Clozapine resistance: augmentation strategies

Eur Neuropsychopharmacol. 2012 Mar;22(3):165-82. doi: 10.1016/j.euroneuro.2011.08.005. Epub 2011 Sep 9.


Background: Clozapine (CLZ) is not effective in more than 50% of treatment-resistant schizophrenic patients. In these cases, several pharmacological strategies are used in clinical practice, with different levels of evidence for both safety and efficacy.

Objectives: In the present paper we critically reviewed literature data regarding the efficacy and safety of adjunctive agents in CLZ-resistant schizophrenics. The following classes of agents were considered: 1) antipsychotics, 2) antidepressants, 3) mood stabilizers, 4) other agents (e.g. fatty acid supplement and glutamatergic agents), 5) electroconvulsive therapy (ECT). For lamotrigine and risperidone sufficient data were available to perform a meta-analysis.

Methods: A Medline literature search covering a 20-year period was performed. For the meta-analysis, data were entered and analyzed with the Cochrane Collaboration Review Manager Software (RevMan version 5).

Results: 62 pertinent studies were identified, including 1556 schizophrenic or schizoaffective patients. Among treatments investigated, there is evidence for CLZ augmentation with 1) amisulpride and aripiprazole, 2) mirtazapine and 3) ethyl eicosapentaenoic acid (E-EPA). Although promising, ECT augmentation needs further validation. The meta-analyses did not support either the use of risperidone or lamotrigine as CLZ adjunct.

Conclusion: Overall, there is scarce evidence of efficacy and safety as regards adjunctive strategies for CLZ-resistant patients. However, several limitations do not allow to draw any definitive conclusion; among these we underline the small sample size of clinical trials, the variable definitions of CLZ resistance, the heterogeneity of outcome measures and methodological designs.

Publication types

  • Review

MeSH terms

  • Antipsychotic Agents / therapeutic use*
  • Clozapine / therapeutic use*
  • Drug Therapy, Combination
  • Humans
  • Risperidone / therapeutic use
  • Schizophrenia / drug therapy*


  • Antipsychotic Agents
  • Clozapine
  • Risperidone