Official Title: “Measurement of GABA and Neurosteroid Levels in Women With Menopausal Major Depression Before and After Treatment With Estrogen Alone, Fluoxetine Alone, or Estrogen and Fluoxetine and Normal Controls Before and After Treatment With Estrogen”

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, allopregnanalone, pregnenolone, and pregnenolone sulfate.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Factorial Assignment

Study Primary Completion Date: June 2008

Intervention(s) in this Clinical Trial

• Drug: estrogen alone
  • Treatment for major depressive disorder occurring in the context of the menopause while participating in brain imaging sessions pre and post treatment. Women receiving treatment for depression will be compared to normal controls receiving estrogen only for physical symptoms of menopause.
• Drug: fluoxetine alone
  • Menopausal women between the ages of 40-70 diagnosed with Major Depressive Disorder receiving treatment with fluoxetine alone.
• Drug: estrogen and fluoxetine together
  • Menopausal women between the ages of 40-70 diagnosed with Major Depressive Disorder receiving treatment with estrogen and fluoxetine combined.

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • Menopausal women between the ages of 40-70 diagnosed with Major Depressive Disorder receiving treatment with estrogen alone.
• Active Comparator: 2
  • Menopausal women between the ages of 40-70 diagnosed with Major Depressive Disorder receiving treatment with fluoxetine alone.
• Active Comparator: 3
  • Menopausal women between the ages of 40-70 diagnosed with Major Depressive Disorder receiving treatment with estrogen and fluoxetine combined.
• Active Comparator: 4
  • Non-depressed menopausal women between the ages of 40-70 receiving treatment with estrogen alone.

Primary Measures

• Comparison of cortical GABA levels in 4 groups of subjects using estrogen alone, fluoxetine alone, estrogen and fluoxetine combined in pre and post 4.0T magnetic resonance spectroscopy sessions.
  • Time Frame: Healthy controls will undergo scans pre and post 3 weeks of estrogen treatment. Women with depression will undergo scans pre and post 6 weeks of treatment with estrogen alone, estrogen and fluoxetine, or fluoxetine alone
    Safety Issue?: No

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.

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 40 Years

Maximum Age for this Clinical Trial: 70 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: Yale University

Overall Clinical Trial Officials and Contacts

Cynthia N Epperson, MD Principal Investigator Yale School of Medicine  

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00626340

Study ID Number: 9907010780

ClinicalTrials.gov Identifier: NCT00626340

Health Authority: United States: Institutional Review Board