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Pharmacopsychiatry 2025; 58(01): 41-44
DOI: 10.1055/a-2381-2117
Letter to the Editor

News on the Role of Antidepressants in and for COVID-19 and Long COVID

Udo Bonnet
1   Department of Mental Health, Evangelisches Krankenhaus Castrop-Rauxel, Academic Teaching Hospital of the University of Duisburg-Essen, Castrop-Rauxel, Germany
2   Department of Psychiatry and Psychotherapy, Faculty of Medicine, Landschaftsverband Rheinland-Hospital Essen, University of Duisburg-Essen, Essen, Germany
,
Georg Juckel
3   Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr University Bochum, Bochum, Germany
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Dear Editor,

The coronavirus disease 2019 (COVID-19) pandemic seems to be over, and COVID-19 vaccinations may have saved the lives of over 1.4 million people (predominantly of those over the age of 60 years) in the World Health Organization (WHO) European Region since December 2020 [1]. The particularly SARS-COV-2 (Severe Acute Respiratory Syndrome Coronavirus Type 2) currently appears to be less pathogenic than at the beginning of the pandemic, when its alpha variant encountered an “immune-naive” human race in 2019. But this virus is still among us, causing the hospitalization of thousands of people worldwide every week [2].

In these hospitalized patients, especially if they do not have basic immunity, SARS-COV-2 is still more lethal than the current variants of the influenza virus [3], producing new variants with impressive (and depressing) regularity. This exceptional ability of SARS-COV-2 to mutate and evade the defences of our immune system has led the WHO to recommend annual updates of COVID-19 vaccines [2]. In addition to vaccine research and the development of antiviral and immunomodulatory drugs against SARS-COV-2 infections and the progression to severe COVID-19, there are clinical projects to find drugs as quickly and cost-efficiently as possible that have been already approved for the treatment of other diseases but also show beneficial effects on COVID-19 and its sequelae (Long COVID) (“drug repurposing”) [4]. Antidepressants (AD), and in particular fluvoxamine from this substance class, are now among the most promising candidates [5] [6] [7]. Preclinically, fluvoxamine and almost all AD studied in this regard showed antiviral and anti-inflammatory properties against SARS-COV-2 infections and the subsequent cellular hyper-inflammation, which is regarded to be primarily responsible for organ damage [5] [8]. This was the rationale for testing the clinical utility of AD against COVID-19 and Long COVID [5] [8]. To date, we found regarding this subject in PUBMED ten retrospective “large scale” studies (>20,000 chart reviews), eight prospective clinical studies (plus four studies on Long COVID), eleven placebo-controlled randomized (RCT) studies (plus two studies on Long COVID) and fifteen (!) meta-analyses ([Table 1] ). Results regarding COVID-19: Retrospective studies with cohorts that had taken AD mostly for psychiatric comorbidities or chronic pain disorders already prior to the SARS-COV-2 infection described that this substance class (most studied: selective serotonin re-uptake inhibitors (SSRIs) and selective serotonin noradrenaline re-uptake inhibitors (SSNRIs)) was associated (i) with significantly lower SARS-COV-2 infection rates and (ii) with a milder course of COVID-19 (“COVID-19 protection”). Ten of the 11 RCTs found regarding COVID-19 tested fluvoxamine, as this old AD appeared especially suitable for prophylaxis against severe COVID-19, taking into account its known in vitro potency against intracellular sepsis cascades. Therefore, most (12 of 15) meta-analyses referred to fluvoxamine ([Table 1]). They found (i) a significant (overall 40–70% reduction) in mortality, intubation and hospitalization rates when fluvoxamine was used as an add-on to standard therapy for mild to moderate COVID-19. Administered in the early stages of this disease, this AD was more successful than when it was used later in advanced, severe COVID-19 (e. g. severe pneumonia, severe sepsis) [5]. Furthermore, a dose dependency was found: 2×50 mg fluvoxamine over 15 days was less effective than 2×100 or even 3×100 mg, with the adverse effect rate remaining at the placebo level ([Table 1]). Direct comparisons between AD and drugs approved against COVID-19 do not exist yet. A first indirect meta-analytical comparison showed an advantage of paxlovid or molnupiravir versus fluvoxamine against the development of severe COVID-19: Risk reduction of 95% (study heterogeneity I2=N/A, only one study) or 78% (I2=0) versus 55% (I2=48). However, adjunctive fluvoxamine was still significantly more effective than the symptom-oriented standard therapy alone [9]. Regarding Long COVID: A common Long COVID phenotype with dominant anxiety and depression symptoms, which responds positively to AD administration, relaxation therapy and/or psychotherapy, has now been identified [10]. Furthermore, case reports showed positive influences of AD on fatigue and cognitive and autonomic dysfunctions ([Table 1]). A first large prospective open-label RCT (N=995) has recently found significantly more favourable courses, less viral load, and less pro-inflammatory cytokines in the treatment of mild to moderate COVID-19 with fluvoxamine versus standard treatment, also with regard to the subsequent development of neuropsychiatric and pulmonary long COVID or fatigue [11]. Overall, there is now promising evidence of a preventive effect of AD (especially fluvoxamine) against the progression of COVID-19 to severe conditions and against the development of Long COVID. The possibility that the entire substance class of AD drugs could be effective here is suggested by the results of retrospective large-scale studies ([Table 1]) but still awaits verification by better-controlled studies. The potential efficacy or effectiveness (currently low and moderate confidence of the evidence for the entire substance class and specifically fluvoxamine, respectively) of AD as an add-on against COVID-19 and possibly also directly against Long COVID could stimulate similar projects in other infectious diseases that also have the potential to weaken the health of those affected in the long term [12]. We believe that the current evidence is meanwhile sufficient enough to underscore a probable positive effect of AD in the psychoeducation of patients with COVID-19 or Long COVID who are already receiving AD for other diseases – particularly, a possible positive effect against the virus itself and the development of severe COVID-19 and Long COVID. In regions where neither vaccinations nor antiviral substances currently approved for the prevention or treatment of COVID-19 are available, AD and fluvoxamine, in particular, would be a cost-effective alternative to protect against a severe COVID-course, although this AD appears to have a weaker effect against COVID-19 than the currently approved antiviral substances, but with presumably better tolerability [9]. This applies in particular to patients at risk of severe COVID-19, i. e. people with obesity (BMI>30), age>60 years, heart disease (coronary heart disease, heart failure, cardiomyopathy), acute cancer, chronic lung disease, chronic renal insufficiency and severe mental disorders (caution: switch risk in bipolar disorder and risk of interaction with other drugs, QTc-prolongation) [12]. A head-to-head comparative clinical trial with approved antiviral agents is pending and should be positive to open the door pretty wide for a guideline-based recommendation of fluvoxamine (or the substance class of AD) for COVID-19 or Long COVID.

Table 1 Brief overview of clinical studies testing the effectiveness/efficacy of antidepressants (AD) on COVID-19 severity and sequels (as of 06/10/2024, found in PubMed; https://pubmed-ncbi-nlm-nih-gov.accesdistant.sorbonne-universite.fr/).

Clinical Studies For COVID-19

Meta-Analyses

Placebo-Controlled Randomized Studies*

Prospective Studies*

Retrospektive Large Scale Studies** 

Vai et al., 2021: 0 AD
Tolerability Not Considered
Doi: 10.1016/S2215–0366(21)00232–7

Lenze et al., 2020:+Fluvoxamine** 
Tolerability: Placebo Niveau
Doi: 10.1001/jama.2020.22760

Seftel and Boulware 2021:+Fluvoxamine
Good Tolerability
Doi: 10.1093/ofid/ofab050

Oskotsky et al., 2021:+SSRI
Doi: 10.1001/jamanetworkopen.2021.33090

Firouzabadi et al., 2022:+SSRI/SNRI
Good Tolerability
Doi: 10.1002/hsr2.892

Lenze et al., 2021: 0 Fluvoxamine***
Tolerability: Placebo Niveau
https://clinicaltrials.gov/ct2/show/NCT04668950

Calusic et al., 2021:-+Fluvoxamine
Good Tolerability
Doi: 10.1111/bcp.15126

Fritz et al., 2022:+AD (Dose dependence)
Doi: 10.1038/s41398–022–02109–3

Fico et al., 2022:+Fluvoxamine
Good Tolerability
Doi: 10.1016/j.euroneuro.2022.10.004

Reis et al., 2022:+Fluvoxamine
Tolerability: Placebo Niveau
Doi: 10.1016/S2214–109X(21)00448–4

Pineda et al., 2022:+Fluvoxamine
Good Tolerability
Doi:0.3389/fphar.2022.1054644

Stauning et al., 2023: - SSRI
Doi: 0.1016/j.cmi.2023.04.028
CRITICISM OF THE VALIDITY OF THE STUDY:
Rus and Kooij 2023
Doi: 10.1016/j.cmi.2024.02.007

Nakhaee et al., 2022:+Fluvoxamine
Good Tolerability
Doi: 10.1371/journal.pone.0267423

Bramante et al., 2022: 0 Fluvoxamine (2×50 mg)
Tolerability: Placebo Niveau
Doi: 10.1056/NEJMoa2201662

Kirenga et al., 2023:+Fluvoxamine
Good Tolerability
Doi: 10.1038/s41380–023–02004–3

Visos-Varela et al., 2023:+SSRI
Doi: 10.1016/j.euroneuro.2023.03.011

Boretti 2022:+Fluvoxamine
Good Tolerability
Doi: 10.1016/j.euroneuro.2022.12.001

Seo et al., 2022: 0 Fluvoxamine (pneumonia)**** 
Tolerability: Placebo Niveau
Doi: 10.3947/ic.2021.0142

Siripongboonsitti et al., 2023:
0 Fluvoxamine***
Good Tolerability
Doi: 10.1016/j.ijid.2023.06.018

Trkulja and Kodvanj 2023:+Fluvoxamine
Doi: 10.1007/s00228–023–03479–3

Lee et al., 2022:+Fluvoxamine
Good Tolerability
Doi: 10.1001/jamanetworkopen.2022.6269

McCarthy et al., 2023: 0 Fluvoxamine (2×50 mg)
Tolerability: Placebo Niveau
Doi: 10.1001/jama.2022.24100

Wannigamnah et al., 2024:+Fluvoxamin
Good Tolerability
Doi: 10.1016/j.eclinm.2024.102517

Schultebraucks et al.,:+AD
Doi: 10.1038/s41380-023-02049-4

Nyirenda et al., 2022:+Fluvoxamine
Good Tolerability
Doi:10.1002/14651858.CD015391

Sedighi et al., 2023: 0 Fluoxetine (pneumonia)**** 
Tolerability: Placebo Niveau
Doi: 10.1002/npr2.12327

McCullumsmith 2022 [81]:+Fluoxetin
Good Tolerability
Doi: 10.1002/rmv.2501
Preprint

Ma et al., 2023:+Sertraline
Doi: 10.1016/j.euroneuro.2022.11.009

Bhuta et al., 2022: 0 Fluvoxamine
Good Tolerability
Doi: 10.1097/MJT.0000000000001496

Steward et al., 2023: 0 Fluvoxamine ***
Tolerability: Placebo Niveau
Doi: 10.1001/jama.2023.23363.

Hasse et al., 2023:+SSRI, especially Sertraline
Doi: 10.1093/jphsr/rmad031

Lu et al., 2022:+Fluvoxamine
Good Tolerability
Doi: 10.1016/j.jiph.2022.10.010

Reiersen et al., 2023: 0 Fluvoxamin***
Tolerability: Placebo Niveau
Doi: 10.1093/ofid/ofad419

Hoertel et al., 2023:+AD
Doi: 10.3390/ph16081107

Wen et al., 2022:+Fluvoxamine
Good Tolerability
Doi: 10.1080/07853890.2022.2034936

Ibrahim and Sheta, 2023:+Fluvoxamin
Tolerability: Placebo Niveau
Doi.org/10.4103/ecdt.ecdt_38_22

Wang et al., 2023:+AD
Doi: 10.1016/j.lanwpc.2023.100716

Cobos-Campos et al., 2023 :+SSRI/SNR
Good Tolerability
Doi: I0.1097/MJT.0000000000001618

Naggie, 2023: 0 Fluvoxamin***
Tolerability: Placebo Niveau
Doi:.org/10.1101/2023.09.12.23295424
Preprint

Vatvani et al., 2023: 0 Fluvoxamine
Good Tolerability
Doi: 10.1177/10600280231162243
CRITICISM OF THE VALIDITY OF THE STUDY: Sanchez-Rico et al., 2024
(Dose Dependence)
Doi: 10.1177/10600280231211304

Deng et al., 2023:+Fluvoxamin, second option: Fluoxetin (Dose dependence)
Good Tolerability
Doi: 10.1016/j.cmi.2023.01.010

Deng et al., 2024:+Fluvoxamine (BMI>30 kg/m2)
Good Tolerability
Doi: 10.1002/rmv.2501

Zhou et al., 2024:+Fluvoxamine
(Dose dependence)
Good Tolerability
Doi: 10.1371/journal.pone.0300512

Clinical Studies For LONG-COVID***** (mainly brain fog, fatigue, sensory overload, dysautonomia, anxiety and depression)

Meta-Analyses

Placebo-Controlled Randomized Studies

Prospective Studies

Retrospective Studies and Case Series

None

Bramante et al., 2022: 0 Fluvoxamine (2×50 mg)
Tolerability: Placebo Niveau
Doi: 10.1101/2022.12.21.22283753

Di Nicola et al., 2023:+Vortioxetine
Good Tolerability
Doi: 10.1016/j.euroneuro.2023.02.006

Gonzalez-Martinez et al., 2022:+Amitryptiline for Long COVID-related headache
Doi: 10.1007/s00415-022-11225-5

Farahani et al., 2023:+Fluoxetine (Fatigue)
Tolerability: Placebo Niveau
Doi: 10.1186/s12879-023-08172-5

Fontera et al., 2022:+AD
Tolerability Not Considered
Doi: 10.1371/journal.pone.0275274

La Sala et al., 2023:+Tricyclic AD (2 cases)
Doi: 10.1097/JCP.0000000000001725

Mazza et al., 2022:+SSRI
Good Tolerability
Doi: 10.1016/j.euroneuro.2021.09.009

Rus et al., 2023:+SSRI
Doi: 10.1038/s41598-023-45072-9

Wannigamnah et al., 2024:+Fluvoxamin
Good Tolerability
Doi: 10.1016/j.eclinm.2024.102517

Sidky et al., 2024:+SSRI
Doi: 10.1016/j.csbj.2023.12.045

*the treatment trials with fluvoxamine tested usually daily doses of 2–3×100 mg over 10–14 days (Exceptions with lower doses: :Bramate et al. 2022: doi: 10.1056/NEJMoa2201662; McCarthy et al. 2023: doi: 10.1001/jama.2022.24100;/ Bramante et al. 2022: doi: 10.1101/2022.12.21.22283753; here the daily doses were 2×50 mg); **>20000 pariticipants/e-health records (with the exception of Long COVID-studies). In PubMed, more than 10 further retrospective studies with<20000 participants supported the use of AD for the reduction of SARS-COV-2 infection rates as well as COVID-19 morbidity and mortality. ***in both, the fluvoxamine and the control group, there were no deaths. This results in the assessment of ”0” (see below) because the mortality rate was the primary endpoint of this study; ****  no influence on COVID-19 pneumonia; ***** in accordance with the definition of the WHO, we did not separate Long-COVID from Post-COVID. Long COVID (=Post COVID) is defined “as the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation.” https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition. Abbreviations: SSRI: selective serotonin re-uptake inhibitors; SNRI: serotonin and norepinephrine reuptake inhibitor. Definitions:+= regarding COVID-19: Reduction of the morbidity (e. g., hospitalization rate, ventilation rate) and mortality by and with COVID-19;+= regarding Long COVID: Reduction of the morbidity rate or severity; 0=no significant influence on the morbidity and mortality: −=Increase in the mortality rate. Meta-analyses, which found no “+” for an AD are marked by bold letters.

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Conflict of Interest

The authors declare that they have no conflict of interest.


Correspondence

Udo Bonnet
Department of Mental Health, Evangelisches Krankenhaus Castrop-Rauxel
Academic Teaching Hospital of the University of Duisburg-Essen
Castrop-Rauxel
Germany   

Publication History

Received: 10 June 2024
Received: 14 July 2024

Accepted: 28 July 2024

Article published online:
26 September 2024

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