Clinical Research Directory

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