The purpose this study is to measure cortical gama-aminobutyric acid levels (GABA) levels in menopausal women with major depressive disorder and healthy subjects using nuclear magnetic resonance spectroscopy (MRS). Measurements will be compared in 1) menopausal healthy subjects before and after estrogen replacement, and after fourteen days of medroxyprogesterone administration; and 2) in depressed menopausal subjects before and after treatment of their depression with antidepressant alone, estrogen alone or antidepressant plus estrogen. Cortical GABA levels will be correlated with plasma GABA and neurosteroid levels. Neurosteroids to be measured include progesterone, allopregnanolone, pregnenolone, and pregnenolone sulfate.

Inclusion criteria for Depressed Patients:

• Aged 40-70 years and able to give voluntary written informed consent.
• Meet DSM-IV criteria for major depression based on a structured clinical interview (SCID).
• Have no medical contraindication to estrogen. (This will include written documentation of a recent normal gynecological evaluation and mammogram).
• A minimum score of 25 on the 25-item Hamilton Depression Rating Scale on initial baseline rating which does not show improvement during the one-week observation period.
• Perimenopausal subjects will be those who have had irregular menses of either <21 days or >35 days for the previous six months to one year. Postmenopausal subjects will be those with no menstrual cycles and no hormone therapy for at least one year and serum FSH >45.

Exclusion criteria:

• Meeting DSM-IV for any other Axis I disorder.
• A history of serious medical or neurological illness, including (but not limited to) major cardiovascular disease, severe hypertension, intracranial mass lesions, seizure disorder, severe hepatic or renal disease, unstable endocrine or metabolic disease, and unstable hematologic disease.
• A history of moderate to severe endometriosis; milder cases will require subject's Gynecologists permission to participate.
• Use of anticonvulsants or benzodiazepines within the last month.
• Use of psychotropic medication in last week (except as stated above).
• Use of alcohol within last month.
• Current pregnancy (for the perimenopausal subjects).
• Positive urine drug screen.
• Metallic implants.

Inclusion Criteria for Healthy Subjects:

• No DSM-IV psychiatric or substance abuse diagnosis by structured diagnostic interview (SCID).
• No medical contraindication to estrogen (this will include written documentation of a recent normal gynecological exam with mammogram).
• Matched to depressed patients by age and menopausal status.
• Have no menstrual cycles or hormone therapy for at least one year or irregular menses of either <21 days or 35 days for the previous six months to one year.

Exclusion Criteria for Healthy Subjects:

• Medical, neurologic or cerebrovascular disorder (CVA, seizure disorder, etc.).
• Evidence of substance use on urine toxicology screen done upon recruitment.
• Current treatment with psychoactive medication.
• Diabetes controlled by means other than diet.
• Use of alcohol within last month.
• Implanted metallic devices.
• Positive urine drug screen.