Study is no longer funded.

This pilot study will assess the efficacy of several sequential pharmacological treatments for patients with Refractory Depression.

This pilot study will recruit 40 patients with Major Depression and a history of at least two failed prior adequate somatic treatments. In addition to usual physical work-up, all patients will have extensive thyroid testing, and then will receive standard dose Tranylcypromine (i.e., max. 60 mg/d). Non-remitters will have dose increased to max. 120 mg/d if tolerated. Non-remitters to high dose Tranylcypromine will then have Dextroamphetamine added with frequent blood pressure monitoring to max. 40 mg/d. Non-remitters will have Triiodothyronine added to the Tranylcypromine.

Inclusion Criteria:

• Ages between 18-65
• Major Depression
• At least two prior ineffective antidepressant trials (at least 2 different mechanisms) or 1 inadequate ECT trial (at least 8 bilateral treatments)
• Physically healthy

Exclusion Criteria:

• Known Tranylcypromine allergy
• Unable to follow tyramine-free diet
• Known allergy, intolerance or prior addiction to any stimulant would preclude patient's inclusion in the Dextroamphetamine portion of the protocol
• Current substance use disorder including alcohol)(past six months); ever dependent on stimulants would preclude Dextroamphetamine portion of the protocol
• Unable or unwilling to discontinue antidepressants including OTC antidepressants such as St. John's Wort
• History of psychosis, such as schizophrenia or psychotic depression; history of bipolar mania will be allowed if on adequate mood stabilizer
• Suicidal ideation/activity that makes outpatient treatment unsafe, unless protocol can be conducted as inpatient
• Current systolic BP > 149 or diastolic BP > 89 mm Hg (two readings); adequately treated hypertension is acceptable
• Evidence of hypo- or hyperthyroidism
• Pregnancy, lactation, refusal to use adequate birth control