COVID-19 mortality among selective serotonin reuptake inhibitor users-results from a nationwide cohort

Abstract

Objective: To examine differences in mortality and/or severe acute respiratory syndrome between selective serotonin reuptake inhibitor- (SSRI) users and non-SSRI users up to 60 days after a positive SARS-CoV-2 real-time reverse transcription PCR test.

Methods: Retrospective cohort study including all Danish residents above the age of eighteen with a positive SARS-CoV-2 PCR test from 26 February, 2020 to 5 October, 2021. The follow-up period was 60 days. The primary outcome was all-cause mortality, and the secondary outcome was severe acute respiratory syndrome. Exposure of interest was SSRI use. Differences between SSRI users and non-users were examined with Cox regression.

Results: Altogether, 286,447 SARS-CoV-2 positive individuals were identified, and 7113 met the criteria for SSRI use. SSRI users had a mean age of 50.4 years, and 34% were males. Non-SSRI users had a mean age of 41.4 years, and 50% were males. Similar vaccination frequency was observed among the two groups. Sertraline was the most commonly used SSRI, followed by citalopram and escitalopram. We found 255 deaths among SSRI users (3.6%) and 2872 deaths among non-SSRI users (1.0%). SSRI use was significantly associated with increased mortality, with a hazard ratio of 1.32 (95% confidence interval, 1.16 -1.50; p 0.015), even when adjusting for age, sex, vaccination status, and comorbidities.

Discussion: We found significantly higher mortality when comparing SSRI users to non-SSRI users within 60 days after a positive SARS-CoV-2 PCR test. Even when considering possible residual confounding, a positive effect of SSRI intake seems highly unlikely. Our study therefore speaks against the hypothesis of repurposing SSRI drugs for COVID-19 treatment.

Keywords: COVID-19; Drug repurposing; SARS-CoV-2; SSRI; Selective serotonin receptor inhibitors.

Fig. 1

Study design and study population. All data were obtained from Danish National Administrative registries available through Statistics Denmark. Selective serotonin reuptake inhibitor (SSRI) intake was defined as pharmacy pickups with sufficient daily dispensing to cover a period of at least two days before and 14 days after a positive SARS-CoV-2 PCR test. The total number of tests included subjects aged <18 years old. According to Statistics Denmark, the Danish population was 5.82 million at the beginning of the study period and 5.85 million at the end of the study period. Of these individuals, 4.67 million were ≥18 years old. Study participants could only enter the study once, and only the first positive test was used.

Fig. 2

60-day mortality of selective serotonin reuptake inhibitor (SSRI) users vs. non-SSRI users. Sixty-day mortality was analysed using the Kaplan–Meier method. Exposed = SSRI users; not exposed = non-SSRI users. Day zero was the date of the positive SARS-CoV-2 PCR test. SSRI use is defined as pharmacy pickups with sufficient daily dispensing to cover a period of at least two days prior to and 14 days after a positive SARS-CoV-2 PCR. The starting time for risk-time calculation was defined as the time of the positive PCR test. Data were obtained from Danish National Administrative registries available through Statistics Denmark; see the method section for details.

Fig. 3

Multivariable analysis including comorbidities and socio-economic variables. HR, hazard ratio; SSRI, selective serotonin reuptake inhibitor. CI₉₅, 95% confidence interval; s, male sex. The endpoint was all-cause mortality within 60 days after a positive SARS-CoV-2 PCR test. SSRI intake was defined as pharmacy pickups with sufficient daily dispensing to cover a period of at least two days prior to and 14 days after a positive SARS-CoV-2 PCR test. Hazard ratios were estimated with Cox regressions. For ethnicity, “Danish” serves as reference. For income, “lowest quartile” serves as reference. For education, “basic school” serves as reference. In case of missingness, cases were omitted from the analysis. Data were obtained from Danish National Administrative registries available through Statistics Denmark; see the method section for definitions and details.