Estrogen and Serotonin on Changing Brain Chemistry

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.

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.

• 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®
• 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
• Drug: Placebo Patch
  placebo
• 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.

• Active Comparator: Estrogen patch
  Intervention: Drug: estradiol transdermal system
• Active Comparator: Amino Acid
  Intervention: Drug: Amino acid
• Placebo Comparator: Placebo Patch
  Intervention: Drug: Placebo Patch
• Placebo Comparator: Lactose (placebo) pills
  Intervention: Drug: Placebo

• Epperson CN, Amin Z, Naftolin F, Cappiello A, Czarkowski KA, Stiklus S, Anderson GM, Krystal JH. The resistance to depressive relapse in menopausal women undergoing tryptophan depletion: preliminary findings. J Psychopharmacol. 2007 Jun;21(4):414-20. Epub 2006 Aug 4.
• Amin Z, Gueorguieva R, Cappiello A, Czarkowski KA, Stiklus S, Anderson GM, Naftolin F, Epperson CN. Estradiol and tryptophan depletion interact to modulate cognition in menopausal women. Neuropsychopharmacology. 2006 Nov;31(11):2489-97. Epub 2006 Jun 7.
• Amin Z, Epperson CN, Constable RT, Canli T. Effects of estrogen variation on neural correlates of emotional response inhibition. Neuroimage. 2006 Aug 1;32(1):457-64. Epub 2006 Apr 27.
• Amin Z, Canli T, Epperson CN. Effect of estrogen-serotonin interactions on mood and cognition. Behav Cogn Neurosci Rev. 2005 Mar;4(1):43-58. Review.
• Kugaya A, Epperson CN, Zoghbi S, van Dyck CH, Hou Y, Fujita M, Staley JK, Garg PK, Seibyl JP, Innis RB. Increase in prefrontal cortex serotonin 2A receptors following estrogen treatment in postmenopausal women. Am J Psychiatry. 2003 Aug;160(8):1522-4.

Women ages 48 to 60 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 with a known Axis I psychiatric disorder per patient report. Family history of substance use/dependence disorders will be allowed;
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;
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;
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).