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Augmentation Strategies of Clozapine With Antipsychotics in the Treatment of Ultraresistant Schizophrenia

Mouaffak, Fayçal*; Tranulis, Constantin; Gourevitch, Raphael; Poirier, Marie-France*; Douki, Saida; Olié, Jean-Pierre*; Lôo, Henri*; Gourion, David

Review Articles

Background: Approximately 40% to 70% of neuroleptic-resistant schizophrenic patients are nonresponders to clozapine. Several clozapine augmentation strategies have come into clinical practice although often without evidence-based support. Among these strategies, the combined use of clozapine with another antipsychotic has been reported for up to 35% of patients receiving clozapine.

Objective: The purposes of the present work were to (1) review the available literature on the efficacy and safety of the clozapine augmentation with another antipsychotic using a MEDLINE search of the literature from 1978 to December 2005 and (2) to propose an operational definition of schizophrenia refractory to clozapine ("ultraresistant schizophrenia") for the implementation and homogenization of future therapeutic trials.

Conclusion: Case controls and open clinical trials largely dominate the literature, and there are only 4 double-blind studies of clozapine augmentation with antipsychotics. The results of these studies are somewhat discrepant. Moreover, the heterogeneity of definitions of resistance to clozapine, of outcome measures and of dose and duration of pharmacological trials is a major limitation for drawing conclusions.

From the *Service Hospitalo-Universitaire de Santé Mentale et de Thérapeutique, Université René Descartes and INSERM E0117, Sainte-Anne Hospital, 7 rue Cabanis, 75014 Paris, France; †Department of Psychiatry, Louis-H La Fontaine Hospital, Montreal, Canada; ‡Service Avicenne, Université Tunis II, Faculté de Médecine de Tunis, Hôpital Razi La Manouba, Tunis, Canada and §Research Unit on Children's Psychosocial Maladjustment (GRIP), University of Montreal, 3050, Édouard-Montpetit, Montreal (QC) Canada H3T 1J7.

Reprints: Dr Fayçal Mouaffak, SHU Ste ANNE, PR Olié, 7 rue Cabanis, 75014 Paris, France (e-mail:

© 2006 Lippincott Williams & Wilkins, Inc.