Although vaccination has greatly advanced the fight against SARS-CoV-2, it is not expected that it alone will eradicate the pandemic. Low vaccination rates in countries with fewer resources, the decrease in protection over time, and the appearance of new variants make it necessary to search for effective alternative treatments.
The development of new drugs involves high costs and time, and further widens the gap between countries in terms of access to COVID-19 treatment. Therefore, the World Health Organization (WHO) recommended repurposing existing available medicines with well-understood safety profiles.
Several studies have suggested that selective serotonin reuptake inhibitors (SSRIs) may have a beneficial effect in subjects with early-stage COVID-19. Fluvoxamine had been proposed as the main molecule responsible for this beneficial effect. However, the possible effect of other molecules in this group remains to be established.
The lack of scientific data based on real patients highlights the importance of conducting observational studies with low risk of bias, which would allow the creation of a body of evidence while minimizing the risk of exposure to potentially harmful or ineffective treatments. Therefore, using the database of a regional health system in northwest Spain, covering ~2.7 million beneficiaries, as well as medications dispensed, comorbidities and services provided in primary and hospital care, a case study was carried out. controls to evaluate the association between SSRI use – both overall and by active ingredient – and the severity of COVID-19, defined as: (1) risk of hospitalization; (2) risk of admission to the intensive care unit (ICU) and (3) risk of mortality. As secondary objectives, their influence on (4) susceptibility to the virus and (5) progression to severe COVID-19 was evaluated.
| Results |
Data were collected from 86,602 subjects , consisting of: 3060 cases (subjects with positive PCR who required hospitalization), of which 228 required admission to the ICU and 413 died; 26,757 non-hospitalized cases (subjects with positive PCR who did not require hospitalization); and 56,785 subjects with positive PCR.
The median age of hospitalized cases was 74 (59-84) years; of the cases admitted to the ICU, 69 (60-76) years; of the deceased 85 (77-89) years; and non-hospitalized COVID+, 47 (33-63) years. The percentage of people ≥ 65 years of age hospitalized was 66.7%; admitted to the ICU, 65.8%; deceased, 94.2%; and COVID+ not hospitalized, 23.4%.
- The most prevalent comorbidities in the cases were high blood pressure, diabetes and obesity.
- The most consumed active ingredients were escitalopram and sertraline.
The risk of hospitalization was evaluated based on 3060 cases and 56,785 controls. While no statistically significant differences were observed for SSRIs overall, citalopram showed a decreased risk of hospitalization. The effect on the risk of ICU admission was evaluated based on 228 cases and 4398 controls.
No statistically significant differences were found for SSRIs overall or for any of the individual active ingredients. No results related to citalopram were obtained, since none of the patients with this drug required admission to the ICU. The effect on mortality risk was evaluated based on 413 cases and 7408 controls. Statistically significant differences were found for SSRIs in general and for paroxetine, showing a decreased risk in both cases.
The analysis of the risk of COVID-19 infection included 86,602 patients: of them, 29,817 were cases (subjects with positive PCR, hospitalized and not hospitalized) and 56,785 were controls. No effect was found for any of the individual active ingredients. The risk of progression to severe COVID-19 infection was determined based on 3,060 cases and 26,757 controls (non-hospitalized cases). No effect was observed for SSRIs overall, but the effect was evident for citalopram.
To analyze the exposure window to SSRIs and COVID-19, periods of 1, 2 and 3 months were considered. There were no relevant changes in the aORs (adjusted odds ratios) for the different exposure windows and the significant results obtained for citalopram and paroxetine remained constant, indicating that the findings are robust. Additionally, the association between SSRIs grouped by sigma-1 receptor affinity and COVID-19 outcomes was evaluated.
The low-affinity agonist group was associated with a significant reduction in mortality risk and the intermediate-affinity agonist group showed a slight but significant decrease in susceptibility.
Regarding functional inhibition of acid sphingomyelinase activity and COVID-19 outcomes, it was observed that the SSRI group with reduced activity showed a slight decrease in susceptibility to the virus. No other significant associations were found, with the ORa being very similar between high and low activity.
The effect of the SSRI dose in the last month was evaluated and it was found that increasing the dose led to a greater reduction in risk, but without a conclusive dose-response relationship, due to the low number of subjects in the strata.
| Discussion |
This large-scale population-based study established that citalopram reduces the risk of hospitalization from COVID-19, possibly in part because it reduces the risk of COVID-19 patients progressing to severe stages that could require hospitalization. Furthermore, a non-significant but suggestive association was observed for the risk of mortality, since none of the patients exposed to this drug required admission to the ICU.
These results suggest that citalopram could be a candidate drug for reuse as a preventive treatment aimed at reducing the risk of COVID-19 patients progressing to severe stages of the disease.
This would be the first outpatient study that allows the evaluation of the effects of the active ingredients that make up the SSRI class of medications, considering a total of 6 drugs, and allowing the identification of the important magnitude of the effect of citalopram on the prognosis of patients. with COVID-19. In addition to displaying anti-inflammatory properties, this SSRI has been shown to have in vitro antiviral activity against HIV and SARS-CoV-2 in some cells.
Furthermore, the results of the sub-studies of susceptibility and progression to severe COVID-19 indicate that the association with a lower risk of hospitalization is due, not to reducing susceptibility to the virus, but to reducing the risk of progression to advanced stages. severe of the disease.
Regarding mortality, a suggestive risk reduction was observed, close to statistical significance and, surprisingly, no patient who had previously taken citalopram was admitted to the ICU for COVID-19. Both the lack of significance and the absence of cases could be due to the fact that citalopram was the second least represented SSRI in the hospitalized PCR+ population.
These results, once confirmed in other studies and/or clinical trials, could have a great clinical impact, since citalopram could be reused as an alternative treatment with a good safety and tolerability profile to reduce the risk of hospitalization due to COVID-19. . In light of these results, it cannot be ruled out that citalopram may slow the progression to severe stages of present or future viral diseases.
In the pandemic, fluvoxamine was considered the leading SSRI candidate for the management of COVID-19. Initially, doubts about its effectiveness in hospitalization, mechanical ventilation, and mortality led to its use being discouraged, although a recent meta-analysis found that medium doses were associated with lower mortality and hospitalization. The low prevalence of its use made it impossible to obtain conclusive results in the present study.
On the contrary, the data analyzed did allow us to find a significant association between the use of paroxetine and the reduction in the risk of mortality from COVID-19. Although this finding coincides with previous studies, it should be interpreted with caution, since the absence of association with the rest of the parameters prevented us from identifying what role it could play in the course of the disease.
This population-based study found an association between overall SSRI use and a lower risk of mortality, but no effect on the risk of hospitalization, ICU admission, or progression to severe forms of the disease. Likewise, the analysis by active ingredient did not detect any effect for the rest of the SSRIs (fluoxetine, sertraline and escitalopram). Given that SSRIs share their main therapeutic indications, the differences in effect found in the different active ingredients cannot be attributed to confusion due to indication bias.
To explain the possible effects of SSRIs on COVID-19, several mechanisms of action have been proposed:
i) Inhibition of the serotonin transporter can reduce platelet aggregation and exert direct anti-inflammatory effects, which may be beneficial in patients with COVID-19. However, the findings of this study do not support this proposal, since inhibition of the serotonin transporter is the common mechanism of action of SSRIs, and a class effect against COVID-19 was not observed in the results.
ii) Agonism of the sigma-1 receptor (S1R), since its activation decreases cytokine production and systemic inflammation. Although not conclusive, the analyzes of the present study suggest slightly superior results for low and intermediate affinity agonists, as observed in previous studies, ruling this out as the mechanism involved.
iii) Finally, the currently most accepted mechanism is the functional inhibition of acid sphingomyelinase, which prevents the entry of SARS-CoV-2 into host cells. Biological and observational data support this hypothesis and, although the results of this study are not conclusive, it should be noted that all the molecules tested in it were functional inhibitors of acid sphingomyelinase activity.
Previous studies have also shown that there could be a relationship between SSRI dosage and COVID-19 outcomes. The data from this study indicate that, for citalopram and paroxetine, a suggestive, although not conclusive, dose-response effect could be observed.
| Clinical and public health implications |
Although immunization against COVID-19 is in continuous development, the difficulty of access to vaccines in countries with fewer resources, the reluctance to vaccinate, the reduction of immunity over time, and the appearance of new variants and/or or new viruses with immune evasion properties have led to the need to find effective, affordable and widely available treatment options.
Therefore, the drug repurposing strategy offers a crucially important alternative, especially if these drugs have already been approved for other indications and have a good safety profile. This is the case of SSRIs, which are some of the most prescribed medications worldwide and, in general, have good tolerance and safety profiles. Specifically, citalopram is among the SSRIs with the greatest acceptability.
Treatment with reused medications can be aimed at: (i) causing a reduction in susceptibility to the virus and, by extension, the number of infections; (ii) reduce the severity of COVID-19 and the number of hospital admissions; and (iii) reduce mortality in hospitalized patients.
From a public health point of view, a drug that reduced the risk of progression to more severe stages more than susceptibility per se would have greater applicability, since it would only need to be administered to infected subjects with a higher risk of progression.
Consequently, the association of the use of citalopram with a lower risk of hospitalization takes on special relevance as a consequence of the decrease in progression to severe stages of the disease. Taking into account its low cost and the low number of doses necessary for the early treatment of COVID-19 (considering the average duration of the disease), citalopram could be considered as an alternative treatment in settings with low vaccine coverage.
| Conclusion |
The pandemic has highlighted the need to evaluate the effect of already marketed drugs on COVID-19. This study suggests that there is no class effect of SSRIs and that citalopram could reduce the risk of hospitalization due to slowing progression to severe stages of COVID-19.
Further research could focus on evaluating the potential effect of citalopram on other current or future viral diseases.
