Antipsychotics medications are approved by the U.S. Food and Drug Administration (FDA) for treatment of schizophrenia and bipolar disorder. These medications are commonly divided into two classes, reflecting two waves of historical development: the conventional antipsychotics and the atypical. The conventional antipsychotics served as the first successful pharmacologic treatment for primary psychotic disorders such as schizophrenia. Having been widely used for decades, the conventional antipsychotics also produced various side effects requiring additional medications, which spurred the development of the atypical antipsychotics. Currently, nine atypical antipsychotic drugs have been approved by FDA: aripiprazole, asenapine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. These drugs have been used off-label for the treatment of various psychiatric conditions. A 2006 study on Efficacy and Comparative Effectiveness of Off-label Use of Atypical Antipsychotics reviewed the scientific evidence on the safety, efficacy, and effectiveness for off-label uses. (Clozapine was excluded because of its association with a potentially fatal blood disorder of bone marrow suppression, and it requires frequent blood tests for safety monitoring.) The 2006 study examined 84 published studies on atypicals and found that the most common off-label uses of the drugs were for treatment of depression, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), personality disorders, Tourette's syndrome, autism, and agitation in dementia. It concluded that with few exceptions, there was insufficient high-strength evidence to reach conclusions about the efficacy of any off-label uses of these medications. It also found strong evidence that atypicals are associated with increased risk of adverse events such as significant weight gain, sedation, and, among the elderly, increased mortality. Future research areas suggested by the report include safe treatment for agitation in dementia, association between the increased risk of death and antipsychotics drugs, and comparison of the development of adverse effects between patients taking atypical antipsychotics and those taking conventional antipsychotics. Since publication of that report, important changes have occurred that make the report out of date. New or increased adverse effects of off-label indications have been observed and new atypicals (asenapine, iloperidone, and paliperidone) have been approved by FDA for the treatment of schizophrenia and bipolar disorder. This report covers the following off-label uses of atypical antipsychotic medications: anxiety, ADHD, dementia and severe geriatric agitation, major depressive disorder (MDD), eating disorders, insomnia, OCD, PTSD, personality disorders, substance abuse, and Tourette's syndrome. This report addresses the following Key Questions: KQ1. 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? KQ2. What does the evidence show regarding the efficacy and comparative effectiveness of atypical antipsychotics for off-label indications? Sub-KQ 2. How do atypical antipsychotic medications compare with other drugs, including first-generation antipsychotics, for treating off-label indications? KQ3. 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? KQ4. 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? KQ5. What is the effective dose and time limit for off-label indications?