Evidence-Based Reviews

Antipsychotics for patients without psychosis?

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What clinical trials support



Controlled clinical trial results can help you make two prescribing decisions:

  • Is an antipsychotic the right choice for this patient?
  • If yes, which agent?

Prescribing antipsychotics off-label can be worthwhile when a patient gets better, but even then two worries remain:

  • Most uses of antipsychotics for nonpsychotic illness are not evidence-based.
  • This practice may expose clinicians to liability if the patient gets worse.

Consider the use of second-generation antipsychotics (SGAs) to manage acute behaviors in patients with dementia. The FDA ordered a black box warning in 2005 that SGAs may increase mortality risk in older patients. In October, the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer’s Disease (CATIE-AD) reported that SGAs’ side effects offset their benefits when compared with placebo (see Will CATIE-AD change dementia treatment?).1

What do you do when FDA-approved drugs fail to help your patient with dementia, unipolar depression, anxiety disorders, or other nonpsychotic symptoms, and SGAs may be the next consideration? The answers lie in managing side effects and knowing which antipsychotic uses are supported by data from controlled clinical trials, which we review here.

Box 1

Why SGAs are widely used in nonpsychotic disorders
  • FGAs showed efficacy for nonpsychotic disorders
  • SGAs are associated with a lower risk of EPS and tardive dyskinesia at therapeutic dosages, compared with FGAs
  • Many patients fail to respond adequately to medications approved for their illnesses
  • Evidence on SGAs’ efficacy in nonpsychotic disorders has grown substantially in the past 10 years.

EPS: extrapyramidal symptoms

FGA: first-generation antipsychotic

SGA: second-generation antipsychotic

Prescribing considerations

For a variety of reasons (Box 1), SGAs have rapidly assumed a major role in treating nonpsychotic disorders. Thirty-one percent of psychotropics are dispensed off-label,2 and Buckley3 reported in a 3-state survey that 70% of SGA prescriptions were written for indications other than schizophrenia.

Using antipsychotics for nonpsychotic symptoms is a longstanding clinical practice. In schizophrenia patients, antipsychotics have been shown to improve psychotic and nonpsychotic symptoms: agitation, violence, negative symptoms, social isolation, depression, suicidality, anxiety, insomnia, poor appetite, compulsions, cognition, smoking, alcohol and drug use, polydipsia, tardive dyskinesia, and tardive dystonia. Some clinicians may view these reports as evidence that antipsychotics might relieve these symptoms in patients with nonpsychotic disorders as well, but the issue is more complicated than that (Box 2).4

Caveats. SGAs do offer clinicians unique tools; no other class of psychotropics can claim efficacy in psychotic disorders, bipolar disorder, depression, and other disorders we describe in this review. On the other hand:

  • Although some SGAs are approved for bipolar disorder and one was recently approved to treat irritability in autism (Table 1), most SGA uses in nonpsychotic disorders are off-label and supported by few—if any—large, randomized, controlled trials.
  • Antipsychotics can cause the very symptoms they relieve, including depression, obsessive-compulsive disorder (OCD), anxiety, poorer cognition, agitation, mania, insomnia, and abnormal movements.
  • Few controlled studies have compared SGAs to usual first-line treatments; most have evaluated SGAs as adjuncts to other psychotropics—such as serotonin reuptake inhibitors (SRIs)—for patients with treatment-resistant disorders.
  • Published head-to-head studies have rarely compared the efficacy of various SGAs in treating nonpsychotic disorders.
  • Long-term safety studies of SGAs for nonpsychotic indications have not been done.
Among the SGAs, more studies of risperidone and olanzapine have been done in nonpsychiatric disorders, compared with quetiapine, ziprasidone, or aripiprazole. Clozapine has shown positive effects in mania, aggressiveness. and tardive dyskinesia, but few controlled studies of off-label uses have been done because of clozapine’s risk of agranulocytosis.

Table 1

Bipolar and other nonpsychotic indications FDA-approved for SGAs

SGABipolar maniaBipolar depressionBipolar maintenanceOther
AripiprazoleAcute mania or mixed episodes Bipolar I disorder, most recent episode manic or mixed
Clozapine Risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorders
OlanzapineAcute mania or mixed episodes; monotherapy or with lithium or valproate for manic episodes Bipolar disorder maintenance monotherapy
Olanzapine/fluoxetine combination Bipolar depressive episodes
QuetiapineAcute manic episodes; monotherapy or with lithium or valproateBipolar depressive episodes
RisperidoneAcute mania or mixed episodes; monotherapy or with lithium or valproate Irritability in autism
ZiprasidoneAcute manic or mixed episodes
SGA: second-generation antipsychotic (oral forms)
Safety issues. SGAs’ safety profiles warrant caution. SGAs are less likely than first-generation antipsychotics (FGAs) to cause extrapyramidal symptoms (EPS) and tardive dyskinesia at therapeutic dosages, but they increase the risks of weight gain, diabetes, glucose intolerance, dyslipidemia, and hyperprolactinemia. Akathisia and hypotension also may occur.

Prescribing decisions. SGA’s potential adverse effects complicate clinical decision-making. First you must decide whether to use an SGA for your patient with a nonpsychotic disorder.

Box 2

How do antipsychotics work in nonpsychotic illness?

Second-generation antipsychotics (SGAs) show efficacy in so many psychotic and nonpsychotic disorders that a specific therapeutic action for each disorder is highly doubtful. One might ask, then: What do they improve, and how do they do it?

The complete answer is beyond current understanding, unfortunately. We do know, however, that SGAs have not shown efficacy for treating nonpsychotic disorders that first-generation antipsychotics (FGAs) did not show—except perhaps for maintenance treatment in bipolar disorder.

Calming action. The major clinical action of SGAs appears to be in calming patients, which also was the first therapeutic effect attributed to the FGA chlorpromazine. This calming effect would explain SGAs’ efficacy in treating agitation, aggressiveness, anxiety, and possibly mania. Other clinical effects specific to psychosis and possibly to depression are possible.

Receptor-blocking action. SGAs’ D2 and 5-HT2A receptor-blocking activity may explain much of the drugs’ therapeutic effect. However, if SGAs’ effect on nonpsychotic symptoms derives from their action on nondopaminergic receptors, then individual SGAs would vary widely in efficacy and pure dopaminergic agents such as amisulpride would be ineffective.

SGAs also bind at other receptor sites, and the clinical importance of this may vary from patient to patient, drug to drug, and dose to dose.4


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