Comparative Effectiveness Research Trial for Antidepressant Incomplete and Non-responders With TRD

Inclusion Criteria:

   1. women and men ages 18-80,

   2. with MDD, of at least 12 weeks duration, according to Diagnostic and Statistical
   Manual of Mental Disorders, Fifth Edition (DSM-5) criteria confirmed by the Mini
   International Neuropsychiatric Interview (MINI; Sheehan et al, 1998),

   3. have a Montgomery-Asberg Depression Rating Scale (MADRS - Montgomery and Asberg, 1979)
   score of at least 20 at screen and baseline as assessed by site clinicians,

   4. meet criteria for TRD during the current major depressive episode documented in the
   MGH Antidepressant Treatment History Questionnaire (ATRQ) (Chandler et al., 2010),
   which will be defined as being non-responders (less than 50% of symptom improvement)
   to two or more depression treatment trials of adequate dose and duration as defined by
   the MGH ATRQ,

   5. are currently on an antidepressant of adequate dose (as defined by the MGH ATRQ) and
   duration (at least 8 weeks), with the antidepressant dose being stable over the past
   four weeks, and with documented (in the MGH ATRQ) non-response (less than 50%
   improvement) to the current antidepressant.

   6. Patients who have passed the MGH CTNI remote assessment, with documentation provided
   to sites by MGH CTNI.

Exclusion Criteria:

   1. pregnant or breastfeeding women, women of childbearing potential who are not using an
   accepted means of birth control, or women with a positive urine pregnancy test,

   2. patients who have received treatment with rTMS, aripiprazole, electroconvulsive
   therapy (ECT), or venlafaxine during the current episode,

   3. patients who express an objection to receiving treatment with at least one of the
   three treatment arms of our study,

   4. patients with any history of bipolar disorder or psychosis (diagnosed by MINI),

   5. patients with active alcohol or substance abuse disorders within the past 6 months
   (diagnosed by MINI),

   6. patients with suicidal ideation of the degree that, in the opinion of the evaluating
   clinician, participation in the study would place them at significantly increased risk
   of suicide,

   7. patients with unstable medical issues of such degree that, in the opinion of the
   evaluating clinician, participation in the study would place them at significant risk
   of a serious adverse event, or patients with a screening hemoglobin A1c level greater
   than 7.5%, or patients with epilepsy, dementia, Parkinson's disease, or Huntington's
   Disease,

   8. patients who have received treatment with vagus nerve stimulation (VNS),

   9. patients who have not responded to more than five FDA-approved antidepressant
   treatment trials of adequate dose and duration during the current episode, or who did
   not respond to ECT in previous episodes

10. patients on excluded medications,

11. patients with a positive urine screen drug test for a substance for which they do not
   have a valid prescription for a valid medical reason,

12. patients with currently abnormal thyroid function tests,

13. patients who have received at least one dose of a monoamine oxidase inhibitor (MAOI)
   four weeks or less prior, and

14. for patients on concomitant psychotropic agents (anticonvulsants, benzodiazepines,
   hypnotics, opiates, triiodothyronine (T3), modafinil, psychostimulants, buspirone,
   melatonin, omega-3 fatty acids, folate, l-methylfolate, s-adenosyl methionine,
   lithium) not on the same dose for at least four weeks prior to study entry or who do
   not agree to continue at the same dose during the acute phase of the study.

15. Patients who do not meet safety criteria for TMS: history of seizures, cardiac
   pacemaker, DBS or VNS, brain aneurism clips or other metallic implants in the
   intracranial space.

16. Also excluded is an individual who has received any administration of ketamine in the
   current episode for the treatment of depression.