Accelerated Versus Standard Intermittent Theta Burst Stimulation for Major Depressive Disorder

A Randomized Rater-Blinded Trial Comparing Accelerated and Standard Intermittent Theta Burst Stimulation Combined With Pharmacotherapy for Major Depressive Disorder

This randomized clinical trial aims to compare the effectiveness and safety of accelerated intermittent theta burst stimulation (iTBS) with standard iTBS in adults with major depressive disorder.

Participants will be randomly assigned to receive either accelerated or standard iTBS targeting the left dorsolateral prefrontal cortex, in addition to pharmacotherapy. The accelerated iTBS group will receive 45 treatment sessions over approximately 15 treatment days, while the standard iTBS group will receive 20 treatment sessions over 4 weeks.

The primary objective is to compare changes in depressive symptom severity between the two treatment groups from baseline to the end of treatment. Depressive symptoms will be assessed using the 17-item Hamilton Depression Rating Scale (HAM-D17). The study will also evaluate other clinical outcomes, cognitive function, quality of life, sleep quality, neurophysiological measures, and treatment safety.

Inclusion Criteria:

• Age 18 to 65 years.
• Diagnosis of major depressive disorder (MDD), confirmed by a specialist according to DSM-5 criteria.
• Hamilton Depression Rating Scale, 17-item version (HAM-D17) score ≥18 at screening/baseline.
• Stable background pharmacotherapy for at least 4 weeks before randomization, with no planned changes in medication regimen or drug class during the intervention period unless clinically required.
• Right-handed.
• Able and willing to provide written informed consent and comply with study procedures.

Exclusion Criteria:

• History of epilepsy or seizures, except childhood febrile seizures.
• Bipolar disorder or psychotic disorder.
• Acute suicide risk, including HAM-D17 item 3 score ≥3 or clear suicidal intent or behavior.
• Alcohol or illicit drug abuse or dependence within the previous 6 months.
• Significant structural brain lesions.
• Intracranial or head/neck metallic objects or implants considered unsafe for TMS, including metallic clips, fragments, or cochlear implants.
• Implanted electronic devices such as pacemakers, implantable cardioverter-defibrillators, or deep brain stimulation devices.
• Other conditions associated with a high risk of seizure or history of cranial surgery considered unsafe for TMS.
• Uncontrolled thyroid dysfunction.
• Severe untreated vitamin D deficiency (<20 ng/mL).
• Acute infection, elevated C-reactive protein, or other clinically significant medical abnormalities that may interfere with study participation.
• Pregnancy or breastfeeding.
• Benzodiazepine use exceeding the equivalent of lorazepam 2 mg/day that cannot be reduced.
• Use of medications associated with a substantially lowered seizure threshold, including clozapine, high-dose tricyclic antidepressants, or bupropion >300 mg/day.
• Unstable doses of antiepileptic medications used as mood stabilizers.
• Previous rTMS treatment.
• Failure to respond to an adequate course of electroconvulsive therapy (≥8 lifetime sessions).
• Unable or unwilling to comply with study procedures.