Analysis of the impact of antidepressants and other medications on COVID-19 infection risk in a chronic psychiatric in-patient cohort

Mendelson

et al. 2021

JCM

SARS-CoV-2 continues to have devastating consequences worldwide. Though vaccinations have helped reduce spread, new strains still pose a threat. Therefore, it is imperative to identify treatments that prevent severe COVID-19 infection. Recently, acute use of SSRI antidepressants in COVID+ patients was shown to reduce symptom severity. The aim of this retrospective observational study was to determine whether COVID+ patients already on SSRIs upon hospital admission had reduced mortality compared to COVID+ patients not on chronic SSRI treatment. Electronic medical records of 9044 patients with laboratory-confirmed COVID-19 from six hospitals were queried for demographic and clinical information. Using R, a logistic regression model was run with mortality as the outcome and SSRI status as the exposure. In this sample, no patients admitted on SSRIs had them discontinued. There was no significant difference in the odds of dying between COVID+ patients on chronic SSRIs vs. those not taking SSRIs, after controlling for age category, gender, and race. This study shows the utility of large clinical databases in determining what commonly prescribed drugs might be useful in treating COVID-19. During pandemics due to novel infectious agents, it is critical to evaluate safety and efficacy of drugs that might be repurposed for treatment.

“…SSRIs and SNRIs were the drivers of this significantly decreased likelihood of COVID-19 infection. Outcome once infected with COVID-19 was not assessed in this analysis [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…Fluvoxamine has been shown to be a sigma-1 receptor (S1R) agonist with the strongest binding affinity to S1R of all the SSRIs [ 41 ]. S1R is a chaperone protein located at the endoplasmic reticulum-mitochondrion interface that regulates autophagy, an important process in viral evasion [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Ongoing Use of SSRIs Does Not Alter Outcome in Hospitalized COVID-19 Patients: A Retrospective Analysis

Mendelson

et al. 2021

JCM

“…In addition to fluoxetine, other psychotropics (fluvoxamine, hydroxyzine, and trazodone) and one antihypertensive (amlodipine) are reported to be associated with reducing risk of death in patients with COVID-19 (Zhang et al, 2020;Darquennes et al, 2021;Sánchez-Rico et al, 2021;Clelland et al, 2022;Reis et al, 2022). Further, Reznikov et al…”

Section: Discussionmentioning

confidence: 99%

Fluoxetine pharmacokinetics and tissue distribution quantitatively supports a therapeutic role in COVID-19 at a minimum dose of 20 mg per day

Eugene

2022

F1000Res

Background. Various in vitro studies have shown fluoxetine inhibits multiple variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen causing the coronavirus disease 2019 (COVID-19) worldwide pandemic and multiple observational clinical studies have shown that patients receiving fluoxetine experienced clinical benefit by lowering the risk of intubation and death. The aim of this study is to conduct population pharmacokinetic dosing simulations to quantify the percentage of patients achieving a trough level for the effective concentration resulting in 50% (EC50) and 90% (EC90) inhibition of SARS-CoV-2 as reported in Calu-3 human lung cells. Methods. Pharmacometric parameter estimates used in this study were obtained from the U.S. FDA website from a new drug application for fluoxetine hydrochloride. A population of 1,000 individuals were simulated at standard fluoxetine antidepressant doses (20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, and 60 mg/day) to estimate the percentage of the patients achieving a trough plasma level for the EC50 and EC90 SARS-CoV-2 inhibition. All analyses and graphing were conducted in the R. Results. By day-10 at 20 mg/day 93.2% and 47% of the population will achieve the trough target plasma EC50 and EC90 concentrations, respectively, which translates to a lung tissue distribution coefficient of 60-times higher EC50 (283.6 ng/ml [0.82 mM]) and EC90 (1390.1 ng/ml [4.02 mM]). Further, by day-10 at an ideal dose of 40 mg/day, 99% and 93% of patients will reach the trough EC50 and EC90 concentrations, respectfully. Lastly, only a dose of 60 mg/day will reach the SARS-CoV-2 EC90 inhibitory concentration in the brain. Conclusion. Overall, with a minimum treatment period of 10-days and a minimum dose of 20 mg/day, this study corroborates in vitro studies reporting fluoxetine inhibiting SARS-CoV-2 titers and also multiple observational clinical studies showing therapeutic benefit of fluoxetine in COVID-19 patients.

“…However, as also noted by Zimniak et al, the ability of SSRI’s to inhibit viral replication is not unique to our findings for HSV. SSRI’s have been shown to suppress efficient replication of many viruses, including Enteroviruses, Dengue, Coxsackie virus, HIV, and SARS-CoV-2, suggesting that targeting 5-HT associated pathways may be a viable means of disrupting replication of a broad range of viral pathogens ( Benton et al, 2010 ; Zuo et al, 2012 ; Ulferts et al, 2013 ; Young et al, 2014 ; Alidjinou et al, 2015 ; Medigeshi et al, 2016 ; Benkahla et al, 2018 ; Bauer et al, 2019 ; Clelland et al, 2021 ; Dechaumes et al, 2021 ; Zimniak et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus-1 Induced Serotonin-Associated Metabolic Pathways Correlate With Severity of Virus- and Inflammation-Associated Ocular Disease

et al. 2022

Herpes simplex virus-associated diseases are a complex interaction between cytolytic viral replication and inflammation. Within the normally avascular and immunoprivileged cornea, HSV ocular infection can result in vision-threatening immune-mediated herpetic keratitis, the leading infectious cause of corneal blindness in the industrialized world. Viral replicative processes are entirely dependent upon numerous cellular biosynthetic and metabolic pathways. Consistent with this premise, HSV infection was shown to profoundly alter gene expression associated with cellular amino acid biosynthetic pathways, including key tryptophan metabolism genes. The essential amino acid tryptophan is crucial for pathogen replication, the generation of host immune responses, and the synthesis of neurotransmitters, such as serotonin. Intriguingly, Tryptophan hydroxylase 2 (TPH2), the neuronal specific rate-limiting enzyme for serotonin synthesis, was the most significantly upregulated gene by HSV in an amino acid metabolism PCR array. Despite the well-defined effects of serotonin in the nervous system, the association of peripheral serotonin in disease-promoting inflammation has only recently begun to be elucidated. Likewise, the impact of serotonin on viral replication and ocular disease is also largely unknown. We therefore examined the effect of HSV-induced serotonin-associated synthesis and transport pathways on HSV-1 replication, as well as the correlation between HSV-induced ocular serotonin levels and disease severity. HSV infection induced expression of the critical serotonin synthesis enzymes TPH-1, TPH-2, and DOPA decarboxylase (DDC), as well as the serotonin transporter, SERT. Concordantly, HSV-infected cells upregulated serotonin synthesis and its intracellular uptake. Increased serotonin synthesis and uptake was shown to influence HSV replication. Exogenous addition of serotonin increased HSV-1 yield, while both TPH-1/2 and SERT pharmacological inhibition reduced viral yield. Congruent with these in vitro findings, rabbits intraocularly infected with HSV-1 exhibited significantly higher aqueous humor serotonin concentrations that positively and strongly correlated with viral load and ocular disease severity. Collectively, our findings indicate that HSV-1 promotes serotonin synthesis and cellular uptake to facilitate viral replication and consequently, serotonin’s proinflammatory effects may enhance the development of ocular disease.