**2. COVID-19 and psychotropic drugs**

Several psychotropic drugs have been associated with antiviral and antitumor properties, suggesting that they may lower the severity of COVID-19 critical illness [16]. For example, imipramine, clomipramine and the phenothiazine class of drugs have demonstrated efficacy against other viruses, including Ebola, Dengue and West Nile [17–20]. In addition, thioridazine, another phenothiazine, was found to slow the progression of lung cancers, probably by enhancing antitumor immunity [21]. Other antipsychotics evidenced some beneficial

effects in patients with glioblastoma and pancreatic cancer, suggesting immunooncological properties [22].

The recently published SARS-CoV-2/host protein–protein interaction and phosphorylation studies demonstrated viral interference with several pathways previously implicated in psychiatric disorders and targeted by psychotropic drugs [23, 24]. For example, upon binding to ACE-2, the SARS-CoV-2 virus ingresses host cells via the endocytic pathway (EP), a vesicular system inhibited by chlorpromazine (CPZ) and linked to schizophrenia and neurodegenerative disorders [25, 26]. Indeed, several antipsychotic drugs were found to interact with both the EP and extracellular vesicles (EVs), demonstrating previously unknown mechanisms of action [27, 28]. Other pathways involved in both the SARS-CoV-2 infection and psychiatric illness include autophagy, redox and calmodulin systems, connecting the virus to neuropathology [23, 29–31].

Several studies have associated NMDARs with sigma-1 nonopioid receptor, a protein hijacked by the SARS-CoV-2 to enable viral entry and replication [24, 32]. Indeed, sigma-1 agonists, such as fluvoxamine, sertraline and the antipsychotic drug, haloperidol inhibit exploitation of sigma-1, dampening viral ingress [33–35]. In addition, fluvoxamine was found to decrease ANG II-induced cardiac hypertrophy, indicating protective effects against both the SARS-CoV-2 infection and its complication [36]. Moreover, ifenprodil, an NMDAR antagonist (and sigma-1 receptor agonist), is currently in phase III clinical trials for COVID-19, linking oxidative stress to the severity of SARS-CoV-2 infection [37] (NCT04382924).

In the immune compartment, both COVID-19 and schizophrenia were associated with dysregulated inflammatory processes and lower levels of regulatory T cells (Tregs), suggesting possible autoimmune pathology [38–40]. In contrast, antipsychotic drugs were found to upregulate Tregs, lowering autoimmune inflammation [39]. Indeed, NMDARs are abundantly expressed not only in the central nervous system (CNS) but also in the immune compartment where they regulate T-cell proliferation in response to antigens. Along these lines, NMDAR antagonists, including antipsychotic drugs upregulate Tregs, enhancing immunological tolerance that in return decreases neuroinflammation [41].

In the following sections, we take a closer look at the SARS-CoV-2 interactome, looking for pathways altered by viral infection, psychiatric disorders and the action mechanism of psychotropic drugs. In other words, learning from the virus to design better psychiatric treatments (**Table 1**).


#### **Table 1.**

*Phenothiazine class of antipsychotic drugs oppose several SARS-CoV-2 actions.*
