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This is a plain English summary of an original research article. The views expressed are those of the author(s) and reviewer(s) at the time of publication.

Among patients with schizophrenia that has not responded to other drugs, the antipsychotic drug clozapine cuts the chances of hospital admissions and drug discontinuation.

Recent trials have questioned the superior efficacy of clozapine compared with other standard antipsychotic drugs. However, a review of real-world data from observational studies confirms its place as a drug that may work when others fail. Patients prescribed clozapine had better outcomes, despite having more severe illness.

As expected the data show that clozapine increases the risk of weight gain and type 2 diabetes. The side effects associated with clozapine prevent its use as a first-line drug.

The findings suggest that clinicians should continue to offer a treatment trial of clozapine to people with schizophrenia who have not benefited from standard antipsychotic drugs.

Why was this study needed?

Around 30% of patients with schizophrenia do not respond sufficiently to standard second-generation antipsychotic drugs. For these patients, clozapine has been seen as the gold standard treatment. This is despite a known raised risk of weight gain and type 2 diabetes, as well as the serious but less common blood reaction agranulocytosis. These risks mean that patients taking clozapine require careful monitoring and blood tests.

However, recent summaries of randomised controlled trials have called the position of clozapine into question, with some finding standard antipsychotics equally effective. Results from systematic reviews of trials have been inconsistent. There is a concern that patients recruited to trials may not be representative of the wider population of people with treatment-resistant schizophrenia.

The authors of this review say cohort studies may better represent real-world patients. They carried out a systematic review of these observational studies to see how clozapine compared to other antipsychotic drugs in this population and if the results were comparable to the existing trials.

What did this study do?

This systematic review included 68 articles on 63 individual cohort studies (109,341 participants).

Studies were included if they of at least four weeks’ duration, with a minimum of 15 adults in each arm (average age 18 or over), and compared the effectiveness or safety of clozapine with that of a standard antipsychotic. At least 70% of patients in each study needed to have a diagnosis of schizophrenia or a related disorder.

The review compared baseline severity of illness in the clozapine and standard antipsychotic groups in the studies where this was reported. This was done to look for potential sampling bias: whether more severely ill and treatment-resistant patients were more likely to be treated with clozapine than with other antipsychotics. If this existed it would be a conservative bias, as it would reduce the difference in effectiveness between clozapine and other antipsychotics. So we can trust the direction of this finding.

What did it find?

  • The risk of hospitalisation was 18% lower for people taking clozapine compared with those taking standard antipsychotics (risk ratio [RR] 0.82, 95% confidence interval [CI] 0.73 to 0.92; 19 studies, 49,453 participants). In absolute terms, 19.4% of people taking clozapine were hospitalised compared with 25.6% of people taking standard antipsychotics.
  • The risk of drug discontinuation was 27% lower for people taking clozapine compared with those taking standard antipsychotics (RR 0.73, 95% CI 0.64 to 0.84; 16 studies, 56,368 participants). In absolute terms, 42% of people taking clozapine discontinued their medication compared with 56% taking standard antipsychotics.
  • The review also found that clozapine was associated with a reduction in overall symptoms (standardised mean difference in symptom scores -0.30, 95% CI -0.57 to -0.03; 10 studies, 7,767 participants).
  • Patients receiving clozapine had more severe illness at baseline than those receiving standard antipsychotics (based on 17 studies with 38,766 participants).
  • Clozapine was associated with an increase in body weight compared with standard antipsychotics (mean difference 1.7kg, 95% CI 0.3 to 3.1; nine studies, 5,329 participants). Risk of type 2 diabetes rose by 78% with clozapine (RR 1.78, 95% CI 1.23 to 2.57; absolute risk 3.8% with clozapine vs 2.2% with standard antipsychotics; five studies, 5,539 participants).

What does current guidance say on this issue?

The NICE guideline on schizophrenia in adults published in 2014 states: “Offer clozapine to people with schizophrenia whose illness has not responded adequately to treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs. At least one of the drugs should be a non-clozapine second-generation antipsychotic.”

If the illness does not respond to an adequate dose of clozapine, clinicians are advised to review the diagnosis, check adherence, consider other possible causes of non-response and measure therapeutic drug levels before adding a second antipsychotic to augment treatment with clozapine.

What are the implications?

The review’s findings add weight to existing guidelines to offer clozapine when schizophrenia has not responded to adequate trials of other standard antipsychotics.

They confirm that this drug retains an important place in treatment of schizophrenia, and may reduce hospitalisation and drug discontinuation, especially in patients with more severe illness.

Citation and Funding

Masuda T, Misawa F, Takase M et al. Association with hospitalization and all-cause discontinuation among patients with schizophrenia on clozapine vs other oral second-generation antipsychotics: A systematic review and meta-analysis of cohort studies. JAMA Psychiatry. Published online July 31, 2019.

No funding information was provided for this study.



NICE. Psychosis and schizophrenia in adults: prevention and management. CG178. London: National Institute for Health and Care Excellence; 2014.

Stroup TS. Clozapine and evidence-based psychopharmacology for schizophrenia. JAMA Psychiatry. Published online July 31, 2019.

Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre


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