Neurobiology of Bulimia Nervosa

Phase 2

Completed

Conditions: Bulimia Nervosa

Interventions: Drug: Estradiol
Drug: Micronized progesterone
Drug: Leuprolide Acetate
Drug: Placebo Oral Capsule

Registration Number: NCT04225221

Lead Sponsor: University of North Carolina, Chapel Hill

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 10

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sequence A: estradiol followed by progesterone	Micronized progesterone	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.
Sequence A: estradiol followed by progesterone	Placebo Oral Capsule	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.
Sequence B: progesterone followed by estradiol	Placebo Oral Capsule	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.
Sequence A: estradiol followed by progesterone	Leuprolide Acetate	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.
Sequence B: progesterone followed by estradiol	Leuprolide Acetate	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.
Sequence A: estradiol followed by progesterone	Estradiol	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.
Sequence B: progesterone followed by estradiol	Estradiol	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.
Sequence B: progesterone followed by estradiol	Micronized progesterone	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.

Primary Outcome Measures

Name	Time	Method
Change in Binge Eating Sum Score	Baseline (Day 14 of baseline) to End of Intervention (Day 14 of each intervention)	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.
Change in Weekly Average Binge-eating Frequency	Baseline (Day 14 of baseline) to End of Intervention (Day 14 of each intervention)	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.
Change in Self-Reported Reward Sensitivity Subscale Score During Estradiol Manipulation	Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention)	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.
Change in Response Latency to Reward During the Monetary Incentive Delay Task During Estradiol Manipulation	Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention)	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.
Change in Delay Discounting Parameter k Using the Monetary Choice Questionnaire With Estradiol Manipulation	Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention)	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.
Change in Self-Reported Behavioral Inhibition Score During Estradiol Manipulation	Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention)	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
Change in Behavioral Activation Score During Estradiol Manipulation	Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention)	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.
Change in Behavioral Activation Reward Responsiveness With Estradiol Manipulation	Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention)	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.
Correlation Between Change in Reward Response and Change in Binge Eating Before and During Estradiol Manipulation	Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention)	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.
Change in Behavioral Inhibition During Estradiol Administration as Assessed Through a Behavioral Task	Baseline (Day 14 of baseline) to End of Intervention (Day 14 of intervention)	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.