Depression
A depressive episode — which can be triggered by inflammation and independently worsens fatigue and cognition.
Depression can be both a consequence of chronic illness and inflammation and an independent driver of fatigue, poor concentration, and unrefreshing sleep. It is cheap to screen for (PHQ-9 or a clinical interview) and treatable, and treating genuine comorbid depression can lift fatigue and function regardless of the other mechanisms in play. This is identified and treated on its own terms — antidepressants, therapy, exercise as tolerated — not as a claim that the rest of the illness is psychological.
How it's tested
Depression screen (PHQ-9)
A short validated questionnaire for depressive symptoms.
Treatment options & their evidence
Graded honestly — including treatments that failed in good trials, which is worth knowing.
Cognitive behavioral therapy (CBT)
Strong evidencepromise 3 · 2 RCTsThe best-evidenced behavioral option for fatigue/coping (e.g. the ReCOVer 'Fit after COVID' RCT). It targets perpetuating factors and does NOT assume a psychological cause; note it improves subjective fatigue more than objective activity or cognition.
Caution: Must not include graded-activity escalation where PEM is present, and must avoid 'dysfunctional beliefs' framing.
Antidepressants (e.g. vortioxetine, SSRIs)
Failed in trialsCautionpromise 0 · 1 RCTVortioxetine missed its primary cognitive endpoint for Long COVID (signal only in high-inflammation subgroups). Clearest role is genuine comorbid depression, not Long COVID cognition itself.
Caution: SSRIs can worsen fatigue and sexual function; don't overstate subgroup findings.