Does clozapine increase susceptibility to COVID-19?

The antipsychotic clozapine appears to contribute to increased risk of COVID-19 infection, a study has shown.

Clozapine users had a 76-percent higher risk of contracting COVID-19 compared with individuals receiving other antipsychotics, the investigators noted. “This is consistent with previous research demonstrating that people treated with clozapine have higher rates of infection and pneumonia than those on other antipsychotics and have alterations in both innate and adaptive immunity.” [J Psychiatry Neurosci 2020;45:200061]

The investigators acknowledged, however, that the clozapine-treated patients in the current study tended to come into greater contact with healthcare services, making them more likely to be tested once they developed symptoms. 

“We have tried to adjust for patient contact, but, given the very large association between in-patient status and infection with COVID-19, we cannot confidently exclude the possibility that the association is explained by residual confounding,” they added.

The study used data from South London and Maudsley NHS Foundation Trust (SLAM) clinical records and included 6,309 patients (mean age 46.5 years, 48 percent had obesity) with schizophrenia-spectrum disorders being treated with antipsychotics at the onset of the COVID-19 pandemic in the UK. Ethnicity-wise, 33.2 percent of patients were White, 50.6 percent were Black, and 13.7 percent were Asian or of other ethnic background.

A total of 102 patients tested positive for COVID-19. This group was more likely to be in-patients and had more contact days with the SLAM services. In terms of clozapine use, the proportion of users was twice as high in the COVID-19–infected than in the noninfected group (41 percent vs 20 percent).

Cox proportional hazards analysis of 5,535 individuals with complete data (mean follow-up 78 days; 92 patients were positive for COVID-19) revealed an association between clozapine treatment and COVID-19, with a crude hazard ratio of 2.62 (95 percent confidence interval [CI], 1.73–3.96). This estimate was attenuated to 1.76 (95 percent CI, 1.14–2.72) following adjustments for potential confounders, including body mass index, smoking status, and clinical contact. [Br J Psych 2021;219:368-374]

“The study is based on a relatively small number of cases, and we would not advocate any change in practice based on these findings alone,” the investigators said.

If the association is to be replicated and becomes firmly established, then clinicians will have to carefully weigh the risk of COVID-19 infection against that of psychotic relapse upon discontinuation of clozapine, as the investigators pointed out. “Given that, for many patients, clozapine is the only effective antipsychotic, and with the well-established association between [the drug] and reduced all-cause mortality, these decisions are likely to be finely balanced and must be taken on a case-by-case basis.”

In the meantime, clinicians are recommended to follow consensus guidelines for clozapine treatment during the COVID-19 pandemic. [J Psychiatry Neurosci 2020;45:200061; Br J Psychiatry 2020;doi:10.1192/bjp.2020.92]

“There should also be a focus on ensuring that clozapine-treated patients follow simple hygiene measures that can be taken to reduce the risks of COVID-19 infection, including handwashing, social distancing, and the rigorous use of face masks and other personal protective equipment in clinical settings,” they added.