Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review

Schizophr Bull. 2012 Sep;38(5):1003-11. doi: 10.1093/schbul/sbr004. Epub 2011 Mar 21.


Background: When schizophrenia patients have insufficient response to clozapine, pharmacological augmentation is often applied. This meta-analysis summarizes available evidence on efficacy of pharmacological augmentation of clozapine treatment in schizophrenia spectrum disorder.

Methods: Only double-blind randomized controlled studies were included. Primary outcome measure was total symptom severity, and secondary outcome measures were subscores for positive and negative symptoms. Effect sizes were calculated from individual studies and combined to standardized mean differences (Hedges's g).

Results: Twenty-nine studies reporting on 15 different augmentations were included. Significant better efficacy than placebo on total symptom severity was observed for lamotrigine, citalopram, sulpiride, and CX516 (a glutamatergic agonist). The positive effect of lamotrigine disappeared after outlier removal. The other positive findings were based on single studies. Significantly better efficacy on positive symptom severity was observed for topiramate and sulpiride. The effect of topiramate disappeared after outlier removal. Results for sulpiride were based on a single randomized controlled trial. Citalopram, sulpiride, and CX516 showed better efficacy for negative symptoms than placebo, all based on single studies.

Conclusions: Evidence for efficacy of clozapine augmentation is currently scarce. Efficacy of lamotrigine and topiramate were both dependent on single studies with deviating findings. The effect of citalopram, sulpiride, and CX516 were based on single studies. Thus, despite their popularity, pharmacological augmentations of clozapine are not (yet) demonstrated to be superior to placebo.

Publication types

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

MeSH terms

  • Antipsychotic Agents / adverse effects
  • Antipsychotic Agents / therapeutic use*
  • Brief Psychiatric Rating Scale
  • Citalopram / adverse effects
  • Citalopram / therapeutic use
  • Clozapine / therapeutic use*
  • Dioxoles / adverse effects
  • Dioxoles / therapeutic use
  • Double-Blind Method
  • Drug Synergism
  • Drug Therapy, Combination
  • Fructose / adverse effects
  • Fructose / analogs & derivatives
  • Fructose / therapeutic use
  • Humans
  • Lamotrigine
  • Piperidines / adverse effects
  • Piperidines / therapeutic use
  • Psychiatric Status Rating Scales
  • Psychotropic Drugs / adverse effects
  • Psychotropic Drugs / therapeutic use*
  • Randomized Controlled Trials as Topic
  • Schizophrenia / diagnosis
  • Schizophrenia / drug therapy*
  • Schizophrenic Psychology*
  • Sulpiride / adverse effects
  • Sulpiride / therapeutic use
  • Topiramate
  • Treatment Outcome
  • Triazines / adverse effects
  • Triazines / therapeutic use


  • 1-(quinoxalin-6-ylcarbonyl)piperidine
  • Antipsychotic Agents
  • Dioxoles
  • Piperidines
  • Psychotropic Drugs
  • Triazines
  • Citalopram
  • Topiramate
  • Fructose
  • Sulpiride
  • Clozapine
  • Lamotrigine