The goal of this clinical trial is to estimate the importance of neuroimaging in accelerated intermittent theta burst stimulation (aiTBS) for depression. Participants will receive aiTBS treatment, but they will not know if their treatment spot was found with neuroimaging or head measurements.

Techniques for modulating human brain networks are rapidly evolving. One of the most exciting new developments is accelerated intermittent theta burst stimulation (aiTBS), a transcranial magnetic stimulation (TMS) protocol that involves multiple daily treatments rather than gold standard once daily treatment. A specific accelerated iTBS protocol called Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) was cleared by the FDA in September 2022 based on two pilot studies in which patients with treatment-resistant depression rapidly and robustly improved with SAINT. Many of these patients had been depressed for decades and had not improved with conventional TMS or electroconvulsive therapy. Despite these promising results, two issues may limit SAINT scalability: 1) SAINT has only been tested at a single site in a small number of patients, 2) SAINT has never been tested without individualized resting state functional connectivity (rsfc) targeting, which is not widely available or covered by insurance. In this pilot trial, patients with treatment-resistant depression (n=40) will be randomized to one of two active treatment arms: 1) Real aiTBS with real individualized rsfc targeting, or 2) Real aiTBS with sham individualized rsfc targeting (i.e. conventional TMS targeting based on scalp landmarks). All patients will receive active stimulation, which will facilitate enrollment and reduce ethical concerns about placebo treatment in a vulnerable population when there is existing evidence of treatment efficacy. Patients and clinicians will be blind to group assignment, and blind integrity will be assessed. All patients will undergo MRI scans immediately before treatment and at one month follow up, which aligns with our clinical outcome measures.

Inclusion Criteria:

• English proficiency sufficient for informed consent, questionnaires/tasks, and treatment
• Primary diagnosis of major depressive disorder per Diagnostic and Statistical Manual (DSM)-V criteria (MINI International Neuropsychiatric Interview)
• >20 on BDI
• >20 on the MADRS 10, 11
• Moderate to severe level of treatment resistance (Maudsley Staging Method)
• Stable antidepressant medication regimen, or remain medication free, for 4 weeks prior to treatment and to remain on this regimen throughout the study (including all follow-up assessments after the 5-day treatment protocol).
• Primary clinician responsible for psychiatric care before, during, and after the trial
• Agreement to lifestyle considerations
• Abstain from becoming pregnant from screening through end of treatment
• Continue usual intake patterns of caffeine- or xanthine-containing products (e.g., coffee, tea, soft drinks, chocolate) throughout treatment
• Abstain from alcohol for at least 24 hours before the start of each MRI and TMS session
• Abstain from tobacco products during treatment day

Exclusion Criteria:

• Active pregnancy as determined by a urine pregnancy test
• Primary psychiatric diagnosis other than major depressive disorder requiring treatment other than comorbid anxiety disorder
• Those who did not respond to electroconvulsive therapy (ECT) after 8 sessions
• Recent (within 4 weeks) or concurrent use of rapid acting antidepressant agent (ketamine/esketamine/ECT)
• History of:
• Prior exposure to TMS
• Neurosurgical intervention for depression
• Autism spectrum disorder
• Intellectual disability
• Severe cognitive impairment
• Significant neurological illness (e.g., dementia, Parkinson's, Huntington's, brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, brain lesion)
• Untreated or insufficiently treated endocrine disorder
• Treatment with investigational drug or intervention during the study period
• Depth-adjusted TMS treatment dose > 65% maximum stimulator output
• ≥ 30% change in MADRS score between screening and baseline
• Anyone presenting with:
• Mania or hypomania
• Psychosis
• Active suicidal ideation or a suicide attempt (defined by C-SSRS) within the past year
• Neurological lesion
• Contraindications to either TMS or MRI (e.g., metallic implants, severe insomnia > 4 hours per night with hypnotic, etc.).
• Current moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal
• Positive urine drug screen for illicit substances
• Severe borderline personality disorder
• Any other condition deemed by the PI to interfere with the study or increase risk to the participant

De-identified survey response data and/or neuroimaging data may be shared with collaborators for further analysis.

Day 1 to day 5 of treatment

Participants will put on a swim cap and undergo treatment site-marking according to standard protocols. All individuals will get two treatment sites marked: 1) Their individualized target based on resting state functional connectivity data, and 2) Beam F3 target based on head measurements. One group will be treated at target #1, and the other group will be treated at target #2.

Neither group will be able to see the computer screen that shows the neuronavigation in real-time, although they will be able to see their MRI scan on a monitor.