key: cord-0262867-1ao4j3qx authors: Nakhaee, H.; Bayati, R.; Rahmanian, M.; Ghaffari Jolfayi, A.; ZANGIABADIAN, M.; Rakhshanderou, S. title: The effect of antidepressants on severity of COVID-19 in hospitalized patients: A systematic review and meta-analysis date: 2022-04-16 journal: nan DOI: 10.1101/2022.04.11.22273709 sha: 22a22e5d58a54b26d4e2f5c9d46c92bb8310b04d doc_id: 262867 cord_uid: 1ao4j3qx Introduction: Clinical depression and the subsequent low immunity is a comorbidity that can act as a risk factor for severity of COVID-19 cases. Antidepressants such as SSRI and SNRI are associated with immune-modulatory effects, which dismiss inflammatory response and reduce lung tissue damage. The current systematic review and meta-analysis aims to evaluate the effect of antidepressant drugs on prognosis and severity of COVID-19 in hospitalized patients. Methods: A systematic search was carried out in PubMed/Medline, EMBASE, and Scopus up to January 16, 2022. The following keywords were used: "COVID-19", "SARS-CoV-2", "2019-nCoV", "SSRI", "SNRI", "TCA", "MAOI", and "Antidepressant". The pooled risk ratio (RR) with 95% CI was assessed using a fixed or random-effect model. We considered P < 0.05 as statistically significant for publication bias. Data were analyzed by Comprehensive Meta-Analysis software, Version 2.0 (Biostat, Englewood, NJ). Results: Twelve studies were included in our systematic review. Three of them were experimental with 1751, and nine of them were observational with 290,950 participants. Seven out of twelve articles revealed the effect of antidepressants on reducing severity of COVID-19. SSRI medications, including Fluvoxamine, Escitalopram, Fluoxetine, and Paroxetine and also among the SNRI drugs Venlafaxine are also reasonably associated with reduced risk of intubation or death. There were four studies showing no significant effect and one study showing the negative effect of antidepressants on prognosis of covid-19. The meta-analysis on clinical trials showed that fluvoxamine could significantly decrease the severity outcomes of COVID-19 (RR: 0.745; 95% CI: 0.580-0.956) Conclusions: Most of the evidence supports that the use of antidepressant medications, mainly Fluvoxamine may decrease the severity and improve the outcome in hospitalizes patients with sars-cov-2. Some studies showed contradictory findings regarding the effects of antidepressants on severity of COVID-19. Further experimental studies should be conducted to clarify the effects of antidepressants on severity of COVID-19. After over two years since the first case of the novel coronavirus was detected in December 2019 71 in Wuhan, China, 483 million infected cases and 6.13 million deaths have been reported worldwide 72 up to January 21, 2022 (1). Covid19 is an acute respiratory disease, resulting in progressive 73 respiratory failure, and eventually leading to death. Common symptoms include fever, dry cough, were less likely to test positive for . Antidepressants are also associated with less 89 severe cases as they significantly reduced the risk of intubation or death in some cohort studies (8, 90 9). Several mechanisms are suggested to justify this finding. Antidepressants could be associated 91 with declined plasma levels of inflammatory cytokines, including IL-10, TNF-α, CCL-2, and IL-92 6, which are related to COVID-19 severity and mortality (10, 11) . Also Some SSRI The records found through database searching were merged, and the duplicates were removed 119 using EndNote X8 (Thomson Reuters, Toronto, ON, Canada). Two reviewers independently 120 screened the records by title/abstract and full text to exclude those unrelated to the study 121 objectives. Any disagreements were resolved by the lead investigator. Included studies met the 122 following criteria: (i) patients were diagnosed with COVID-19 based on the WHO criteria; (ii) 123 patients were received anti-depressants; and (iii) severity predictors (hospitalization due to 124 COVID-19 and/or ARDS and/or need to NIV or mechanical ventilation and/or ICU admission 125 and/or death). Conference abstracts, editorials, reviews, study protocols, molecular or 126 experimental studies on animal models and studies with focusing on infection risk were 127 excluded. Two reviewers designed a data extraction form. These reviewers extracted data from all eligible 132 studies, and differences were resolved by consensus. Two blinded reviewers assessed the quality of the studies using three different assessment tools 142 (checklists): two for observational studies (case controls and cohorts) and one for experimental 143 studies (14). Items such as study population, measure of exposures, confounding factors, extent 144 of outcomes, follow-up data, and statistical analysis were evaluated. The pooled risk ratios (RRs) with 95% CI were assessed using random or fixed-effect models. The fixed-effects model was used because of the low estimated heterogeneity of the true effect 150 sizes. The between-study heterogeneity was assessed by Cochran's Q and the I2 statistic. Publication bias was evaluated statistically by using Egger's and Begg's tests as well as the 152 funnel plot (p < 0.05 was considered indicative of statistically significant publication bias; funnel 153 plot asymmetry also suggests bias) (15). All analyses were performed using "Comprehensive 154 Meta-Analysis" software, Version 2.0 (Biostat, Englewood, NJ). The selection process of articles is shown in Figure 1 . Twelve articles were included and 159 classified into the followings: six cohort studies (8, (16) (17) (18) (19) (20) , three case-control studies (21-23) and 160 three clinical trials (24-26). There were 872 cases and 879 controls in clinical trials, 15950 cases . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The checklists for observational studies (14) showed that the included observational studies had a 172 low risk of bias except Bora et al. study (16) . (Table 2 & 3) In contrast, the checklist for 173 experimental studies (14) showed that the included experimental studies had a high risk of bias for 174 randomization, group concealment and participants, treatment delivers and outcome assessors 175 blinding except Lenze et al. study (25) . (Table 4) 176 177 According to nine studies (8, (16) (17) (18) (21) (22) (23) (24) (25) , the mean age of total patients was 58.1 years old 180 with 40 and 56.5 years old in case and control groups in eight studies, respectively (8, 17, 18, 20, 181 21, 23-25). 49.6 percent of patients were female according to eleven studies (8, (16) (17) (18) (19) (20) (21) (23) (24) (25) (26) Seven studies (18, 20, 21, (23) (24) (25) (26) only used or surveyed SSRIs as anti-depressant in case groups 190 (fluvoxamine in five studies (18, 20, (24) (25) (26) , fluoxetine in two studies (18, 23) and Escitalopram 191 in one study (21)). In remain five studies (8, 16, 17, 19, 22) After adjustment, seven studies (8, 16, 18, 20, 21, 23, 25) showed significant association 198 between anti-depressant use and reducing severity outcomes of COVID-19. On the other hand, 199 five studies (17, 19, 22, 24, 26) presented that either there are not any significant effect for anti- antidepressants, and specifically the SSRIs escitalopram, fluoxetine, and paroxetine, the SNRI . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Four studies have discussed about the relation of using fluvoxamine and COVID-19 severity. One cohort study (20) and three clinical trials (24-26). Lenze et al. (25) represented that patients 231 treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration 232 over 15 days (absolute difference:8.7% 95% CI:1.8%-16.4%). Also serious adverse events in 233 fluvoxamine group were less than placebo group (1.3% vs 6.9%). They suggested that this effect 234 is because of the influence of fluvoxamine on the S1R-IRE1 pathway and anti-inflammatory 235 (Cytokine reduction) actions resulting from S1R activation. Also according to Seftel et al. (20) 236 study the incidence of subsequent hospitalization was lower in fluvoxamine group (0% vs 237 12.5%) and elevated respiratory rates were improved faster by day 7 in this group so 238 fluvoxamine seems to be promising as early treatment for COVID-19 to prevent clinical 239 deterioration requiring hospitalization and to prevent possible long haul symptoms persisting 240 beyond 2 weeks. On the other hand, Reis et al. (26) suggested that There were no significant 241 differences between fluvoxamine and placebo for viral clearance at day 7 (RR:0·67; 95% . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 16, 2022. ; https://doi.org/10.1101/2022.04.11.22273709 doi: medRxiv preprint Serotonin inhibits IL-12 and TNF-α release in human alveolar macrophages, but it increases IL-. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 16, 2022. ; https://doi.org/10.1101/2022.04.11.22273709 doi: medRxiv preprint 8 298 10 production via 5-HT2 receptors (38). Therefore, SSRIs and SNRIs may influence COVID-19 299 patients' lung function. Considering that other antidepressants with the ability to block serotonin 300 transporters did not show similar beneficial effects for COVID-19 patients, it is unlikely that 301 serotonin transporter inhibition may play a significant role in SSRIs' beneficial effects for COVID-302 19 patients. However, the anti-inflammatory effects of serotonin transporter inhibition may be a 303 factor for the beneficial effects of SSRIs such as fluoxetine and fluvoxamine (31). On the other hand, animal studies indicated that Some SSRIs, such as fluvoxamine, sertraline, 322 fluoxetine, and citalopram, have a high to moderate affinity for sigma-1 receptors in the rat brain. Another mechanism proposed to explain the anti-inflammatory effects of SSRIs is increasing 332 melatonin levels due to cytochrome P450 enzyme CYP1A2 inhibition by fluvoxamine (49, 50). Melatonin which is naturally synthesized in the pineal gland and immune cells from the amino 334 acid tryptophan, has anti-inflammatory, immunomodulatory, and antioxidant effects and is a 335 therapeutic candidate to treat covid-19 (51). . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 16, 2022. ; https://doi.org/10.1101/2022.04.11.22273709 doi: medRxiv preprint Another important clinical issue is to either continue or discontinue SSRIs when a COVID-19 345 patient is hospitalized or admitted to an ICU. There is evidence showing adverse ICU outcomes 346 after discontinuation of SSRIs. This is probably due to increased agitation and need for sedation 347 among these patients that can result in respiratory depression (52, 53) . SSRI use may sometimes 348 be contraindicated in ICU patients due to ECG changes and abnormal coagulation effects(54). A 349 systematic review regarding the use of antidepressants in Critical Care, suggested that there may 350 be excess morbidity in critically ill SSRI/SNRI users, but whether this is due to chronic effects, 351 ongoing use, or drug withdrawal is unclear (53). Among the studied experiment, seven studies showed anti-depressant ability to reduce the severity 382 of covid-19, and five studies didn't mention any significant effect on it. The covid-19 reducing 383 effect of the mentioned medications can be concluded from the decline in the risk of intubation 384 and death, clinical outcomes, and biological markers demonstrating the disease's severity. Among 385 the SSRI medication, the most common studied drug was fluvoxamine, which has a less 386 subsequent hospitalization rate, less likelihood of 15-day-deterioration, and fewer adverse events 387 than placebo, attributable to the S1R-IRE1 pathway and anti-inflammatory actions. Other SSRI 388 medications, including Escitalopram, Fluoxetine, and Paroxetine and also among the SNRI drugs 389 Venlafaxine are also reasonably associated with reduced risk of intubation or death. Still, they 390 didn't study as much as fluvoxamine. Although most of the evidence supports the effectiveness . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 16, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 16, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 Figure1. Flow chart of study selection for inclusion in the systematic review and meta-analysis. the ICD-10 classification confirmed by the test results . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 16, 2022. ; https://doi.org/10.1101/2022.04.11.22273709 doi: medRxiv preprint 433 434 2. Were the exposures measured similarly to assign people to both exposed and unexposed groups? is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 16, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 16, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 Mean:47.6 46.6/53.4 1:9 patients treated by antidepressants with no limit to the types of these medications patients not treated by antidepressants mortality . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 16, 2022. ; https://doi.org/10.1101/2022.04.11.22273709 doi: medRxiv preprint 479 Fluvoxamine 50-to 100-mg loading dose 50 mg --twice daily 14 days . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 16, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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