The Journal of the American Medical Association has featured a meta-analysis of trials assessing the efficacy and safety of atypical antipsychotic medications for use in conditions lacking approval for labeling and marketing by the US Food and Drug Administration.

Controlled trials comparing an atypical antipsychotic (risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, asenapine, iloperidone, or paliperidone) with placebo, another atypical antipsychotic medication, or other pharmacotherapy for adult off-label conditions were included to assess efficacy. Furthermore, observational studies with sample sizes of greater than 1000 patients were included for the safety analysis.

A total of 162 citations met inclusion criteria for the efficacy analysis, and the following results were reported:

• Among 14 placebo-controlled trials of elderly patients with dementia reporting a total global outcome score that includes symptoms such as psychosis, mood alterations, and aggression, small but statistically significant effects sizes ranging from 0.12 and 0.20 were observed for aripiprazole, olanzapine, and risperidone.
• For generalised anxiety disorder, a pooled analysis of 3 trials showed that quetiapine was associated with a 26% greater likelihood of a favorable response (defined as at least 50% improvement on the Hamilton Anxiety Scale) compared with placebo.
• For obsessive-compulsive disorder, risperidone was associated with a 3.9-fold greater likelihood of a favourable response (defined as a 25% improvement on the Yale-Brown Obsessive Compulsive Scale) compared with placebo.
• In elderly patients, adverse events included an increased risk of death (number needed to harm [NNH] = 87), stroke (NNH = 53 for risperidone), extrapyramidal symptoms (NNH = 10 for olanzapine; NNH = 20 for risperidone), and urinary tract symptoms (NNH range = 16-36). In nonelderly adults, adverse events included weight gain (particularly with olanzapine), fatigue, sedation, akathisia (for aripiprazole), and extrapyramidal symptoms.

In their conclusion, the authors noted the following limitations for this meta-analysis:
• First, unidentified, unpublished, or excluded studies might have reported results different from those included
• Studies published after June 1, 2011, including a recent large randomised controlled trial of risperidone therapy for patients with military-related PTSD and symptoms resistant to SSRIs, were not included in this review, and
• Unexplained heterogeneity was detected which may indicate the presence of publication bias in the pooled results for OCD.

They however conclude that for symptoms of psychosis, agitation, and global behavioural symptoms in elderly patients with dementia, small but statistically significant benefits were observed for risperidone, aripiprazole, and olanzapine. Quetiapine was associated with benefits in the treatment of generalised anxiety disorder, and risperidone was associated with benefits in the treatment of OCD. However, adverse effects should also be taken into account.