key: cord-0768997-z33m2vub
authors: Zheng, Wei; Sun, He-Li; Cai, Hong; Zhang, Qinge; Ng, Chee H.; Xiang, Yu-Tao
title: Antidepressants for COVID-19: A systematic review
date: 2022-03-23
journal: J Affect Disord
DOI: 10.1016/j.jad.2022.03.059
sha: 63b818fa169db6c499734c8ca2cee8bde36bd448
doc_id: 768997
cord_uid: z33m2vub

OBJECTIVE: To systematically examine the efficacy and safety of antidepressants for the treatment of coronavirus disease 2019 (COVID-19). METHODS: A systematic search was performed independently by two researchers based on Chinese Journal Net, WanFang, PsycINFO, Cochrane Library, PubMed, and EMBASE. RESULTS: Seven studies (n = 92,947) including three retrospective studies (n = 91,083), two randomized clinical trials (RCTs, n = 1649), two prospective cohort study (n = 215) involving (n = 92,947) patients with COVID-19 were examined. For RCTs, fluvoxamine outperformed placebo in reducing clinical deterioration and hospitalisation for COVID-19 patients. For retrospective studies, antidepressants (2 studies) and fluoxetine (1 study) possibly reduced the risk of mortality in patients with COVID-19. Results from two remaining studies supported the superiority of fluvoxamine in reducing risk of mortality in COVID-19 patients. The two RCTs that examined the safety of fluvoxamine for COVID-19 patients found inconsistent results but no significant group differences in the dropout rate. CONCLUSION: This systematic review found emerging evidence for fluvoxamine in reducing the risk of mortality and hospitalisation in COVID-19 patients, but inconsistent evidence for the safety of fluvoxamine in COVID-19 patients. More studies are needed to determine the efficacy and safety of antidepressants for the treatment of COVID-19.

Coronavirus disease 2019 pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a rapid and substantial increase in the rates of hospitalization, intensive care unit admission, and death globally (Wiersinga et al., 2020) . Although a number of safe and effective COVID-19 vaccines have been developed, major challenges remained with regard to their production, distribution, and affordability particularly in many developing countries (Torres et al., 2020) . Accumulating evidence has indicated that lung damage caused by COVID-19 is associated with an uncontrolled immune-mediated inflammatory response, which has led to a growing interest in anti-COVID-19 immunomodulatory drugs (Asif et al., 2020; Mehta et al., 2020; Rizk et al., 2020) .

Current evidence suggests that the nonopioid receptor sigma 1 receptor (encoded by SIGMAR1) could be a promising inhibitor of SARS-CoV-2 replication (Gordon DE, 2020a; Gordon DE, 2020b) . As a single polypeptide composed of 223 amino acids, the sigma-1 receptor contains an endoplasmic reticulum-retention signal (Hanner et al., 1996; Hashimoto, 2021) . The sigma-1 receptor (S1R) might play a role in interfering with the early steps of virus-induced host cell reprogramming (Vela, 2020) . A preclinical study found that S1R could restrict the endonuclease activity of endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1 (IRE1) and cytokine expression, but does not inhibit the classical inflammatory signalling pathways (Rosen et al., 2019b) . Hence, it is possible that fluvoxamine may protect mice from lethal septic shock and dampen the inflammatory response in human blood leukocytes.

Thus, drugs with sigma affinity could be useful in the early intervention for those suffering from COVID-19 via interactions with the sigma-1 receptor (Brimson JM, 2020) . The anti-inflammatory properties of antidepressants may be associated with decreased levels of proinflammatory cytokines (Hannestad et al., 2011), including interleukin (IL)-10 and tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1), which are related to the severity of COVID-19 (Hoertel et al., 2021; Hojyo et al., 2020) . Two recent randomized controlled studies (RCTs) found that fluvoxamine, an SSRI with high affinity for the sigma-1 receptor, could potentially prevent clinical deterioration and reduce the need for hospitalisation (Lenze et al., 2020; Reis et al., 2021) in COVID-19 patients. However, they reported inconsistent findings regarding the safety of adjunctive fluvoxamine for COVID-19.

A recent review (Facente et al., 2021) of two RCTs (Lenze et al., 2020; Reis et al., 2021) and one prospective cohort study (Seftel and Boulware, 2021) found that fluvoxamine could effectively reduce morbidity and mortality caused by COVID-19. To date, however, there is no published systematic review that examined the efficacy and safety of antidepressants for treating COVID-19. Thus, this systematic review systematically evaluated the efficacy and safety of adjunctive antidepressants for COVID-19 patients.

This systematic review was conducted following the PRISMA guidelines (Moher et al., 2009) . The registration number of this systematic review was INPLASY202210030 (https://inplasy.com/).

All types of studies that examined the efficacy and safety of antidepressants added to treatment as usual (TAU) for COVID-19 patients were eligible for inclusion such as case report/series, RCTs, prospective cohort studies, prospective observational studies (single-group or with matched controls) and

open-label retrospective studies. Review articles were excluded. The primary outcome was clinical deterioration as defined by respective studies. Additional J o u r n a l P r e -p r o o f Journal Pre-proof outcomes reported in this systematic review were all-cause mortality, adverse drug reactions (ADRs), and dropout rate.

Both Chinese (Chinese Journal Net, WanFang) and international (PsycINFO, Cochrane Library, PubMed, and EMBASE) 

The same two researchers independently screened studies and extracted data. If there was any ambiguity, it was resolved by a discussion with a senior researcher.

We contacted with the first/corresponding authors to obtain any missing data if necessary.

open-label retrospective studies), Newcastle-Ottawa Scale (NOS) (Stang, 2010) was used to assess the study quality.

As shown in Figure 1 , the literature search yielded 390 trials. Finally, seven studies (Calusic et al., 2021a; Hoertel et al., 2021; Lenze et al., 2020; Németh et al., 2021; Oskotsky et al., 2021; Reis et al., 2021; Seftel and Boulware, 2021) that investigated the efficacy and safety of antidepressants for COVID-19 patients met the study entry criteria and were included in this systematic review.

Meta-analysis was not performed due to the substantial heterogeneity between the included studies, particularly in terms of study design (RCTs versus prospective cohort studies versus retrospective studies)

The seven studies (n=92,947) included three retrospective studies (n=91,083) (Hoertel et al., 2021; Németh et al., 2021; Oskotsky et al., 2021) , two RCTs (n=1,649) (Lenze et al., 2020; Reis et al., 2021) and two prospective cohort study (n=215) (Calusic et al., 2021b; Seftel and Boulware, 2021) , all of which are summarized in Table 1 . Among the seven included studies, antidepressants included fluvoxamine (4 studies, n=1,864) (Calusic et al., 2021a; Lenze et al., 2020; Reis et al., 2021; Seftel and Boulware, 2021) , fluoxetine (1 study, n=269) (Németh et al., 2021) and multiple antidepressants (2 studies, n=90,814) (Hoertel et al., 2021; Oskotsky et al., 2021) . Table 1 , Jadad total scores were 5 for two RCTs and NOS total scores ranged from 6 to 8 for other types of studies.

Clinical deterioration and all-cause mortality Table 2 shows the rates of clinical deterioration and all-cause mortality for the included studies. In the two RCTs, fluvoxamine was associated with a lower likelihood of clinical deterioration (Lenze et al., 2020) and hospitalisation (Reis et al., 2021) in patients with COVID-19 when compared with placebo groups. In the three retrospective studies, antidepressants (2 studies) (Hoertel et al., 2021; Oskotsky et al., 2021 ) and fluoxetine (1 study) (Németh et al., 2021) possibly reduced the risk of all-cause mortality. The remaining two studies (Calusic et al., 2021a; Seftel and Boulware, 2021) found that fluvoxamine had a positive effect in reducing mortality in patients with COVID-19.

Compared to placebo, fluvoxamine was associated with less frequent pneumonia and gastrointestinal symptoms such as nausea and vomiting in one RCT (Lenze et al., 2020) . Another RCT reported similar rates of ADRs in both fluvoxamine and placebo groups (Reis et al., 2021) (Table 3 ). In two prospective study, no serious ADRs occurred with fluvoxamine. ADRs were not reported in the three retrospective studies (Calusic et al., 2021b; Hoertel et al., 2021; Németh et al., 2021; Oskotsky et al., 2021) .

In the two RCTs, no significant difference was found between the fluvoxamine than placebo groups regarding the dropout rate (all Ps>0.05) (Lenze et al., 2020; Reis et al., 2021) . The prospective cohort study (Calusic et al., 2021b; Seftel and Boulware, 2021) did not describe discontinuation rates. (Rosen et al., 2019a) . Other mechanisms of actions could be involved. SSRIs, such as fluoxetine, could decrease mRNA levels of protease-1 in MCs, and hence reduce cytokine storms in COVID-19 patients (Chen et al., 2008) . Treatment of mice with S1R agonists, such as fluoxetine (Hashimoto, 2015) , may reduce acid sphingomyelinase activity and protein levels in neurons (Gulbins et al., 2013) . Fluoxetine may also inhibit entry and spread of SARS-CoV-2-2 in the Vero-E6 cell line (Schloer et al., 2020) . S1R agonists, such as escitalopram and fluoxetine (Hashimoto, 2015) , could prevent the SARS-CoV-2 from infecting Vero cells (Carpinteiro et al., 2020) . J o u r n a l P r e -p r o o f 

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Abbreviations: ADRs=adverse drug reactions; NR=not reported; NA=not applicable; RCT=randomized controlled trial; Serious adverse events a = One patient in the placebo group had more than 1 serious adverse event. The total No. of serious adverse events was 1 in the fluvoxamine group and 6 in the placebo group; Other adverse events b = There were patients in the placebo group who had more than 1 other adverse event. J o u r n a l P r e -p r o o f

The authors have no conflicts of interest to declare.J o u r n a l P r e -p r o o f