The Role of Serotonin in Hot Flashes After Breast Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this proposal is to improve our understanding of the role of tryptophan and serotonin in hot flashes. The main hypothesis is that alterations in tryptophan and serotonin levels are involved in the induction of hot flashes in women with breast cancer and genetic variations in the serotonin receptors and transporters also play a role.

Detailed Description
-----------------
Among women with breast cancer, hot flashes are a frequent, severe and bothersome symptom. For this group, hot flashes are negatively related to mood, affect, and daily activities and can compromise compliance with life-saving medications (e.g., tamoxifen). Over 60% of breast cancer survivors report hot flashes, with 59% stating they are extremely severe and 44% reporting them to be extremely bothersome. Unfortunately, limitations in our understanding of hot flash physiology limit clinicians' abilities to fully treat this symptom. Although the current non-hormonal treatment of choice for hot flashes after breast cancer targets the central serotonin system (e.g., paroxetine, venlafaxine), the role of serotonin in hot flashes has not been directly tested. Because the effectiveness of these agents has been based largely on improvement in subjective reporting of hot flashes, it is not clear whether benefits are due to physiological effects on hot flashes or due to improvements in mood or other related symptoms. In addition, these and other currently available treatments are not acceptable, appropriate, or effective for all women with breast cancer. Understanding the physiological mechanisms involved in hot flashes after breast cancer will enable us to develop more targeted behavioral and/or pharmacological therapies to be used in lieu of, or in addition to, currently available therapies so that we can eradicate hot flashes and improve the quality of life for women with breast cancer. Results implicating direct effects of tryptophan and serotonin on objective hot flashes will help guide the development of improved interventions for alleviating hot flashes in women with breast cancer. These interventions may target the central serotonin system either behaviorally (e.g., diet) or pharmacologically (e.g., alternative drug therapeutics). If direct manipulation of tryptophan and serotonin does not affect hot flashes, these findings will be equally as useful in guiding future research on non-serotonin related etiologies and interventions. Findings from this study will ultimately be used to eradicate hot flashes as a frequent, severe and bothersome breast cancer treatment related condition, thereby, improving quality of life for all women with breast cancer.

Official Title
-----------------
The Role of Serotonin in Hot Flashes After Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Dietary Supplement: Acute tryptophan depletion
* Dietary Supplement: Half-strength tryptophan depletion (Control)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: At least 18 years of age Willing and able to provide informed consent Reporting daily hot flashes Able to read, write, and speak English Postmenopausal to limit sample variability (> 12 months amenorrhea) Greater then 1 month but < 5 years post-treatment (surgery, radiation, chemotherapy) for non-metastatic breast cancer. These criteria allow inclusion of women successfully treated for recurrent breast cancer since there is no known reason to exclude them. Menopausal status is assessed using self-reports due to problems in reliably measuring follicle-stimulating hormone levels and estradiol in tamoxifen users. Exclusion Criteria: Exclusion criteria are current depression, history of migraines or hepatitis, abnormal chemistry profile (e.g., sodium, potassium, glucose), or a positive urine drug screen for illegal substances.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acute tryptophan depletion<br>Full-strength tryptophan depletion | Dietary Supplement: Acute tryptophan depletion<br>* L-alanine (5.5g), L-arginine (4.9g), L-cysteine (2.7g), glycine (3.2g), L-histidine (3.2g), L-isoleucine (8.0g), L-leucine (13.5g), L-lysine (11.0g), L-methionine (3.0g), L-phenylalanine (5.7g), L-proline (12.2g), L-serine (6.9g), L-threonine (6.9g), L-tyrosine (6.9g), L-valine (8.9g)<br>|
| Active Comparator: Control<br>Half-strength tryptophan depletion drink used as a control | Dietary Supplement: Half-strength tryptophan depletion (Control)<br>* L-alanine (1.4g), L-arginine (1.2g), L-cysteine (0.7g), glycine (0.8g), L-histidine (0.8g), L-isoleucine (2.0g), L-leucine (3.4g), L-lysine (2.8g), L-methionine (0.8g), L-phenylalanine (1.4g), L-proline (3.1g), L-serine (1.7g), L-threonine (1.7g), L-tyrosine (1.7g), L-valine (2.2g), and fillers (7.95g).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Tryptophan Levels | Mean serum tryptophan levels (blood draw) at the end of the nadir period. | baseline, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours | 
| Objective Subject Hot Flash Frequency | Mean of the 24 hour monitoring sessions for each patient based on one 24 hour monitoring session after each intervention using an electronic monitor. | One 24 hour monitoring session per week for 8 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Breast cancer survivorship, Hot Flashes, Serotonin