Background: The effects of the COVID-19 pandemic have been devastating. Given the novelty of the virus, only a few effective treatments have emerged to decrease mortality from SARS-CoV-2 infection. The morbidity and mortality of SARS-CoV-2 is thought to be due to increased proinflammatory markers including interlukin-6 activity, tumor necrosis factor, and cytokine storm.¹ As the search for novel treatments have progressed, the association between treatment with selective serotonin reuptake inhibitors (SSRI) and decreased mortality has emerged.

Previous studies have demonstrated that SSRIs may have anti-inflammatory effects that mitigate the significant proinflammatory response of SARS-CoV-2 infection.^2,3 Studies specifically evaluating the benefits of SSRIs on patients infected with SARS-CoV-2 have demonstrated an association with decreased mortality and rates of intubation,⁴ decreased clinical deterioration,⁵ and decreased hospitalization and residual symptoms.⁶ Unfortunately, these studies were either retrospective in nature, or small prospective clinical trial with a short follow-up time (30 days) and inadequate power.

Paper: Oskotsky T, et al. Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants. JAMA Netw Open. 2021 PMID: 34779847; PMCID: PMC8593759.⁷

Clinical Question: Are selective serotonin reuptake inhibitors (SSRIs) associated with a lower mortality risk among patients with COVID-19?

What They Did:

Population:

• Retrospective cohort study using propensity score matching data from the Cerner Real World Data COVID-19 deidentified EHR database (January to September 2020)
  • 83,584 patients across 87 healthcare centers
  • Diagnosis of COVID-19 or COVID-19 exposure and
    • Emergency department visit or urgent care visit, or
    • Admitted for observation or hospitalized
  • Inclusion Criteria:
    • Adults 18 years and older
    • Confirmed COVID-19 diagnosis:
      • Positive SARS-CoV-2 nucleic acid amplification test and immunoassay, and/or
      • ICD-10 code (COVID-19 confirmed by laboratory testing)
    • Medication order for an SSRI 10 days prior and 7 days after COVID-19 diagnosis
      • Order status = active or completed
      • Order status as needed
    • Exclusion Criteria:
      • Other SSRI order status (inactive, discontinued, or unknown)
      • SSRI prescription outside of the 10 days prior and 7 days after COVID diagnosis

Intervention:

• COVID-19 diagnosis and treatment with an SSRI within the prespecified timeframe
• SSRIs included:
  • citalopram hydrobromide, escitalopram oxalate, paroxetine hydrochloride, paroxetine mesylate, sertraline hydrochloride, fluoxetine, vortioxetine hydrobromide, fluvoxamine, and vilazodone hydrochloride

Comparator:

• Propensity score matched patients by demographic characteristics, comorbidities, and medication indication (using ICD-9 and ICD-10 diagnosis codes):
  • Hypertension
  • Diabetes
  • COPD
  • Heart conditions
  • Cerebrovascular disease
  • Cancer
  • CKD
  • Mood and anxiety disorders
  • Other psychiatric disorders not mood or anxiety disorders
  • Obesity (BMI 30)

Outcome:

• Primary Outcome: Death after onset of COVID-19

Results:

• 3,401 patients with COVID-19 prescribed SSRIs
  • Fluoxetine only = 470 patients
  • Fluoxetine or Fluvoxamine = 481 patients
  • Other SSRIs = 2,898 patients
  • Inpatient = 44.1% of patients
  • ED Visit = 50.8% of patients
  • Age 40 – 69 = 48.3% of patients
  • Obesity = 37.4% of patients
• Mortality:
  • SSRI-Treated Patients: 14.6% (497/3401)
  • Untreated Controls: 16.3% (1107/6802)
  • Relative reduction (RR): 8% (0.92 [95% CI 0.85-0.99]; adjusted P = 0.03)
  • Absolute risk reduction (ARR): 1.7%
• Mortality:
  • Fluoxetine-Treated Patients: 9.8% (46/470)
  • Untreated Controls: 13.3% (937/7050)
  • RR: 28% (0.72 [95% CI 0.54-0.97]; adjust P = 0.03)
  • ARR: 3.5%
• Mortality:
  • Fluoxetine- or Fluvoxamine Treated Patients: 10% (48/481)
  • Untreated Controls: 13.3-13.4% (956 or 964/7215)
  • RR: 26% (0.74 [95% CI 0.55-0.99]; adjusted P = 0.04)
  • ARR: 3.3%
• Mortality:
  • SSRI Other than Fluoxetine or Fluvoxamine: 4% (447/2898)
  • Untreated Controls: 17.0% (1474/8694)
  • RR: 8% (0.92 [95% CI 0.84-1.00], adjusted P = 0.06)
  • ARR: 1.6%
  • NOT STATISTICALLY SIGNIFICANT

Strengths:

• Asks a relevant clinical question to possible treatment options to decrease mortality in COVID-19
  • Relatively safe and cost-effective treatment with few side-effects
• Only included patients with a medication order for SSRI (proof the patient was taking the medication and it was not just prescribed and not taken)
• Robust propensity score matching
• Large study population in the United States
• Adequately powered study

Limitations:

• Retrospective study and can only infer associations, NOT causation
• Small number of patients taking fluvoxamine (n = 11) vs fluoxetine (n=270). Although they share similar mechanisms of action, the number is too small to draw any robust conclusions about fluvoxamine.
• Other SSRIs were included in the study but were not looked at specifically like fluvoxamine and fluoxetine were. Given this, it is difficult to draw conclusions regarding other SSRI than fluoxetine.
• Although there was robust propensity score matching, some unknown unmatched confounding variables may be present between groups
• Using ICD codes to identify diagnoses may miss risk factors or other diagnoses not documented in the EHR
• May have excluded patients taking an SSRI not documented in the EHR
• May not be externally valid for centers outside of the United States

Discussion:

• There was a small, statistically significant reduction of 8% in the relative risk (absolute risk reduction 1.7%) of mortality among patients with COVID-19 prescribed SSRIs when compared with matched control patients
• Subgroup analysis found a statistically significant reduction of 28% in the relative risk (absolute risk reduction 3.5%) of mortality among patients with COVID-19 prescribed fluoxetine compared with matched control patients
• Hypothetical Pathophysiologic Reasoning for SSRIs in COVID-19:
  • Decrease Potential for Cytokine Storm: Decrease levels of cytokines and interleukin 6 signaling activity
  • Decrease Inflammation: Modulate the sigma-1 receptor-IRE1 pathway
  • Inhibit Viral Entry/Infection: Inhibiting effect on acid sphingomyelinase/ceramide system
  • Antiviral Effects

Author Conclusions:

“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.”

Conclusion:

Multiple studies, including this one have demonstrated the potential benefit of SSRIs in patients infected with SARS-CoV-2. The pathophysiology of the benefit seems justified (decreased inflammatory and cytokine response). Unfortunately, although some treatments have sound pathophysiology, they may not demonstrate true clinical benefit when evaluated in prospective clinical trials (i.e. there may be confounding variables unaccounted for).

References:

1. Costela-Ruiz VJ, et al. SARS-CoV-2 Infection: the role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev. PMID: 32513566; PMCID: PMC7265853
2. Hannestad J et al. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. 2011. PMID: 21796103; PMCID: PMC3194072.
3. Sacre S, et al. Fluoxetine and citalopram exhibit potent anti-inflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptors. Arthritis Rheum. PMID: 20131240.
4. Hoertel N, et al. Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study. Mol Psychiatry. PMID: 3353545.
5. Lenze EJ, et al. Fluoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. 2020. PMID: 33180097; PMCID: PMC7662481
6. Seftel D, Boulware DR. Prospective cohort of fluvoxamine for early treatment of coronavirus disease 19. Open Forum Infect Dis. PMID: 33623808; PMCID: PMC7888564.
7. Oskotsky T, et al. Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants. JAMA Netw Open. 2021 PMID: 34779847; PMCID: PMC8593759.

Statistical Analysis Footnotes:

• Propensity score matching characteristics with control patients:
  • SSRI-treated patients (1:2)
  • Fluoxetine-treated patients (1:15)
  • Fluoxetine- or fluvoxamine-treated patients (1:15)
  • SSRI other than fluoxetine or fluvoxamine (1:3)
• Logistic regression based on:
  • Age, sex, race, and ethnicity
  • Encounter type
  • Comorbidities
  • SSRI prescription indication
• Age = continuous variable. All others as categorical variables
• Standard deviation before and after propensity scores calculated
• Density plots of the distribution of propensity scores before and after matching to ensure equal groups
• Bootstrapping to explore variability and demonstrate robustness (10 iterations for each comparison)
• Benjamini-Hochberg-corrected P values (attempt to control for significant P values that occur by chance i.e false discovery rate)
  • Increased power at the risk of increased Type I error (difference when indeed there is no difference)

Guest Post By:

Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srrezaie)

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