Neurobiology of Bulimia Nervosa

Study Overview
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Brief Summary
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This pilot study experimentally manipulates ovarian hormones to examine the direct impact of estrogen (E2) and progesterone (P4) on binge eating symptom burden and the behavioral reward response in women with bulimia nervosa (n=15). This is completed by taking medications that change ovarian hormone levels. This line of research could lead to the development of pharmacological interventions developed to target specific areas of the brain, brain receptors, or pathways identified to be involved in the mechanism underlying ovarian hormone change and binge eating.

Detailed Description
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Eating disorders (EDs) affect 15 million women in the United States and have one of the highest mortality rates of any mental illness. Despite this, the underlying neurobiology remains poorly understood. EDs predominantly occur in women, and the frequency of certain symptoms change in a predictable pattern over the menstrual cycle; specifically, symptom changes appear to be triggered by normal fluctuations in the ovarian hormones estradiol (E2) and progesterone (P4). The objective of this study is to examine the direct and mechanistic role of E2 and P4 on binge eating in women with bulimia nervosa (BN; n = 15). The experimental design parallels an established design developed to determine the hormonal triggers of premenstrual dysphoric disorder and depression: temporarily stopping the menstrual cycle using a Gonadotropin-releasing hormone (GnRH) agonist (Lupron) and addback E2 and P4 independently in a double-blind crossover design. The overarching hypothesis is that BN represents a hormone-sensitive phenotype, and this sensitivity is modulated by E2's effects on aspects of the reward response such that reward-motivated behaviors increase in the context of low E2. This line of research will provide direction for future research addressing neuroendocrine, neurobiological, and brain activity and function in BN. To date, there are no medications that have been developed specifically for the treatment of individuals with BN. Our specific aims are to: Aim 1: Quantify the direct effect of E2 and P4 on binge eating in women with BN. Aim 2: Determine the effect of E2 on reward response in women with BN. Aim 3: Examine the association between reward response and binge eating before and after E2 addback.

Official Title
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Ovarian Hormones, Reward Response, and Binge Eating in Bulimia Nervosa: An Experimental Design

Conditions
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Bulimia Nervosa

Intervention / Treatment
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* Drug: Estradiol
* Drug: Micronized progesterone
* Drug: Leuprolide Acetate
* Drug: Placebo Oral Capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Participants will be women aged 18-42 with a current DSM-5 bulimia nervosa (BN) diagnosis who meet the below criteria. Only participants capable of giving informed consent and understanding the risks associated with the study will be enrolled. A regular menstrual cycle for at least three months < 35 BMI > 18.5 Free of medication or medical condition that impacts ovarian hormones or is contraindicated for use with study interventions (including birth control pills) Speaks English Exclusion Criteria Patients will not be permitted to enter this protocol if they have any of the following: peanut allergy bipolar or psychotic disorder; current substance use disorder or frequent binge drinking behavior; frequent diuretic or laxative use, ipecac use; currently smoking > 10 cigarettes daily; history of a suicide attempt or current suicidal ideation; endometriosis; abnormal genital/vaginal bleeding; undiagnosed enlargement of the ovaries; liver disease; breast cancer; personal history of blood clots (a history of blood clots in the legs or lungs; DVT); pregnancy related blood clots history of seizures or epilepsy; porphyria; diabetes mellitus; malignant melanoma; gallbladder or pancreatic disease; heart or kidney disease; cerebrovascular disease (stroke); history of osteoporosis or osteopenia; recurrent migraine with aura; first degree relative (immediate family) with premenopausal breast cancer or breast cancer presenting in both breasts or any woman who has multiple family members (greater than three relatives) with postmenopausal breast cancer will also be excluded from participating in this protocol; Refusal to use non-hormonal contraception throughout study; Pregnant women will be excluded from participation (patients will be warned not to become pregnant during the study and will be advised to employ barrier contraceptive methods), and women who become pregnant (although unlikely because of the hormone manipulation) will be withdrawn; Any condition or symptoms considered by the study team to detrimentally impact subject safety.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 42 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence A: estradiol followed by progesterone<br>Participants are randomly assigned to treatment Sequence A: after achieving hormone suppression using Lupron, participants begin the addback period and take study medications for 8 weeks. During the 8 week period, participants will take placebo or estradiol or progesterone. Participants will not know when or for how long they are on active medication (i.e., estradiol or progesterone) or inactive (i.e., placebo) medication. When active medication is administered, participants randomized to treatment sequence A will receive estradiol addback first, followed by progesterone. Estradiol and progesterone are never given simultaneously. Participants are on active medication for a total of 4 weeks. | Drug: Estradiol<br>* During estradiol administration, 2mg of estradiol is given twice daily via oral capsule.<br>* Other names: Estrace;Drug: Micronized progesterone<br>* During progesterone administration, 200mg of progesterone is given twice daily via oral capsule.<br>* Other names: Prometrium;Drug: Leuprolide Acetate<br>* Initial 3.75 mg intramuscular injection administered approximately Day 6 of menstrual cycle and then monthly thereafter for a total of 3 months.<br>* Other names: Lupron Depot;Drug: Placebo Oral Capsule<br>* Placebo is administered during the addback phase when participants are not taking active medication. Placebo is given so that medication administration occurs throughout the entire 8-week addback period in order to blind participants to when and for how long they are on the active medication.<br>* Other names: Sugar pill;|
| Experimental: Sequence B: progesterone followed by estradiol<br>Participants are randomly assigned to treatment Sequence B: after achieving hormone suppression using Lupron, participants begin the addback period and take study medications for 8 weeks. During the 8 week period, participants will take placebo or estradiol or progesterone. Participants will not know when or for how long they are on active medication (i.e., estradiol or progesterone) or inactive (i.e., placebo) medication. When active medication is administered, participants randomized to treatment sequence B will receive progesterone first followed by estradiol. Estradiol and progesterone are never given simultaneously. Participants are on active medication for a total of 4 weeks. | Drug: Estradiol<br>* During estradiol administration, 2mg of estradiol is given twice daily via oral capsule.<br>* Other names: Estrace;Drug: Micronized progesterone<br>* During progesterone administration, 200mg of progesterone is given twice daily via oral capsule.<br>* Other names: Prometrium;Drug: Leuprolide Acetate<br>* Initial 3.75 mg intramuscular injection administered approximately Day 6 of menstrual cycle and then monthly thereafter for a total of 3 months.<br>* Other names: Lupron Depot;Drug: Placebo Oral Capsule<br>* Placebo is administered during the addback phase when participants are not taking active medication. Placebo is given so that medication administration occurs throughout the entire 8-week addback period in order to blind participants to when and for how long they are on the active medication.<br>* Other names: Sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Binge Eating Sum Score | Binge eating will be measured using the 8-item binge eating subscale of the Eating Pathology Symptoms Inventory (EPSI), which measures features of binge eating (e.g., consumption of large quantities of food, mindless eating) on a 5-point Likert scale from never to very often. The EPSI scale is designed to assess behavior over the past 28 days; however, to be sensitive to the timeframe of the present study, the instructions will be modified to ask participants to consider the past week. Items are summed for a scale score ranging from 0-32. Higher scores indicate more frequent experiences with binge eating behavior. Change is defined by an average change score. | Baseline (Day 14 of baseline) to End of Intervention (Day 14 of each intervention) | 
| Change in Weekly Average Binge-eating Frequency | Binge eating frequency is based on a daily diary of self-reported binge eating frequency. Scores can range from 0 to infinity as they represent a self-reported frequency. Subjects self-report the number of binge eating episodes they had each day. Higher numbers indicate more frequent binge eating episodes. Average weekly frequency will be determined based on daily reported binge eating frequency. Change is defined by an average change score. | Baseline (Day 14 of baseline) to End of Intervention (Day 14 of each intervention) | 
| Change in Self-Reported Reward Sensitivity Subscale Score During Estradiol Manipulation | Sensitivity to Punishment/Sensitivity to Reward Questionnaire will be used to measure reward sensitivity during estradiol intervention. The reward sensitivity subscale will be used, which is rated on a true/false scale with scores ranging 0-24. Higher scores indicate more sensitivity to reward. Change is defined by an average change score. | Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention) | 
| Change in Response Latency to Reward During the Monetary Incentive Delay Task During Estradiol Manipulation | Time (ms) between stimulus and response will be measured during the Monetary Incentive Delay (MID) task during the win trials during the estradiol intervention. During the MID task, participants need to select the correct response during win and lose conditions by pressing a button. Higher scores indicate a longer response time to the win trials. Change is defined by an average change score. | Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention) | 
| Change in Delay Discounting Parameter k Using the Monetary Choice Questionnaire With Estradiol Manipulation | During the estradiol intervention, participants will be asked to make a series of hypothetical choices between small, sooner (impulsive) vs. larger, later (self controlled) hypothetical monetary outcomes. k is a hyperbolic function with larger k values indicating more valuation of a larger delayed reward and smaller values indicating preference for more immediate, smaller rewards (more impulsivity). Change is defined as the average change in k. | Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention) | 
| Change in Self-Reported Behavioral Inhibition Score During Estradiol Manipulation | This measures assesses individual disposition toward avoidance of activities during the estradiol intervention. The Behavioural Inhibition subscale of the Behavioural Inhibition Scale/Behavioral Activation Scale (BIS/BAS) assesses behavioural inhibition (BI) using participant self-reports. The minimum score on the BIS subscale is 7, maximum 28. Greater scores indicate greater behavioural inhibition. Change is defined by an average change score | Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention) | 
| Change in Behavioral Activation Score During Estradiol Manipulation | This measures assesses individual disposition toward engaging in activities during the estradiol intervention. Two BIS/BAS behavioural activation (BA) subscales will be used. The BA subscales used are Fun Seeking and Drive. Each subscale is summed to get the respective subscale scores. The minimum score on BA Fun Seeking and BA Drive are minimum 4 and maximum 16. Higher scores indicate greater behavioral activation. Change is defined by an average change score. | Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention) | 
| Change in Behavioral Activation Reward Responsiveness With Estradiol Manipulation | This measures assesses individual disposition toward avoiding and engaging in activities during estradiol intervention. The BIS/BAS reward responsiveness subscale will be used. The minimum score on the BA Reward Responsiveness subscale is 5, maximum 20. Higher scores indicate greater reward responsiveness. Change is defined by an average change score. | Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention) | 
| Change in Behavioral Inhibition During Estradiol Administration as Assessed Through a Behavioral Task | Behavioral response inhibition will be examined during a go/no-go computerized task during the estradiol intervention. Inhibitory control is defined by the response accuracy of the go no/go trials. Percent of errors is calculated as the number of go responses on a no/go trial divided by the total number of no/go trials. Fewer errors (go response on a no/go trial) indicates better inhibitory control. Change is defined by an average change score. | Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention) | 
| Correlation Between Change in Reward Response and Change in Binge Eating Before and During Estradiol Manipulation | Pearson correlations between change in self-reported reward response and change in binge eating between baseline and estradiol intervention will be examined. Binge eating is defined as the sum score from the Eating Pathology Symptom Inventory (EPSI). Self-reported reward response is defined as the BAS reward responsiveness subscale score and the Sensitivity to Reward/Sensitivity to Punishment Questionnaire (SPSRQ) sensitivity to reward subscale score. Change in binge eating and change in reward response between baseline and estradiol intervention was calculated and a correlation conducted between change scores. | Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bulimia nervosa, binge eating, eating disorder, estrogen