This is a monocentric, randomized pilot study conducted at the Max Planck Institute of Psychiatry, Munich. The study investigates the effects of two different intermittent theta-burst stimulation (iTBS) schedules on biological and clinical outcomes in patients with depression and comorbid Post-COVID-19 condition (PCC). Participants will be randomized into two arms, both receiving a total of 30 active iTBS sessions applied to the left dorsolateral prefrontal cortex (DLPFC) at 90% resting motor threshold using a PowerMAG 100 ppTMS stimulator:
* Standard Arm: One iTBS session per day, five days per week, over six weeks. * Intensified Arm: Six iTBS sessions per day, approximately one-hour apart, over five consecutive days.
The primary outcomes are changes in immunological blood markers (C-reactive protein \[CRP\], tumor necrosis factor \[TNF\], interleukin-1β \[IL-1β\], interleukin-6 \[IL-6\]) and depressive symptomatology measured by Beck Depression Inventory-II (BDI-II) and Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes include fatigue (Fatigue Severity Scale \[FSS\], Fatigue Scale for Motor and Cognitive Functions \[FSMC\], Post-Exertional Malaise questionnaire \[PEM\]), sleep quality (Pittsburgh Sleep Quality Index \[PSQI\]), daytime sleepiness (Epworth Sleepiness Scale \[ESS\]), functioning (Sheehan Disability Scale \[SDS\]), anxiety (Beck Anxiety Inventory \[BAI\]) and an exploratory adverse effect screening. Follow-up assessments will be performed three days after treatment completion and again at three months post-intervention to evaluate both short- and medium-term effects. Biospecimen collection will include approximately 141 ml of peripheral blood per participant across three time points (baseline, post-treatment, +3 days). Samples will be analyzed for inflammatory markers and securely stored in the institutional biobank of the Max Planck Institute of Psychiatry in accordance with data protection and ethical guidelines. Safety and tolerability will be continuously monitored, including documentation of adverse events. The results of this pilot study are expected to provide preliminary evidence on whether accelerated iTBS protocols may exert differential effects on neuroinflammatory processes and depressive symptomatology in patients with Post-COVID-19 condition, thereby informing larger controlled clinical trials.
Age 18-65 years
Capacity to consent (legally competent, written informed consent including data protection)
Diagnosis of depression (at least moderate severity, BDI-II ≥ 20), including major depressive episode in bipolar disorder
Comorbid diagnosis of Post-COVID-19 condition (WHO definition)
Age <18 years or >65 years
Pregnancy, planned pregnancy, or breastfeeding
Legal guardianship or cognitive impairment preventing valid informed consent
Severe developmental disorder or intellectual disability
Parallel
Intermittent theta-burst stimulation (iTBS) using PowerMAG 100 ppTMS
DeviceiTBS at 90% resting motor threshold; bursts of 3 pulses at 50 Hz repeated at 5 Hz; \~3 minutes per session; applied to left dorsolateral prefrontal cortex; 30 total sessions; schedule per arm as specified.
Change in immunophenotypic marker CRP from baseline to post-treatment
Differences in CRP from baseline to post-treatment between intensified iTBS and standard iTBS in inflammatory markers (based on material extracted from peripheral blood)
Change in immunophenotypic marker TNF from baseline to post-treatment
Differences in TNF from baseline to post-treatment between intensified iTBS and standard iTBS in inflammatory markers (based on material extracted from peripheral blood)
Change in immunophenotypic marker IL-1ß from baseline to post-treatment
Differences in IL-1ß from baseline to post-treatment between intensified iTBS and standard iTBS in inflammatory markers (based on material extracted from peripheral blood)
Change in immunophenotypic marker IL-6 from baseline to post-treatment
Differences in IL-6 from baseline to post-treatment between intensified iTBS and standard iTBS in inflammatory markers (based on material extracted from peripheral blood)
Change in Fatigue Severity Scale (FSS, self-rating)
Change in fatigue severity. Comparison between two arms. Overall score range 9-63, higher scores indicate more severe fatigue.
Change in Fatigue Scale for Motor and Cognitive Functions (FSMC, self-rating)
Change in fatigue across motor and cognitive domains. Comparison between two arms. Overall score range 20-100, higher scores indicate more severe fatigue.
Change in Post-Exertional Malaise (PEM) Questionnaire (self-rating)
Change in post-exertional malaise symptoms, comparison between arms. Exploratory; no standardized range universally defined.
Change in Pittsburgh Sleep Quality Index (PSQI, self-rating)
Change in sleep quality, comparison between arms. Global score range 0-21, higher scores indicate worse sleep quality
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