Effect of fluvoxamine on preventing neuropsychiatric symptoms of post COVID syndrome in mild to moderate patients, a randomized placebo-controlled double-blind clinical trial
Ramin Hamidi Farahani, Ali Ajam, Alireza Ranjbar Naeini
BMC Infectious Diseases, doi:10.1186/s12879-023-08172-5
Background Shortly after the Coronavirus disease 2019 (COVID-19) pandemic, a considerable number of recovered patients reported persisting symptoms, especially neuropsychological manifestations, which were later named post-COVID syndrome (PCS). Immune dysregulation was suggested as one of the main mechanisms for PCS. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) that is mostly used to treat depression, anxiety disorders, and obsessivecompulsive disorder, has been suggested as an anti-COVID drug due to its anti-inflammatory effects, mainly through the sigma-1 receptor. Therefore, we aimed to evaluate fluvoxamine's effect on PCS neuropsychiatric symptoms.
Method In this double-blind randomized clinical trial, we included confirmed mild to moderate COVID-19 outpatients using polymerase chain reaction (PCR) by an infectious disease specialist. The presence of severe COVID-19 symptoms was evaluated by the infectious disease specialist and included dyspnea, SpO2 < 94% on room air, PaO2/ FiO2 < 300 mm Hg, a respiratory rate > 30 breaths/min, and lung infiltrates > 50%. Then we performed permuted block randomization and assigned patients 1:1 into two groups to either receive fluvoxamine 100 mg tablet or a placebo daily for 10 days. Eligible patients were evaluated after 12 weeks for the presence of fatigue, as the primary, and other PCS symptoms as secondary outcomes.
Results We screened a total of 486 patients from March to June 2022. After 12 weeks, 42 patients receiving fluvoxamine and 43 patients receiving Placebo were evaluated for PCS. Patients had a mean age of 38.5 ± 14.1 and 48% of them were women. Fatigue was significantly lower in the fluvoxamine group (p-value 0.026). No significant differences were observed in other symptoms.
Conclusion We concluded that taking fluvoxamine during active COVID-19 can reduce the chance of fatigue but the advantage of fluvoxamine was not observed for other symptoms. Further studies are necessary to confirm these preliminary results.
Authors' contributions A. Ajam contributed to interpreting the data, draft writing, and final editing. A. Ranjbar Naeini contributed to research design and final editing. R. Hamidi Farahani contributed to the research design and revised it critically. The author(s) read and approved the final manuscript.
Funding All funding support was provided by the AJAUMS.
Declarations Ethics approval and consent to participate Informed consent was obtained from all study participants. The protocol of this study is by the 2013 Helsinki declaration and was approved by the Ethics Committee of AJA University of Medical Sciences (AJAUMS), Ethics ID: IR.AJAUMS.REC.1400.302. This RCT was registered in the Iranian registry of clinical trials (IRCT), a primary registry in the WHO registry network (registration number: IRCT20220526054990N1) on 01/06/2022.
Consent for publication Not applicable.
Competing interests The authors declare no competing interests.
Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Bech, Rasmussen, Olsen, Noerholm, Abildgaard, The sensitivity and specificity of the Major Depression Inventory, using the Present State Examination as the index of diagnostic validity, J Affect Disord
Cao, Liu, Xiong, Cai, Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2: A systematic review and metaanalysis, J Med Virol
Carfì, Bernabei, Landi, Persistent symptoms in patients after acute COVID-19, JAMA
Carroll, Neumann, Aguero-Rosenfeld, Lighter, Czeisler et al., Post-COVID-19 inflammatory syndrome manifesting as refractory status epilepticus, Epilepsia
Davido, Seang, Tubiana, De Truchis, Post-COVID-19 chronic symptoms: a postinfectious entity?, Clin Microbiol Infect
De, Michielsen, Heck, Drent, Measuring fatigue in sarcoidosis: the Fatigue Assessment Scale (FAS), Br J Health Psychol
Desgranges, Tadini, Munting, Regina, Filippidis et al., PostCOVID19 syndrome in outpatients: a Cohort Study, J Gen Intern Med
Fernandez-De-Las-Penas, Palacios-Cena, Gomez-Mayordomo, Cuadrado, Florencio, Defining Post-COVID Symptoms (Post-Acute COVID, Long COVID, Persistent Post-COVID): An Integrative Classification, Int J Environ Res Public Health
Hamilton, The assessment of anxiety states by rating, Br J Med Psychol
Hashimoto, Suzuki, Hashimoto, Mechanisms of action of fluvoxamine for COVID-19: a historical review, Mol Psychiatry
Kamal, Omirah, Hussein, Saeed, Assessment and characterisation of post-COVID-19 manifestations, Int J Clin Pract
Kayaaslan, Eser, Kalem, Kaya, Kaplan et al., Post-COVID syndrome: A single-center questionnaire study on 1007 participants recovered from COVID-19, J Med Virol
Lee, Vigod, Bortolussi-Courval, Hanula, Boulware et al., Fluvoxamine for outpatient management of COVID-19 to prevent hospitalization: A systematic review and meta-analysis, JAMA Netw Open
Lenze, Mattar, Zorumski, Stevens, Schweiger et al., Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: A randomized clinical trial, JAMA
Mazza, Lorenzo, Conte, Poletti, Vai et al., Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors, Brain Behav Immun
Mccain, Antidepressants and suicide in adolescents and adults: a public health experiment with unintended consequences?, P T
Moreno-Perez, Merino, Leon-Ramirez, Andres, Ramos et al., Post-acute COVID-19 syndrome. Incidence and risk factors: A Mediterranean cohort study, J Infect
Nalbandian, Sehgal, Gupta, Madhavan, Mcgroder et al., Post-acute COVID-19 syndrome, Nat Med
Nasserie, Hittle, Goodman, Assessment of the frequency and variety of persistent symptoms among patients with COVID-19: A systematic review, JAMA Netw Open
Papakostas, Perlis, Scalia, Petersen, Fava, A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder, J Clin Psychopharmacol
Posternak, Zimmerman, Is there a delay in the antidepressant effect? A meta-analysis, J Clin Psychiatry
Reis, Moreira-Silva, Silva, Thabane, Milagres et al., Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial, Lancet Glob Health
Rosen, Seki, Fernández-Castañeda, Beiter, Eccles et al., Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis, Sci Transl Med
Salehi, Abedi, Balakrishnan, Gholamrezanezhad, Coronavirus disease 2019 (COVID-19): A systematic review of imaging findings in 919 patients, AJR Am J Roentgenol
Sayed, Shokry, Gomaa, Post-COVID-19 fatigue and anhedonia: A cross-sectional study and their correlation to post-recovery period, Neuropsychopharmacol Rep
Sukhatme, Reiersen, Vayttaden, Sukhatme, Fluvoxamine: A review of its mechanism of action and its role in COVID-19, Front Pharmacol
Szegedi, Jansen, Van Willigenburg, Van Der Meulen, Stassen et al., Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a metaanalysis including 6562 patients, J Clin Psychiatry
Taylor, Freemantle, Geddes, Bhagwagar, Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis, Arch Gen Psychiatry
Tenforde, Kim, Lindsell, Rose, Shapiro et al., Symptom duration and risk factors for delayed return to usual health among outpatients with Covid-19 in a multistate health care systems network -United States, March, MMWR Morb Mortal Wkly Rep
Wijeratne, Crewther, Post-COVID 19 Neurological Syndrome (PCNS); a novel syndrome with challenges for the global neurology community, J Neurol Sci