To the Editor

We read the study by Hoertel et al. [1] with great interest. The authors used a Cox’s regression model to evaluate the impact of individuals treated with antidepressants on the outcome following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Of the 7230 patients hospitalized following SARS-CoV-2 infection, 4.8% were treated with antidepressants within the first 48 h of admission.

The analysis suggests a 27–57% risk reduction (HR, 0.56; 95% CI, 0.43–0.73, p < 0.001) of intubation or COVID-19 related death in antidepressant-treated subjects. Although the study’s retrospective nature does not allow for establishing a causal link that will require a randomized controlled trial, this is an important observational study, which illustrates the possibility that antidepressants might have properties that protect against the action of SARS-CoV-2 virus.

There is growing evidence for substantial neurological and psychiatric morbidity following COVID-19 infection, with the greatest risk in patients who had severe COVID-19 [2]. It is of interest that psychotropic compounds commonly used to treat mental disorders exercise a putative preventive effect against the most catastrophic outcomes related to SARS-CoV-2 infection. In complementarity with Hoertel’s explanation, we carried out a literature search of PubMed, Google Scholar, and Scopus by using the name of each drug commonly used in mental health or the class of psychotropic drugs as keywords combined with ‘antiviral’ or ‘SARS’ or ‘COVID-19’. The aim was to identify psychotropic compounds, the level of supporting preclinical or clinical evidence for anti SARS-CoV-2 action, and the putative mechanisms of action. Table 1 reports the emerging evidence for different psychotropics for their anti-SARS CoV-2 action. While the current evidence supports a potential anti SARS-CoV-2 role for several antidepressants including the antipsychotic chlorpromazine, the mood stabilizer lithium, and the anti-dementia drug memantine, the level and strength of evidence remain diverse. The evidence for mood stabilizers, chlorpromazine, and memantine is more speculative at this moment than that for certain antidepressants with substantial clinical, observational, and preclinical data.

Table 1 Psychotropic drugs and their putative anti-COVID-19 properties.

The literature reports an in vitro action of antidepressants against the activity of acid sphingomyelinase [3, 4]. There is also recent observational evidence to support the potential usefulness of functional inhibitors of acid sphingomyelinase, including antidepressants and antipsychotics, among patients hospitalized for severe COVID-19 [5]. In addition, a possible mechanism of action of psychotropic drugs is related to virus cell entry via clathrin-mediated endocytosis. Another potential action of psychotropic drugs is modifying the balance between pro and anti-inflammatory cytokines, which could protect against the most deleterious consequences of an indiscriminate immunological response [6]. One of the advantages of psychotropic drugs is the efficient crossing of the blood-brain barrier and the affinity for synaptic receptors, most of which trigger functions that could interact with the immune system at different levels [6]. Tolerance and safety are vital parameters for drug repurposing to treat or prevent infections with SARS COV-2. Psychotropic medications are widely used in clinical practice with well-known safety and tolerability parameters. Antidepressants, compared to antipsychotics or mood stabilizers, have a favorable safety profile [4] and are better tolerated in older individuals.

In conclusion, the realization that psychotropic compounds have potentially significant antiviral properties in the context of SARS-CoV-2 can improve our understanding of these molecules [7], and also offers a new opportunity for repurposing their role in our pharmacological armamentarium if antiviral characteristics are better characterized in controlled studies. It is premature to launch a meta-analysis or a systematic review because of the number and heterogeneity of clinical studies completed or underway. However, the diversity of the antiviral mechanisms of psychotropic drugs deserves to be studied in a translational way.