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Clozapine Treatment for Suicidality in Schizophrenia
International Suicide Prevention Trial (InterSePT)
Herbert Y. Meltzer, MD;
Larry Alphs, MD, PhD;
Alan I. Green, MD;
A. Carlo Altamura, MD;
Ravi Anand, MD;
Alberto Bertoldi, MD;
Marc Bourgeois, MD;
Guy Chouinard, MD;
M. Zahur Islam, PhD;
John Kane, MD;
Ranga Krishnan, MD;
J.-P. Lindenmayer, MD;
Steven Potkin, MD;
for the InterSePT Study Group
Arch Gen Psychiatry. 2003;60:82-91.
Background Approximately 50% of patients with schizophrenia or schizoaffective disorder attempt suicide, and approximately 10% die of suicide. Study results suggest that clozapine therapy significantly reduces suicidal behavior in these patients.
Methods A multicenter, randomized, international, 2-year study comparing the risk for suicidal behavior in patients treated with clozapine vs olanzapine was conducted in 980 patients with schizophrenia or schizoaffective disorder, 26.8% of whom were refractory to previous treatment, who were considered at high risk for suicide because of previous suicide attempts or current suicidal ideation. To equalize clinical contact across treatments, all patients were seen weekly for 6 months and then biweekly for 18 months. Subsequent to randomization, unmasked clinicians at each site could make any interventions necessary to prevent the occurrence of suicide attempts. Suicidal behavior was assessed at each visit. Primary end points included suicide attempts (including those that led to death), hospitalizations to prevent suicide, and a rating of "much worsening of suicidality" from baseline. Masked raters, including an independent suicide monitoring board, determined when end point criteria were achieved.
Results Suicidal behavior was significantly less in patients treated with clozapine vs olanzapine (hazard ratio, 0.76; 95% confidence interval, 0.58-0.97; P = .03). Fewer clozapine-treated patients attempted suicide (34 vs 55; P = .03), required hospitalizations (82 vs 107; P = .05) or rescue interventions (118 vs 155; P = .01) to prevent suicide, or required concomitant treatment with antidepressants (221 vs 258; P = .01) or anxiolytics or soporifics (301 vs 331; P = .03). Overall, few of these high-risk patients died of suicide during the study (5 clozapine vs 3 olanzapine-treated patients; P = .73).
Conclusions Clozapine therapy demonstrated superiority to olanzapine therapy in preventing suicide attempts in patients with schizophrenia and schizoaffective disorder at high risk for suicide. Use of clozapine in this population should lead to a significant reduction in suicidal behavior.
From the Department of Psychiatry, Vanderbilt University, Nashville, Tenn (Dr Meltzer); Pfizer Inc, Ann Arbor, Mich (Dr Alphs); the Departments of Psychiatry, Dartmouth Medical School, Hanover, Mass (Dr Green), and University of Milan, Milan, Italy (Dr Altamura); Organon, Oss, the Netherlands (Dr Anand); the Departments of Psychiatry, La Plata University, La Plata, Argentina (Dr Bertoldi), University of Bordeaux, Bordeaux, France (Dr Bourgeois), McGill University, Montreal, Quebec (Dr Chouinard), and University of Montreal, Montreal (Dr Chouinard); Novartis Pharmaceuticals Corp, East Hanover, NJ (Dr Islam); and the Departments of Psychiatry, Hillside Hospital, Glen Oaks, NY (Dr Kane), Albert Einstein University, Bronx, NY (Dr Kane), Duke University, Durham, NC (Dr Krishnan), Manhattan Psychiatric Center–Nathan Kline Institute for Psychiatric Research, Wards Island, NY (Dr Lindenmayer), and University of California, Irvine (Dr Potkin). Drs Meltzer, Green, Chouinard, Kane, Lindenmayer, and Potkin have received grants from or are consultants to Novartis Pharmaceuticals Corp. Dr Chouinard has also received research support from Merck Frosst Canada, Inc, Dorval, Quebec; Janssen-Ortho Inc, Toronto, Ontario; and Pfizer Canada Inc, Dorval; and is a consultant to Janssen-Ortho Inc and Organon.
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