Mass General - Division of Clinical Research

In addition to fulfilling the diagnostic criteria for MDD, the following conditions must be met for patient eligibility: 1. Written informed consent 2. Men or women aged 18 to 60 years old 3. A score of 16 or greater on the Hamilton Depression Rating Scale -32 items (HAM-D- 32) 4. Continuing to meet criteria for current MDD at baseline and Clinical Global Impression Improvement (CGI) scores ≤ 3 (i.e. minimally improved or less) from the screen to the baseline visit 5. Only one failed one prior antidepressant in the current episode or are currently taking an antidepressant as defined by the MGH-ATRQ, in the current episode and are willing to take bupropion or placebo as augmentation, since we are using subjects as their own controls and we are comparing changes within subjects. Subjects with secondary anxiety disorders, like panic, GAD or simple phobia will be allowed, in order to make the population studied more representative of the general population of MDD.

1. Pregnant women or women of child bearing potential not using a medically accepted means of contraception. 2. Serious suicide or homicide risk. 3. Unstable medical illnesses, any history of seizure disorder. 4. The following DSM-IV diagnoses: a) organic mental disorders; b) substance use disorders, including alcohol abuse, within the last year; c) psychotic disorders; d) bipolar disorder; e) acute bereavement; f) severe borderline or antisocial personality disorder; g) history of eating disorder unless if in remission for ≥5 years prior to screening and presenting no current electrolyte abnormalities; h) current primary diagnoses of panic disorder, social phobia, PTSD, GAD, or OCD; i) mood congruent or mood incongruent psychotic features. 5. History of hepatic impairment or congestive heart failure. 6. Any history of abuse of stimulants or opiates. 7. Currently taking any exclusionary medications (i.e., antipsychotics, anticonvulsants, stimulants, dopaminergic agents), potential augmenting agents (e.g., T3, SAMe, St. John's Wort, lithium,). Gabapentin and pregabalin are allowed. Patients must have either no antidepressant treatment or stable (for at least 4 weeks prior to screening). No dose changes are allowed during the study. Monoamine oxidase inhibitors are excluded. Concomitant use of trazodone (up to 200 mg daily) is allowed. In agreement with patient's treating provider and under clinical monitoring, exclusionary drugs can be tapered and washed out prior to baseline visit. 8. Any investigational psychotropic drug within the last year. 9. Subjects who have not responded to two or more antidepressant trials of adequate doses (e.g., fluoxetine 40 mg/day or higher) and duration (e.g., ≥6 weeks) over the past five years according to the ATRQ. 10. History of inadequate response/poor tolerability to bupropion. 11. Subjects with medical contraindications to bupropion (e.g., history of seizures, uncontrolled electrolyte imbalance due to eating disorders, etc.) unless stable for 8 weeks prior to screening and there will be no changes during participation in the study. 12. Any unstable concomitant form of psychotherapy (depression-focused). Concomitant psychotherapy would be allowed if the frequency and the modality have been stable for the 8 weeks prior to screening and there will be no changes during the participation to the study 13. Receiving or have received during the index episode VNS, ECT or rTMS. 14. Color-blindness for blue or green (see fMRI task).