The investigators aim to find the optimal dosage of the pBFS-guided rTMS treatment for patients with moderate to severe depression.

In 2022, the FDA cleared a large dosage of repetitive transcranial magnetic stimulation for treatment-resistant depression (TRD), which requires 10 sessions per day of 1,800 pulses per session for a total of 18,000 pulses per day. The inter-session interval is 50 min, and it costs patients 9 hours for the intervention. The investigators assume that patients with moderate to severe depression may not need 10 sessions per day, patients may achieve response or remission with a less amount of dosage, which will save the cost of treatment. Hence, the investigators try to find the optimal treatment dosage for patients with moderate to severe depression.

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 1:1:1:1:1 ratio to each active rTMS group with different pulses (4×1800 pulses, 6×1800 pulses, 8×1800 pulses, 10×1800 pulses) and sham-control group. And then all participants will undergo a 5-day rTMS treatment followed by four- and eight weeks follow-up visits. Participants will keep a stable treatment regime during treatment and the four-week follow-up.

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 depression disorder without psychotic symptoms, and currently experiencing a recurrence episode.
• Total HAMD17 score ≥20 before randomization.
• Total MADRS score of ≥25 before randomization.
• Inadequate response to at least one antidepressant trial of adequate doses and duration.
• Participants currently are on a stable or no-drug use for at least 4 weeks before randomization. The type and dose of antidepressant drugs remained unchanged throughout the intervention period.
• Voluntarily participate in the trial and able to provide 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 (such as schizophrenia spectrum disorders, bipolar and related disorders, neurodevelopmental disorders, neurocognitive disorders, or depressive disorders due to substances and/or medications, depressive disorders due to other medical problems, etc.);
• 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 plan 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.