Augmentation strategies for clozapine resistance: a systematic review and meta-analysis

Acta Neuropsychiatr. 2023 Apr;35(2):65-75. doi: 10.1017/neu.2022.30. Epub 2022 Nov 16.


Background: Several augmentation strategies have been used to improve symptomatology in patients not adequately responding to clozapine. Several randomised controlled trials (RCTs) have evaluated the efficacy of different strategies to augment clozapine. This systematic review and meta-analysis reviewed the available RCTs that have evaluated the clinical efficacy of various pharmacological agents, non-pharmacological strategies (occupational therapy, cognitive behaviour therapy), and somatic treatment [electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation, etc.)] as augmenting agents to clozapine.

Methods: Data were extracted using standard procedures, and risk of bias was evaluated. Effect sizes were computed for the individual studies.

Results: Forty-five clinical trials were evaluated. The pooled effect size for various antipsychotic medications was 0.103 (95% CI: 0.288-0.493, p < 0.001); when the effect size was evaluated for specific antipsychotics for which more than one trial was available, the effect size for risperidone was -0.27 and that for aripiprazole was 0.57. The effect size for lamotrigine was 0.145, and that for topiramate was 0.392. The effect size for ECT was 0.743 (CI: 0.094-1.392). Risk of bias was low (mean Jadad score - 3.93). Largest effect sizes were seen for mirtazapine (effect size of 5.265). Most of the studies can be considered underpowered and limited by small sample sizes.

Conclusions: To conclude, based on the findings of the present systematic review and meta-analysis, it can be said that compared to other treatment strategies, clozapine non-responsive patients respond maximum to mirtazapine followed by ECT.

Keywords: augmentation; clozapine; meta-analysis; resistance.

Publication types

  • Meta-Analysis
  • Systematic Review
  • Review

MeSH terms

  • Antipsychotic Agents* / therapeutic use
  • Clozapine* / therapeutic use
  • Humans
  • Mirtazapine / therapeutic use
  • Risperidone / therapeutic use
  • Schizophrenia* / drug therapy


  • Clozapine
  • Mirtazapine
  • Antipsychotic Agents
  • Risperidone