COVID-19 Update: An Interesting Study on Serotonin Antagonism

Background: We have tried to decrease the number of updates on COVID-19, as I am sure everyone is getting tired of all the trials coming out on this.  I know I am exhausted just reading through everything.  However, every so often I will try to bring updates that are relevant.  In this post we will cover an interesting trial that should be on your radar as more evidence arises on this treatment option. Paper: Lenze EJ et al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients with Symptomatic COVID-19: A Randomized Clinical Trial. JAMA 2020. PMID: 33180097

Clinical Question: Does fluvoxamine, given during mild COVID-19 infection, prevent clinical deterioration and decrease the severity of disease compared to placebo?

What They Did:

• Double-blind, placebo-controlled, randomized, fully remote (contactless) clinical trial of fluvoxamine vs placebo in the St. Louis metropolitan area
  • Fluvoxamine: 50mg in evening after baseline assessment, then 100mg BID x2d, then 100mg 3x/d through 15d
  • Placebo: Same schedule as above
• After completion of 15d of fluvoxamine or placebo, patients were given the option to receive a 6d open-label course of fluvoxamine (This was a change from the original study protocol)

Outcomes:

• Primary: Clinical deterioration within 15d of randomization meeting both criteria below:
  • Shortness of breath or hospitalization for shortness of breath or pneumonia
  • Oxygen saturation <92% on room air or need for supplemental oxygen to achieve O2 saturation of ≥92%
• Secondary:
  • Rating of clinical deterioration
  • Number of days requiring supplemental O2, hospitalization, and ventilator support

Inclusion:

• Non-hospitalized adults
• Confirmed severe acute respiratory syndrome COVID-19 infection
• Symptom onset within 7d
• O2 saturation ≥92%

Exclusion:

• COVID-19 requiring hospitalization
• Evidence of the primary endpoint with O2 saturation <92% on RA at the time of randomization
• Severe underlying lung disease (i.e. COPD or requiring home O2, ILD, pulmonary hypertension)
• Decompensated cirrhosis
• CHF (NYHA class III or IV)
• Immunocompromised (i.e. solid organ transplant or donor, bone marrow transplant, AIDS, or taking immunosuppressant biologic drugs or high dose corticosteroids [>20mg/d of prednisone])

Results:

• 152 patients enrolled
  • 115 (76%) completed the trial
  • Loss of smell was present in 29% of patients (Most common symptom)
• Clinical Deterioration (Primary Outcome):
  • Fluvoxamine: 0/80 patients (0%)
  • Placebo: 6/72 patients (8.3%)
  • Absolute Diff by Survival Analysis: 8.7%; 95% CI 1.8 to 16.4%; p = 0.009
• Adverse Events:
  • Fluvoxamine group had 1 serious adverse event and 11 other adverse events
  • Placebo group had 6 serious adverse events and 12 other adverse events

Strengths:

• Double-blind, placebo-controlled trial demonstrates feasibility of a fully remote study
• Focuses on a vulnerable population that has been neglected in research
• Follow up was done by email and by phone call to ensure patients without internet access were able to participate
• All outcome assessors, investigators, and research staff in contact with participants were blinded to treatment assignment
• Patients were fairly well balanced between groups in terms of demographics and clinical characteristics (i.e. baseline O2 sat)
• Evaluated missing data for randomness

Limitations:

• Shortness of breath is a subjective outcome and makes it difficult to objectively evaluate the effect of fluvoxamine
• 20% of patients did not complete their 15d assessment
• 13% of surveys were not filled out by participants
• Study performed in a single geographic region, with lack of heterogeneity in the population
• Small number of end point events making the results fragile

Discussion:

• This was a fully remote (contactless) trial, which shows that even during a pandemic, good research can be done. Study supplies were delivered to self-quarantined patients as a package left at their door along with the study materials (i.e. study medication, pulse oximeter, automated BP monitor, and a thermometer).  All assessments of vital signs were performed by patients and study staff called to follow up on these results.
• A rate of 20% for clinical deterioration in the placebo group and a reduction of 75% in the risk of clinical deterioration in the fluvoxamine group were chosen to determine the power calculation.
• Advantages of fluvoxamine for outpatient treatment of COVID-19 is it is safe, has widespread availability, low cost, and is a pill. Additionally it does not promote QT prolongation unlike other SSRIs, but can cause drug-drug interactions via inhibition of cytochromes P450, 1A2, and 2C19
• Follow up study is enrolling patients at Washington University —> STOP COVID-19 Trial [Link is HERELink is HERE]
• Why am I talking about this trial?
  • Because of the musings of Farid Jalali, MD (@farid__jalali) on the possibility that COVID19 may hypothetically have a component of serotonin dysregulation that may contribute to pathogenesis and morbidity in this illness (this is all plausible but also hypothetical)
  • A state of florid platelet/endothelial activation in the lung in severe COVID-19 has been repeatedly demonstrated in multiple studies. This platelet/endothelial activation cascade is a highly plausible target to intervene upon in severe cases, given the overwhelming evidence showing that micro- and macro-thrombosis appear to portend poor outcomes in COVID19. Treatment of this platelet/endothelial activation cascade requires 4 inter-related factors to be considered:
    • Platelets = in severe COVID19, a highly plausible goal may be to reduce the excess immune and thrombotic function of hyperreactive platelets (intervention choice is unclear – traditional anti-platelets, versus immunomodulators targeting immune signaling of activated platelets)
    • Endothelium = COVID19 lung injury has been demonstrated to cause endothelialitis in the affected lung regions. A plausible goal will be to avoid further endothelial injury in the “healthy” lung regions by reducing risk of VILI, by avoiding unnecessarily early IMV, and if requiring IMV, to reduce endothelial injury by avoiding alveolar hyperdistention that may occur with high PEEP, and/or high TV
    • Microthrombi = heparin-based products, properly dosed, may not only begin to resolve the relatively high burden of micro thrombi demonstrated in severe COVID19 lung, but these heparin-based products also have been shown to stabilize endothelium, and thereby curtail further exacerbation of the platelet-endothelial activation cascade brought on by COVID19. One word of caution is that DOACs typically lack the endothelial (and thereby platelet) stabilization characteristics of heparin-based products.
    • Platelet Mediators (i.e. serotonin) = Among many pro-aggregant and angiogenic mediators released by activated platelets, serotonin is an omnipotent mediator with a wide range of actions on multiple organs. Excess plasma serotonin is pathogenic, and therefore plasma levels of serotonin are regulated at very low levels under normal conditions, by actively storing 95% of total serotonin content of the body inside platelet granules. COVID19 has been demonstrated to be associated with quantifiably high levels of extracellular plasma serotonin. This is a natural product of platelet activation and degranulation (of serotonin out of platelet granules), combined with poor reuptake of serotonin due to co-existing pulmonary vasculopathy of acute COVID19. This excess plasma serotonin can have untoward and pathologic manifestations such as hyperactive delirium and inappropriate hyperpnea, which may be important contributors to the severity of COVID19.
    • SSRI have been shown to reduce the pool of serotonin available within platelets, thereby reducing the bioavailability of serotonin that could potentially be released in a pathologic manner in a case of severe COVID19. In addition to this, SSRIs have anti-inflammatory capabilities via the recently described sigma-1 receptor agonism.
    • Alternatively, on a case-by-case basis, serotonin antagonism with cyproheptadine can be employed during acute severe COVID19, should suspicion exist for signs of serotonin toxicity. In a cohort of ICU delirium (pre-COVID study), 16% of cases of delirium were due to unsuspected serotonin toxicity, with no classic culprits of serotonin toxicity present to predict such toxicity. The incidence of serotonin toxicity may theoretically be higher in COVID19 given the pathophysiologic nature of this disease (florid platelet degranulation of serotonin combined with pulmonary vasculopathy limiting reuptake of serotonin). The emphasis here is to be vigilant in monitoring for signs of serotonin toxicity, recognize it as a byproduct of severe COVID19, and not rule it out simply because patient lacks the typical medication culprits of serotonin toxicity (TCA, MAOI, etc).
    • A large question remains on whether or not SSRIs should be started de novo in hospitalized COVID19 patients on presentation, which is something that the JAMA RCT did not evaluate. In light of severe COVID19 being associated with excess plasma serotonin and given that SSRI use requires some length of time to reduce platelet content of serotonin (platelet lifespan is 10-12 days), caution is advised in extrapolating the JAMA RCT result to hospitalized patients.

Author Conclusion: “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.” 

Clinical Take Home Point: Although promising, the results of this study should be interpreted as hypothesis generating rather than as a demonstration of efficacy.  I suspect we will be hearing more about serotonin antagonism going forward as more trials come out.

References:

1. Lenze EJ et al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients with Symptomatic COVID-19: A Randomized Clinical Trial. JAMA 2020. PMID: 33180097

Post Peer Reviewed By: Farid Jalali, MD (@farid__jalali)

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