Effects of Antidepressants on COVID-19 Outcomes: Retrospective Study on Large-Scale Electronic Health Record Data
Authors: Rahman Md Mahmudur , Mahi Atqiya Munawara , Melamed Rachel , Alam Mohammad Arif Ul 
Published: March 2023

Background
Antidepressants exert an anticholinergic effect in varying degrees, and various classes of antidepressants can produce a different effect on immune function. While the early use of antidepressants has a notional effect on COVID-19 outcomes, the relationship between the risk of COVID-19 severity and the use of antidepressants has not been properly investigated previously owing to the high costs involved with clinical trials. Large-scale observational data and recent advancements in statistical analysis provide ample opportunity to virtualize a clinical trial to discover the detrimental effects of the early use of antidepressants.

Objective
We primarily aimed to investigate electronic health records for causal effect estimation and use the data for discovering the causal effects of early antidepressant use on COVID-19 outcomes. As a secondary aim, we developed methods for validating our causal effect estimation pipeline.

Methods
We used the National COVID Cohort Collaborative (N3C), a database aggregating health history for over 12 million people in the United States, including over 5 million with a positive COVID-19 test. We selected 241,952 COVID-19–positive patients (age >13 years) with at least 1 year of medical history. The study included a 18,584-dimensional covariate vector for each person and 16 different antidepressants. We used propensity score weighting based on the logistic regression method to estimate causal effects on the entire data. Then, we used the Node2Vec embedding method to encode SNOMED-CT (Systematized Nomenclature of Medicine-Clinical Terms) medical codes and applied random forest regression to estimate causal effects. We used both methods to estimate causal effects of antidepressants on COVID-19 outcomes. We also selected few negatively effective conditions for COVID-19 outcomes and estimated their effects using our proposed methods to validate their efficacy.

Results
The average treatment effect (ATE) of using any one of the antidepressants was −0.076 (95% CI −0.082 to −0.069; P<.001) with the propensity score weighting method. For the method using SNOMED-CT medical embedding, the ATE of using any one of the antidepressants was −0.423 (95% CI −0.382 to −0.463; P<.001).

Conclusions
We applied multiple causal inference methods with novel application of health embeddings to investigate the effects of antidepressants on COVID-19 outcomes. Additionally, we proposed a novel drug effect analysis–based evaluation technique to justify the efficacy of the proposed method. This study offers causal inference methods on large-scale electronic health record data to discover the effects of common antidepressants on COVID-19 hospitalization or a worse outcome. We found that common antidepressants may increase the risk of COVID-19 complications and uncovered a pattern where certain antidepressants were associated with a lower risk of hospitalization. While discovering the detrimental effects of these drugs on outcomes could guide preventive care, identification of beneficial effects would allow us to propose drug repurposing for COVID-19 treatment.