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2.
JAMA Netw Open ; 4(11): e2133090, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1516696

ABSTRACT

Importance: Antidepressant use may be associated with reduced levels of several proinflammatory cytokines suggested to be involved with the development of severe COVID-19. An association between the use of selective serotonin reuptake inhibitors (SSRIs)-specifically fluoxetine hydrochloride and fluvoxamine maleate-with decreased mortality among patients with COVID-19 has been reported in recent studies; however, these studies had limited power due to their small size. Objective: To investigate the association of SSRIs with outcomes in patients with COVID-19 by analyzing electronic health records (EHRs). Design, Setting, and Participants: This retrospective cohort study used propensity score matching by demographic characteristics, comorbidities, and medication indication to compare SSRI-treated patients with matched control patients not treated with SSRIs within a large EHR database representing a diverse population of 83 584 patients diagnosed with COVID-19 from January to September 2020 and with a duration of follow-up of as long as 8 months in 87 health care centers across the US. Exposures: Selective serotonin reuptake inhibitors and specifically (1) fluoxetine, (2) fluoxetine or fluvoxamine, and (3) other SSRIs (ie, not fluoxetine or fluvoxamine). Main Outcomes and Measures: Death. Results: A total of 3401 adult patients with COVID-19 prescribed SSRIs (2033 women [59.8%]; mean [SD] age, 63.8 [18.1] years) were identified, with 470 receiving fluoxetine only (280 women [59.6%]; mean [SD] age, 58.5 [18.1] years), 481 receiving fluoxetine or fluvoxamine (285 women [59.3%]; mean [SD] age, 58.7 [18.0] years), and 2898 receiving other SSRIs (1733 women [59.8%]; mean [SD] age, 64.7 [18.0] years) within a defined time frame. When compared with matched untreated control patients, relative risk (RR) of mortality was reduced among patients prescribed any SSRI (497 of 3401 [14.6%] vs 1130 of 6802 [16.6%]; RR, 0.92 [95% CI, 0.85-0.99]; adjusted P = .03); fluoxetine (46 of 470 [9.8%] vs 937 of 7050 [13.3%]; RR, 0.72 [95% CI, 0.54-0.97]; adjusted P = .03); and fluoxetine or fluvoxamine (48 of 481 [10.0%] vs 956 of 7215 [13.3%]; RR, 0.74 [95% CI, 0.55-0.99]; adjusted P = .04). The association between receiving any SSRI that is not fluoxetine or fluvoxamine and risk of death was not statistically significant (447 of 2898 [15.4%] vs 1474 of 8694 [17.0%]; RR, 0.92 [95% CI, 0.84-1.00]; adjusted P = .06). Conclusions and Relevance: These results support evidence that SSRIs may be associated with reduced severity of COVID-19 reflected in the reduced RR of mortality. Further research and randomized clinical trials are needed to elucidate the effect of SSRIs generally, or more specifically of fluoxetine and fluvoxamine, on the severity of COVID-19 outcomes.


Subject(s)
Antidepressive Agents , COVID-19/mortality , Fluoxetine , Fluvoxamine , Serotonin Uptake Inhibitors , Severity of Illness Index , Adult , Aged , Antidepressive Agents/pharmacology , COVID-19/metabolism , Citalopram/pharmacology , Cytokines/metabolism , Female , Fluoxetine/pharmacology , Fluvoxamine/pharmacology , Humans , Male , Middle Aged , Prescription Drugs , Retrospective Studies , Risk , SARS-CoV-2 , Serotonin Uptake Inhibitors/pharmacology , Sertraline , United States
3.
Zh Nevrol Psikhiatr Im S S Korsakova ; 121(5. Vyp. 2): 122-128, 2021.
Article in Russian | MEDLINE | ID: covidwho-1362772

ABSTRACT

Since the WHO declared the COVID-19 outbreak a pandemic, the most actual problem has been a change in the lifestyle of the population of Russia and the rest of the world. Fear of illness, self-isolation/quarantine, and decreased quality of life have dramatically increased the level of stress-related disorders in the population. The main mental disorders arising from stress refer to anxiety disorders (post-traumatic stress disorder (PTSD), panic disorder, agoraphobia, social phobia, generalized anxiety disorder), obsessive-compulsive disorder, depressions of varying severity and conversion reactions. The symptoms and early warning signs of stress-related disorders may be chronic or episodic. Stress-related disorders are corrected with psychotropic therapy, which aims to restore the balance of neurotransmitters. Current first choice agents for the treatment of both pathological anxiety and depression are selective serotonin reuptake inhibitors (SSRIs). During the pandemic, the SSRI fluvoxamine is of special interest. Its mechanisms of action are recognized as potentially useful for treating COVID-19 infection. Two studies confirming the efficacy and safety of fluvoxamine in the treatment of coronavirus infection are described.


Subject(s)
COVID-19 , Stress Disorders, Post-Traumatic , Anxiety Disorders , Fluvoxamine , Humans , Quality of Life , SARS-CoV-2
8.
In Vivo ; 35(2): 965-968, 2021.
Article in English | MEDLINE | ID: covidwho-1100485

ABSTRACT

BACKGROUND/AIM: Adult outpatients with symptomatic COVID-19 treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days. Fluvoxamine strongly binds to the sigma-1 receptor (S1R) that regulates inflammation by inhibiting the production of cytokines, believed to be responsible for severe COVID-19. We evaluated the S1R locus on chr 9p13.3 in subjects tested positive for SARS-CoV-2. We focused on SNP rs17775810 that has been previously identified by examining loss-of-function mutations in the S1R gene associated with distal hereditary motor neuropathy. PATIENTS AND METHODS: We utilized UK Biobank (UKB) data. Data processing was performed on Minerva, a Linux mainframe with Centos 7.6, at the Icahn School of Medicine at Mount Sinai. RESULTS: The effect of rs17775810 genotype on survival was significant (p=0.036, 2 tailed Fisher exact test). The minor allele homozygotes (TT) had the lowest death rate (0%), whereas the non-TT genotypes (i.e. CT and CC) had the highest death rate (16.2%). CONCLUSION: The rs17775810 analysis corroborates the favorable effect of fluvoxamine on COVID-19 survival.


Subject(s)
Biological Specimen Banks/statistics & numerical data , COVID-19/genetics , Polymorphism, Single Nucleotide , Receptors, sigma/genetics , Alleles , Anti-Anxiety Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Cohort Studies , Female , Fluvoxamine/therapeutic use , Genotype , Homozygote , Humans , Male , Middle Aged , Receptors, sigma/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Survival Analysis , United Kingdom
9.
Int J Mol Sci ; 22(4)2021 Feb 11.
Article in English | MEDLINE | ID: covidwho-1079663

ABSTRACT

Lysosomotropism is a biological characteristic of small molecules, independently present of their intrinsic pharmacological effects. Lysosomotropic compounds, in general, affect various targets, such as lipid second messengers originating from lysosomal enzymes promoting endothelial stress response in systemic inflammation; inflammatory messengers, such as IL-6; and cathepsin L-dependent viral entry into host cells. This heterogeneous group of drugs and active metabolites comprise various promising candidates with more favorable drug profiles than initially considered (hydroxy) chloroquine in prophylaxis and treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections/Coronavirus disease 2019 (COVID-19) and cytokine release syndrome (CRS) triggered by bacterial or viral infections. In this hypothesis, we discuss the possible relationships among lysosomotropism, enrichment in lysosomes of pulmonary tissue, SARS-CoV-2 infection, and transition to COVID-19. Moreover, we deduce further suitable approved drugs and active metabolites based with a more favorable drug profile on rational eligibility criteria, including readily available over-the-counter (OTC) drugs. Benefits to patients already receiving lysosomotropic drugs for other pre-existing conditions underline their vital clinical relevance in the current SARS-CoV2/COVID-19 pandemic.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Discovery , Lysosomes/drug effects , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Chlorpromazine/pharmacokinetics , Chlorpromazine/pharmacology , Chlorpromazine/therapeutic use , Cytokine Release Syndrome/drug therapy , Drug Discovery/methods , Drug Repositioning/methods , Fluvoxamine/pharmacokinetics , Fluvoxamine/pharmacology , Fluvoxamine/therapeutic use , Humans , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Interleukin-1/antagonists & inhibitors , Interleukin-1/immunology , Interleukin-6/antagonists & inhibitors , Interleukin-6/immunology , Lung/drug effects , Lung/immunology , Lung/metabolism , Lung/virology , Lysosomes/immunology , Lysosomes/metabolism , Lysosomes/virology , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Small Molecule Libraries/pharmacokinetics , Small Molecule Libraries/therapeutic use , Virus Replication/drug effects
10.
JAMA ; 324(22): 2292-2300, 2020 12 08.
Article in English | MEDLINE | ID: covidwho-1017844

ABSTRACT

Importance: Coronavirus disease 2019 (COVID-19) may lead to serious illness as a result of an excessive immune response. Fluvoxamine may prevent clinical deterioration by stimulating the σ-1 receptor, which regulates cytokine production. Objective: To determine whether fluvoxamine, given during mild COVID-19 illness, prevents clinical deterioration and decreases the severity of disease. Design, Setting, and Participants: Double-blind, randomized, fully remote (contactless) clinical trial of fluvoxamine vs placebo. Participants were community-living, nonhospitalized adults with confirmed severe acute respiratory syndrome coronavirus 2 infection, with COVID-19 symptom onset within 7 days and oxygen saturation of 92% or greater. One hundred fifty-two participants were enrolled from the St Louis metropolitan area (Missouri and Illinois) from April 10, 2020, to August 5, 2020. The final date of follow-up was September 19, 2020. Interventions: Participants were randomly assigned to receive 100 mg of fluvoxamine (n = 80) or placebo (n = 72) 3 times daily for 15 days. Main Outcomes and Measures: The primary outcome was clinical deterioration within 15 days of randomization defined by meeting both criteria of (1) shortness of breath or hospitalization for shortness of breath or pneumonia and (2) oxygen saturation less than 92% on room air or need for supplemental oxygen to achieve oxygen saturation of 92% or greater. Results: Of 152 patients who were randomized (mean [SD] age, 46 [13] years; 109 [72%] women), 115 (76%) completed the trial. Clinical deterioration occurred in 0 of 80 patients in the fluvoxamine group and in 6 of 72 patients in the placebo group (absolute difference, 8.7% [95% CI, 1.8%-16.4%] from survival analysis; log-rank P = .009). The fluvoxamine group had 1 serious adverse event and 11 other adverse events, whereas the placebo group had 6 serious adverse events and 12 other adverse events. Conclusions and Relevance: In this preliminary study of adult outpatients with symptomatic COVID-19, patients treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days. However, the study is limited by a small sample size and short follow-up duration, and determination of clinical efficacy would require larger randomized trials with more definitive outcome measures. Trial Registration: ClinicalTrials.gov Identifier: NCT04342663.


Subject(s)
COVID-19/drug therapy , Clinical Deterioration , Fluvoxamine/therapeutic use , Adult , Double-Blind Method , Female , Fluvoxamine/adverse effects , Humans , Illinois , Male , Middle Aged , Missouri , Outpatients , Treatment Outcome
12.
Psychopharmacology (Berl) ; 238(2): 611, 2021 02.
Article in English | MEDLINE | ID: covidwho-1002070
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