Safety and tolerability of antipsychotic polypharmacy

Expert Opin Drug Saf. 2012 Jul;11(4):527-42. doi: 10.1517/14740338.2012.683523. Epub 2012 May 8.


Introduction: Antipsychotic polypharmacy (APP), the concomitant use of ≥ 2 antipsychotics, is common in clinical practice. Prior reviews have focused on the efficacy of APP, but no systematic review exists regarding the safety and tolerability of this practice.

Areas covered: A systematic review of adverse effects associated with APP was conducted to prepare this review; case series with ≥ 2 patients, chart reviews, naturalistic, database, cohort and randomized studies that reported on the association between APP in general or specific APP combinations and global or specific adverse effect were included. Methodological limitations of available studies are discussed and recommendations for clinicians and future research are provided.

Expert opinion: Across mostly small and uncontrolled studies, APP has been associated with increased global side effect burden, rates of Parkinsonian side effects, anticholinergic use, hyperprolactinemia, sexual dysfunction, hypersalivation, sedation/somnolence, cognitive impairment and diabetes. Effects on akathisia and mortality were inconclusive. Although some combinations, particularly aripiprazole augmentation of an agent with greater side effect burden, may reduce weight gain, dyslipidemia, hyperprolactinemia and sexual dysfunction, APP should remain a last-resort treatment option after monotherapy, switching and non-antipsychotic combinations have failed. More data are needed to further inform the individualized risk-benefit evaluation of APP.

MeSH terms

  • Antipsychotic Agents / adverse effects*
  • Basal Ganglia Diseases / chemically induced
  • Drug Tolerance
  • Electrocardiography / drug effects
  • Humans
  • Hyperprolactinemia / chemically induced
  • Metabolic Syndrome / chemically induced
  • Polypharmacy*
  • Weight Gain / drug effects


  • Antipsychotic Agents