Off-Label Use of Atypical Antipsychotics: An Update [Entered Retrospectively]

Project Summary Title and Description

Off-Label Use of Atypical Antipsychotics: An Update [Entered Retrospectively]
Objectives: Antipsychotic medications are approved by the U.S. Food and Drug Administration (FDA) for treatment of schizophrenia, bipolar disorder, and for some drugs, depression. We performed a systematic review on the efficacy and safety of atypical antipsychotic drugs for use in conditions lacking FDA approval. Data Sources: We searched PubMed, Embase, PsycINFO, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Cochrane DARE (Database of Abstracts of Reviews of Effects), and Cochrane CENTRAL (Cochrane Central Register of Controlled Trials) from inception to May 2011. We included only English-language studies. Review Methods: Controlled trials comparing an atypical antipsychotic (risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, asenapine, iloperidone, paliperidone) to either placebo, another atypical antipsychotic drug, or other pharmacotherapy, for the off-label conditions of anxiety disorder, attention deficit hyperactivity disorder, dementia and severe geriatric agitation, major depressive disorder, eating disorders, insomnia, obsessive compulsive disorder (OCD), post traumatic stress disorder (PTSD), personality disorders, substance abuse, and Tourette’s syndrome were included. Observational studies with sample sizes greater than 1,000 were included to assess rare adverse events. Two investigators conducted independent article review, data abstraction, and study quality assessment. Results: One hundred seventy trials contributed data to the efficacy review. Among the placebocontrolled 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 effect sizes ranging from 0.12 and 0.20 were observed for aripiprazole, olanzapine, and risperidone. For generalized anxiety disorder, pooled analysis of three large trials showed that quetiapine was associated with a 26 percent greater likelihood of "responding," defined as at least 50 percent improvement on the Hamilton Anxiety Scale, compared with placebo. For obsessive-compulsive disorder, risperidone was associated with a 3.9-fold greater likelihood of "responding," defined as a 25 to 35 percent improvement on the Yale Brown Obsessive Compulsive Scale (YBOCS) compared with placebo. We identified 6 trials on eating disorders, 12 on personality disorder, an existing metaanalysis and 10 trials of risperidone or olanzapine for PTSD, 36 trials for depression of which 7 assessed drugs without an FDA-approved indication, and 33 trials of aripiprazole, olanzapine, quetiapine, or risperidone for treating substance abuse disorders. We identified one small trial (N=13) of atypical antipsychotics for insomnia which was inconclusive. For eating disorder patients specifically, evidence shows that atypicals are do not cause significant weight gain. The level of evidence is mixed regarding personality disorders and moderate for an association of risperidone with improving post-traumatic stress disorder. Evidence does not support efficacy of atypical antipsychotics for substance abuse. In elderly patients, adverse events included an increased risk of death (number needed to harm [NNH]=87), stroke (for risperidone, NNH=53), extrapyramidal symptoms (for olanzapine (NNH=10) and risperidone (NNH=20), and urinary symptoms (NNH= from 16 to 36). In nonelderly adults, adverse events included weight gain (particularly with olanzapine), fatigue, sedation, akithisia (for aripiprazole) and extrapyramidal symptoms. Direct comparisons of different atypical antipsychotics for off-label conditions are rare. Conclusions: Benefits and harms vary among atypical antipsychotics for off-label usage. For symptoms associated with dementia in elderly patients, small but statistically significant benefits were observed for aripiprazole, olanzapine, and risperidone. Quetiapine was associated with benefits in the treatment of generalized anxiety disorder, and risperidone was associated with benefits in the treatment of OCD; however, adverse events were common.
Authors of Report
Methodology description
We conducted an initial update search on June 1, 2008, as part of a project to determine if Comparative Effectiveness Reviews (CERs) funded by AHRQ needed updating; this search included only the drugs aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone. Regular update searches continued through May 2011. The search for off-label use of the newly approved atypicals (iloperidone, paliperidone and asenapine) included all years available in the electronic databases through May 2011. Searches for utilization data were conducted, as were searches for use for new conditions (anxiety, ADHD, eating disorders, insomnia, and substance abuse). Databases searched include: DARE (Database of Abstracts of Reviews of Effects), Cochrane Database of Systematic Reviews, CENTRAL (Cochrane Central Register of Controlled Trials), PubMed (National Library of Medicine, includes MEDLINE), Embase (biomedical and pharmacological bibliographic database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), and PsycINFO. A summary of detailed search strategies is available in Appendix A. Other sources of literature include, references of included studies, references of relevant reviews, and personal files from related topic projects. In addition, the AHRQ Effective Health Care Program Scientific Resource Center (SRC) at Oregon Health Sciences University requested unpublished studies from pharmaceutical manufacturers and searched the FDA and Health Canada databases. Two trained researchers reviewed the list of titles resulting from our electronic searches and selected articles to obtain. Each article retrieved was reviewed with a brief screening form (see Appendix B: screener) that collected data on medication, psychiatric condition, study design, population, sample size, and study duration. Only studies on humans were included. Studies that did not report any outcomes of efficacy, effectiveness, safety/adverse events, or utilization patterns were excluded. As single dose or short term trials (less than 6 weeks in length) are common for several of the new uses, we decided, at the TEP’s suggestion, not to limit inclusion by study duration. Clinical trials were used to review efficacy outcomes. In the case that no clinical trials were found for a given condition or drug of interest, we turned to observational studies. All reported side effects and adverse events were abstracted from clinical trials, even if the trial did not report efficacy or effectiveness results. We also included large observational studies of adverse events. Reports of utilization and prescribing patterns were accepted if they discussed use in the United States since 1995. Data were independently abstracted by a health services researcher and a psychiatrist trained in the critical assessment of evidence. The following data were abstracted from included trials: trial name, setting, population characteristics (including sex, age, ethnicity, and diagnosis), eligibility and exclusion criteria, interventions (dose, frequency, and duration), any co-interventions, other allowed medication, comparisons, and results for each outcome.
The systematic review data of this published project was retrospectively imported into SRDR by the Brown EPC on behalf of the RAND/Southern California EPC and the Agency for Healthcare Research and Quality (AHRQ). For access to the full report available on the AHRQ website, follow this link:
Funding Source
The Agency for Healthcare Research and Quality (AHRQ)

Key Questions

1. What are the leading off-label uses of atypical antipsychotics in utilization studies? How have trends in utilization changed in recent years, including inpatient versus outpatient use? What new uses are being studied in trials?
2. What does the evidence show regarding the efficacy and comparative effectiveness of atypical antipsychotics for off-label indications? Sub Key Question: How do atypical antipsychotic medications compare with other drugs, including first-generation antipsychotics, for treating off-label indications?
3. What subset of the population would potentially benefit from off-label uses? Do effectiveness and harms differ by race/ethnicity, gender, and age group? By severity of condition and clinical subtype?
4. What are the potential adverse effects and/or complications involved with off-label prescribing of atypical antipsychotics? How do they compare within the class and with other drugs used for the conditions?

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