Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials

Schizophr Bull. 2009 Mar;35(2):443-57. doi: 10.1093/schbul/sbn018. Epub 2008 Apr 15.


Context: Despite lacking evidence for its safety and efficacy, antipsychotic cotreatment is common in schizophrenia.

Objective: To evaluate therapeutic and adverse effects of antipsychotic cotreatment vs monotherapy in schizophrenia.

Data sources: Cochrane Schizophrenia Group register and hand searches of relevant journals/conference proceedings.

Study selection: Randomized controlled trials comparing antipsychotic monotherapy to cotreatment with a second antipsychotic.

Data extraction and analysis: Two authors independently extracted data. For homogenous dichotomous data, we calculated random effects, relative risk (RR), 95% confidence intervals (CIs), and numbers needed to treat (NNT). For continuous data, weighted mean differences were calculated.

Results: In 19 studies (1229 patients) with 28 monotherapy and 19 cotreatment arms, antipsychotic cotreatment was superior to monotherapy regarding 2 a priori defined coprimary outcomes: less study-specific defined inefficacy (N = 22, n = 1202, RR = 0.76, CI = 0.63-0.90, P = .002, NNT = 7, CI = 4-17, P = .0008, I(2) = 78.9%) and all-cause discontinuation (N = 20, n = 1052, RR = 0.65, CI = 0.54-0.78, P < .00001). Results were consistent using Clinical Global Impressions thresholds of less than much (P = .006) and less than minimally (P = .01) improved. Specific psychopathology and adverse event data were insufficient to yield meaningful results. In sensitivity analyses, 5 efficacy moderators emerged: concurrent polypharmacy initiation, clozapine combinations, trial duration >10 weeks, Chinese trials, and second-generation + first-generation antipsychotics. In a meta-regression, similar dose combinations, second-generation + first-generation antipsychotics and concurrent polypharmacy initiation remained significant.

Conclusions: In certain clinical situations, antipsychotic cotreatment may be superior to monotherapy. However, the database is subject to possible publication bias and too heterogeneous to derive firm clinical recommendations, underscoring the need for future research.

Publication types

  • Meta-Analysis
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antipsychotic Agents / therapeutic use*
  • Clozapine / therapeutic use
  • Databases as Topic / statistics & numerical data
  • Drug Therapy, Combination
  • Female
  • Humans
  • Male
  • Middle Aged
  • Polypharmacy
  • Psychiatric Status Rating Scales
  • Randomized Controlled Trials as Topic / statistics & numerical data
  • Schizophrenia / drug therapy*
  • Schizophrenic Psychology
  • Treatment Outcome


  • Antipsychotic Agents
  • Clozapine