Clozapine and Suicide Risk in Schizophrenia: What the InterSePT Trial Found

Clozapine has an FDA indication for reducing the risk of recurrent suicidal behavior in people with schizophrenia or schizoaffective disorder who are judged to be at chronic risk.¹ The indication rests on one trial. Over two years in 980 high-risk patients, suicidal behavior was 24% lower with clozapine than with olanzapine.²

In a crisis: call or text 988, or go to the nearest emergency department. A first episode of psychosis belongs in a hospital-based or coordinated specialty care program.

What the InterSePT trial did

The International Suicide Prevention Trial enrolled 980 patients with schizophrenia or schizoaffective disorder who were considered at high risk because of previous attempts or current suicidal thoughts. They were randomly assigned to clozapine or olanzapine and followed for two years. To keep clinical contact equal, every patient was seen weekly for six months and then every two weeks.²

The results favored clozapine on the measures of suicidal behavior:²

• Suicidal behavior overall: hazard ratio 0.76 (95% CI 0.58 to 0.97)
• Suicide attempts: 34 patients on clozapine and 55 on olanzapine
• Hospitalizations to prevent suicide: 82 and 107
• Rescue interventions to prevent suicide: 118 and 155

Patients on clozapine also needed fewer added antidepressants and anxiolytics.²

What the trial did not show

Deaths by suicide did not differ between the groups. Five patients assigned to clozapine and three assigned to olanzapine died by suicide, a difference that was not statistically significant.² Deaths were too few to compare the groups reliably, and clinicians at every site were free to intervene to prevent attempts, which likely lowered deaths in both groups.

The trial was open-label, although suicidal behavior was assessed by masked raters. The label states that the result should be read as evidence that clozapine delays recurrent suicidal behavior, and is not a demonstration of superior efficacy over olanzapine.¹ InterSePT supports fewer attempts and fewer emergency interventions. A difference in deaths remains unproven.

What the wider evidence adds

A 2005 meta-analysis of six studies found that suicidal behavior was about three times less frequent with clozapine than with other treatments, and deaths by suicide were 2.9 times less frequent. The authors noted that the findings were inconsistent across studies and that well-designed studies were rare.³

In the FIN11 study, which followed 66,881 people with schizophrenia in Finland from 1996 to 2006, clozapine was associated with the lowest all-cause mortality of the antipsychotics studied, with an adjusted hazard ratio of 0.74 compared with perphenazine.⁴ This was an observational study of deaths from all causes. People who are prescribed clozapine and stay on it differ from those who are not, and the results cannot establish that clozapine caused the difference.

Who this applies to

Only 26.8% of the patients in InterSePT had treatment-resistant illness.² The suicide indication is separate from the indication for treatment-resistant schizophrenia and does not require that other antipsychotics have failed.¹ A person with schizophrenia or schizoaffective disorder, a history of attempts, and persistent suicidal thoughts is a candidate for a clozapine discussion on that basis alone.

The decision weighs a reduction in suicidal behavior against clozapine's monitoring and side effects, and it belongs to the patient, the family, and the psychiatrist together. The page on when to start clozapine covers the treatment-resistance indication.

Limitations of the evidence

This evidence has limitations. First, the indication rests on a single randomized trial completed more than 20 years ago. Second, that trial did not show a difference in deaths. Third, the supporting studies are observational and inconsistent. Nevertheless, it was a large randomized trial that ran for two years, and it is the basis of an FDA indication.

In a crisis: call or text 988, or go to the nearest emergency department. A first episode of psychosis belongs in a hospital-based or coordinated specialty care program.

I start and manage clozapine in an outpatient practice in Chelsea, Manhattan. Details are on the schizophrenia care in NYC page. Clozapine should not be stopped, skipped, or restarted without the prescriber. This page is general information and does not replace an evaluation.

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