Depressive Disorder, Post-Acute COVID-19 Syndrome
Conditions
Keywords
Major depressive disorder, Post-COVID-19-condition, neuropsychology, psychometry, Immunemarkers, IL-6, TNF, CRP, repetitive transcranial magnetic stimulation, intermittent theta burst, accelerated rTMS, neuroinflammation
Brief summary
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.
Interventions
DEVICEIntermittent theta-burst stimulation (iTBS) using PowerMAG 100 ppTMS
iTBS 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.
Sponsors
Max-Planck-Institute of Psychiatry
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Two active iTBS schedules: once-daily for 6 weeks vs six times daily for 5 days; total 30 sessions per participant.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 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) * Insufficient improvement of depressive symptoms under psychopharmacological treatment * Stable psychopharmacological medication for at least 4 weeks prior to start of iTBS
Exclusion criteria
* 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 * Acute or chronic substance abuse (alcohol, prescription drugs, or illicit drugs) * Current treatment with benzodiazepines or Z-substances * Acute suicidality * Psychotic symptoms * Severe neurological disorder (e.g., major brain injury, neurodegenerative disease) * Ongoing treatment with another neurostimulation method (ECT, TMS, VNS) * Contraindications to TMS, including: Intracranial metal, implants, shunts, Cochlear implant, pacemaker, implantable defibrillator, History of seizures or epileptiform EEG * Severe general medical illness (e.g., anemia requiring transfusion, severe arrhythmias, cardiomyopathy)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in immunophenotypic marker TNF from baseline to post-treatment | baseline (day of first treatment), day of 15th treatment, 3 days after 30th (last) 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 CRP from baseline to post-treatment | baseline (day of first treatment), day of 15th treatment, 3 days after 30th (last) 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 IL-1ß from baseline to post-treatment | baseline (day of first treatment), day of 15th treatment, 3 days after 30th (last) 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 | baseline (day of first treatment), day of 15th treatment, 3 days after 30th (last) 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) |
| Total score change in the Becks Depression Inventory, version 2 (BDI-II, self-rating) | baseline (day of first treatment), day of 15th treatment, 3 days after 30th (last) treatment, follow-up 3 months after treatment completion | Change in depression symptomatology, comparison between two arms. Range of the test is 0-63, a higher score indicates a worse condition. |
| Total score change in the clinician-rated Montgomery Asberg Depression scale (MADRS) | baseline (day of first treatment), day of 15th treatment, 3 days after 30th (last) treatment, follow-up 3 months after treatment completion | Change in depression symptomatology, comparison between two arms. Overall score range 0-60, a higher score indicates a more severe depression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Beck Anxiety Inventory (BAI, self-rating) | baseline (day of first treatment), day of 15th treatment, 3 days after 30th (last) treatment, follow-up 3 months after treatment completion | Change in self-rated anxiety severity. Total score range 0-63, higher scores indicate more severe anxiety. Comparison between arms. |
| Change in Fatigue Severity Scale (FSS, self-rating) | baseline (day of first treatment), day of 15th treatment, 3 days after 30th (last) treatment, follow-up 3 months after treatment completion | Change in fatigue severity. Comparison between two arms. Overall score range 9-63, higher scores indicate more severe fatigue. |
| Adverse Event Screening (Exploratory) | baseline (day of first treatment), day of 15th treatment, 3 days after 30th (last) treatment, follow-up 3 months after treatment completion | Incidence of adverse events related to iTBS treatment: headache, scalp discomfort, dizziness, sleepiness, fatigue, and other stimulation-related complaints |
| Change in Fatigue Scale for Motor and Cognitive Functions (FSMC, self-rating) | baseline (day of first treatment), day of 15th treatment, 3 days after 30th (last) treatment, follow-up 3 months after treatment completion | 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) | baseline (day of first treatment), day of 15th treatment, 3 days after 30th (last) treatment, follow-up 3 months after treatment completion | Change in post-exertional malaise symptoms, comparison between arms. Exploratory; no standardized range universally defined. |
| Change in Pittsburgh Sleep Quality Index (PSQI, self-rating) | baseline (day of first treatment), day of 15th treatment, 3 days after 30th (last) treatment, follow-up 3 months after treatment completion | Change in sleep quality, comparison between arms. Global score range 0-21, higher scores indicate worse sleep quality |
| Change in Epworth Sleepiness Scale (ESS, self-rating) | baseline (day of first treatment), day of 15th treatment, 3 days after 30th (last) treatment, follow-up 3 months after treatment completion | Change in daytime sleepiness, comparison between arms. Total score range 0-24, higher scores indicate greater daytime sleepiness. |
| Change in Sheehan Disability Scale (SDS, self-rating) | baseline (day of first treatment), day of 15th treatment, 3 days after 30th (last) treatment, follow-up 3 months after treatment completion | Change in functional impairment across work/school, social, and family life. Each domain scored 0-10; higher scores indicate greater impairment, comparison between arms. |
Countries
Germany
Contacts
Primary ContactAlexandros Balaskas, MD
Backup ContactAngelika Erhardt-Lehmann, MD, Prof.
Outcome results
None listed