Neuropsychiatric Drugs Against COVID-19: What is the Clinical Evidence?

Abstract

Since the beginning of the coronavirus disease (COVID)-19 pandemic, the need for effective treatments for COVID-19 led to the idea of “repurposing” drugs for antiviral treatment. Several antipsychotics and antidepressants have been tested for in vitro activity against the severe acute respiratory syndrome coronavirus 2. Chlorpromazine, other phenothiazine antipsychotics, and the antidepressant fluoxetine were found to be rather potent in these studies. However, whether effective plasma concentrations can be obtained with clinically accepted doses of these drugs is not clear. Data of COVID-19 patients are not yet available but several clinical studies are currently underway.

The specific serotonin reuptake inhibitor fluvoxamine is a potent Sigma-1 receptor agonist and reduces inflammation in animal models of cytokine-stress. Accordingly, fluvoxamine treatment was superior to placebo in reducing impaired respiratory function and other symptoms of inflammation in COVID-19 patients in a placebo-controlled clinical study and another open clinical trial. The beneficial effects of fluvoxamine on the course of COVID-19 were recently confirmed in a large placebo-controlled double-blind trial with several hundred patients.

Inflammation represents a major risk factor for many psychiatric disorders which explains the high susceptibilitiy of COVID-19 patients for psychiatric diseases. Many antidepressants and antipsychotics possess anti-inflammatory properties independent of sigma-1 activity which might be important to reduce psychiatric symptoms of COVID-19 patients and to improve respiratory dysfunction and other consequences of inflammation. This might explain the rather unspecific benefit which has been reported for several cohorts of COVID-19 patients treated with different psychotropic drugs.

 

MissingLinkText

Key words

COVID-19 - antipsychotics - antidepressant drugs - anti-viral and anti-inflammatory effects

Introduction

Repurposing licensed drugs to treat COVID-19

The World Health Organization (WHO) declared COVID-19 a pandemic by March 2020 after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in China by the end of 2019 and until now has led to massive challenges for people and healthcare systems worldwide.

The fast outbreak of the COVID-19 pandemic required a rapid development of effective drugs to prevent the infection, ideally to reduce the virus load and even more important to treat the severe consequences of the virus-induced inflammation. While the fast development of several effective vaccinations represents a remarkable story of success, research has been less successful in developing drugs against COVID-19. The mainly used drugs to treat COVID-19 are still corticosteroids like dexamethasone or budesonide [1].

To save time and money especially in the preclinical phases of drug development, many known drugs were tested for “anti-COVID” activity. This approach to “repurpose” old drugs has been quite successful [2] [3] [4] and many substances with “anti-COVID” activity in vitro could be identified [4] [5]. However, there is only limited clinical data, as only very few of those drugs have been tested yet in COVID-19 patients.

During the course of these studies, many antidepressants and antipsychotic drugs were reported to be active against the SARS-CoV-2 virus in vitro confirming older studies indicating in vitro activity against several other viruses [5] [6] [7] [8] [9] [10]. In some cases, the results appeared quite promising and led to further studies about their possible clinical use to treat COVID-19. Accordingly, we addressed this point in the present manuscript by reviewing specifically all psychotropic drugs for which at least some initial clinical data in patients has been published.

 

MissingLinkText

 

MissingLinkText

Chlorpromazine and other antipsychotics

Antiviral activities of chlorpromazine and other phenothiazine antipsychotics against various coronavirus species are known for many years and have been confirmed for SARS-CoV-2. But since the effective concentrations are rather high (between 5 and 10 μmol/L), the effect was not considered relevant for a possible therapeutic application [6] [8].

The possible clinical use of chlorpromazine as an antiviral drug was reconsidered following the report by Plaze et al. [11] [12] of a very low prevalence of COVID-19 infections in psychiatric inpatients relative to the clinical staff which was explained by the authors as a consequence of possible antiviral effects of the psychiatric treatment. Since most of the patients received phenothiazine antipsychotics as part of their therapy, the authors speculated about a protective effect of these drugs due to their antiviral activity against SARS-CoV-2 [12]. However, their potency as antiviral drugs was rather low. Nevertheless, the concept of repurposing chlorpromazine or other antipsychotics to treat COVID-19 was seen rather enthusiastically [13].

Based on these in vitro findings, two clinical studies about the efficacy of chlorpromazine for the treatment of COVID-19 have already been approved several months ago but apparently have not yet started to recruit ([Table 1]). Other clinical data is not available except for some results from a large observational study in Paris [14]. In this study, the outcome (death) was not different for the 55 COVID-19 patients treated with chlorpromazine (on the average 71 mg/day for 14 days) when compared to a matched control group of COVID-19 patients without chlorpromazine treatment [15]. Furthermore, specific concern was raised in respect to the well-known side effects of chlorpromazine and the rather high concentrations needed for antiviral effects as outlined by Girgis and Lieberman [16]. Therapeutic plasma levels of chlorpromazine range up to about 1 μmol/l and may overlap with the critical or already toxic plasma levels which start around 2–3 μmol/l [17].

Table 1 The efficacy of antipsychotics and antidepressants for the treatment of COVID-19.

Title	Design	Intervention	Location	Status
Repurposing of Chlorpromazine in COVID-19 Treatment (reCoVery)	open	Chlorpromazine (CPZ) Combination Product: Standard of Care (SOC)	Centre Hospitalier St Anne Paris, France	Not yet recruiting
Administration of Chlorpromazine as a Treatment for COVID-19	open	Chlorpromazine	Cairo University Cairo, Egypt	Not yet recruiting
Fluoxetine to Reduce Intubation and Death After COVID19 Infection	open	Fluoxetine	University of Toledo Health Science Campus Toledo (USA)	Recruiting
TDCS in Pediatric and Teenage Patients With Major Depressive Disorder During COVID-19 Pandemic	double-blind	Transcranial Direct Current Stimulation Fluoxetine	Mexico	Recruiting
Fluvoxamine for Early Treatment of COVID-19 (Stop COVID 2)	double-blind	Fluvoxamine Placebo	Washington University School of Medicine. Chicago, USA	Active, not recruiting
Fluvoxamine Administration in Moderate SARS-CoV-2 (COVID-19) Infected Patients	double-blind	Placebo Fluvoxamine	Budapest, Hungary,	Recruiting
ACTIV-6: COVID-19 Study of Repurposed Medications	double-blind	Ivermectin Fluvoxamine Fluticasone Placebo	USA	Recruiting
Outpatient Treatment of SARS-CoV-2 With Ivermectin, Fluvoxamine, and Metformin (COVID-19)	double-blind	Metformin Placebo Fluvoxamine Ivermectin	University of Minnesota Minneapolis, USA	Recruiting
Repurposed Approved and Under Development Therapies for Patients With Early-Onset COVID-19 and Mild Symptoms	double-blind	Fluvoxamine Doxazosin Ivermectin Placebo Peginterferon Lambda-1a Peginterferon Beta-1A	Brazil	Recruiting
Valproate Alone or in Combination With Quetiapine for Severe COVID-19 Pneumonia With Agitated Delirium	double-blind	Valproate Quetiapine Standard of Care	University of Miami Miami, USA	Not yet recruiting
Cannabidiol for COVID-19 patients With Mild to Moderate Symptoms (CANDIDATE)	double-blind	Cannabidiol Placebo	University of Sao Paulo Sao Paulo, Brazil	Active, not recruiting
Cannabidiol Treatment for Severe and Critical Coronavirus (COVID-19) Pulmonary Infection	open	Cannabidiol 150 mg twice daily during 14 days	Rabin Medical Center	Recruiting
Cannabidiol in Patients With COVID-19 and Cardiovascular Disease or Risk Factors	double-blind	Cannabidiol Placebo	USA Sponsor: Cardiol Therapeutics Inc.	Recruiting
Synthetic CBD as a Therapy for COVID-19	double-blind	Cannabidiol Placebo	Sheba Medical Center Tel-Hashomer, Israel	Not yet recruiting

An overview of the approved clinical studies on psychotropic drugs and/or cannabis in Covid-19 patients and their current status. Data are from the US government ClinicalTrials.gov home page by July 30, 2021 [91] [92].

Similar to chlorpromazine, several older antipsychotics have in vitro activity against SARS-CoV-2 but offer no advantage while the second-generation antipsychotics (SGA) are generally much less active with the possible exception of lurasidone [18]. Nevertheless, clinical data is still missing. Haloperidol has been suggested as a possible treatment against COVID-19 but was not effective to prevent death at an average daily dose of 4.5 mg per day in an observational study [19].

On the other hand, a retrospective observational study [20] reported a substantially better outcome of COVID-19 in schizophrenic patients treated with long-acting antipsychotics relative to a control group. Outcome criteria included infection rates, hospitalization rates, ICU admission, and deaths. The antipsychotics aripiprazole and risperidone/paliperidone which made up about 90% of the antipsychotics used in this study showed well-defined anti-inflammatory properties [21]. Other clinical data about the possible therapeutic effects of SGA against COVID-19 have not yet been published. The use of clozapine in COVID-19 patients is not recommended because of its side effects [22]. For the treatment of therapy-resistant schizophrenic symptoms in COVID-19 patients, ursodeoxycholic acid has been proposed as an option but clinical data is still missing [23].

 

MissingLinkText

Antidepressant drugs

Fluoxetine

Antiviral properties in vitro have been known for many but not all antidepressant drugs in the past years and could be confirmed in many cases for SARS-CoV-2 with effective concentrations in the micromolar range [4] [5] [9]. Fluoxetine turned out to be one of the more potent molecules but its half-maximal inhibitory concentration was never lower than about 1 to 2 μmol/L. As lipophilic molecules with a cationic structure (secondary or tertiary amine), these compounds are easily taken up into acidic cell organelles (e.g. lysosomes) (lysosomotropic properties). Once inside the lysosome, they are trapped and can interfere with the release of the virus from the lysosome probably by reducing the concentration of ceramide [24] [25].

For some antidepressants, antiviral properties could be linked to the enzyme acid sphingomyelinase (ASM) which is widely expressed in lysosomes [26]. ASM releases ceramide from sphingomyelin. Its inhibition by fluoxetine and a few other antidepressants including amitriptyline has been shown to reduce ceramide levels in the brain causing antidepressant-like effects at the behavior and biochemical level [26]. Because of the important role of ceramide in the processing of different virus species in the lysosome the antivirus activity of fluoxetine has been explained by its inhibitory effect on ASM and the reduction of ceramide [27] [28] [29]. The antiviral activity of fluoxetine has recently been shown to be additive to the antiviral effects of the RNA-dependent RMA polymerase inhibitor remdesivir [30].

While these data appear quite interesting it should be realized that fluoxetine was always active in the low micromolar range only with IC50 values at best around 1 μmol/l [28]. Considering the recommended therapeutic plasma levels for the treatment of depression (about 0.5 to 1.0 μmol/l) [17] further studies are needed to show if these concentrations are sufficient to achieve antiviral effects in patients. One double-blind study examining the effects of fluoxetine on COVID-19 patients is currently in progress using time of intubation and/or death as endpoints ([Table 1]). Other clinical data about the use of fluoxetine to treat COVID-19 patients has not yet been published except for an observational study in France. Hoertel et al. [14] reported that the concomitant use of fluoxetine in COVID-19 patients was associated with a reduced risk of death or intubation. Still, similar effects were reported in the same study for other SSRIs not showing specific antiviral properties and also for many other antidepressant drugs independent of inhibitory effects on ASM [14]. On the other hand, a recent analysis of the same data set reported a similarly reduced risk of death or intubation for 15 different drugs with inhibitory activity against ASM [31]. Besides fluoxetine, several other antidepressants, but also some antipsychotics, and cardiovascular drugs were included.

 

MissingLinkText

Fluvoxamine and the relevance of Sigma-1 binding sites

Sigma-1 binding sites or receptors are chaperone proteins mainly at the level of the endoplasmatic reticulum (ER) [32] [33] and are involved in the regulation of many cellular functions especially in the brain. Many antipsychotic and antidepressant drugs are potent ligands for sigma-1 sites in addition to their main mechanism of action, but whether this additional property contributes significantly to their pharmacological or therapeutical effects is still a matter of dispute.

During the search for targets of possible anti-COVID drugs, sigma-1 receptors were identified as functional host-dependency factors for SARS-CoV-2 and were initially suggested as a target for drugs to inhibit SARS-CoV-2 replication [34]. Knocking down sigma-1 sites or treatment with several antipsychotics as sigma-1 antagonists caused a reduction of SARS-CoV-2 replication [32]. However, their binding affinity for sigma-1 sites did not correlate with their potency as inhibitors of virus replication and their potency probably was too low to suggest therapeutic usefulness at the recommended dose ranges of those drugs [32].

On the other hand, findings that sigma-1 receptors play a role in the regulation of the massive inflammation and cytokine storm following sepsis are another link suggesting beneficial effects of fluvoxamine in COVID-19 patients [35]. Knocking down sigma-1 sites enhances the release of proinflammatory cytokines [35] and increases depressive-like behavior [36]. On the other hand, Sigma-1 agonists like fluvoxamine and many other antidepressants have been shown to reduce ER stress in several preclinical models of sepsis and inflammation [35] which mirror the massive inflammation and the cytokine storm following SARS-CoV-2 infections [35] [37]. Fluvoxamine also shows specific anti-inflammatory effects in different cell models with relevance for the cytokine activation induced by SARS-CoV-2 [32] [35] [37]. Most importantly, contrary to chlorpromazine and other antipsychotics the therapeutic plasma levels of fluvoxamine are sufficient for similar effects in patients, as a daily fluvoxamine dose of 300 mg leads to complete occupation of sigma-1 sites in the human brain [38].

The hypothesis that the sigma-1 agonist fluvoxamine might be beneficial during the course of the massive inflammation following SARS-CoV-2 infections was confirmed in a double-blind placebo-controlled study by Lenze et al. [39]. Fluvoxamine was given for 15 days at a daily dose of 300 mg, the maximum therapeutic dose. One hundred fifty-two COVID-19 patients with the severe acute respiratory syndrome were included. The primary outcome was clinical deterioration within the 15 days of randomization defined by meeting both criteria of (1) shortness of breath or hospitalization for shortness of breath or pneumonia and (2) oxygen saturation less than 92% on room air or need for supplemental oxygen to achieve oxygen saturation of 92% or greater. Clinical deterioration occurred in none of the 80 patients in the fluvoxamine group but in 6 of the 72 patients in the placebo group. The difference was highly significant. This is the first controlled study about the successful use of a psychotropic drug to treat COVID-19 patients. These findings were recently confirmed in a prospective open exploratory study where 50 COVID-19 patients treated with fluvoxamine 100 mg daily for 15 days showed a much better outcome than 35 control patients at the same clinic who received no fluvoxamine treatment [40]. A very recent well-designed placebo-controlled double-blind study in about 1500 COVID-19 patients confirmed the beneficial effects of fluvoxamine again using the need for hospitalization or emergency care as the primary outcome criterium [41]. Taken together, there is substantial evidence for the possible usefulness of fluvoxamine in COVID-19 treatment. Several further prospective studies with fluvoxamine are currently underway intended to replicate these results ([Table 1]).

The concept to reduce the inflammation response in COVID-19 patients [37] by sigma-1 receptors ligands is gaining more and more attention. Another example of this concept is the old antihistaminic drug hydroxyzine which is still used in many European countries not only as an antihistaminic but also as an anxiolytic sedative alternatively to benzodiazepines. Together with some other H₁-antihistaminic drugs, hydroxyzine has been shown to exhibit moderate antiviral properties in vitro but with potencies too low to suggest a therapeutic potential to treat COVID-19 patients [42]. This is in contrast to a recent observational study in France [43] in which 140 patients treated with hydroxyzine showed a significantly lower death rate relative to a control group without hydroxyzine treatment (10.9 vs 16.6%). Moreover, the patients treated with hydroxyzine showed a significantly larger reduction of several inflammation markers than the control group [43]. Hydroxyzine has a moderate affinity for sigma-1 receptors [42] [44] with IC50 concentrations of about 200 nmol/mL which is probably too low for relevant effects mediated by sigma-1 sites under therapeutic conditions. However, its in vivo interaction with the sigma-1 receptor requires substantially lower doses than one would expect from the in vitro binding affinity. This is probably caused by a metabolite with much higher in vivo activity [44] which would suggest sigma-1 sites as possible targets of hydroxyzine.

A possible protective role of sigma-1 sites for the clinical course of COVID-19 is also suggested by the genetic findings of Lehrer and Rheinstein [45]. Using a UK Biobank cohort the authors investigated the sigma-1 locus on chromosome 9p13.3 in a cohort of COVID-19 patients. The longer alleles are associated with loss of function mutations. Homozygosity of the rs 17775810 minor allele phenotype was strongly associated with the survival of the patients. This was not seen for the patients heterozygotic for the minor allele or homozygotic for the longer alleles.

 

MissingLinkText

 

MissingLinkText

Other neuropsychiatric drugs

Within the large screening programs initiated at the beginning of the COVID-19

pandemic many other psychotropic drugs have been identified with antiviral activity in vitro (inhibition of the cellular uptake of SARS-CoV-2 or its replication), but in most cases, the concentrations needed for the antiviral effects were too high for considering a possible therapeutic effect [5] [7] [8] [24]. Therefore, only a few other psychotropic drugs have been investigated in COVID-19 patients.

Lithium

Antiviral effects of lithium against several classes of viruses including some coronavirus species are known for several years but require rather high concentrations in vitro [46]. Specific effects on SARS-CoV-2 have not yet been reported. Spuch et al., [47] reported of 6 patients who possibly responded to lithium during COVID-19 and proposed lithium as a possible candidate for COVID-19 treatment. A similar case report was published recently by Sönmez and Hocaogu [48]. However, other data except these 7 case reports have not yet been published.

Moreover, there is some concern about the use of lithium in COVID-19 patients because of its significant side effects and toxicity [10] [46]

 

MissingLinkText

Memantine and amantadine

Amantadine has been introduced many years ago as an antiviral drug to treat influenza A2 but has not been widely used. Besides the antiviral activity, it also possesses a broad spectrum of pharmacological properties [49] including anti-inflammatory effects probably related to its activity as a sigma-1 receptor agonist [49]. The structurally related compound memantine is predominantly an NMDA-receptor antagonist and is used clinically as an antidementia drug [50]. Both compounds show in vitro activity against SARS-CoV-2 [51] and have anti-inflammatory properties [52]. A few case reports suggest a possible beneficial effect of amantadine on the clinical course of COVID-19 [53]. An observational study using a national Korean database found no effect of memantine on the course of COVID-19 disease [54]. Further clinical data for either drug in COVID-19 patients is not available.

 

MissingLinkText

Cannabis

Cannabis and/or cannabidiol show several properties making it a potential candidate

for the treatment of COVID-19 [55]. Cannabis and cannabidiol possess rather potent antiviral activity against SARS-CoV-2 in vitro with IC50 values around 1–2 μmol/L [56] [57] [58] and also potent anti-inflammatory properties [56]. Cannabis users seem to have a lower risk for COVID-19 relative to non-users [58]. Thus, several authors proposed cannabis and/or cannabidiol as a candidate for COVID-19 treatment [55] [59] as an antiviral drug but also against different psychiatric symptoms like depression, anxiety, or psychosis related to a SARS-CoV-2 infection [55] [59]. Still, clinical data about the possible use of cannabis and/or cannabidiol to treat COVID-19 patients is not available. However, several studies have been registered so far to investigate the possible effects of cannabidiol on inflammation during the course of COVID-19 ([Table 1]).

 

MissingLinkText

 

MissingLinkText

Psychotropic drugs as multifactorial protection

Contrary to the concept of specific pharmacological mechanisms explaining the protective effects of individual psychotropic drugs against COVID-19 (see above) several researchers have speculated about a common rather non-specific effect of many different psychotropic drugs against COVID-19. These speculations were based on the many psychotropic drugs used on psychiatric wards where only a few patients got infected with SARS-CoV-2. This preventive effect was not associated with a single specific drug and was also not associated with a specific class of psychotropic drugs [11] [24] [60] [61]. Thus, it appeared that rather common properties of many different drugs or classes of drugs were leading to the improved outcome of SARS-CoV-2 infected patients.

Do effects on catecholamines and serotonin play a role?

Antidepressant drugs have been associated with beneficial effects on the course of COVID-19 [14]. This observation was found for most classes of antidepressants and did not differentiate specific serotonin reuptake inhibitors from noradrenaline reuptake inhibitors [14]. Thus, there is little evidence that the beneficial effects of these drugs in COVID-19 are mediated by the classical effects of antidepressants on catecholaminergic and serotoninergic neurotransmission and that these neurotransmitters are specifically affected by COVID-19 [62] [63] [64] [65]. It seems however that a common additional property or properties independent of the primary mechanisms of the psychotropic activities are probably relevant.

 

MissingLinkText

Antiviral activity due to cationic amphiphilic activity (cationic amphiphilic drugs, CAD)

Many antidepressants are amphiphilic cationic drugs (CAD) with lysosomotropic properties and can impair lysosomal function. As lysosomes play a major role in virus processing many CAD show antiviral activity in vitro [24] [25]. However, this effect is not specific to antidepressant drugs since CAD like properties are a common feature of many other drugs including antipsychotics, antihistaminics, and others. Several antidepressant drugs with CAD properties have been found to possess comparable antiviral activity against SARS-CoV-2 in vitro including clomipramine, doxepin, amitriptyline, vortioxetine. On the other hand, other drugs with CAD like properties are not showing any antiviral activity against SARS-CoV-2. [24] [25]. Accordingly, further studies are needed to show if CAD-like properties are sufficient for antiviral effects in COVID-19 patients.

 

MissingLinkText

Anti-inflammatory effects of psychotropic drugs as a common property

The concept of inflammation as one of the contributing factors to the pathophysiology of neuropsychiatric disorders like schizophrenia and depression is quite old and has received more and more support over the recent years (as are reports that the comedication with certain anti-inflammatory drugs might be of some benefit in addition to therapy with antipsychotic and/or antidepressant drugs) [66] [67] [68] [69] [70] [71] [72]. Moreover, therapy with antipsychotics and antidepressants can reduce the elevation of inflammatory markers which is common in both groups of patients [69] [70] [71] [73] [74] [75]. The mechanism of these anti-inflammatory effects is not yet finally understood but seems to be an intrinsic property of some of the psychotropic drugs independent of their antidepressant or antipsychotic properties [70]. The anti-inflammatory properties of the individual antidepressants and antipsychotics vary considerably in respect to the effects on the immune system and/or the inflammatory markers [70]. The large variability could be a plausible explanation for the broad and rather non-specific effect of psychotropic drug treatment on inflammation in COVID-19 patients and on the outcome of inflammation-induced respiratory complications. This would also match the observation that the effects are variable and of moderate magnitude only. Thus, unless further data is available the use of psychotropic drugs to treat COVID-19 patients except for neuropsychiatric indications cannot be recommended.

 

MissingLinkText

 

MissingLinkText

Neuroinflammation and the bidirectional relationship between psychiatric illnesses and a SARS-CoV-2 infection: the specific role of proinflammatory cytokines like interleukin-6 (IL-6)

In line with the important interplay between inflammation and the development of neuropsychiatric disorders the profound neuroinflammation taking place in the brain as a consequence of a SARS-CoV-2 infection was seen as one of the pathophysiological factors [75] [76] underlying depressive and psychotic symptoms in COVID-19 patients [77] [78] [79] [80]. Immunological markers of depression seem to be correlated with the severity of depression and anxiety in COVID-19 patients at baseline [81] and at a follow-up three months later [82]. Among the many genes relevant for neuropsychiatric disorders whose expression seems to be altered in COVID-19 patients many markers of inflammation have been identified [64]. Moreover, in a genome-wide association study, a substantial overlap of genes relevant for signaling and inflammation was seen between COVID-19 and psychiatric disorders [83]. A genomic analysis linked inflammatory genes altered by aripiprazole treatment with genes altered in COVID-19 patients [84].

Neuroinflammation seems to be an important link within the bidirectional relationship between psychiatric illness and COVID-19 infection ([Fig. 1]). Neuroinflammation also represents an important trigger for depressive disorders in general and affective symptoms during COVID-19 infection in specific. Therefore, treatment with antidepressant drugs obviously reduces affective symptoms not only by the classical effects on neurotransmitters but also by their direct anti-inflammatory effects [70]. Accordingly, parts of their beneficial effects on the psychiatric symptoms in COVID-19 patients will come from their anti-inflammatory effects. Moreover, symptoms caused by inflammation and impaired pulmonary function in COVID-19 patients might be positively affected by these properties of antidepressants and antipsychotics, explaining the rather beneficial outcome of COVID-19 patients treated with different psychiatric drugs. Whether depressive and/or psychotic symptoms caused by SARS-CoV-2 are specifically sensitive to the anti-inflammatory properties of psychiatric drugs has not yet been demonstrated. In one observational study the positive response to the anxiolytic drug hydroxyzine was associated with a reduction of inflammation markers [43] (see also paragraph 3.2).

Fig. 1 The bidirectional relationship between COVID-19, psychiatric disorders, inflammation, and psychotropic drugs. For further details see text.

Inflammation during COVID-19 is characterized by the release of large amounts of cytokines sometimes even leading to a cytokine storm syndrome (CSS) [85] [86] [87]. While many different pro-inflammatory cytokines are part of the COVID-CSS, Interleukin-6 (IL-6) plays a prominent role with elevations more than one hundred-fold over baseline in some patients [85] [86] [87] The two first anti-COVID-19 drugs approved recently by the WHO are antagonizing IL-6 function (the IL-6 receptor antagonist Tocilizumab and the IL-6 receptor antibody Sarilumab) [32]. Interestingly, IL-6 also represents the major cytokine elevated in the plasma of depressive and schizophrenic patients [88]. Furthermore, the treatment of patients with antidepressants has a major impact on IL-6 levels [69] [88].

IL-6 also represents the major cytokine released in animal models of cytokine storm where cytokine release is initiated by lipopolysacchaccharide (LPS). LPS induced cytokine release and elevation of IL-6 is regulated by sigma-1 sites leading to elevated IL-6 levels in sigma-1 knockout animals [32] [35]. Both key parameters of the LPS model (depression-like behavior and cytokine release) respond well to sigma-1 ligands like fluvoxamine but also other antidepressants without relevant sigma-1 activity [32] [35]. The reduction of cytokines by many antidepressants with different primary mechanisms of action is paralleled by their activity in several behavioral models of antidepressant activity in mice [89]. Thus, inflammatory cytokine-like IL-6 might represent the link between depression and anxiety of COVID-19 patients with beneficial effects of antidepressant drugs not only on the psychiatric symptoms but also on the systemic inflammation of the patients. This interplay is also supported by the observations of Benedetti et al., [90] that COVID-19 patients who had been treated during hospitalization with anti-cytokine drugs including the IL-6 antagonist tocilicumab complained less of depressive symptoms three months after discharge than patients without anti-cytokine drugs.

 

MissingLinkText

Conclusions

In conclusion, the most likely concept to explain the rather unspecific positive effect of antidepressants and antipsychotics on the course of COVID-19 seems to be the underlying inflammation in COVID-19 as the causative factor not only for the clinical course of COVID-19 including respiratory distress but also for the development of psychiatric symptoms. Thus, the inflammation during COVID-19 may not only represent a therapeutic target of many psychotropic drugs for improving the course of the illness including respiratory impairment but may also contribute to their beneficial effects on psychiatric symptoms, and illness ([Fig. 1]).

 

MissingLinkText

 

MissingLinkText

Conflict of Interest

The authors declare that they have no conflict of interest.

• References

• 1 Pagliano P, Scarpati G, Sellitto C. et al. Experimental pharmacotherapy for COVID-19: The latest advances. J Exp Pharmacol 2021; 13: 1-13
• 2 Bonnet U, Juckel G, Scherbaum N. et al. Are persons treated with antidepressants and/or antipsychotics possibly better Protected against severe COVID 19?. Pharmacopsychiatry 2021; 54: 142-143
• 3 Müller JK, Müller WE. Psychopharmaka: Therapeutische Perspektiven gegen Covid-19. Psychopharmakotherapie 2021; 28: 102-110
• 4 Yousefi H, Mashouri L, Okpechi SC. et al. Repurposing existing drugs for the treatment of COVID-19/SARS-CoV-2 infection: A review describing drug mechanisms of action. Biochem Pharmacol 2021; 183: 114296
• 5 Weston S, Coleman CM, Haupt R. et al. Broad anti-coronavirus activity of food and drug administration-approved drugs against SARS-CoV-2 in vitro and SARS-CoV in vivo . J Virol 2020; 94: e01218-e01220
• 6 Cong Y, Hart BJ, Gross R. et al. MERS-CoV pathogenesis and antiviral efficacy of licensed drugs in human monocyte-derived antigen-presenting cells. PLoS One 2018; 13: e0194868
• 7 Javelot H, Petrignet J, Addiego F. et al. Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances. Med Hypotheses 2020; 144: 110025
• 8 Otręba M, Kośmider L, Rzepecka-Stojko A. Antiviral activity of chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine towards RNA-viruses. A review. Eur J Pharmacol 2020; 887: 173553
• 9 Villoutreix BO, Krishnamoorthy R, Tamouza R. et al. Chemoinformatic analysis of psychotropic and antihistaminic drugs in the light of experimental anti-SARS-CoV-2 activities. Adv Appl Bioinform Chem 2021; 14: 71-85
• 10 Khosravi M. Candidate Psychotropics against SARS - CoV - 2: A narrative review. Pharmacopsychiatry. 2021; Epub ahead of print. PMID: 34399430
• 11 Plaze M, Attali D, Petit AC. et al. Repurposing chlorpromazine to treat COVID-19: The reCoVery study. Encephale 2020; 46: 169-172
• 12 Plaze M, Attali D, Prot M. et al. Inhibition of the replication of SARS-CoV-2 in human cells by the FDA-approved drug chlorpromazine. Int J Antimicrob Agents 2021; 57: 106274
• 13 Stip E, Rizvi TA, Mustafa F. et al. The large action of chlorpromazine: translational and transdisciplinary considerations in the face of COVID-19. Front Pharmacol 2020; 11: 577678
• 14 Hoertel N, Sánchez-Rico M, Vernet R. et al. Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: Results from an observational study [published online ahead of print, 2021 Feb 4]. Mol Psychiatry 2021; 4
• 15 Hoertel N, Sánchez-Rico M, Vernet R. et al. Observational study of chlorpromazine in hospitalized patients with COVID-19. Clin Drug Investig 2021; 41: 221-233
• 16 Girgis RR, Lieberman JA. Anti-viral properties of antipsychotic medications in the time of COVID-19. Psychiatry Res 2021; 295: 113626 Epub 2020 Nov 30. PMID: 33290940; PMCID: PMC7833567.
• 17 Hiemke C, Bergemann N, Clement HW. et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: Update 2017. Pharmacopsychiatry 2018; 51: 9-62
• 18 Milani M, Donalisio M, Bonotto RM. et al. Combined in silico and in vitro approaches identified the antipsychotic drug lurasidone and the antiviral drug elbasvir as SARS-CoV2 and HCoV-OC43 inhibitors. Antiviral Res 2021; 189: 105055
• 19 Hoertel N, Sánchez-Rico M, Vernet R. et al. Observational study of haloperidol in hospitalized patients with COVID-19. PLoS One 2021; 16: e0247122
• 20 Canal-Rivero M, Catalán-Barragán R, Rubio-García A. et al. IBIS Translational Psychiatry Group. Lower risk of SARS-CoV2 infection in individuals with severe mental disorders on antipsychotic treatment: A retrospective epidemiological study in a representative Spanish population. Schizophr Res 2021; 229: 53-54
• 21 Racki V, Marcelic M, Stimac I. et al. Effects of haloperidol, risperidone, and aripiprazole on the immunometabolic properties of BV-2 microglial cells. Int J Mol Sci 2021; 22: 4399
• 22 Veerman SRT, Bogers JPAM, Cohen D. et al. COVID-19: Risks, complications and monitoring in patients on clozapine. Pharmacopsychiatry. 2021; Epub ahead of print. PMID: 34470068
• 23 Khosravi M. Ursodeoxycholic acid in patients with treatment-resistant schizophrenia suffering from coronavirus disease 2019: A hypothesis letter. Front Psychiatry 2021; 12: 657316 PMID: 33935842; PMCID: PMC8079749.
• 24 Villoutreix BO, Beaune PH, Tamouza R. et al. Prevention of COVID-19 by drug repurposing: Rationale from drugs prescribed for mental disorders. Drug Discov Today 2020; 25: 1287-1290
• 25 Blaess M, Kaiser L, Sommerfeld O. et al. Drugs, metabolites, and lung accumulating small lysosomotropic molecules: Multiple targeting impedes SARS-CoV-2 infection and progress to COVID-19. Int J Mol Sci 2021; 22: 1797
• 26 Gulbins E, Palmada M, Reichel M. et al. Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs. Nat Med 2013; 19: 934-938
• 27 Carpinteiro A, Edwards MJ, Hoffmann M. et al. Pharmacological inhibition of acid sphingomyelinase prevents uptake of SARS-CoV-2 by epithelial cells. Cell Rep Med 2020; 1: 100142
• 28 Schloer S, Brunotte L, Goretzko J. et al. Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine. Emerg Microbes Infect 2020; 9: 2245-2255
• 29 Zimniak M, Kirschner L, Hilpert H. et al. The serotonin reuptake inhibitor fluoxetine inhibits SARS-CoV-2 in human lung tissue. Sci Rep 2021; 11: 5890
• 30 Schloer S, Brunotte L, Mecate-Zambrano A. et al. Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro. Br J Pharmacol 2021; 178: 2339-2350
• 31 Hoertel N, Sánchez-Rico M, Gulbins E. et al. Association between FIASMAs and reduced risk of intubation or death in individuals hospitalized for severe COVID-19: An observational multicenter study. Clin Pharmacol Ther 2021; Epub ahead of print
• 32 Hashimoto K. Repurposing of CNS drugs to treat COVID-19 infection: Targeting the sigma-1 receptor. Eur Arch Psychiatry Clin Neurosci 2021; 271: 249-258
• 33 Schmidt HR, Kruse AC. The molecular function of σ receptors: Past, present, and future. Trends Pharmacol Sci 2019; 40: 636-654
• 34 Gordon DE, Jang GM, Bouhaddou M. et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020; 583: 459-468
• 35 Rosen DA, Seki SM, Fernández-Castañeda A. et al. Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis [published correction appears in Sci Transl Med 2019; 11: eaax3130 Sci Transl Med 2019; 11(478): eaau5266. doi: 10.1126/scitranslmed.aau5266
• 36 Zhang B, Wang L, Chen T. et al. Sigma-1 receptor deficiency reduces GABAergic inhibition in the basolateral amygdala leading to LTD impairment and depressive-like behaviors. Neuropharmacology. 2017; 116: 387-398
• 37 Sukhatme VP, Reiersen AM, Vayttaden SJ. et al. Fluvoxamine: A review of its mechanism of action and its role in COVID-19. Front Pharmacol 2021; 12: 652688
• 38 Ishikawa M, Ishiwata K, Ishii K. et al. High occupancy of sigma-1 receptors in the human brain after single oral administration of fluvoxamine: A positron emission tomography study using [11C]SA4503. Biol Psychiatry 2007; 62: 878-883
• 39 Lenze EJ, Mattar C, Zorumski CF. et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: A randomized clinical trial. JAMA 2020; 324: 2292-2300
• 40 Seftel D, Boulware DR. Prospective cohort of fluvoxamine for early treatment of coronavirus disease 19. Open Forum Infect Dis 2021; 8: ofab050
• 41 Reis G, Moreira-Silva EA, Meideiros Silve DC. et al. Effect of early treatment with fluvoxamine on the risk of emergency care and hospitalization among patients with COVID-19: the TOGETHER randomized, platform clinical trial. The Lancet. in press 2021
• 42 Reznikov LR, Norris MH, Vashisht R. et al. Identification of antiviral antihistamines for COVID-19 repurposing. Biochem Biophys Res Commun 2021; 538: 173-179
• 43 Hoertel N, Sánchez M, Vernet R. et al. Association between hydroxyzine use and reduced mortality in patients hospitalized for coronavirus disease 2019: Results from a multicenter observational study. medRxiv 2020;
• 44 Müller WE, Siebert B, Holoubek G. et al. Neuropharmacology of the anxiolytic drug opipramol, a sigma site ligand. Pharmacopsychiatry 2004; 37: S189-S197
• 45 Lehrer S, Rheinstein PH. Homozygosity for rs17775810 minor allele associated with reduced mortality of COVID-19 in the UK Biobank Cohort. In Vivo 2021; 35: 965-969
• 46 Murru A, Manchia M, Hajek T. et al. Lithium’s antiviral effects: A potential drug for CoViD-19 disease?. Int J Bipolar Disord 2020; 8: 21
• 47 Spuch C, López-García M, Rivera-Baltanás T. et al. Does lithium deserve a place in the treatment against COVID-19? A preliminary observational study in six patients. Case Report. Front Pharmacol 2020; 11: 557629
• 48 Sönmez D, Hocaoğlu Ç. Could lithium be a new hope in COVID-19 treatment? A Case Report. Psychiatr Danub 2021; 33: 254-255
• 49 Danysz W, Dekundy A, Scheschonka A. et al. Amantadine: Reappraisal of the timeless diamond-target updates and novel therapeutic potentials. J Neural Transm (Vienna) 2021; 128: 127-169
• 50 Müller WE, Mutschler E, Riederer P. Noncompetitive NMDA receptor antagonists with fast open-channel blocking kinetics and strong voltage-dependency as potential therapeutic agents for Alzheimer's dementia. Pharmacopsychiatry 1995; 28: 113-124
• 51 Fink K, Nitsche A, Neumann M. et al. Amantadine inhibits SARS-CoV-2 in vitro. Viruses 2021; 13: 539
• 52 Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E. et al. Anti-inflammatory effects of amantadine and memantine: Possible therapeutics for the treatment of Covid-19?. J Pers Med 2020; 10: 217
• 53 Cortés-Borra A, Aranda-Abreu GE. Amantadine in the prevention of clinical symptoms caused by SARS-CoV-2. Pharmacol Rep 2021; 73: 962-965
• 54 Park MH, Kwon DY. A retrospective review of memantine use and COVID-19-associated mortality from a national database. J Med Virol 2021; 93: 168-169 Epub 2020 Jul 14. PMID: 32633865; PMCID: PMC7361750.
• 55 Malinowska B, Baranowska-Kuczko M, Kicman A. et al. Opportunities, challenges and pitfalls of using cannabidiol as an adjuvant drug in COVID-19. Int J Mol Sci 2021; 22: 1986
• 56 Paland N, Pechkovsky A, Aswad M. et al. The immunopathology of COVID-19 and the cannabis paradigm. Front Immunol 2021; 12: 631233
• 57 Anil SM, Shalev N, Vinayaka AC. et al. Cannabis compounds exhibit anti-inflammatory activity in vitro in COVID-19-related inflammation in lung epithelial cells and pro-inflammatory activity in macrophages. Sci Rep 2021; 11: 1462
• 58 Nguyen LC, Yang D, Nicolaescu V. et al. Cannabidiol inhibits SARS-CoV-2 replication and promotes the host innate immune response. bioRxiv [Preprint] 2021; 2021.03.10.432967
• 59 Esposito G, Pesce M, Seguella L. et al. The potential of cannabidiol in the COVID-19 pandemic. Br J Pharmacol 2020; 177: 4967-4970
• 60 Javelot H, Weiner L, Petrignet J. et al. Psychoactive compounds as multifactorial protection factors against COVID-19. Ir J Med Sci 2021; 190: 849-850
• 61 Bonnet U, Claus B, Schaefer M. et al. Impact of psychiatric and related somatic medications on the duration and severity of COVID-19: A retrospective explorative multi-center study from the German Metropolitan Ruhr-area. Pharmacopsychiatry. 2021; Epub ahead of print. PMID: 34530483.
• 62 Attademo L, Bernardini F. Are dopamine and serotonin involved in COVID-19 pathophysiology?. Eur J Psychiatry 2021; 35: 62-63
• 63 Nataf S. An alteration of the dopamine synthetic pathway is possibly involved in the pathophysiology of COVID-19. J Med Virol 2020; 92: 1743-1744
• 64 Quincozes-Santos A, Rosa RL, Tureta EF. et al. COVID-19 impacts the expression of molecular markers associated with neuropsychiatric disorders. Brain Behav Immun Health 2021; 11: 100196
• 65 Riederer P, Ter Meulen V. Coronaviruses: A challenge of today and a call for extended human postmortem brain analyses. J Neural Transm (Vienna) 2020; 127: 1217-1228
• 66 Kiecolt-Glaser JK, Derry HM, Fagundes CP. Inflammation: Depression fans the flames and feasts on the heat. Am J Psychiatry 2015; 172: 1075-1091
• 67 Meyer JH, Cervenka S, Kim MJ. et al. Neuroinflammation in psychiatric disorders: PET imaging and promising new targets. Lancet Psychiatry 2020; 7: 1064-1074
• 68 Müller N. Inflammation in schizophrenia: Pathogenetic aspects and therapeutic considerations. Schizophr Bull 2018; 44: 973-982
• 69 Mosiołek A, Pięta A, Jakima S. et al. Effects of antidepressant treatment on peripheral biomarkers in patients with major depressive disorder (MDD). J Clin Med 2021; 10: 1706
• 70 Baumeister D, Ciufolini S, Mondelli V. Effects of psychotropic drugs on inflammation: Consequence or mediator of therapeutic effects in psychiatric treatment?. Psychopharmacology (Berl) 2016; 233: 1575-1789
• 71 Hannestad J, DellaGioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: A meta-analysis. Neuropsychopharmacol 2011; 36: 2452-2459
• 72 Steiner J, Frodl T, Schiltz K. et al. Innate immune cells and C-reactive protein in acute first-episode psychosis and schizophrenia: Relationship to psychopathology and treatment. Schizophr Bull 2020; 46: 363-373
• 73 Capuzzi E, Bartoli F, Crocamo C. et al. Acute variations of cytokine levels after antipsychotic treatment in drug-naïve subjects with a first-episode psychosis: A meta-analysis. Neurosci Biobehav Rev 2017; 77: 122-128
• 74 Hiles SA, Baker AL, de Malmanche T. et al. Interleukin-6, C-reactive protein and interleukin-10 after antidepressant treatment in people with depression: A meta-analysis. Psychol Med 2012; 42: 2015-2026
• 75 Jansen van Vuren E, Steyn SF, Brink CB. et al. The neuropsychiatric manifestations of COVID-19: Interactions with psychiatric illness and pharmacological treatment. Biomed Pharmacother 2021; 135: 111200
• 76 Troyer EA, Kohn JN, Hong S. Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms. Brain Behav Immun 2020; 87: 34-39
• 77 Ahrens KF, Neumann RJ, Kollmann B. et al. Differential impact of COVID-related lockdown on mental health in Germany. World Psychiatry 2021; 20: 140-141
• 78 Rogers JP, David AS. A longer look at COVID-19 and neuropsychiatric outcomes. Lancet Psychiatry 2021; 8: 351-352
• 79 Taquet M, Luciano S, Geddes JR. et al. Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA. Lancet Psychiatry 2021; 8: 130-140 Erratum in: Lancet Psychiatry 2021;8: e1. PMID: 33181098
• 80 Taquet M, Geddes JR, Husain M. et al. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: A retrospective cohort study using electronic health records. Lancet Psychiatry 2021; 8: 416-427
• 81 Mazza MG, De Lorenzo R, Conte C. et al. Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors. Brain Behav Immun 2020; 89: 594-600
• 82 Mazza MG, Palladini M, De Lorenzo R. et al. Persistent psychopathology and neurocognitive impairment in COVID-19 survivors: Effect of inflammatory biomarkers at three-month follow-up. Brain Behav Immun 2021; 94: 138-147
• 83 Moni MA, Lin PI, Quinn JMW. et al. COVID-19 patient transcriptomic and genomic profiling reveals comorbidity interactions with psychiatric disorders. Transl Psychiatry 2021; 11: 160 doi:10.1038/s41398-020-01151-3, PMID: 33723208; PMCID: PMC7957287
• 84 Crespo-Facorro B, Ruiz-Veguilla M, Vázquez-Bourgon J. et al. Aripiprazole as a candidate treatment of COVID-19 identified through genomic analysis. Front Pharmacol 2021; 12: 646701
• 85 Chen LYC, Hoiland RL, Stukas S. et al. Confronting the controversy: Interleukin-6 and the COVID-19 cytokine storm syndrome. Eur Respir J 2020; 56: 2003006
• 86 Leisman DE, Ronner L, Pinotti R. et al. Cytokine elevation in severe and critical COVID-19: A rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir Med 2020; 8: 1233-1244
• 87 Liu K, Yang T, Peng XF. et al. A systematic meta-analysis of immune signatures in patients with COVID-19. Rev Med Virol 2021; 31: e2195
• 88 Tynan RJ, Weidenhofer J, Hinwood M. et al. A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav Immun 2012; 26: 469-479
• 89 Tomaz VS, Chaves Filho AJM, Cordeiro RC. et al. Antidepressants of different classes cause distinct behavioral and brain pro- and anti-inflammatory changes in mice submitted to an inflammatory model of depression. J Affect Disord 2020; 268: 188-200
• 90 Benedetti F, Mazza M, Cavalli G. et al. Can cytokine blocking prevent depression in COVID-19 survivors?. J Neuroimmune Pharmacol 2021; 16: 1-3 Erratum in: J Neuroimmune Pharmacol 2021; PMID: 33107012
• 91 83.https://clinicaltrials.gov/ct2/results?cond = covid-19+&term = psychotropic+drugs&cntry=&state=&city=&dist=(search from 08.07.2021)
• 92 https://clinicaltrials.gov/ct2/results?cond=covid19&term=Amantadine&cntry=&state=&city=&dist=(search from 08.15.2020)

Publication History

Received: 14 September 2021
Received: 10 November 2021

Accepted: 29 November 2021

Article published online:
25 January 2022