Comparative Treatment Response to Intermittent Theta Burst Stimulation in Long COVID-Associated Depression Versus Major Depressive Disorder: A Propensity Score-Matched Retrospective Cohort Study.

Background

Long COVID has emerged as a global health challenge characterized by persistent neuropsychiatric symptoms, including depression, fatigue, and cognitive impairment. Growing evidence indicates that sustained neuroinflammation, endothelial dysfunction, and fronto-limbic network disruption may underlie these symptoms, representing pathophysiological features distinct from major depressive disorder (MDD). Although repetitive transcranial magnetic stimulation (rTMS) is an established treatment for MDD, its therapeutic efficacy in Long COVID-associated depression remains uncertain.

Methods

Long COVID was defined as laboratory-confirmed SARS-CoV-2 infection followed by persistent neuropsychiatric symptoms lasting ≥3 months, including cognitive impairment ("brain fog"), fatigue, and new-onset depressive symptoms. We conducted a retrospective registry-based cohort study using real-world clinical data from two TMS clinics in Tokyo (May 2022-April 2026). Forty-four medication-free patients with Long COVID-associated MDD were compared with eighty-eight propensity score-matched patients with primary MDD (1:2 nearest-neighbor matching based on age, sex, and baseline Montgomery-Åsberg Depression Rating Scale (MADRS)). All participants received left dorsolateral prefrontal cortex intermittent theta burst stimulation (iTBS). Treatment outcomes were evaluated using MADRS and 17-item Hamilton Depression Rating Scale (HAM-D17) improvement rates, HAM-D17 response, and remission. Statistically adjusted analyses (inverse probability of treatment weighting (IPTW) and doubly robust estimation) were used to reduce measured confounding; however, residual unmeasured confounding cannot be excluded due to the retrospective observational design.

Results

Long COVID patients showed significantly attenuated antidepressant response. Improvement rates were markedly lower for MADRS (38.4% vs. 61.5%) and HAM-D17 (36.7% vs. 58.4%). IPTW and doubly robust models demonstrated large adjusted percentage-point differences (MADRS: -23.0 percentage points; HAM-D17: -21.8 percentage points; both p < 0.001). While HAM-D17 response did not differ significantly, remission rates were substantially reduced (27.3% vs. 61.4%).

Conclusions

These findings indicate an adjusted association suggesting reduced rTMS responsiveness in Long COVID-associated depression. Given the retrospective observational design and the possibility of residual unmeasured confounding, the results should be interpreted as associations rather than evidence of a causal effect.