Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis

source extracted confidence: high 2026-04-09
#antipsychotic-agents #clozapine #drug-resistance #drug-therapy-combination #electroconvulsive-therapy

Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis

Siskind et al., 2018 | Aust N Z J Psychiatry | Meta Analysis

Citation

Siskind Dan J, Lee Michael, ... Kisely Steve. Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis. Aust N Z J Psychiatry. 2018-Aug;52(8):751-767. doi:10.1177/0004867418772351

Abstract

BACKGROUND: Although clozapine is the most effective medication for treatment refractory schizophrenia, only 40% of people will meet response criteria. We therefore undertook a systematic review and meta-analysis of global literature on clozapine augmentation strategies. METHODS: We systematically reviewed PubMed, PsycInfo, Embase, Cochrane Database, Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database for randomised control trials of augmentation strategies for clozapine resistant schizophrenia. We undertook pairwise meta-analyses of within-class interventions and, where possible, frequentist mixed treatment comparisons to differentiate treatment effectiveness Results: We identified 46 studies of 25 interventions. On pairwise meta-analyses, the most effective augmentation agents for total psychosis symptoms were aripiprazole (standardised mean difference: 0.48; 95% confidence interval: -0.89 to -0.07) fluoxetine (standardised mean difference: 0.73; 95% confidence interval: -0.97 to -0.50) and, sodium valproate (standardised mean difference: 2.36 95% confidence interval: -3.96 to -0.75). Memantine was effective for negative symptoms (standardised mean difference: -0.56 95% confidence interval: -0.93 to -0.20). However, many of these results included poor-quality studies. Single studies of certain antipsychotics (penfluridol), antidepressants (paroxetine, duloxetine), lithium and Ginkgo biloba showed potential, while electroconvulsive therapy was highly promising. Mixed treatment comparisons were only possible for antipsychotics, and these gave similar results to the pairwise meta-analyses. CONCLUSIONS: On the basis of the limited data available, the best evidence is for the use of aripiprazole, fluoxetine and sodium valproate as augmentation agents for total psychosis symptoms and memantine for negative symptoms. However, these conclusions are tempered by generally short follow-up periods and poor study quality.

Key Findings

We identified 46 studies of 25 interventions. On pairwise meta-analyses, the most effective augmentation agents for total psychosis symptoms were aripiprazole (standardised mean difference: 0.48; 95% confidence interval: -0.89 to -0.07) fluoxetine (standardised mean difference: 0.73; 95% confidence interval: -0.97 to -0.50) and, sodium valproate (standardised mean difference: 2.36 95% confidence interval: -3.96 to -0.75). Memantine was effective for negative symptoms (standardised mean differenc

Outcomes Measured

  • Requires manual extraction

Population

Field Value
Population See abstract
Sample Size 46
Age Range See abstract
Condition See abstract

MeSH Terms

  • Antipsychotic Agents
  • Clozapine
  • Drug Resistance
  • Drug Therapy, Combination
  • Electroconvulsive Therapy
  • Humans
  • Schizophrenia

Evidence Classification

  • Level: Meta Analysis
  • Publication Types: Journal Article, Meta-Analysis, Systematic Review
  • Vertical: ginkgo

Provenance

Source extracted via PubMed E-utilities API on 2026-04-09