The project was halted prematurely because of insufficient funds.

We aim to evaluate the safety and efficacy of pBFS-guided high-dose rTMS therapy with short inter-session interval for patients with treatment-resistant depression

Repetitive transcranial magnetic stimulation (rTMS) is an established therapy for treatment-resistant depression. Currently, the FDA cleared the SAINT Neuromodulation System for the treatment of Treatment-Resistant Depression(TRD) over the left dorsolateral prefrontal cortex (L-DLPFC). This methodology has been effective in a short period of time for treatment-resistant depression. The limitation of this approach includes the long inter-session interval (~50min) of the treatment, patients need to wait about 8 hours for 10 session's intervention per day. Therefore, it is urgent to explore the efficacy and safety of rTMS with a short inter-session interval (e.g. 20 min) that is more acceptable for TRD patients.

After being informed about the study and potential risks. All patients giving written informed consent will undergo a screening period to determine eligibility for study entry. At week 0, patients who meet the eligibility requirements will be randomized in a double-blind manner in a 1:1:1 ratio to the active short-interval rTMS group, active short-interval rTMS group, and active long-interval rTMS group. Then all participants will undergo a 5 day rTMS modulation followed by a four-week follow-up visit.

Inclusion Criteria:

• Hospitalized/outpatient patients aged 18-65 years (inclusive), male or female.
• Meet the diagnostic criteria of DSM-5(Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) for the depression disorder without psychotic symptoms, and currently experiencing the first episode or recurrence episode.
• Total HAMD17 score ≥18 before randomization.
• Total MADRS score ≥20 before randomization.
• A stable or no-drug use for at least 4 weeks before randomization. The type and dose of the antidepressant regimen remained unchanged throughout the study.
• No response (symptom improvement≥50%) in previous treatments with at least two antidepressants for a full dose and full course.
• Voluntarily participate in the trial and sign informed consent. Able to comply with the planned visit, examination and treatment plan, and other study procedures.

Exclusion Criteria:

• Meet DSM-5 diagnostic criteria for other mental disorders (e.g., schizophrenia spectrum disorders, bipolar and related disorders, anxiety disorders, compulsion, and related disorders, trauma and stress-related disorders, etc.), or secondary depression;
• Patients with a cardiac pacemaker, cochlear implant, or other metal foreign body and any electronic equipment implanted in the body, patients with claustrophobia and other contraindications to magnetic resonance scanning, and patients with contraindications to rTMS treatment;
• Patients with serious or unstable diseases of the cardiovascular, liver, kidney, blood, endocrine, neurological system, and other systems or organs, especially those with organic brain diseases (such as ischemic stroke, cerebral hemorrhage, brain tumor, etc.) and a history of severe brain trauma as judged by the researcher;
• History of epilepsy (presence of at least 2 uninduced seizures more than 24 hours apart, or diagnosis of the epileptic syndrome, or seizures within the past 12 months); Or currently received medications or other treatments that will lower the seizure threshold;
• History of ECT, rTMS, VNS, DBS, tDCS, light therapy, or other physical therapy related to mental illness within 3 months;
• Currently receiving or planning to start formal cognitive or behavioral therapy, or systemic psychological therapy (interpersonal therapy, dynamic therapy, cognitive behavioral therapy, etc.) during the trial.
• Substance abuse or dependence (including alcohol, drugs, and other psychoactive substances) in the past 1 year;
• Female of childbearing potential who plans to become pregnant during the trial.
• Female that is pregnant or breastfeeding.
• Patients in any clinical trials of other drugs or physical therapy within 1 month before the screening.
• Investigators think that was inappropriate to participate.