Atypical Antipsychotics May Dysregulate Immune Response, Increase Risk for COVID-19

person pouring bottle of pills
person pouring bottle of pills
Short- to intermediate-term exposure to atypical antipsychotic medications may dysregulate adaptive immune responses, increasing susceptibility to respiratory infections like COVID-19.

Study data published in Brain, Behavior, & Immunity – Health suggest that short-term exposure to atypical antipsychotic medications may increase risk for coronavirus disease 2019 (COVID-19).

In this preclinical study, mice given short-term treatment with risperidone (RIS) displayed dysregulated innate and adaptive immune responses. Investigators hypothesized that clinically relevant doses of RIS may similarly dysregulate immune response in humans, which may affect susceptibility to respiratory infections, including COVID-19.

This study randomly assigned 8-week-old male mice to receive either low-dose RIS (1 mg/kg) or vehicle (DVEH; 0.1% acetic acid) for 14 days. To assess the impact of RIS on adaptive immunity, all mice were immunized by intramuscular injection with either Pneumovax®23 (PPSV23) or vehicle (VVEH; sterile water) after 5 days of treatment. PPSV23 is a vaccine designed to immunize recipients to pneumococcal disease.

On day 14, after mice were euthanized by CO2 asphyxiation, anti-pneumococcal immunoglobulin G (IgG) antibodies were measured by direct enzyme-linked immunosorbent assay. A one-tailed t-test was used to determine differential capacity for antibody production between mice who received DVEH and PPSV23 (DVEH/VAX) and mice who received RIS and PPSV23 (RIS/VAX).

To assess the impact of RIS on the acute inflammatory response, all mice were given an intraperitoneal injection of either lipopolysaccharide (LPS; 500 ng/kg) or vehicle (LVEH; phosphate buffer solution) after 14 days of treatment, prior to euthanasia. LPS was intended to mount an inflammatory challenge. Two hours post-injection, blood was collected to assess levels of circulating cytokine, chemokine, and other immune factor levels. Change in response to inflammatory challenge was measured by two-tailed t-tests comparing DVEH/LVEH mice with DVEH/LPS mice and RIS/LVEH mice with RIS/LPS mice. For all mice, plasma concentrations of RIS were assessed at the time of necropsy to ensure that RIS had been properly metabolized.

In the adaptive immunity experiment, overall mean anti-pneumococcal antigen IgG response values were significantly greater in mice given DVEH/VAX than in mice given RIS/VAX (P <.05). On the individual level, mice given RIS were significantly less likely (P <.05) to mount an antibody response following PPSV23 compared with mice given DVEH.

In the acute inflammatory challenge study, low-dose treatment with RIS was associated with significant dysregulation of the acute inflammatory response upon challenge with LPS. Only 3 of 24 pathways were completely functional upon challenge, and all respiratory tract infection response pathways were at least partially dysregulated.

Additionally, of 31 measured cytokines, 19 were significantly altered or dysregulated in mice given RIS relative to DVEH after challenge with LPS. Dysregulated cytokines included tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, which are measurable clinical markers in humans.   

These data implicate short-term treatment with RIS in the dysregulation of both innate and adaptive immune response. Mice treated with RIS were less likely to mount an immune response following vaccination and displayed significantly dysregulated immune response pathways. Taken together, these results suggest that atypical antipsychotic use may increase risk for COVID-19. These medications may also increase the risk for severe outcomes once infected.

“[O]ur findings strongly indicate that consideration of [atypical antipsychotic] use should be carefully weighed against the risk of adverse outcomes during infection in both outpatient and inpatient settings,” the investigators concluded.


May M, Slitzky M, Rostama B, Barlow D, Houseknecht KL. Antipsychotic-induced immune dysfunction: a consideration for COVID-19 risk [published online July 23, 2020]. Brain Behav Immun Health. doi: 10.1016/j.bbih.2020.100097