Biomarker-guided rTMS for Treatment Resistant Depression

Inclusion Criteria:

• Age 22 to 65 years

• Major Depressive Disorder (by M.I.N.I., Diagnostic Statistical Manual V (DSM-Vcriteria)); Verification by evaluation by licensed study psychiatrist orpsychologist

• At least moderately severe depression (17-item Hamilton Depression Rating Scalegreater than or equal to 18)

• Failure to respond in the current episode to at least 1 antidepressant medication atan adequate dose and duration as measured by a modified Antidepressant TreatmentHistory Form. The Maudsley Staging Method will also be used to quantify treatmentresistance.

• Any and all medication intended to treat depression or reduce symptoms of depressionmust be discontinued or maintained at the same daily dose for ≥ 4 weeks prior toenrollment and for the duration of the study

• Capacity to consent

• Written consent to allow communication between members of the research team and thepatient's outpatient clinician(s) (psychiatrist, psychotherapist, nursepractitioner, primary care physician, or equivalent) as needed to ensure safety

• Ability to safely participate in MRI

• Fluent in English

Exclusion Criteria:

• Imminent risk of suicide (based on the Columbia-Suicide Severity Rating Scale)

• Current depressive episode greater than or equal to 2 years duration

• Presence of primary psychiatric diagnoses other than MDD and/or comorbid generalizedanxiety disorder (GAD) or phobia (e.g., post-traumatic stress disorder;obsessive-compulsive disorder; MDD w psychotic features; primary psychotic illness;Bipolar I or II)

• DSM-5 defined addiction to, dependence on, abuse of, or misuse of any substanceduring the prior 12 months, excluding nicotine

• Evidence of cognitive impairment (MMSE score falling greater than or equal to 1 SDbelow the mean score for his or her age and education)

• Recent onset (within 8 weeks of screening) psychotherapy, including, but not limitedto: any form of treatment, aid, or therapy that has intensively and extensivelyexamined the patient's psychological history, including, but not limited to:cognitive behavioral therapy, dialectical behavioral therapy, interpersonal therapy,and family-focused therapy

• Prior exposure to an adequate dose and duration of the TMS treatment protocoladministered in this study during the current depressive episode.

• Participated in any clinical trial with an investigational drug or device within thepast 6 weeks prior to screening

• History of neurosurgery to treat a neurological or psychiatric disorder

• Evidence or history of significant neurological disorder, including moderate-severehead trauma, stroke, Parkinson's disease or other movement disorder (except benignessential tremor), epilepsy, history of seizures, cerebrovascular disease, dementia,increased intracranial pressure, history of repetitive or severe head trauma, orprimary or secondary tumors within the central nervous system

• Implanted electronic devices and/or conductive objects in or near the head,including metal plates, aneurysm coils, cochlear implants, ocular implants, deepbrain stimulation devices and stents

• Any implanted device that is activated or controlled in any way by physiologicalsignals, including, but not limited to: deep brain stimulators, cochlear implants,and vagus nerve stimulators

• Patients with major depressive disorder who have failed to receive clinical benefitfrom Vagus Nerve Stimulation (VNS) or are currently receiving these therapies.

• History of seizures (except juvenile febrile seizures) or any condition/concurrentmedication that could notably lower seizure threshold

• Individuals who are pregnant, nursing, contemplating pregnancy within the length ofthe study or, in the opinion of the investigator, not adherent to a medicallyacceptable method of birth control

• History or presence of any disease, medical condition or physical condition that, inthe opinion of the investigator, may compromise, interfere, limit, effect, or reducethe participant's ability to complete a treatment study lasting up to 21 weeks

• Abnormal bloodwork for electrolytes, thyroid and liver function

• Individuals who are taking > 300 mg daily dose of bupropion in any formulation (immediate, extended, or slow-release)

• Individuals who are taking tricyclic antidepressants.