Estrogen and Serotonin on Changing Brain Chemistry

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by University of Pennsylvania
Sponsor:
Collaborator:
Information provided by (Responsible Party):
C. Neill Epperson, University of Pennsylvania
ClinicalTrials.gov Identifier:
NCT01208324
First received: September 22, 2010
Last updated: May 2, 2014
Last verified: May 2014
  Purpose

The aim of this study is to examine the effects of estrogen and serotonin on cognition, emotional processing, and brain activation. The investigators will study the effects of acute tryptophan (TRP) depletion on cognition and mood in healthy menopausal women before and after estrogen replacement treatment (ERT). Using functional magnetic resonance imaging (fMRI), the investigators will identify differences in brain activation during memory tasks with and without TRP depletion and before and after estrogen therapy in order to determine which brain regions and cognitive functions are affected by each manipulation.


Condition Intervention
Menopause
Drug: estradiol transdermal system
Drug: Amino acid
Drug: Placebo Patch
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Interaction of Estrogen and Serotonin in Modulating Brain Activation in Menopause

Resource links provided by NLM:


Further study details as provided by University of Pennsylvania:

Primary Outcome Measures:
  • To replicate and extend our previous behavioral findings of an interaction between estrogen therapy (ET) and tryptophan depletion on verbal memory in a group of early menopausal women randomized to receive ET. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To evaluate the extent to which effects of ET (estrogen therapy) and TRP-D (tryptophan depletion) on verbal working memory are mediated through the dorsolateral prefrontal cortex. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 96
Study Start Date: September 2009
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Estrogen patch Drug: estradiol transdermal system
96 subjects will be enrolled in a double blind placebo controlled study where they will be randomized to receive either treatment with 17β-estradiol (Vivelle Dot® 0.10 - 0.15 mg/day) or a look-alike placebo patch for a total of approximately 8 weeks. There will be four fMRI test sequences: two test sequences one week apart prior to estrogen treatment (ET) or placebo treatment (PT), and two sequences one week apart following approximately 6-weeks of double-blind ET or PT. During each test day, all subjects will have their blood drawn at specific time intervals and undergo a battery of cognitive testing.While on the ET or PT treatment, all subjects will be instructed to change the patch every 3.5 days.
Other Name: Vivelle-Dot®
Active Comparator: Amino Acid Drug: Amino acid
31.5 mg of amino acids or 31.5 mg of lactose will be administered to subjects on each of their 4 test days. On 2 of the test days subjects will receive the active pills (amino acids) and on the other 2 test days subjects will receive the placebo pills (lactose).
Other Names:
  • L-Isoleucine
  • L-Leucine
  • L-Lysine
  • L-Methionine
  • L-Phenylalanine
  • L-Threonine
  • L-Valine
Placebo Comparator: Placebo Patch Drug: Placebo Patch
placebo
Placebo Comparator: Lactose (placebo) pills Drug: Placebo
There are 4 test days in this study. Each test day will involve the ingestion of 70 capsules. During one of each pair of tests, the 70 capsules will contain 31.5 g of lactose (sham depletion), while during the other test they will contain a total of 31.5 g of amino acids.

Detailed Description:

The overarching purpose of this study is to further our understanding of the individual and interactive effects of the hormone estrogen and the neurotransmitter serotonin on certain aspects of cognition and brain activation in menopausal women ages 48 to 60 years. Women will undergo cognitive testing and fMRI sessions both before and after 6 weeks of either estrogen or placebo administration. We will recruit women who are across the first 10 years since their last menstrual period so that the investigators can gather information regarding the potential impact of time since menopause on our outcomes of interest. We anticipate that findings from this study will help scientist and clinicians to refine their use of estrogen therapy in menopausal women. In addition, should the role of serotonin be of utmost importance for maintenance of healthy cognition, these data aid future drug development to preserve health cognition and/or to treat dementias in which serotonin is an important factor. This proposal is both novel and timely as results from this study are likely to provide information critical to the on-going discussion regarding the risks and benefits of ET use in menopausal women.

  Eligibility

Ages Eligible for Study:   48 Years to 60 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Key Inclusion Criteria:

Women ages 48 to 60 (at the time of enrollment) will be eligible for this study if they:

  1. Have no history of major depressive disorder, generalized anxiety disorder, and or panic disorder within the last three years according to the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-NP) (First et al., 1995), or a history of major depressive disorder, generalized anxiety disorder, and or panic disorder greater than 3 years ago, but now resolved according to the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-NP) (First et al., 1995);
  2. Have no substance abuse disorders (this includes alcohol, prescription, and illicit substances) within the last three years according to the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-NP) (First et al., 1995);
  3. Subject has history of substance abuse disorders (this includes alcohol, prescription, and illicit substances) >3 years ago but the period of abuse did not last more than 5 years according to the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-NP) (First et al., 1995);
  4. No first-degree relative (excluding children) with a known psychotic disorder or bi-polar disorder per patient report. Psychotic disorders include schizophrenia, schizoaffective disorder, psychotic disorder;
  5. Have not taken hormonal contraceptives, ET or HT for at least 3 months;
  6. Are within 10 years and 11 months of LMP;
  7. Have a follicular stimulating hormone level (FSH) of >30 IU/ml; women with an FSH below 30 will have the option to undergo an additional blood draw between 3-9 months following the initial blood draw (see note 2 below);
  8. Are able to give written informed consent;
  9. Provide written documentation of having had a normal mammogram within the last year, and a PAP, pelvic and breast examination within the previous three years. Normal PAP smears conducted within the previous 3 years will be allowable if all previous PAPs have been normal per the guidelines of the American College of Obstetricians and Gynecologists (ACOG);
  10. Must have clear urine toxicology screen upon recruitment;
  11. Are fluent in written and spoken English;
  12. Are right-handed.

Key Exclusion Criteria

  1. Currently smoking more than 10 cigarettes/day by self report;
  2. History of clinical CVD including myocardial infarction, angina, or congestive heart failure;
  3. History of thromboembolic disease (deep vein thrombosis or pulmonary embolus);
  4. History of untreated (no cholecystectomy) gallbladder disease;
  5. History of triglyceridemia by subject report;
  6. Undiagnosed vaginal bleeding;
  7. History of estrogen responsive cancers;
  8. Known hypercoagulable state (thrombophilias);
  9. Severe lactose intolerance (sham depletion requires lactose/microcellulose administration; mild to moderate lactose intolerance is acceptable); Dr. Epperson will make the final decision whether an individual's lactose intolerance is severe enough to require exclusion;
  10. Use of estrogen- or progestin-containing medication or phytoestrogen containing supplements (e.g. soy concentrates or extracts) within 3 months of participation; foods containing soy (e.g. tofu, soy milk) will be permissible; estrogen-based localized treatments such as creams and vaginal inserts will be permissible, so long as said treatments do not effect systemic estrogen levels (women using localized treatments must have estrogen levels similar to other women in the study of their age and menopause status). PI will have final decision about enrollment (see note 3 below);
  11. Have a Mini Mental Status Score of < 25;
  12. Hamilton Depression Score > 14;
  13. Pre-pubertal ACE score of 1;
  14. Have taken a psychotropic medication within the previous month, with the exception of sleeping aids if the participant is willing to forgo use during study participation;
  15. Have a metallic implant;
  16. Are claustrophobic;
  17. Are pregnant (pertains to peri-menopausal women only).

Note 1: In the case of participants with full or partial hysterectomy, timing of final menstrual period will be determined by Dr. Epperson (the study PI) or one of the study MDs. In cases in which final menstrual period cannot be established, subjects will be excluded from the study.

Note 2: Women who undergo the repeat FSH blood test will be enrolled if their levels are > 30. Women will not be required to repeat all admission procedures unless they report experiencing a life event which would impact their mental or physical health and well-being. The PI will make the final determination regarding what, if any, screening procedures need to be repeated.

Note 3: Women on localized estrogen treatments who show elevated systemic estrogen levels will not be enrolled. Instead, they will need to discontinue use for 1 month and then have their estrogen levels retested with an additional blood draw. PI will have the final decision regarding eligibility.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01208324

Contacts
Contact: Claudia Schinstine, M.A. 215-417-8839 sclaud@mail.med.upenn.edu
Contact: Jeanette Bradley, B.A. 215-573-8884 jbradl@mail.med.upenn.edu

Locations
United States, Pennsylvania
Penn Center for Women's Behavioral Wellness, University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Principal Investigator: C. Neill Epperson, M.D.         
Sponsors and Collaborators
University of Pennsylvania
Investigators
Principal Investigator: C. Neill Epperson, M.D. University of Pennsylvania
  More Information

Additional Information:
Publications:
Responsible Party: C. Neill Epperson, Associate Professor of Psychiatry, University of Pennsylvania
ClinicalTrials.gov Identifier: NCT01208324     History of Changes
Other Study ID Numbers: 809690, P50MH099910
Study First Received: September 22, 2010
Last Updated: May 2, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Pennsylvania:
Cognitive difficulties
memory impairment
mood changes
brain activation

Additional relevant MeSH terms:
Estradiol
Estrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 23, 2014