Study TRD subjects' resistance to at least 2 different antidepressants, we hypothesize that because of their significant depression and treatment resistant status they are most likely to exhibit BSMN pathway abnormalities.

Potential subjects will be identified during clinical visits. If a patient qualifies to participate in the study they will have to stop any antidepressants that they are taking to prepare for the use of MAOIs. After a two week washout period, subjects will have an fMRI and will be started on a MAOI. They will then be followed up for 8 weeks, which is routine and considered standard care.

Inclusion Criteria - TRD:

1. age: 18 - 65 yrs.;
2. satisfy criteria for DSM-IV major depressive disorder (MDD);
3. 17-item Hamilton Depression Rating Scale (17-item HDRS) score > 18;
4. treatment resistance depression as defined as report of inadequate response (patient report of minimal improvement or nonresponse) despite past treatment with at least 2 different classes of antidepressants acting on the 5-HT and/or DA monoamine systems(except MAOIs) (as determined with the Antidepressant Treatment History Form (ATHF)20 with score of >3 on each of the items and verified by medical records if available);
5. able to give informed consent;
6. no use of alcohol in the past 1 week and negative urine toxicology screen;
7. MAOI treatment indicated as assessed by an independent psychiatrist not affiliated with the study;
8. voluntary consent to treatment with an MAOI after reviewing all other options and agree to follow safeguards and precautions during treatment.

Inclusion criteria for healthy subjects

1. ages 18-65 years and ability to give voluntary informed consent;
2. no history of psychiatric illness or substance abuse or dependence;
3. no significant family history of psychiatric or neurological illness;
4. not currently taking any prescription or centrally acting medications; no use of alcohol in the past 1 week;
5. and no serious medical or neurological illness.

Exclusion Criteria - TRD:

1. schizophrenia, schizoaffective or primary anxiety disorder;
2. serious medical or neurological illness;
3. history of significant head injury;
4. on fluoxetine treatment;
5. on lithium or have received ECT or rTMS in the last 3 months to avoid long-term effects of such medications;
6. substance or alcohol dependence in the past 6 months or substance abuse in the past 3 months;
7. unable to give informed consent.

Exclusion criteria for both groups:

1. pregnant or breast-feeding;
2. metallic implants or other contraindication to MRI.

Treatment Resistant Depression and Healthy Controls