This study employs functional magnetic resonance imaging to compare brain activation patterns during a depressive episode in patients diagnosed with bipolar disorder, major depressive disorder, and a group of healthy control subjects. Depressed patients will be treated with a combination of fluoxetine and olanzapine and undergo MRI scans before, during, and after pharmacotherapy.

The purpose of this study is to further characterize the neural correlates of affective processing in BD and MDD subjects using fMRI. Subjects who meet criteria for a major depressive episode in the context of BD (n=15); MDD (n=15) and a group of psychiatrically unaffected control subjects (CS, n=15) will undergo four fMRI scans while experiencing a temporary mood induction through the presentation of affective imagery from the International Affective Picture System (IAPS). Both BD and MDD subjects will receive the same combination pharmacotherapy to treat the depression, with fMRI data acquired before, and 1, 3, 6 weeks following pharmacotherapy initiation. Positive, negative, and neutral affective visual stimuli will be presented in a blocked design.

Comparison(s): The effects of time and group will be analyzed in factorial models. Regions of interest that demonstrate significant group-by-time interactions will be further correlated with self-report and clinician-rated psychometric indices.

Inclusion Criteria: (All three groups)

• age 18-55 years
• satisfactory physical health
• education level and a degree of understanding to communicate effectively with the investigator c
• capable of providing informed consent
• female subjects of childbearing potential, a medically accepted means of contraception.

Additional inclusion criteria for the patient groups include

• DSM-IV-TR criteria for a diagnosis of BD or MDD
• currently meeting criteria for an MDE and
• a Hamilton Depression Rating Scale 17 Item (HDRS-17) score of > 17
• blood indices within normal clinical ranges.

Exclusion Criteria: (All three groups)

• DSM-IV-TR criteria for substance abuse or dependence (except nicotine or caffeine) within the past 6 months
• comorbid neurological or other major psychiatric disorders as defined in the DSM-IV-TR;
• history of neurological trauma resulting in loss of consciousness;
• uncorrected hypothyroidism or hyperthyroidism, including elevated thyroid stimulating hormone (TSH);
• other unstable medical condition;
• female subjects who are pregnant or nursing;

Additional exclusion criteria for the BD and MDD group include:

• prior failure to respond to fluoxetine and olanzapine in combination at adequate dose and duration;
• evidence of serious risk of suicide based on clinician assessment and/or HRSD suicide item > 3;
• course of ECT (electroconvulsive therapy) in the preceding 6 months;
• Young Mania Rating Scale (YMRS) > 7;
• administration of fluoxetine within previous 4 weeks;
• treatment resistance as defined by the failure of two antidepressant trials from dissimilar classes
• Hyperglycemia or diabetes mellitus as defined by a fasting blood glucose value of > 125 mg/dl.