Estrogen and Serotonin on Changing Brain Chemistry

NCT01208324 | Completed Results DMC

• 2 other identifiers: 809690P50MH099910
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Menopause

Keywords

Cognitive difficulties; memory impairment; mood changes; brain activation

Outcome Measures

Primary Outcomes (1)

• Percent Change in BOLD Signal

  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. Blood-oxygen-level dependent or BOLD signal is the outcome of BOLD imaging, which is a technique used in functional MRI. BOLD signal reflects changes in regional cerebral blood flow which delineate regional activity. A positive BOLD signal marks an increase in regional blood flow, while a negative BOLD signal marks a decrease in regional blood flow. A positive percent change means that between scans the BOLD signal i.e. blood flow in that region has increased, a negative percent change means that the BOLD signal has decreased between scans.

  8 weeks

Secondary Outcomes (1)

• Evaluate the Changes in Verbal Working Memory Mediated Through the Dorsolateral Prefrontal Cortex.

  8 weeks

Study Arms (4)

Estrogen patch

ACTIVE COMPARATOR

Vivelle Dot® 0.10 - 0.15 mg/day for 8 weeks

Drug: estrogen patch

Amino Acids

ACTIVE COMPARATOR

L-Isoleucine (4.2 g), L-Leucine (6.6 g), L-Lysine (4.8 g), L-Methionine (1.5 g), L-Phenylalanine (6.6 g), L-Threonine (3.0 g), L-Valine (4.8 g)

Drug: Amino acids; Drug: Placebo pills

Placebo Patch

PLACEBO COMPARATOR

Placebo

Drug: Placebo Patch

Placebo pills

PLACEBO COMPARATOR

31.5 g of lactose or microcellulose

Drug: Placebo pills

Interventions

estrogen patch DRUG

150 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.

Also known as: Vivelle-Dot®

Estrogen patch

Amino acids DRUG

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).

Also known as: L-Isoleucine, L-Leucine, L-Lysine, L-Methionine, L-Phenylalanine, L-Threonine, L-Valine

Amino Acids

Placebo Patch DRUG

placebo

Also known as: Placebo

Placebo Patch

Placebo pills DRUG

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.

Also known as: lactose

Amino Acids; Placebo pills

Eligibility Criteria

• Age: 48 Years - 60 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Women ages 48 to 60 (at the time of enrollment) will be eligible for this study if they:
• 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 (Diagnostic and Statistical Manual) 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);
• 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);
• 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);
• 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;
• Have not taken hormonal contraceptives, ET (estrogen therapy) or HT (hormone therapy) for at least 3 months as per self-report;
• Are within 10 years and 11 months of LMP (last menstrual period) as per self-report;
• Have a follicular stimulating hormone level (FSH) of \>30 IU/ml as per hormone testing results; 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);
• Are able to give written informed consent;
• Provide written documentation of having had a normal mammogram and a PAP smear (Papanicolaou test) within the recommended timeframe as defined by the American College of Obstetricians and Gynecologists (ACOG) - please visit their website for current recommendations;
• Must have clear urine toxicology screen upon recruitment;
• Are fluent in written and spoken English;
• Are right-handed.

You may not qualify if:

• Currently smoking more than 10 cigarettes/day by self report;
• History of clinical CVD (cardiovascular disease) including myocardial infarction, angina, or congestive heart failure;
• History of thromboembolic disease (deep vein thrombosis or pulmonary embolus);
• History of untreated (no cholecystectomy) gallbladder disease as per self-report during PE;
• History of triglyceridemia by subject report;
• Undiagnosed vaginal bleeding as per self-report;
• History of estrogen responsive cancers as per self-report;
• Known hypercoagulable state (thrombophilias) as per self-report;
• Use of estrogen- or progestin-containing medication or phytoestrogen containing supplements (e.g. soy concentrates or extracts) within 3 months of participation as per self-report; 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);
• Have a Mini Mental Status Score of \< 25;
• Hamilton Depression Score \> 14;
• As per self-report, 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;
• Have a metallic implant as per self-report;
• Are claustrophobic as per self-report;
• Are pregnant (pertains to peri-menopausal women only).

Sponsors & Collaborators

• University of Colorado, Denver: lead
• National Institute of Mental Health (NIMH): collaborator
• University of Pennsylvania: collaborator

Study Sites (1)

Penn Center for Women's Behavioral Wellness, University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (5)

• 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. doi: 10.1177/0269881106067330. Epub 2006 Aug 4.

  PMID: 16891341 BACKGROUND

• 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. doi: 10.1038/sj.npp.1301114. Epub 2006 Jun 7.

  PMID: 16760926 BACKGROUND

• 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. doi: 10.1016/j.neuroimage.2006.03.013. Epub 2006 Apr 27.

  PMID: 16644236 BACKGROUND

• 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. doi: 10.1177/1534582305277152.

  PMID: 15886402 BACKGROUND

• 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. doi: 10.1176/appi.ajp.160.8.1522.

  PMID: 12900319 BACKGROUND

Related Links

• Program Website

MeSH Terms

Conditions

Memory Disorders

Interventions

Estradiol; Amino Acids; Isoleucine; Leucine; Lysine; Methionine; Phenylalanine; Threonine; Valine; Lactose

Condition Hierarchy (Ancestors)

Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Amino Acids, Peptides, and Proteins; Amino Acids, Branched-Chain; Amino Acids, Essential; Amino Acids, Basic; Amino Acids, Diamino; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids, Neutral; Amino Acids, Aromatic; Amino Acids, Cyclic; Disaccharides; Oligosaccharides; Polysaccharides; Carbohydrates; Sugars

Results Point of Contact

• Title: C. Neill Epperson, M.D
• Organization: University of Pennsylvania

cepp@mail.med.upenn.edu

215-573-8871

Study Officials

• Cynthia Neill Epperson, M.D.

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 22, 2010
• First Posted: September 23, 2010
• Study Start: March 4, 2010
• Primary Completion: November 1, 2018
• Study Completion: November 1, 2018
• Last Updated: April 2, 2021
• Results First Posted: April 2, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)