rapid dose escalation. As newer drugs are developed,
this categorization may prove less meaningful.
Intramuscular administration results in higher plasma drug concentrations sooner than oral administration, and therefore in more rapid onset of action (within
30 minutes), as well as more consistent plasma drug
concentrations. Oral administration should be substituted as soon as practical; it is as effective as parenteral
administration in maintaining therapeutic gains. A substantial proportion of patients with schizophrenia today
have histories of substance abuse that can complicate
their treatment; however, antipsychotic drugs remain
the treatment of choice for these patients as well.
(Drugs of abuse complicate treatment by producing
psychopathologic symptoms, which make the differential diagnosis more difcult and also may affect neurotransmitter function in ways that alter the effects of antipsychotic drugs.)
The choice of an antipsychotic drug should be inuenced by the patients previous response and proneness
to adverse effects. If the rst antipsychotic drug does
not produce clinical improvement in two to three weeks,
compliance should be evaluated. Measurements of plasma drug concentrations can be helpful, both to assess
compliance and, if compliance is established, to determine whether the concentration is within the therapeutic range. (Unfortunately, therapeutic ranges have not

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Table 1. Typical Doses and Estimated Relative Potency of Antipsychotic Drugs Available in the United States.
DRUG

EQUIVALENT
DOSE*

jority of patients, and that at this dose the drug has relatively few extrapyramidal side effects (at higher doses,
their incidence increases).

USUAL TOTAL DAILY DOSE

SHORT - TERM

MAINTENANCE

THERAPY

THERAPY

mg

Phenothiazines
Chlorpromazine
Thioridazine
Mesoridazine
Acetophenazine
Prochlorperazine
Perphenazine
Triuoperazine
Triupromazine
Fluphenazine
Thioxanthenes
Thiothixene
Chlorprothixene
Butyrophenones
Haloperidol
Dibenzoxazepines
Loxapine
Dihydroindolones
Molindone
Dibenzodiazepines
Clozapine
Benzisoxazoles
Risperidone
Long-acting injectable
preparations
Fluphenazine decanoate
Haloperidol decanoate

35

mg/day

100
100
50
20
15
10
5
25
2

2001000
200800
100400
60150
60200
1264
1060
30150
550

50400
50400
25200
4080
2060
824
430
20100
115

5
100

1060
50600

630
50400

550

115

10

20160

1060

10

40225

15100

50

300900

200400

48

Unknown

6100 every 24 wk
50200 every 4 wk

*Numbers shown are the numbers of milligrams of the drug required for the dose to be
equivalent to the doses of the other drugs in the table (e.g., 100 mg of chlorpromazine is equivalent to 2 mg of haloperidol). Relative potency may not be the same at higher dosages as at
lower ones.

been established for all drugs.) If compliance is established and the drug is ineffective, a different class of antipsychotic drug should be tried. A second failure would
be an indication for the use of clozapine.
The two new antipsychotic drugs that have been approved in the United States in recent years deserve specic comment. One of them, risperidone, should be included among the rst-line antipsychotic drugs, whereas
the other, clozapine, is indicated only for patients who
do not respond to or cannot tolerate the rst-line drugs.
Risperidone

Risperidone is a benzisoxazole derivative with combined dopamine D2receptor and serotonin 5-HT2
receptorblocking properties; its efcacy was established in seven clinical studies of acutely psychotic
patients.16-22 The extent to which it may be superior to
existing agents for routine treatment or similar to clozapine for refractory patients has not been established. In
a multicenter trial conducted in the United States and
Canada,20,22 6 or 16 mg of risperidone per day was superior to 20 mg of haloperidol per day on some measures of clinical improvement, but other doses (2 and 10
mg per day) were not. It is difcult to draw rm conclusions about the relative efcacy of these agents,
since only one dose of haloperidol but four doses of risperidone were used per day. The available data suggest
that 6 mg of risperidone per day is effective in the ma-

Clozapine

Clozapine has atypical neuropharmacologic characteristics.23 It has relatively high afnity for dopamine
D1 and D4, 5-HT2 , muscarinic, and alpha-adrenergic
receptors, but it is also a dopamine D2receptor antagonist.3,4 It remains the only antipsychotic drug proved
to have superior efcacy in patients in whom multiple
trials of other antipsychotic drugs have failed.11 Whether it is indicated after the failure of only one or two
drugs is not known. Since clozapine causes agranulocytosis current estimates suggest a frequency of 0.8
percent during one year of treatment24 it was approved in 1990 specically for the treatment of patients
who did not respond adequately to standard antipsychotic drug therapy, either because the therapy was not
effective or because it could not be given in adequate
doses as a result of intolerable side effects. Clozapine is
at present the best treatment for patients with refractory psychosis.25 (Other alternatives that are sometimes
helpful for such patients include risperidone, lithium,
benzodiazepines, and electroconvulsive therapy.) In addition to its antipsychotic actions, clozapine may also
help reduce aggressive and hostile behavior 26 and the
risk of suicide.27
Though both clozapine and risperidone have some
advantages over other drugs in terms of reducing socalled negative symptoms (attened affect, avolition,
and impoverished speech or behavior), their benet has
been demonstrated only in relatively short-term trials.11,20,22 Because it is difcult in such studies to distinguish between negative symptoms and drug-induced
parkinsonism, long-term trials focusing on persistent
negative symptoms are needed.
Dosage

None of the studies comparing doses higher than

2000 mg of chlorpromazine per day or equivalent doses
of other drugs (Table 1) with lower doses have demonstrated superiority for high-dose treatment.28-33 Despite
these results, an analysis of dosing practices revealed
that clinicians often prescribed high doses.34 Given the
lack of proof of efcacy, the use of high doses continues
to arouse concern, particularly with regard to patients
with poor or partial responses and those whose behavior is violent or aggressive.35 High doses are more likely
than lower doses to cause extrapyramidal side effects,
which can have a deleterious effect on patients attitudes toward medication and on compliance.
The results of several well-designed studies suggest
that there is no added benet to doses of haloperidol or
uphenazine in excess of 10 to 20 mg per day for shortterm treatment, and even doses of 20 mg per day often
have extrapyramidal effects, particularly if prophylactic antiparkinsonian medication is not given concomitantly.36-39 Although antipsychotic drugs may have benecial effects in the rst 24 to 48 hours after therapy is

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THE NEW ENGLAND JOURNAL OF MEDICINE

initiated and considerable improvement may occur within three to ve days, their full effects may not be evident for many weeks or even months. As a rule, half of
the ultimate improvement in psychotic symptoms and
signs (e.g., delusions or hallucinations) occurs in the
rst three to four weeks.40
As measured by PET, 70 to 90 percent of dopamine
receptors are blocked by doses of 300 to 400 mg of
chlorpromazine or thioridazine or 4 to 12 mg of haloperidol.41 In some studies, patients who did not respond
adequately to standard doses still had 80 to 85 percent
blockade of dopamine receptors,42 but in other studies
the antipsychotic effect and the degree of dopamine
D2receptor occupancy were positively correlated.43
Clozapine has good therapeutic efcacy with relatively low dopamine D2receptor occupancy in the basal ganglia (38 to 63 percent).41 Its afnity for dopamine D1 and D4 receptors or other neurotransmitter
systems probably accounts for some of its efcacy.41
The resolution of PET studies, however, is such that receptor occupancy is measured mostly in brain areas
more closely related to adverse effects (extrapyramidal
symptoms) than to therapeutic response.
Equivalent doses of antipsychotic drugs, with chlorpromazine used as the standard, are shown in Table 1.
These estimates are based on group comparisons and
are not necessarily the result of careful studies designed
to establish minimal effective doses or dosage ranges.
For most of these drugs, all or most of the dose can be
given at bedtime, if necessary, in order to minimize adverse effects during the day.
Adverse Effects

Although antipsychotic drugs have an array of adverse effects, their therapeutic index is high. Adverse
effects are rarely serious or irreversible. The most troublesome are neurologic and include acute dystonia,
akathisia (restlessness), parkinsonism, and tardive dyskinesia or tardive dystonia (Table 2).44 Akathisia may
be misdiagnosed as anxiety or psychotic agitation, and
akinesia as depression or as the apathy and restricted
affect that can be associated with schizophrenia. Among
patients receiving short-term treatment, 50 to 70 percent will have some clinically important extrapyramidal side effects. These effects may diminish after two or
three months, but they often persist in some form as
long as the antipsychotic drug is taken.45
The neuroleptic malignant syndrome is a relatively
rare, potentially fatal complication of antipsychotic drug
therapy.46 It usually occurs within the rst few weeks of
treatment or after an increase in the dose and is characterized by high fever, severe muscle rigidity, autonomic
instability, altered consciousness, and elevated serum
creatine kinase concentrations. Treatment consists of
the immediate discontinuation of the antipsychotic drug;
the administration of dantrolene, bromocriptine, or pergolide; and supportive therapy. The mortality in untreated cases can be as high as 20 percent.
Antipsychotic drugs also have a variety of adverse

Jan. 4, 1996

Table 2. Adverse Effects of Antipsychotic

Drugs.*
Central nervous system
Extrapyramidal reactions
Acute dystonia
Akathisia
Parkinsonism
Tardive dyskinesia
Drowsiness, oversedation
Cognitive impairment
Dysregulation of temperature
Seizure
Toxic psychosis
Neuroleptic malignant syndrome
Autonomic reactions
Dry mouth
Blurred vision
Urinary retention
Constipation
Hypotension
Tachycardia
Cardiovascular
Electrocardiographic changes (prolonged
QT interval, attening of T wave)
Torsade de pointes
Endocrine
Galactorrhea
Amenorrhea
Hyperprolactinemia
Sexual dysfunction
Weight gain
Dermatologic
Cutaneous allergic reactions
Photosensitivity
Discoloration of skin
Ophthalmic
Increased intraocular pressure
Opacities of cornea and lens
Retinitis pigmentosa
Gastrointestinal
Decreased bowel motility
Cholestatic jaundice
Respiratory
Pharyngeal and laryngeal dysfunction
Respiratory dyskinesia and distress
Hematologic
Leukopenia
Agranulocytosis
*This is a partial list emphasizing adverse effects that are
common or potentially serious. Life-threatening or serious, irreversible adverse effects are rare.

autonomic, neuroendocrine, cardiac, ophthalmic, and

hematologic effects (Table 2). The serious effects are
rare. Agranulocytosis is the most important adverse effect of clozapine. The period of maximal risk is 4 to 18
weeks after the initiation of therapy. Older women appear to be at highest risk,24 and genetic factors may
also be involved.47 Seizures may occur more often with
clozapine than with other antipsychotic drugs,48 and
the emergence or exacerbation of obsessivecompulsive symptoms has been reported in a small percentage
of patients.49 Clozapine is the only antipsychotic drug
for which the risk of tardive dyskinesia is low or nonexistent.50,51 The most common adverse effects of risperidone are headache, rhinitis, insomnia, agitation, and
weight gain. It can also cause tardive dyskinesia and

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Vol. 334

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DRUG THERAPY

the neuroleptic malignant syndrome; however, the relative risk in relation to that with other drugs has not
been established.
Overall, depot therapy with antipsychotic drugs has
the same adverse effects as oral administration of the
same drugs and a similar incidence of adverse neurologic effects.52 Antipsychotic drugs are not known to
have teratogenic effects, but they should be used cautiously in pregnant women. Many antipsychotic drugs
are present in small quantities in breast milk, and nursing should therefore be avoided.
Other Drugs Used in the Treatment of Schizophrenia
Lithium

Lithium can have some therapeutic benet in patients with schizophrenia53 and can help as adjunctive
treatment in patients who respond poorly to antipsychotic drugs.54-56 However, the benecial effects of lithium are limited at best, and it is clearly inferior to antipsychotic drugs. Predictors of the response to lithium
in this context have not been established.
Benzodiazepines

Benzodiazepines, which are anxiolytics or sedative

hypnotic agents, are often administered as an adjunct
to treatment with antipsychotic drugs in patients who
are having acute exacerbations of schizophrenia, particularly with severe anxiety, irritability, or agitation.57
Concomitant administration of a benzodiazepine and
an antipsychotic drug may allow the use of lower doses
of the antipsychotic agent.58-61 Whether benzodiazepines can reduce core psychotic symptoms such as delusions, hallucinations, or thought disorders is controversial, and in a few studies benzodiazepine therapy
was associated with the worsening of symptoms in
some patients.62,63 Benzodiazepines may be most effective in patients with negative symptoms (apathy, withdrawal, or alogia), but the benet may be transient.64,65
Benzodiazepines may also be useful as an adjunct to
antipsychotic drugs in patients with refractory schizophrenia,27 but the evidence in this regard is limited. In
addition, benzodiazepines can produce temporary remission of catatonic symptoms,66 but subsequent treatment should be guided by the presumed cause of the
psychosis, because this state may occur in conditions
other than schizophrenia. There is no conclusive evidence that any one benzodiazepine is superior to another in patients with schizophrenia (though lorazepam is
frequently used because of its high potency and short
duration of action).
The adverse effects of benzodiazepines include sedation, fatigue, and ataxia. A paradoxical disinhibition
leading to increased hostility, exacerbation of psychosis, or agitation62 has been described, but such an effect
is uncommon. Case reports of serious adverse effects
(respiratory arrest, severe hypotension, and loss of consciousness) in patients receiving both a benzodiazepine
and clozapine have aroused concern about this combination, but studies have not conrmed a clear associa-

37

tion.67 Dependence and withdrawal reactions can occur

in patients with schizophrenia, but their frequency is
not known. Prolonged benzodiazepine therapy is generally not recommended, and discontinuation should be
gradual.
Anticonvulsant Drugs

Although anticonvulsant drugs such as carbamazepine and valproate are effective in patients with manic
depressive illness,68,69 their value in schizophrenia is less
clear. Among these drugs, only carbamazepine has been
studied as an adjunct to antipsychotic drugs. In controlled studies, carbamazepine had some benet as adjunctive therapy, but the effects were small at best.27,70,71
Carbamazepine alone is not an effective maintenance
treatment.72
Antidepressant Drugs

Antidepressant drugs have no role as the sole treatment for schizophrenia but are indicated as an adjunctive treatment in patients with schizophrenia and depression and possibly those with obsessivecompulsive
symptoms or panic attacks. Depression may occur in
patients with schizophrenia after recovery from an
acute psychotic episode73 or at other times. Moreover,
schizophrenia is associated with a high rate of suicide
(lifetime risk, approximately 10 percent). The extent
to which prophylactic treatment with antidepressant
drugs could reduce this risk in selected patients is not
known.
Adjunctive treatment with a tricyclic antidepressant
drug is effective in alleviating symptoms of depression.74 For patients with substantial depressive symptoms, a trial of antidepressant therapy is therefore
justied, as long as clear goals are identied (e.g., amelioration of particular symptoms) and the patient is reassessed regularly. The antidepressant drug should be
given to such patients in the same dosage as to patients
with a major depressive disorder, but combined therapy
with an antipsychotic and an antidepressant drug can
result in higher plasma concentrations of both drugs
than when either is given alone. The risk of exacerbating core psychotic symptoms with an antidepressant
drug is minimal when an antipsychotic drug is also being given and when there is no acute psychotic exacerbation.75 The most appropriate duration of antidepressant therapy, if it is effective, is not known. In a study
of the discontinuation of therapy in patients who had
been treated with imipramine for 6 months, the rate of
relapse was higher among those who were switched
from imipramine to placebo than among those who
continued to receive imipramine during a 12-month follow-up period.76
Antiparkinsonian Drugs

Because antipsychotic drugs often cause adverse extrapyramidal or parkinsonian effects, such as acute
dystonia, akinesia, tremor, rigidity, and akathisia, it is
common practice to administer antiparkinsonian drugs

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38

THE NEW ENGLAND JOURNAL OF MEDICINE

(e.g., benztropine, procyclidine, and trihexyphenidyl)

at the same time, either to treat the adverse effects or
to prevent them. The results of prospective trials77,78
and retrospective reviews79 support the value of such
prophylaxis in substantially reducing the frequency of
major extrapyramidal symptoms in patients treated
with an antipsychotic drug. (An alternative approach to
reducing these symptoms is to lower the dose of the antipsychotic drug.) Prophylaxis with an antiparkinsonian drug is most likely to be useful in patients who are
vulnerable to extrapyramidal symptoms (as indicated
by their history), those receiving high doses of highpotency antipsychotic agents, and those in whom the
occurrence of these symptoms is likely to increase the
risk of noncompliance. Whether or not an antiparkinsonian drug is given prophylactically, the most important factor in minimizing side effects of antipsychotic
drug therapy is the clinicians sensitivity to their occurrence and his or her ability to manage them, either by
altering the dosage of the antipsychotic or antiparkinsonian drug or by initiating therapy with the latter.
MAINTENANCE TREATMENT
The value of maintenance treatment has been well established in numerous double-blind, placebo-controlled
trials.80-82 Among patients with a schizophrenic illness
who have been in remission for a year or more, about 75
percent will relapse within 12 to 18 months after the discontinuation of antipsychotic drug therapy.83,84 (Relapse
is usually dened as clinically important deterioration
resulting in the need for the reinstitution of medication.)
Patients recovering from their rst episode of illness
should probably be treated for one to two years, but
even so, 75 percent will have relapses after therapy is
discontinued. Patients who have had two or more episodes should receive maintenance treatment for at least
ve years, and many experts believe they should be
treated indenitely.84 Subgroups of patients to whom
these recommendations do not apply cannot be identied. Some patients (15 to 20 percent in any one year)
will relapse despite continued medication.
One focus of recent research has been to improve the
overall benet-to-risk ratio of long-term antipsychotic
drug treatment by establishing optimal strategies for
maintenance therapy. Studies comparing different xed
doses and comparing continuous with intermittent therapy have been conducted. Six studies involving different doses given for at least one year have been reported.85-92 All involved long-acting, injectable medication
given at intervals of two to four weeks, and the results
were similar (Fig. 1). The results suggest that low-dose
maintenance treatment is feasible, but that the risk of
relapse during therapy is somewhat greater than if the
maintenance dose is higher. Although lower doses are
associated with fewer adverse effects in general, this relation has not been clearly demonstrated with respect
to tardive dyskinesia.
Intermittent treatment is a strategy intended to take
advantage of the observation that many patients do not

Kane et al.85,86
Fluphenazine (1.25 5 mg)
Fluphenazine (2.5 10 mg)
Fluphenazine (12.5 50 mg)

Jan. 4, 1996

56
24
14

Marder et al.87,88
Fluphenazine (5 10 mg)
Fluphenazine (25 50 mg)
Johnson et al.89
Fluphenazine (mean, 12 mg)
Fluphenazine (mean, 25 mg)
Hogarty et al.90
Fluphenazine (mean, 3.8 mg)
Fluphenazine (mean, 25 mg)
Kane et al.91
Haloperidol (25 mg)
Haloperidol (50 mg)
Haloperidol (100 mg)
Haloperidol (200 mg)
Schooler et al.92
Fluphenazine (2.5 10 mg)
Fluphenazine (12.5 50 mg)

22
20

32
10

22
14

60
25
23
15

29
20

0 10 20 30 40 50 60 70

Rate of Relapse (%)

Figure 1. Cumulative Rates of Relapse among Patients with
Schizophrenia after One Year of Maintenance Therapy with Various Doses of Antipsychotic Drugs, in Six Studies.
Most patients had had more than one prior psychotic episode.
Fluphenazine decanoate was given biweekly, and haloperidol
decanoate was given monthly. Doses of upenthixol decanoate,
which was used in some of the studies, are expressed in terms
of estimated equivalent doses of uphenazine decanoate. The
number of patients in each group in these studies ranged from
29 to 63.

relapse for several months after the discontinuation of

antipsychotic drug therapy. The strategy involves the
discontinuation of medication in stable outpatients in
remission and its reinstitution when prodromal symptoms occur, with the hope of preventing a full-blown
psychotic relapse. The objective is to reduce the cumulative exposure to antipsychotic drugs and limit adverse effects. Five major studies have examined this
strategy.92-97 All the patients were treated for two to six
months before therapy was discontinued in those assigned to the intermittent-treatment groups (Fig. 2).
The cumulative rates of relapse after one year in the
groups that received continuous treatment were quite
similar to those reported for the conventional doses of
antipsychotic drugs in the trials of low-dose therapy.
The results with intermittent treatment were discouraging. The rates of relapse during the one-year study period were high, and there was little benet in terms of

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DRUG THERAPY

33

Carpenter et al.93

55
10

Herz et al.94

29
7

95,96

Jolley et al.

30
15

Pietzcker et al.97

35
20

92

Schooler et al.

32

10

20

30

40

50

60

Rate of Relapse (%)

Figure 2. Rates of Relapse in Patients with Schizophrenia after
One Year of Continuous or Intermittent Maintenance Therapy, in
Five Studies.
Black bars represent continuous treatment, and shaded bars intermittent treatment. Most patients had had more than one prior
psychotic episode. The number of patients in each group in
these studies ranged from 27 to 121.

improved psychosocial adjustment, diminished tardive

dyskinesia, or an enhanced sense of well-being. In view
of the twofold increase in the risk of relapse, this approach is difcult to justify. The intermittent-treatment
approach may be useful for patients who refuse to take
medication when in remission, however.
LONG-ACTING, INJECTABLE ANTIPSYCHOTIC DRUGS
Long-acting, injectable drugs have been used in almost all the studies of maintenance treatment conducted in recent years. During routine care, however, most
patients receive oral maintenance therapy and the longacting parenteral preparations are given only after
noncompliance has led to one or more psychotic relapses. (Noncompliance with medication remains a leading
cause of psychiatric hospitalization.) With proper dosing, there is no evidence that long-acting preparations
(among which uphenazine decanoate and haloperidol
decanoate are the two currently available in the United
States) are associated with any increase in the risk of untoward effects,52 and therefore their underuse does not
seem justied. A substantial number of relapses (and
hospital days) could be prevented if these preparations
were used routinely.84 When a patient is switching from
oral to depot preparations, some oral medication may
be needed for four to six weeks until a steady state is
achieved.
CONCLUSIONS
Drug therapy remains the principal method for the
treatment of schizophrenia. Important progress is being made in areas relevant to the development of antipsychotic drugs, and more new drugs are currently under investigation than ever before. Progress is also
being made in determining the most effective strategies
for using the available drugs and for integrating them
with effective psychosocial treatments.
The principles of informed consent are as applicable

39

to patients with schizophrenia as to all other patients.

Although aspects of insight and judgment may be impaired, most patients are competent to participate in
the consent process. When treatment is expected to be
prolonged (longer than 6 to 12 months), there should
be further discussion of the long-term benets (e.g., the
prevention of relapse) and risks (particularly that of
tardive dyskinesia). The process of informed consent
should be ongoing, with continual discussion and reevaluation of treatment goals, options, benets, and
risks.
In the majority of patients, schizophrenic illness is
not identied, properly diagnosed, or treated for many
months or even years after its onset, and this delay
probably increases long-term morbidity. Although the
diagnosis can be difcult to make in the early stages of
the disorder, it is important that health care professionals promptly refer patients with suspected schizophrenia for appropriate psychiatric examination. Any person with a sudden or gradual onset of bizarre speech or
behavior, attened affect or avolition, marked deterioration in social, intellectual, or vocational functioning,
hallucinations, or delusions should be referred for evaluation. Clearly, further efforts at educating the public
and professionals about this illness are necessary to improve its early detection and appropriate treatment.
REFERENCES
1. Kendler KS, Diehl SR. The genetics of schizophrenia: a current, geneticepidemiologic perspective. Schizophr Bull 1993;19:261-85.
2. Kirch DG. Infection and autoimmunity as etiologic factors in schizophrenia:
a review and reappraisal. Schizophr Bull 1993;19:355-70.
3. Seeman P, Niznik HB. Dopamine receptors and transporters in Parkinsons
disease and schizophrenia. FASEB J 1990;4:2737-44.
4. Seeman P. Dopamine receptor sequences: therapeutic levels of neuroleptics
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