Introduction: Methods, Commentary, and Summary
J Clin Psychiatry 2003;64(suppl 12):5-20
© Copyright 2015 Physicians Postgraduate Press, Inc.
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Objectives. A growing number of atypical antipsychotics are
available for clinicians to choose from in the treatment of psychotic
disorders. However, a number of important questions
concerning medication selection, dosing and dose equivalence,
and the management of inadequate response, compliance problems,
and relapse have not been adequately addressed by clinical
trials. To aid clinical decision-making, a consensus survey of
expert opinion on the pharmacologic treatment of psychotic disorders
was undertaken to address questions not definitively
answered in the research literature.
Method. Based on a literature review, a written survey was
developed with 60 questions and 994 options. Approximately
half of the options were scored using a modified version of the
RAND 9-point scale for rating the appropriateness of medical
decisions. For the other options, the experts were asked to write
in answers (e.g., average doses) or check a box to indicate their
preferred answer. The survey was sent to 50 national experts on
the pharmacologic treatment of psychotic disorders, 47 (94%) of
whom completed it. In analyzing the responses to items rated on
the 9-point scale, consensus on each option was defined as a nonrandom
distribution of scores by chi-square "goodness-of-fit"
test. We assigned a categorical rank (first line/preferred choice,
second line/alternate choice, third line/usually inappropriate) to
each option based on the 95% confidence interval around the
mean rating. Guideline tables indicating preferred treatment
strategies were then developed for key clinical situations.
Results. The expert panel reached consensus on 88% of the
options rated on the 9-point scale. The experts overwhelmingly
endorsed the atypical antipsychotics for the treatment of psychotic
disorders. Risperidone was the top choice for first-episode
and multi-episode patients, with the other newer atypicals rated
first line or high second line depending on the clinical situation.
Clozapine and a long-acting injectable atypical (when available)
were other high second line options for multi-episode patients.
The experts’ dosing recommendations agreed closely with the
package inserts for the drugs, and their estimates of dose equivalence
among the antipsychotics followed a linear pattern.
The experts considered 3–6 weeks an adequate antipsychotic
trial, but would wait a little longer (4–10 weeks) before making
a major change in treatment regimen if there is a partial
response. The experts recommended trying to improve response
by increasing the dose of atypical and depot antipsychotics
before switching to a different agent; there was less agreement
about increasing the dose of conventional antipsychotics before
switching, probably because of concern about side effects at
higher doses. If it is decided to switch because of inadequate
response, risperidone was the experts’ first choice to switch to,
no matter what drug was initially tried. Although there was
some disparity in the experts’ recommendations concerning
how many agents to try before switching to clozapine, the
experts’ responses suggest that switching to clozapine should be
considered after failure to respond to two atypical antipsychotics.
Clozapine was also the antipsychotic of choice for
patients with suicidal behavior. When switching oral antipsychotics,
the experts considered cross-titration the preferred
strategy. When switching to an injectable antipsychotic, the
experts stressed the importance of continuing the oral antipsychotic
until therapeutic levels of the injectable agent are
The experts considered psychosocial interventions the first
choice strategy for partially compliant patients, with pharmacologic
interventions the first choice for patients with clear evidence
of noncompliance. However, because it can be difficult to
distinguish partially compliant from noncompliant patients, the
editors recommended combining psychosocial and pharmacologic
interventions to improve compliance whenever possible.
When patients relapse because of compliance problems or if
there is any doubt about compliance, the experts recommended
the use of a long-acting injectable antipsychotic and would
select an injectable atypical when this option becomes available.
The experts would also consider using an injectable atypical
antipsychotic (when available) in many clinical situations that
do not involve compliance problems.
The experts stressed the importance of monitoring for health
problems—especially obesity, diabetes, cardiovascular problems,
HIV risk behaviors, medical complications of substance
abuse, heavy smoking and its effects, hypertension, and amenorrhea—in
patients being treated with antipsychotics.
Although many patients are prescribed adjunctive treatments,
multiple antipsychotics, and combinations of different
classes of drugs (e.g., antipsychotics plus mood stabilizers or
antidepressants) in an effort to enhance response, the experts
gave little support to any of these strategies, with the exception
of antidepressants for patients with dysphoria/depression, antidepressants
or ECT for patients with suicidal behavior, and
mood stabilizers for patients with aggression/violence.
When asked about indicators of remission and recovery, the
experts considered acute improvement in psychotic symptoms
the most important indicator of remission, whereas they considered
more sustained improvement in multiple outcome
domains (e.g., occupational/educational functioning, peer relationships,
independent living) important in assessing recovery.
Conclusions. The experts reached a high level of consensus on
many of the key treatment questions in the survey. Within the
limits of expert opinion and with the expectation that future
research data will take precedence, these guidelines provide
direction for addressing common clinical dilemmas that arise in
the pharmacologic treatment of psychotic disorders. They can
be used to inform clinicians and educate patients regarding the
relative merits of a variety of interventions. Clinicians should
keep in mind that no guidelines can address the complexities
involved in the care of each individual patient and that sound
clinical judgment based on clinical experience should be used in
applying these recommendations.