A Systematic Review of Complex Polypharmacy in Bipolar Disorder: Prevalence, Clinical Features, Adherence, and Preliminary Recommendations for Practitioners.

Extensive combination pharmacotherapy regimens for bipolar disorder have gained increasing use in routine practice in ways that outpace data from evidence-based clinical trials. The present review examined the prevalence of complex pharmacotherapy regimens in bipolar disorder patients and sought to characterize factors that most influence polypharmacy prescribing patterns. The authors independently systematically searched the MEDLINE, PsycINFO, and Embase databases for English-language observational/naturalistic or randomized controlled polypharmacy trials, using the keywords and or and and . From among 3,566 publications, 49 ultimately met study inclusion criteria. Information was obtained regarding prevalence rates of extensive polypharmacy as well as clinical characteristics and naturalistic outcomes for patients with simple (≤ 2) or complex (≥ 3) regimens of psychotropic agents. A weighted mean percentage of 32.7% of bipolar outpatients (4,535/13,863) taking ≥ 3 psychotropic medications was identified. Factors associated with complex polypharmacy use include female sex, White race, age > 50 years, history of psychosis, greater burden of depressive illness, subtherapeutic dosing, lower treatment adherence, more extensive psychiatric comorbidity, and a greater history of suicide attempts. Extensive or complex combination pharmacotherapy regimens are common in many patients with bipolar disorder and often reflect greater overall illness severity. Naturalistic studies do not point to better outcomes for patients receiving more complex drug regimens, suggesting likely confounding by indication, high severity, or comorbid conditions. Formal clinical trials are needed to identify optimal drug combinations and durations when using ≥ 3 psychotropic medications to treat patients with bipolar disorder.