Primary Outcome Measures:

Evaluate the changes in neuroimaging and biochemistry measures with ketamine treatment.

Secondary Outcome Measures:

Evaluate the effects of ketamine on depression symptoms, manic symptoms, global change in psychiatric symptoms, and suicidal ideation.

Inclusion Criteria:Male patients, ages 18 to 65 years with a diagnosis of MDD, currently depressed or in a current major depressive episode of BD without psychotic features will be recruited into this substudy.

Current or past history of lack of response to one adequate antidepressant trial, operationally defined using the Antidepressant Treatment History Form (ATHF); a failed adequate trial of ECT would count as an adequate antidepressant trial.

Exclusion Criteria:Subjects with a history of DSM-IV drug or alcohol dependency or abuse (except for caffeine or nicotine dependence) within the preceding 3 months. In addition, subjects who currently are using oher antidepressant drugs in the 2 weeks prior to screen and must have a negative alcohol and drug urine test (except for prescribed benzodiazepines) urine test at screening.

Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.

Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications.

Clinically significant abnormal laboratory tests.

Subjects with clinical hypothyroidism or hyperthyroidism.

Subjects with one or more seizures without a clear and resolved etiology.

Presence of metallic (ferromagnetic) implants (e.g, heart pacemaker, aneurysm clip).

Subjects who, in the investigator's judgment, pose a current serious suicidal or homicidal risk, or who have a MADRS item 10 score