Investigators found that second-generation antipsychotics were associated with a 48% lower risk of COVID-19, while valproic acid was associated with a 39% increased risk of the disease.
“Exposures to several psychotropic medications were associated with risk of COVID-19 infection among inpatients with serious mental illness; decreased risk was observed with the use of second generation antipsychotics, with paliperidone use associated with the largest effect size. Valproic acid use was associated with an increased risk of infection,” the investigators, led by Katlyn Nemani, MD, at NYU Langone Medical Center, New York, write.
NYU Grossman School of Medicine
Dr. Katlyn Nemani
The study was published online in JAMA Network Open.
Vulnerable population
Patients with serious mental illness are particularly vulnerable to COVID-19. Several psychotropic medications have been identified as potential therapeutic agents to prevent or treat COVID-19, but they have not been systematically studied in this patient population.
The researchers analyzed data from 1,958 adults who were continuously hospitalized with serious mental illness from March 8 to July 1, 2020. The mean age was 51.4 years, and 1,442 (74%) were men.
A total of 969 patients (49.5%) had laboratory-confirmed COVID-19 while hospitalized, and 38 (3.9%) died – a mortality rate four times higher than estimates from the general population in New York during the same time frame, the researchers note.
“This finding is consistent with prior studies that have found increased rates of infection in congregate settings and increased mortality after infection among patients with serious mental illness,” the investigators write.
The use of second-generation antipsychotic medications, as a class, was associated with a lower likelihood of COVID-19 (odds ratio, 0.62; 95% confidence interval, 0.45-0.86), while the use of mood stabilizers was associated with increased likelihood of infection (OR, 1.23; 95% CI, 1.03-1.47).
In a multivariable model of individual medications, use of the long-acting atypical antipsychotic paliperidone was associated with a lower odds of infection (OR, 0.59; 95% CI, 0.41-0.84), and use of valproic acid was associated with increased odds of infection (OR, 1.39; 95% CI, 1.10-1.76).
Valproic acid downregulates angiotensin-converting enzyme 2 in endothelial cells, which may impair immune function and contribute to poor outcomes for patients with COVID-19, the researchers say.
The use of clozapine was associated with reduced odds of COVID-related death (unadjusted OR, 0.25; 95% CI, 0.10-0.62; fully adjusted OR, 0.43; 95% CI, 0.17-1.12).
“Although there have been concerns about clozapine use during the pandemic as a risk factor for pneumonia and potential toxic effects during acute infection, clozapine use was not associated with an increased risk of COVID-19 infection or death in the present study. In fact, unadjusted estimates suggested a significant protective association,” the investigators write.
However, they note, data on clozapine and COVID-19 have been mixed.
Two prior studies of health record data showed an increased risk of COVID-19 associated with clozapine treatment, while a study that was limited to inpatients found a lower risk of infection and a lower risk of symptomatic disease in association with clozapine use.
The researchers also found a lower mortality risk in patients taking antidepressants; there were no COVID-related deaths among patients taking escitalopram, venlafaxine, bupropion, or fluvoxamine.
Although the association was not statistically significant, this observation is in line with larger studies that showed reduced risk of adverse outcomes associated with antidepressant use, the researchers note.
A matter of debate
In an accompanying commentary, Benedetta Vai, PhD, and Mario Gennaro Mazza, MD, with IRCCS San Raffaele Scientific Institute, Milan, point out that the link between psychopharmacologic compounds, in particular antipsychotics, and severe COVID-19 outcomes remains “a matter of debate, with inconsistent findings between studies.”
They note further research is needed to determine whether the protective role of second-generation antipsychotics on risk of COVID-19 is mediated by an immune effect or by the direct antiviral properties of these molecules.
The study had no specific funding. Dr. Nemani, Dr. Vai, and Dr. Mazza have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.