Clozapine is considered the drug of choice for treatment-resistant schizophrenia in guidelines globally, but it remains significantly underutilized. This is largely due to its range of side effects, particularly its increased infection risk which prompted the US Food and Drug Administration (FDA) to mandate regular blood testing to monitor neutrophil counts.
The COVID-19 pandemic raised new concerns about the care of clozapine-treated patients, leading clinicians and patients to urge the FDA to relax prescription requirements for the drug under the Risk Evaluation and Mitigation Strategy (REMS) program.
As the FDA prepares for a public hearing in November on proposed adjustments to the drug’s REMS criteria, a growing body of research is challenging the previous understanding of clozapine and infection risk.
Clarifying the Risk
Research on the link between clozapine and respiratory infections has produced conflicting results. Some studies indicate little to no increased risk for mild COVID-19 and other respiratory illnesses, while others have shown a higher likelihood of severe infection.
A recent nationwide Danish registry study of respiratory infections in people with a schizophrenia spectrum disorder could bring some clarity, Maxime Taquet, MD, a clinical lecturer at the University of Oxford, Warneford Hospital, Oxford, England, told this news organization.
By tracking periods when patients were on and off clozapine and other antipsychotics, the study offers more precise risk estimates, distinguishing the risks associated with the antipsychotic from those related to underlying schizophrenia, said Dr. Taquet, who authored an accompanying editorial on the study.
“It’s very important to try to disentangle the effects of schizophrenia, its severity, from the medication,” Dr. Taquet said. “I think that the Danish study is the first to try and really do that with as much precision as possible.”
After adjusting for key confounders including economic status and COVID-19 vaccination status, the researchers found that individuals taking antipsychotics had lower odds of testing positive for SARS-CoV-2 and similar rates of filled anti-infective prescriptions as those not taking the drugs.
Although antipsychotic use was not linked to higher rates of mild infection, it was linked to an increased risk for COVID-19 hospitalization in individuals older than 70 years, as well as hospitalization and death from other respiratory infections, mainly pneumonia, in those older than 40 years.
Notably, there was no excess risk for any outcome with clozapine vs other antipsychotics.
Strong Link to Pneumonia Risk
Results from a longitudinal Finnish study, just published in The American Journal of Psychiatry, also show an increased risk for severe outcomes from ileus and pneumonia among more than 2600 patients with schizophrenia taking clozapine.
Twenty years after initiating clozapine, the cumulative incidence estimate for ileus was 5.3% — more than sixfold higher than previously reported. The incidence of pneumonia was also high, at 29.5%.
Both illnesses were significantly associated with mortality, with odds ratios of 4.5 and 2.8, respectively.
These findings align with previous pharmacovigilance studies, with reported mortality rates for gastrointestinal hypomotility and pneumonia that were 4-10 times higher than those for agranulocytosis, the researchers said.
The study “really adds to a growing body of research suggesting a connection between clozapine use and a higher risk of developing pneumonia,” Robert O. Cotes, MD, a professor of psychiatry and behavioral sciences at Emory University, Atlanta, who specializes in the use of clozapine, told this news organization.
“Additionally, when people on clozapine do contract pneumonia, there’s concern the condition may be more dangerous,” he added.