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Somatic Augmentation Strategies in Clozapine Resistance-What Facts?

Tranulis, Constantin MD, MSc*; Mouaffak, Faycal MD†¸; Chouchana, Laurent MD, MSc; Stip, Emmanuel MD, MSc*‡; Gourevitch, Raphael MD; Poirier, Marie France MD; Olie´, Jean-Pierre MD; Loo, Henri MD†ˆ; Gourion, David MD, PhD

Review Articles

Background: Polypharmacy without evidence-based support is sometimes needed for patients treated with 40% to 70% clozapine who are clozapine nonresponders. Several somatic augmentation strategies are proposed in the scientific literature, with different levels of evidence for safety and efficacy.

Objectives: The purpose of the present study is to review the available literature on the efficacy and safety of clozapine augmentation with somatic agents other than antipsychotics. The following classes of agents are considered: (1) mood stabilizers, (2) antidepressants, (3) electroconvulsive therapy and repetitive transcranial magnetic stimulation, (4) glutamatergic agents, (5)fatty acids supplements, and (6) benzodiazepines.

Results: Case controls and small-size clinical trials largely dominate the literature, limiting the power to draw conclusions concerning safety issues and the meaning of negative studies. Moreover, variable definitions of clozapine resistance, heterogeneous outcome measures, and short duration of treatment trials are additional limitations.

Conclusion: Generally, adjunctive strategies for clozapine-resistant patients remain based on scarce evidence of efficacy and significant safety concerns. Low-frequency repetitive transcranial magnetic stimulation, fatty acids supplements, and mirtazapine showed good tolerability and some efficacy, but the results need replication.

From the *Psychiatry Department, University of Montreal Montréal, Québec, Canada; †Service Hospitalo-Universitaire de Santé Mantale et de Thérapeutique, Université René Descartes, INSERM E0117, Sainte-Anne Hospital, Paris, France and ‡Louis-H. Lafontaine Hospital, Montréal, Québec, Canada.

Reprints: Constantin Tranulis, MD, MSc, Department of Psychiatry, University of Montreal, 2900, boul. Édouard-Montpetit, Montréal (Québec) H3T 1J4 Canada. (e-mail:

© 2006 Lippincott Williams & Wilkins, Inc.