We propose to investigate structural and biochemical brain abnormalities in depressed subjects, and the relationship between the presence of such abnormalities and treatment outcome. We will recruit N=20 subjects with major depression disorder and N=20 matched normal controls. The depressed subjects would have previously not responded to an adequate trial with a selective serotonin reuptake inhibitor (SSRI). These depressed subjects will be treated for 4 weeks with the same SSRI antidepressant and with adjuvant triiodothyronine (T3). Structural magnetic resonance images (MRI) and then Phosphorus-31 magnetic resonance spectroscopic imaging (31P-MRSI) data will be obtained two times for each patient (at the beginning and at the end of the study) and one time for the normal controls. We will measure for each depressed subject the number of white matter hyperintensities (WMH); we will also measure the degree of change from baseline in several compounds characteristic for the cellular high-energy phosphate metabolism: the phosphocreatine/inorganic phosphate ratio and the beta-nucleoside triphosphate. We will compare the severity of WMH and the high-energy phosphate metabolism in two groups of depressed subjects (those responding and those not responding to thyroid hormone augmentation) and the normal controls.

We hypothesize that:

1. All depressed subjects, when compared with normal controls, will present lower baseline levels of compounds characteristic for the high-energy phosphate metabolism.
2. Depressed subjects responding to T3 augmentation, when compared with subjects not responding to T3 augmentation, will present a larger increase of the high-energy phosphate metabolism.

Inclusion Criteria:

• DSM-IV diagnostic criteria for MDD (diagnosed with the use of SCID)
• Written informed consent
• Men or women aged 18-65
• A baseline Hamilton-D17 score of > 16.

Exclusion Criteria:

• Subjects with suicidal ideation where outpatient treatment is determined unsafe by the study clinician. These patients will be immediately referred to appropriate clinical treatment.
• Pregnant women or women of childbearing potential who are not using a medically accepted means of contraception (defined as oral contraceptive pill or implant, condom, diaphragm, spermicide, IUD, s/p tubal ligation, partner with vasectomy)
• Serious or unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic or hematologic disease
• History of seizure disorder,
• History or current diagnosis of the following DSM-IV psychiatric illness: organic mental disorder, schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorders not otherwise specified, bipolar disorder, patients with mood congruent or mood incongruent psychotic features, patients with substance dependence disorders, including alcohol, active within the last 12 months.
• History or current diagnosis of dementia, or a score of < 26 on the Mini Mental Status Examination (Folstein, 1975) at the screening visit.
• History of multiple adverse drug reactions or allergy to the study drugs.
• Patients with mood congruent or mood incongruent psychotic features.
• Patients having shown minimal or no response to a standard course of antidepressant treatment with an SSRI. A standard course will be defined as the following medications taken for > 4 weeks: fluoxetine > 20 mg/day, sertraline > 50 mg/day, paroxetine > 20 mg/day, fluvoxamine > 50 mg/day, citalopram > 20 mg/day, venlafaxine > 150 mg/day.
• Clinical or laboratory evidence of hypothyroidism.
• Patients who have had electroconvulsive therapy (ECT) within the 6 months preceding baseline.
• History of intolerance to Cytomel
• History of cardiac pathology or diabetes