Fluvoxamine modestly reduced long COVID fatigue over 90 days; metformin was inconclusive

Design

Randomised, placebo-controlled, adaptive Bayesian trial

Population

399 adults in Brazil with fatigue 90 days to 24 months after SARS-CoV-2 infection

Primary outcome

Change in Fatigue Severity Scale score

Effect

Fluvoxamine vs placebo: −0.43 at day 60, −0.58 at day 90; posterior probability of superiority 99%

This adaptive, placebo-controlled trial at outpatient sites in Brazil enrolled 399 adults with fatigue 3 to 24 months after confirmed SARS-CoV-2 infection. Participants took fluvoxamine 100 mg twice daily, extended-release metformin, or placebo for 60 days and were followed to day 90. The metformin dose was cut from 750 mg to 500 mg twice daily because of side effects, and the arm was later stopped for futility.

On the Fatigue Severity Scale, scored 1 to 7 with a median baseline of about 5.6 to 5.9, fluvoxamine lowered scores more than placebo by 0.43 points at day 60 and 0.58 at day 90, with a Bayesian probability of superiority of 99%. Quality of life also improved. Adverse events were less frequent with fluvoxamine (24.0%) than with placebo (35.5%) or metformin (over 42%).

The benefit is consistent but small, and nothing is known beyond 90 days or about other long COVID symptoms. For patients with disabling fatigue and few options, it is a reasonable conversation; it is not yet an established treatment, and fluvoxamine's interactions need checking first.

• Fluvoxamine 100 mg twice daily is worth discussing with adults whose long COVID fatigue persists, as an off-label option.
• Check interactions before prescribing: fluvoxamine strongly inhibits CYP1A2, raising levels of clozapine, theophylline and tizanidine.
• Set expectations: the average improvement was about half a point on a seven-point scale.
• Review at 8–12 weeks; benefit beyond 90 days is unknown.
• Metformin did not show benefit for fatigue and was poorly tolerated at the higher dose.

Why it matters

It is a rare randomised positive result in long COVID, using a cheap, widely available drug.

Don't overread it

A small, short-term improvement in one symptom does not make fluvoxamine a treatment for long COVID as a whole.

The statistics, in plain English

A 99% posterior probability of superiority means the data make it very likely fluvoxamine is better than placebo, but not that it is much better. The difference of 0.4–0.6 points is close to what many consider the smallest change patients notice on this scale.

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