This study is a multicenter, randomized, double-blind, and sham-controlled trial using most intensive aiTBS protocol (10 sessions daily over 5 consecutive days at triple the standard per-session dose) to investigate the antidepressant efficacy for treatment-resistant depression (TRD). Patients will be recruited and randomly assigned (1:1 ratio) to receive active or sham groups from 5 hospitals in China. The interventions will last for 5 days and both groups will be followed up for 8 weeks on the same time schedules. During the intervention and at least the first 4 weeks of post-treatment, participants will keep a stable antidepressant regimen. The individualized target in the left dorsolateral prefrontal cortex (DLPFC) will be generated from 30 minutes of resting-state functional MRI collected at baseline.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique approved by the U.S. Food and Drug Administration (FDA) for the treatment of TRD. Despite FDA approval, conventional TMS is limited by a remission rate of approximately one-third and a prolonged treatment schedule of 4-6 weeks, which poses substantial practical and accessibility challenges.

Accelerated TMS protocols-delivering multiple sessions per day to compress standard multi-week regimens into just a few days-offer a potential strategy to enhance accessibility and accelerate clinical response. In 2022, the FDA approved a high-dose intervention, Stanford Neuromodulation Therapy (SNT), for rapid symptom relief in TRD. This protocol administers 10 sessions of 1,800-pulse iTBS per day over five consecutive days to the DLPFC, with 50-minute inter-session intervals. At treatment end, the response rate was 71.4% (vs. 13.3% in the sham group); at the 4-week follow-up, the response rate was 69.2% (vs. 7.1% in the sham group). Although these findings have generated optimism for patients with TRD, the efficacy and safety of accelerated iTBS (aiTBS) require further validation in multicenter, randomized, double-blind, placebo-controlled parallel-group trials

Inclusion Criteria:

• 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;
• Hamilton Depression Scale (HAMD-17) scores for 17 items ≥ 20 points, and the Montgomery Asberg Depression Rating Scale (MADRS) score is ≥ 20 points;
• hospitalized/outpatient patients aged ≥ 22 and ≤ 65 years old, male or female;
• The Maudsley Staging Method (MSM) assesses patients as at least moderate refractory (MSM score ≥ 7 points);
• Stable use of antidepressants for 4 weeks before randomization, with the type of antidepressant used being selective serotonin reuptake Selective serotonin reuptake inhibitors (SSRIs) or/and serotonin and norepinephrine reuptake Serotonin-norepinephrine reuptake inhibitors (SNRIs), the therapeutic dose is within the dosage range as the drug manual recommended;
• Understand the trial and sign the informed consent form.

Exclusion Criteria:

• Meets DSM-5 diagnostic criteria for other mental disorders, including schizophrenia spectrum disorders, bipolar and related disorders, and psychiatric disorders Developmental disorders, neurocognitive disorders, or depression caused by substances and/or drugs, or other medical problems;
• Individuals with pacemakers, cochlear implants, or other metal objects, as well as any electronic devices implanted in the body, and those with claustrophobia Contraindications for magnetic resonance imaging scans such as fear, and contraindications for rTMS treatment;
• 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 Syndromes, or seizures within the past 12 months;
• Received TMS treatment before participating in the trial;
• Individuals who have received ECT or phototherapy within three months;
• No response to ECT treatment (>8 times);
• Previously received antidepressant treatment with implanted devices (such as DBS, VNS);
• Concomitant organic brain diseases (such as ischemic stroke, cerebral hemorrhage, brain tumors, etc.) and a history of severe brain injury;
• Complicated with serious heart, liver, kidney diseases, diabetes, and other serious physical diseases, which cause abnormal symptoms and signs of brain nerves, Or physical exhaustion;
• Women of childbearing age who are currently pregnant, breastfeeding, or planning or may become pregnant during the trial period;
• Substance abuse or dependence (including alcohol, drugs, and other psychoactive substances) in the past year;
• First-degree relatives suffer from bipolar disorder;
• High risk of suicide;
• Difficulty in communication to understand or follow instructions, and unable to cooperate with treatment and evaluation;
• Current in clinical trials of other drugs or physical therapies (DBS, ECT, rTMS);
• The researchers believe it is not suitable to participate.