“Mr. D” is a 35-year-old man with an 11-year history of treatment-resistant depression. From the onset of his disorder, he was unable to achieve a sustained euthymic mood despite multiple adequate trials of medications (including MAOIs), psychotherapy, transcranial magnetic stimulation, ECT, and vagus nerve stimulation. In 2005, he underwent subcallosal cingulate gyrus DBS under a study protocol (3). Within 6 months, his score on the 17-item Hamilton Depression Rating Scale (HAM-D) fell from a baseline of 22 to 7. Despite this initial response, Mr. D relapsed 4 years later, and DBS parameters were adjusted without benefit. In 2010, his pulse generator was replaced, also without a noticeable improvement in mood. Adjunctive medication trials and augmentation regimens were all unsuccessful. Based on our preclinical findings, we decided to add tranylcypromine, 40 mg p.o., b.i.d. (as taken in the preoperative period), alongside DBS (2.5 V, 90 µsec, 130 Hz, contacts 1 and 5 used as cathodes/case as the anode). After this medication change, Mr. D’s depression severity score declined markedly from a pretreatment HAM-D-17 score of 22 to 16 after 2 weeks, to 8 after 2 months, and to 9 after 4 months.