12-year HK data: Clozapine reduces suicide mortality risk in patients with schizophrenia

Continuous use of clozapine reduces the risk of suicide mortality in patients with schizophrenia, according to a 12-year population-based cohort study in Hong Kong.

“Clozapine is the only medication approved by the US FDA for treatment-resistant schizophrenia,” wrote the researchers. “Understanding its association with long-term mortality risk is crucial.” [Br J Psychiatry 2025;doi:10.1192/bjp.2025.10312]

Long-term anti-suicidal effect

In the population-based cohort study, the researchers retrieved electronic health data from propensity score–matched patients with schizophrenia who received either clozapine or nonclozapine antipsychotics (n=9,456; median age, 39.13 years; female, 50.73 percent) from all public hospitals in Hong Kong. Patients were categorized into four groups: continuous clozapine users (n=2,020), clozapine discontinuers (n=1,132), continuous nonclozapine antipsychotic users (n=4,326), and nonclozapine antipsychotic discontinuers (n=1,978).

After a median follow-up of 12.37 years, adjusted failure time models revealed that continuous clozapine users had a lower risk of suicide mortality (acceleration factor, 3.01; 99 percent confidence interval [CI], 1.41–6.44) vs continuous nonclozapine antipsychotic users.

Patients with schizophrenia have a 12- to 45-fold higher risk of suicide vs the general population. “Our findings add to the existing evidence on the effectiveness of clozapine, particularly its anti-suicidal effects, and emphasize the need for continuous clozapine use,” the researchers commented.

Additionally, co-prescription of other antipsychotics and continuous clozapine use were associated with lower risks of suicide mortality (acceleration factor, 3.67; 99 percent CI, 1.41–9.60) and all-cause mortality (acceleration factor, 1.42; 99 percent CI, 1.07–1.88) vs continuous nonclozapine antipsychotic use.

Clozapine use in the post-REMS era

Despite these benefits, the use of clozapine has been limited due to its side effect profile.

On 24 February 2025, the US FDA determined that the risk evaluation and mitigation strategies (REMS) programme for clozapine is no longer necessary to ensure the benefits of the medicine outweigh the risk. [www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/information-clozapine]

“While this abolition of REMS is meant to expand clozapine access, it also means a transition that could result in confusion among prescribers and patients,” commented Dr Jonathan Meyer of the University of California San Diego, US. [J Clin Psychiatry 2025;86:25ac15898]

“Indefinite and frequent monitoring of absolute neutrophil count [ANC] is not evidence-based and not the standard of care,” highlighted Meyer. Most of the neutropenia occur within the initial 18 weeks of treatment, and after a sharp decline, the risk plateaus after year 2. In early 2025, an expert statement from the European Clozapine Task Force recommended a phased reduction in the frequency of ANC monitoring for patients taking clozapine. Initially, weekly monitoring is recommended for the first 18 weeks, followed by monthly monitoring from 18 to 52 weeks, quarterly monitoring from 52 to 104 weeks, and finally annual monitoring from 104 to 156 weeks if there is no history of neutropenia in the first year of treatment. [Eur Psychiatry 2025;68:e17]

“It is important to consider the risks of using clozapine, but also the risks of not starting or not remaining on clozapine — the only approved drug for treatment-resistant schizophrenia,” emphasized Meyer.