Brain Imaging Study in Menopausal Women With and Without Major Depressive Disorder

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Menopause, Depression

Intervention / Treatment
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* Drug: MDD diagnosis and Estrogen treatment
* Drug: MDD diagnosis and Fluoxetine treatment
* Drug: MDD diagnosis with both Estrogen and Fluoxetine treatment
* Drug: No depression and estrogen treatment


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: MDD diagnosis and Estrogen treatment<br>Menopausal women between the ages of 40-70 diagnosed with Major Depressive Disorder receiving treatment with estrogen alone. | Drug: MDD diagnosis and Estrogen treatment<br>* 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.<br>|
| Active Comparator: MDD diagnosis and Fluoxetine treatment<br>Menopausal women between the ages of 40-70 diagnosed with Major Depressive Disorder receiving treatment with fluoxetine alone. | Drug: MDD diagnosis and Fluoxetine treatment<br>* Menopausal women between the ages of 40-70 diagnosed with Major Depressive Disorder receiving treatment with fluoxetine alone.<br>|
| Active Comparator: MDD diagnosis with both Estrogen and Fluoxetine treatment<br>Menopausal women between the ages of 40-70 diagnosed with Major Depressive Disorder receiving treatment with estrogen and fluoxetine combined. | Drug: MDD diagnosis with both Estrogen and Fluoxetine treatment<br>* Menopausal women between the ages of 40-70 diagnosed with Major Depressive Disorder receiving treatment with estrogen and fluoxetine combined.<br>|
| Active Comparator: No depression and estrogen treatment<br>Non-depressed menopausal women between the ages of 40-70 receiving treatment with estrogen alone. | Drug: No depression and estrogen treatment<br>* Control participants with no MDD diagnosis received estrogen only for the treatment of physical symptoms of menopause.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | This study was conducted at Yale University almost two decades ago. Our group at the University of Pennsylvania only has very basic information about this study. This includes the number of participants, which was 18, and the fact that no adverse events occurred. Staff members at the University of Pennsylvania do not have access to any additional study data. The contact person who initially entered this study protocol information is no longer at the University of Pennsylvania and we are unable to contact for additional information. We only know that 18 participants completed, but as far as we know data was never analyzed for these 18 participants. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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menopause, women, major depressive disorder, Magnetic Resonance Spectroscopy