Clozaril, known by its generic name clozapine, is an atypical antipsychotic medication. It is a treatment option reserved for specific and difficult-to-manage psychiatric conditions. The use of this medication is carefully managed, a result of clinical studies that have defined its effectiveness alongside its potential for serious side effects.
Foundational Research on Efficacy
Clozapine’s efficacy was established for patients who did not respond to other medications. This condition is clinically defined as treatment-resistant schizophrenia (TRS), which is diagnosed after a patient has shown an inadequate response to trials of at least two different antipsychotic drugs. For these individuals, clozapine emerged as a uniquely effective option, a finding that was solidified by a landmark U.S. multicenter trial in the late 1980s.
A 1988 study led by John Kane demonstrated clozapine’s superior capabilities. This large, double-blind clinical trial directly compared clozapine with chlorpromazine, a standard antipsychotic at the time, in a group of 268 patients with TRS. The patients selected for the study had historically failed to improve after trials with at least three different neuroleptics, ensuring the population was genuinely treatment-resistant.
The results of the Kane et al. study showed that 30% of patients treated with clozapine were classified as responders, compared to only 4% of those treated with chlorpromazine. The improvements were not limited to one symptom type; clozapine produced significantly greater reductions in both “positive” symptoms, like hallucinations and thought disorders, and “negative” symptoms, such as emotional withdrawal and apathy. These findings established clozapine as a primary treatment for schizophrenia that had not responded to other available therapies.
Studies on Reducing Suicidal Behavior
Beyond its general antipsychotic effects, research has investigated clozapine’s impact on suicidality. The most definitive evidence comes from the International Suicide Prevention Trial (InterSePT), a large-scale, randomized study of 980 patients with schizophrenia or schizoaffective disorder who were at high risk for suicide. The trial compared the effects of clozapine against another atypical antipsychotic, olanzapine, over two years, measuring outcomes like suicide attempts and hospitalizations to prevent suicide.
Patients receiving clozapine showed a significantly lower risk of suicidal behavior compared to those receiving olanzapine. There were fewer suicide attempts and fewer hospitalizations or emergency interventions to prevent suicide in the clozapine group. As a result of this evidence, the U.S. Food and Drug Administration (FDA) granted clozapine a specific indication for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder.
Investigating Major Adverse Effects
Clozapine’s efficacy is coupled with the risk of significant adverse effects. The most serious of these is agranulocytosis, a potentially fatal condition characterized by a severe decrease in neutrophils, a type of white blood cell, which leaves the body vulnerable to infection. Early reports of this side effect led to research into its cause and prevention.
This research resulted in mandatory patient monitoring protocols, which in the United States is the Clozapine Risk Evaluation and Mitigation Strategy (REMS) program. The REMS program requires every patient be enrolled in a central registry and undergo regular blood monitoring to check their absolute neutrophil count (ANC). This surveillance allows for the early detection of neutropenia, enabling immediate discontinuation of the drug before a severe infection can occur.
Studies have identified other health risks, including myocarditis (an inflammation of the heart muscle) and cardiomyopathy (a weakening of the heart muscle). Significant metabolic effects are also well-documented, including substantial weight gain, elevated blood sugar, and an increased risk of developing type 2 diabetes. These findings require comprehensive patient monitoring that extends beyond blood counts to include cardiovascular and metabolic health.
Contemporary Comparative Trials
Large-scale studies continue to affirm clozapine’s position. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), a study funded by the National Institute of Mental Health, provided real-world insight into how different antipsychotic medications compare. This trial was designed to reflect everyday clinical practice more closely than the highly controlled registration trials.
In the second phase of the CATIE trial, which focused on patients who had stopped taking their initially assigned medication due to either a lack of efficacy or intolerable side effects, clozapine was offered as a treatment option.
Among the various antipsychotics available in this phase of the trial, clozapine demonstrated superior effectiveness. Patients who were switched to clozapine had the longest time before discontinuing the medication for any reason. These findings solidified clozapine’s status as an effective option for patients who have not found success with other treatments.