With great interest we read the article by Rosolen et al. in EAPCN, which describes that in an Italian case-control study, people who had contracted the SARS-COV-2 virus were more likely to be prescribed antidepressants (ADs) afterwards [1]. This was particularly the case in unvaccinated and elderly people, as well as in patients who had suffered a more severe COVID-19 [1]. These data support the finding that the COVID pandemic, but especially COVID-19 (i.e. the disease), promotes the development of anxiety and depression [2], provided that ADs are to be understood as a surrogate marker. Comparable data can also be found for other substance classes such as opioids and sleeping pills, which in turn could mean the (COVID-19) disease-related induction of sleep disorders and pain syndromes [3]. However, there is insufficient mention of the fact that there are hints that the depression-related risk appears to normalize again over time, whereas an increased risk of inducing psychotic disorders and dementia after COVID seems to remain [4].

Another point that needs to be mentioned in our opinion is that there is evidence that ADs can also be helpful in preventing severe COVID-19 and alleviating Long COVID symptoms such as depression, anxiety, cognitive dysfunction (“brain fog”) and fatigue [5, 6]. Specifically, for fluvoxamine there are currently at least 8 positive meta-analyses, 7 placebo-controlled randomized and 5 prospective studies that supported that this AD, when used for 10 to 14 days in addition to standard therapy for mild to moderate COVID-19, resulted in significantly fewer severe courses and deaths than placebo or standard therapy alone, with good tolerability [5]. Whether this applies to the entire class of AD substances warrants future well-controlled clinical studies on this issue. At least four large retrospective studies (each with more than 20,000 hospitalized patients) now indicate this [5]. Initial small clinical trials show relief of at least fatigue, cognitive dysfunctions and other psychiatric Long COVID symptoms with various ADs [5]. Not only fluvoxamine [7] but also the entire AD substance class are thought to have a pronounced protective (anti-inflammatory) effect against oxidative stress-mediated destruction in affected tissues that occurs following an excessive and prolonged inflammatory response („hyperinflammation“) to SARS-COV-2 virus entry into cells [5]. Furthermore, antiviral properties have been described for many ADs, including against SARS-COV-2 infections [5].

In addition to organic sequelae (e.g. pulmonary fibrosis, heart disease, strokes, kidney damage), the persistence of SARS-COV-2 viruses in immune-privileged regions of the body (e.g. eye, brain, testis), reactivation of other latent viruses, autoimmunity or misdirected immune responses to SARS-COV-2, persistent hyperinflammation with subsequent mitochondrial dysfunction, dysbiosis in the respiratory and gastrointestinal microbiome as well as protracted sickness behavior are discussed as biological mechanisms for Long COVID [5, 8]. Much of the neuropsychiatric symptoms of Long COVID, including depression, anxiety, fatigue and cognitive dysfunction, may also be promoted by premature (and hopefully reversible) “aging” of midbrain dopaminergic neurons [5, 8]. In line with (or in addition to) their general antidepressant, anxiolytic, anti-inflammatory and antiviral properties, ADs could be beneficial for Long COVID symptoms, as more than 95% of the 5-hydroxytryptamine (serotonin) in the body is localized in the gastrointestinal tract and SARS-COV-2-related dysbiosis of the microbiome there could promote and then maintain the development of a serotonin deficit, as recently found in the serum of affected individuals [6, 7]. This serotonin deficit could then be compensated by the serotonergic properties of ADs [6, 7] (which most ADs have, including ketamine and bupropion [5, 9]). In the context of the bio-psycho-social explanatory approach, it is becoming increasingly clear that psychosomatic and psychosocial factors can play a decisive symptom-maintaining role [5]. Good medical education about the potential adverse effects of AD, taking into account their placebo and nocebo properties [10], can also improve adherence and effectiveness of ADs in the COVID-19 and post-COVID population [5].