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Clinical Context

Persons living with psychiatric disorders have been disproportionately affected by the COVID-19 pandemic. The authors of the current study provide a brief review of what is known and what remains unknown about psychiatric illness and COVID-19.

Adults with psychiatric disorders have a higher rate of mortality with COVID-19, independent of the presence of other chronic medical disease. It does not appear that the use of antipsychotic drugs explains the higher risk for mortality among these patients.

Nonetheless, some research has found lower rates of COVID-19 among adults with major psychiatric disorders. This finding may be because of increased social isolation among these individuals and/or lower rates of COVID-19 testing. In addition, a growing body of literature suggests that the antiviral properties of antipsychotic medications may play a role.

The current study by Nemani and colleagues explores the prevalence of COVID-19 among persons hospitalized for serious psychiatric illness (Defined in this study as schizophrenia, schizoaffective disorder, bipolar I disorder, or depression with psychotic features) as well as how the use of psychotropic medications may modify the risk for COVID-19.

Study Synopsis and Perspective

Different psychotropic medications are associated with different risks for COVID-19 in hospitalized patients with serious mental illness, a new study suggests.

Investigators found that second-generation antipsychotics were associated with a 48% lower risk for COVID-19 whereas valproic acid was associated with a 39% increased risk for 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, New York, wrote.

The study was published May 2 in JAMA Network Open.^[1]

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 1958 adults who were continuously hospitalized with serious mental illness from March 8 to July 1, 2020. The mean age was 51.4 ± 14.3 years, and 1442 (73.6%) were men.

A total of 969 patients (49.5%) had laboratory-confirmed COVID-19 while hospitalized, and 38 (3.9%) died: a mortality rate 4 times higher than estimates from the general population in New York during the same time frame, the researchers noted.

"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 wrote.

The use of second-generation antipsychotic medications, as a class, was associated with a lower likelihood of COVID-19 (odds ratio [OR] 0.62 [95% CI: 0.45, 0.86]) whereas 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 for infection (OR 0.59 [95% CI: 0.41, 0.84]), and use of valproic acid was associated with increased odds for infection (OR 1.39 [95% CI: 1.1, 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 said.

The use of clozapine was associated with reduced odds for COVID-19--related death (unadjusted OR 0.25 [95% CI: 0.1, 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 for COVID-19 infection or death in the present study. In fact, unadjusted estimates suggested a significant protective association," the investigators wrote.

Still, they noted, data on clozapine and COVID-19 have been mixed.

Two prior studies of health record data showed an increased risk for COVID-19 associated with clozapine treatment whereas a study that was limited to inpatients found a lower risk for infection and a lower risk for symptomatic disease in association with clozapine use.

The researchers also found a lower mortality risk in patients taking antidepressants; there were no COVID-19--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 for adverse outcomes associated with antidepressant use, the researchers noted.

In an accompanying commentary,^[2] Benedetta Vai, PhD, and Mario Gennaro Mazza, MD, with IRCCS San Raffaele Scientific Institute, Milan, Italy, pointed 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 noted further research is needed to determine whether the protective role of second-generation antipsychotics on risk for COVID-19 is mediated by an immune effect or by the direct antiviral properties of these molecules.

The study had no specific funding. Nemani, Vai, and Mazza have disclosed no relevant financial relationships.

Clinical Implications

• Adults with psychiatric disorders have a higher rate of mortality with COVID-19, independent of the presence of other chronic medical disease. It does not appear that the use of antipsychotic drugs explains the higher risk for mortality among these patients. Some research has found lower rates of COVID-19 among adults with serious psychiatric disorders.
• In the current study by Nemani and colleagues identifies trends that merit further investigation regarding psychotropic medications and the risk for COVID-19.
• Implications for the healthcare team: A team-based approach in the management of adults with psychiatric disorders is vital to ensure adherence to prescribed psychotropic medication regimens which may modify the risk for COVID-19.

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