Donepezil ameliorates fatigue and depression in PASC patients with HHV-6B SITH-1-induced acetylcholine deficiency

The pathogenesis of post-acute sequelae of SARS-CoV-2 infection (PASC) remains poorly understood, and no effective treatment has been established. Reactivation of latent herpesviruses, particularly human herpesvirus 6B (HHV-6B), has been proposed as a possible contributor to the neuropsychiatric symptoms observed in PASC. SITH-1, a latency-associated protein expressed during HHV-6B reactivation in olfactory bulb astrocytes, induces specific antibody responses that can be detected in peripheral blood. Importantly, SITH-1 has also been identified as a risk factor for depression, suggesting a mechanistic link between HHV-6B reactivation and the development of neuropsychiatric symptoms.

We measured serum anti-SITH-1 antibody titers in 156 PASC patients and compared them to healthy controls. In this PASC cohort, neuropsychiatric symptoms were assessed using numerical rating scales. In parallel, we developed a mouse model in which SITH-1 was transiently expressed in the olfactory bulb to assess its impact on brain function and behavior. We also conducted a subgroup analysis of a previously reported randomized clinical trial (RCT) of donepezil, stratifying PASC patients by anti-SITH-1 antibody status.

Anti-SITH-1 antibody positivity was observed in 62.8% of PASC patients, a significantly higher proportion than in controls. Seropositive patients exhibited more severe fatigue and depressive symptoms. In the mouse model, SITH-1 expression led to reduced acetylcholine production and depression-like behavior, both of which were ameliorated by donepezil. In the clinical trial subgroup of 73 PASC patients, 71.7% were seropositive for anti-SITH-1 antibodies. Among these individuals, donepezil significantly improved fatigue and depression scores, as measured by the Chalder Fatigue Scale and the depression subscale of the Hospital Anxiety and Depression Scale (HADS).

These findings suggest that HHV-6B reactivation in the olfactory bulb, as indicated by anti-SITH-1 antibody titers, may contribute to fatigue and depression in a subset of PASC patients. Donepezil may be effective in this subgroup, and these findings support the use of anti-SITH-1 antibody titers as a companion diagnostic marker for targeted treatment in PASC.