Fatigue, cognitive problems, post-exertional malaise (PEM) and postural orthostatic tachycardia syndrome (POTS) are common and debilitating symptoms after COVID-19. The pathophysiology of post-COVID is not well understood and there is no established biomedical treatment. Treatment options for post-COVID are thus much needed.

A promising candidate intervention is fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), that may reduce post-COVID symptoms because of its regulatory effect on the (neuro) immune system, the hypothalamic-pituitary-adrenal (HPA) axis and the tryptophan system. The investigators will randomize 160 participants to either fluvoxamine or placebo for 12 weeks.

The investigators will use advanced functional neuroimaging techniques during cognitive challenge (optional substudy) and plasma biomarkers (inflammatory markers, cortisol, serotonin, IDO-2 activity), to facilitate identifying potential mechanistic pathways of post -COVID treatment.

In this randomized placebo-controlled trial, the investigators will study the effectiveness of fluvoxamine in reducing fatigue severity (primary outcome), cognitive problems, PEM and POTS after 12 weeks of treatment in 160 post-COVID patients.

Moreover, the investigators will study treatment-emergent changes in plasma biomarkers, including blood-based neuro)inflammatory markers, cortisol, serotonin, aryl hydrocarbon receptor -indoleamine 2,3-dioxygenase-2 (IDO-2) and kynurenine pathway (KP) metabolites for potential mechanistic pathways of post-COVID treatment.

Numerous studies have indicated involvement of brain dysfunction in post COVID, which also relate to the degree of symptom severity (e.g. fatigue / cognitive problems). In an optional neuro-imaging sub-study, the investigators will use functional neuroimaging techniques with and without cognitive challenge to gain a better understanding of the brain functioning and structure in long COVID during fluvoxamine treatment versus placebo.

Objectives:

• To determine if fluvoxamine treatment (50 mg to 200 mg daily dosing) results in lower levels of fatigue severity than placebo after 12 weeks of treatment (primary).
• To determine if fluvoxamine treatment results in lower levels of PEM and POTS and a better cognitive functioning and health-related quality of life (HRQL) than placebo.
• To determine if changes in symptoms, i.e. fatigue severity, PEM, POTS, cognitive symptoms, are related to changes in biomarkers, i.e., (neuro)inflammation markers, cortisol, serotonin and IDO-2 -KP metabolites.
• To determine if biomarkers, i.e., (neuro)inflammation markers, cortisol, serotonin and IDO-2- KP metabolites, change from baseline to week 12 in participants who received fluvoxamine.

Optional Neuro-imaging sub-study:

-To determine which changes occur on functional brain imaging, brain metabolites and neuroinflammation during cognitive challenge and to determine if this brain response to cognitive challenge changes after fluvoxamine treatment versus placebo.

Inclusion Criteria:

• Adults aged 18 to 70 years
• Severely fatigued (CIS fatigue score ≥ 35) at screening
• Fatigue started/increased significantly after Covid-19 (self-declared)
• Fatigue symptoms must be present for at least 3 months following the acute infection.
• Self-reported confirmation of having a SARS-CoV-2 infection by: Positive SARS-CoV-2 nucleic acid amplification test (NAAT), such as PCR; Positive SARS-CoV-2 rapid diagnostic test, including home-administered tests; COVID-19 diagnosis by a medical specialist (GP or in-hospital), based on the above or other clinical test or assessments. The above information will not be verified in medical records.
• Command of Dutch or English language to complete questionnaires
• Able to participate in video calling.
• Willing and able to provide informed consent
• Allowing the trial team to exchange medical information that is relevant for the participants' safety and trial assessments with their GP and pharmacy.

Exclusion Criteria:

• Use of medication with interaction with fluvoxamine that cannot be discontinued
• Hospitalized in the acute phase of Covid-19
• Psychiatric/somatic disorders that could explain the severity of fatigue
• Neurodegenerative disorders (i.e. M Parkinson, Multiple sclerosis, M Alzheimer)
• Suicidality (current or recent) (according to WHO suicide screener)
• Starting or started with other medication intended to reduce post-covid symptoms during the last 2 months
• Pregnancy (a positive urine or serum pregnancy test) or unwilling to use standard contraception
• Brugada- or Long QT interval syndrome
• epilepsy, porphyria, history of severe liver impairment
• known allergies to fluvoxamine or placebo/excipients
• known current alcohol or drug use problems.
• Bleeding disorders and past medical history of bleeding gastric or duodenal ulcers or other significant bleeding disorders
• claustrophobia (optional MRI substudy)
• having metal implants (optional MRI substudy)
• inability to lay still for 45 minutes (optional MRI substudy)
• Neurotrauma/ large stroke or brain abnormalities interfering with image analyses (optional MRI substudy)
• Inability to come to the Amsterdam UMC (optional MRI substudy).

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