Augmentation of clozapine with a second antipsychotic - a meta-analysis

Acta Psychiatr Scand. 2012 Jan;125(1):15-24. doi: 10.1111/j.1600-0447.2011.01792.x. Epub 2011 Nov 12.


Objective: To examine using meta-analysis the effect of adding a second antipsychotic to established clozapine monotherapy.

Method: A literature search was conducted in April 2011, and randomised placebo-controlled double-blind studies were identified. We performed a meta-analysis of efficacy (as standardised mean difference) and tolerability (withdrawals from trials) and a regression analysis of duration of study versus effect size. We also examined publication bias using funnel-plot analysis.

Results: Overall, 14 studies were included (734 subjects). Individual study numbers ranged from 10 to 207 (mean 52.6, median 40). Augmentation of clozapine with a second antipsychotic conferred a small benefit over placebo (effect size -0.239 (95% CI: -0.452, -0.026); P = 0.028). Meta-regression of the effect of length of treatment on effect size showed no relationship (P = 0.254). The risk of discontinuing antipsychotic augmentation was no greater than the risk of discontinuing placebo (RR = 1.20, 95% CI 0.80-1.82). There was no evidence of publication bias.

Conclusion: Augmentation with a second antipsychotic is modestly beneficial in patients not responding fully to clozapine. Tolerability seems not to be adversely affected, at least in the short term. Longer studies do not appear to increase the probability of showing positive effects for augmentation.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antipsychotic Agents* / pharmacokinetics
  • Antipsychotic Agents* / therapeutic use
  • Bibliometrics
  • Clozapine* / pharmacokinetics
  • Clozapine* / therapeutic use
  • Drug Synergism
  • Drug Therapy, Combination / methods*
  • Drug Tolerance
  • Humans
  • Outcome Assessment, Health Care
  • Randomized Controlled Trials as Topic
  • Schizophrenia / drug therapy*
  • Therapeutic Equivalency
  • Time Factors


  • Antipsychotic Agents
  • Clozapine