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Benefits and harms of atypical antipsychotics for off-label use

Clinical Question:
How effective and safe are atypical antipsychotics when used for off-label conditions?

Bottom Line:
The risks and benefits of various atypical antipsychotics are mixed for off-label conditions. See the synopsis for individual conditions and associated effective drugs. Risks in the elderly are significant, including death, stroke, and extrapyramidal symptoms. (LOE = 1a-)

Maher AR, Maglione M, Bagley S, et al. Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label use in adults. A systematic review and meta-analysis. JAMA 2011;306(12):1359-1369.  [PMID:21954480]

Study Design:
Systematic review


Various (meta-analysis)

Atypical antipsychotics are commonly used in clinical practice for off-label conditions including agitation in dementia, anxiety, eating disorders, insomnia, substance abuse, and obsessive-compulsive disorder (OCD). These investigators thoroughly searched multiple databases including PubMed, EMBASE, PsycInfo, and the Cochrane Registry. Other sources included FDA and Health Canada regulatory documents and references of relevant publications. English-language-only randomized trials were used to assess efficacy outcomes and both clinical trials and large observational trials were used to assess adverse events. Four investigators independently critiqued studies for inclusion criteria and methodologic quality using standard rating scales. Disagreements were resolved by consensus. The overall strength of evidence was classified as high, moderate, or low. Formal assessments were also performed to detect publication bias and heterogeneity. Studies meeting inclusion criteria included 162 clinical trials for efficacy outcomes and 231 observational trials for adverse events. In the treatment of elderly patients with dementia and symptoms including psychosis, mood alterations, and aggression, small but statistically significant effect sizes were observed for aripiprazole (Abilify), olanzapine (Zyprexa), and risperidone (Resperdal). Only quetiapine (Seroquel) was significantly associated with an improvement in generalized anxiety. Similarly, only risperidone was effective for OCD. However, the level of evidence for the use of risperidone for OCD was classified as moderate on the basis of potential publication bias. There was no conclusive evidence of effectiveness for any of the atypical antipsychotics for insomnia, eating disorders, or substance abuse. The evidence was noted as mixed regarding personality disorders and PTSD. Adverse events in the elderly included an increased risk of death (number needed to treat to harm [NNTH] = 87), stroke (NNTH = 53 for risperidone), extrapyramidal symptoms (NNTH = 10 for olanzapine and 20 for risperidone), and urinary tract symptoms (NNTH = 16-36). Adverse events in the nonelderly included weight gain, fatigue, akathisia, and extrapyramidal symptoms.


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