Table 1.
Accepted studies that evaluated the activity of SSRI and COVID-19 antidepressants
| Reference | Type of study | Study design | Sample characteristics | Main results | Study limitations |
|---|---|---|---|---|---|
| Hoertel et al. [73] | Multicenter observational retrospective cohort study | 7345 adults hospitalized with COVID-19: 460 patients (6.3%) received some antidepressant during hospitalization (257 patients received SSRIs, 71 received SNRIs, 59 received tricyclic antidepressants, 94 tetracyclic antidepressants, 44 α2-antagonist antidepressants) and 6885 did not received treatment with antidepressants | All adults aged 18 years and older who were hospitalized with COVID-19 at the evaluated medical centers were included | Significant association between the use of any antidepressant and reduced risk of intubation or death, especially when there was exposure to escitalopram, fluoxetine and venlafaxine | Missing data for some characteristics (clinical and biological severity of COVID-19); inaccuracies in electronic records (lack of documentation of diseases or medications); incorrect identification of treatment administration method, dosage and frequency |
| Lenze et al. [74] | Randomized, double-blind clinical trial | 80 patients received 100 mg fluvoxamine 3 times daily for 15 days after PCR-confirmed SARS-CoV-2 infection, while 72 patients received placebo. This was a fully remote clinical trial (contact occurred electronically) | Mean age of 46 years; 38 participants (25%) were black adults | Clinical deterioration (defined as onset or hospitalization for dyspnea or pneumonia or decrease in oxygen saturation levels below 92%) occurred in 0 of 80 patients in the fluvoxamine group and in 6 of 72 (8.0%) patients in the placebo group; the fluvoxamine group had 1 serious adverse event and 11 other adverse events, while the placebo group had 6 serious adverse events and 12 other adverse events | Small number of samples; short duration of follow-up (the effect of fluvoxamine on persistent or late symptoms has not been evaluated); the study was conducted within a single geographic area; 20% of participants stopped taking the survey during the 15-day trial |
| Schloer et al. [75] | In vitro | Fluoxetine was tested against human bronchioepithelial cell line (Calu-3) and Vero E6 cell line for 16 h before infection or 1 h after infection | - | Fluoxetine inhibited SARS-CoV-2 infection in Calu-3 epithelial cells and Vero E6 cells, with an EC50 value below 1 μM; application of 10 μM fluoxetine severely reduced viral titers up to 99% | - |
| Eugene [76] | In sílico and in vitro | A population of 1000 subjects was simulated with standard doses of fluoxetine (20 mg/day, 40 mg/day and 60 mg/day) over 10 days of treatment facing SARS-CoV-2 in Calu-3 human lung cells | - | Standard doses of the antidepressant fluoxetine resulted in a range of 79% to 97% of the patient population achieving a minimum plasma concentration of 25.1 ng/ml | CYP2D6 poor or intermediate metabolizers were not monitored; not all medications used by patients and their clinical status were evaluated |
| Seftel and Boulwar [77] | Prospective cohort study | 113 infected workers: 65 opted to receive fluvoxamine (attack dose of 50 to 100 mg, then 50 mg twice daily for 14 days) and 48 opted for observation only without drug therapy. All patients were followed-up in person on day 7 and day 14 of infection | Mean age of 42 years; 75% of participants were men; 84% were latinos; 14% were white | Incidence of hospitalization of 0% with fluvoxamine and 12.5% of patients under observation only; at 14 days, residual symptoms persisted in 0% of patients on fluvoxamine and 60% of patients on observation; the incidence of subsequent hospitalization was 0% in patients on fluvoxamine and 12.5% in observation | Quasi-randomized nature of the comparison |
| Dechaumes et al. [78] | In vitro | Fluoxetine was tested against Vero E6 cells infected by a positive respiratory sample of SARS-CoV-2 | - | The cell viability index was reduced to 86 ± 4% and 98 ± 6% 48 h post-inoculation when treated with 5 and 10 M fluoxetine, respectively, while the value was less than 20% when infected cells were not treated | - |
| Zimniak et al. [79] | In vitro | A concentration of 1.6 μg/ml (~ 5.17 μM) of fluoxetine was tested for 72 h against SARS-CoV-2-infected Vero cells | - | Fluoxetine significantly inhibited SARS-CoV-2 at a concentration of 0.8 μg/ml and the EC50 was determined at 387 ng/ml | - |
| Schloer et al. [80] | In vitro | Fluoxetine/remdesivir combination was tested against human bronchioepithelial cell line (Calu-3) and Vero E6 cell line for 48 h | - | The combination of fluoxetine/remdesivir showed synergistic effects and inhibited the production of SARS-CoV-2 infectious particles > 90% | - |
| Reis et al. [81] | Randomized trial | 9803 participants were selected, of whom 741 received fluvoxamine 100 mg twice a day for 10 days and 756 participants received placebo | Patients hospitalized with COVID-19 are over 18 years old; mean age of 50 years and 58% were women | Fluvoxamine reduced the need for hospitalization and decreased the transfer of critically ill patients to a tertiary hospital compared to placebo; also decreased COVID-19-related deaths by 90% and the need for intensive medical care by about 65% | Tests with a disease that is not well characterized, with no standard of care for early treatment; uncertainty whether the treatment would be applicable in an environment outside Brazil |
| Calusic et al. [82] | Prospective cohort study | 51 hospitalized COVID-19 ICU patients were treated with fluvoxamine 100 mg three times daily for 15 days in addition to standard therapy | 66.7% of the participants were men; 100% were Caucasian | Mortality was lower in the fluvoxamine group (58.8%) compared to the control group (76.5%) | Small sample size, lack of randomization, open design and selection bias. All Caucasian patients (lack of racial diversity) |
| Fred et al. [83] | In vitro | Fluoxetine, citalopram, paroxetine, and fluvoxamine in doses ranging from 0.01 to 20 uM were tested against human embryonic kidney cells expressing ACE2/TMPRSS2 and Calu-1 human lung epithelial cells | - | The drugs inhibited the infection with minimal effects on cell viability; antiviral action was verified in Calu-1 cells against the SARS-CoV-2 lineage | - |
(-) Information not provided by the authors, EC50 effective concentration 50, PCR C-reactive protein, ACE2 angiotensin-2 converting enzyme, SSRIs selective serotonin reuptake inhibitors, SNRIs selective serotonin and noradrenaline receptor inhibitors