Background Major depression is associated with morbidity and increased mortality. Along with the psychological strain depression represents a high socioeconomic burden costing Europe more than €113 billion/year. About one third of patients do not respond to appropriate therapy. Theta-burst stimulation (TBS), a form of transcranial magnetic stimulation is an emerging treatment for patients for whom pharmacological treatment is ineffective or not appropriate. Based on two different theories of prefrontal dysfunction two TBS-protocols should have the most antidepressant effects. However, no study so far has compared the two approaches or systematically investigated their differential effects on brain function and on a symptom level.

Objectives of the study The aim of this study is to test two TBS protocols on symptom improvement and associated brain function in patients with treatment resistant depression (TRD): iTBS over bilateral DLPFC and iTBS over left and cTBS over right DLPFC. As stimulation over non-motor regions offers no direct readout, fMRI at baseline and after treatment will be harnessed to quantify an effect on brain activity and functional network metrics.

Study population 80 patients with TRD will be enrolled with 40 patients receiving the one, and 40 patients receiving the other TBS protocol for a treatment period of three weeks.

Study design The study is designed as a longitudinal, randomized and double-blind clinical trial. At baseline and after treatment, patients will undergo psychiatric testing using several symptom scales including the Hamilton Depression Rating Scale (HAMD-17), the Beck Depression Inventory (BDI-II), the Inventory of Depressive Symptomatology (IDS-C) and the State-Trait Anxiety Inventory (STAI). Changes in HAMD-17 scores are defined as primary endpoint. Moreover MRI scans before and after treatment will include structural and functional MRI sequences as well as diffusion weighted imaging (DWI) sequence. Functional connectivity and BOLD responses will serve as primary imaging endpoints. A follow-up visit 2 weeks and a final examination 4 weeks after treatment will elucidate durability of effects.

Relevance and implications of the study By investigating which approach is superior for which symptoms our study will contribute to the development of personalized treatment, the reduction of personal suffering and the reduction of costs and occupational disability.

Inclusion Criteria:

• DSM-5 diagnosis of a single or recurrent major depression
• Failure of at least two adequate antidepressant treatments
• HAMD-17 total score of ≥ 23 and a Clinical Global Impression Scale (CGI-S) of ≥ 4
• Stable psychopharmacological treatment within 2 weeks prior inclusion
• Age 18-65 years
• Right-handedness (assessed with the Edinburgh Handedness Inventory)

Exclusion Criteria:

• Seizures in medical history
• Medical history of major systemic illness, neurological disorders and previous brain injuries
• Ferromagnetic implants, cardiac pacemaker, deep brain stimulation and other common MRI and TMS exclusion criteria
• Current psychotic symptoms
• Substance abuse or dependence within last 3 months
• Borderline personality disorder (based on DSM-5 criteria)
• Pregnancy
• Active suicidal intent
• Benzodiazepines other than Lorazepam < 2mg/d
• failure to comply with the study protocol or to follow the instructions of the investigating team