Background: Post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID, affects 31–69% of COVID-19 survivors and presents with heterogeneous symptom clusters including cognitive impairment ("brain fog") and elevated cardiovascular risk. Despite affecting millions globally, no approved treatments exist that address both symptom domains simultaneously. Objective: This paper presents a novel therapeutic hypothesis—that selective serotonin reuptake inhibitors (SSRIs) may serve as dual-mechanism therapy for Long COVID by simultaneously improving cognitive function and reducing cardiovascular risk—generated through automated cross-paper knowledge synthesis. Methods: We employed the Sovereign Causal Graph architecture, a neuro-symbolic system combining local LLM extraction with P11-verification protocols, to build a causal knowledge base from 28 peer-reviewed publications (962 verified triplets). Gap-detection algorithms identified under-represented connections, and Claude Opus 4.5 performed cross-paper synthesis to identify emergent hypotheses. Results: Three convergent pathways were identified: (1) COVID-19 depletes serotonin by 23% through interferon-mediated tryptophan malabsorption, increased MAO activity, and kynurenine pathway diversion; (2) Serotonin deficiency impairs vagus nerve signaling via 5-HT3 receptors, leading to hippocampal dysfunction; (3) Reduced platelet serotonin storage contributes to hypercoagulability. A critical "bridge triplet" demonstrates that SSRIs simultaneously increase synaptic serotonin while depleting platelet serotonin. Conclusion: This AI-generated hypothesis suggests SSRIs may provide dual therapeutic benefit in Long COVID patients presenting with combined cognitive and cardiovascular symptoms. A randomized controlled trial with dual primary endpoints is proposed.
David Tom Foss (Tue,) studied this question.