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Effects of the mu-opioid receptor antagonist GSK1521498 on hedonic and consummatory eating behaviour: a proof of mechanism study in binge-eating obese subjects.

ABSTRACT: The opioid system is implicated in the hedonic and motivational processing of food, and in binge eating, a behaviour strongly linked to obesity. The aim of this study was to evaluate the effects of 4 weeks of treatment with the mu-opioid receptor antagonist GSK1521498 on eating behaviour in binge-eating obese subjects. Adults with body mass index ? 30 kg m(-2) and binge eating scale scores ? 19 received 1-week single-blind placebo run-in, and were then randomized to 28 days with either 2 mg day(-1) GSK1521498, 5 mg day(-1) GSK1521498 or placebo (N=21 per arm) in a double-blind parallel group design. The outcome measures were body weight, fat mass, hedonic and consummatory eating behaviour during inpatient food challenges, safety and pharmacokinetics. The primary analysis was the comparison of change scores in the higher-dose treatment group versus placebo using analysis of covariance at each relevant time point. GSK1521498 (2 mg and 5 mg) was not different from placebo in its effects on weight, fat mass and binge eating scores. However, compared with placebo, GSK1521498 5 mg day(-1) caused a significant reduction in hedonic responses to sweetened dairy products and reduced calorific intake, particularly of high-fat foods during ad libitum buffet meals, with some of these effects correlating with systemic exposure of GSK1521498. There were no significant effects of GSK1521498 2 mg day(-1) on eating behaviour, indicating dose dependency of pharmacodynamics. GSK1521498 was generally well tolerated and no previously unidentified safety signals were detected. The potential for these findings to translate into clinically significant effects in the context of binge eating and weight regain prevention requires further investigation.

SUBMITTER: Ziauddeen H

PROVIDER: S-EPMC3835938 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Effects of the mu-opioid receptor antagonist GSK1521498 on hedonic and consummatory eating behaviour: a proof of mechanism study in binge-eating obese subjects.

Ziauddeen H H Chamberlain S R SR Nathan P J PJ Koch A A Maltby K K Bush M M Tao W X WX Napolitano A A Skeggs A L AL Brooke A C AC Cheke L L Clayton N S NS Sadaf Farooqi I I O'Rahilly S S Waterworth D D Song K K Hosking L L Richards D B DB Fletcher P C PC Bullmore E T ET

Molecular psychiatry 20121113 12

The opioid system is implicated in the hedonic and motivational processing of food, and in binge eating, a behaviour strongly linked to obesity. The aim of this study was to evaluate the effects of 4 weeks of treatment with the mu-opioid receptor antagonist GSK1521498 on eating behaviour in binge-eating obese subjects. Adults with body mass index ≥ 30 kg m(-2) and binge eating scale scores ≥ 19 received 1-week single-blind placebo run-in, and were then randomized to 28 days with either 2 mg day( ...[more]

PMID: 23147384

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Project description:BackgroundCurrent guidelines recommend cognitive behavior therapy (CBT) as the treatment of choice for binge eating disorder (BED). Although CBT is quite effective, a substantial number of patients do not reach abstinence from binge eating. To tackle this problem, various theoretical conceptualizations and treatment models have been proposed. Dialectical behavior therapy (DBT), focusing on emotion regulation, is one such model. Preliminary evidence comparing DBT adapted for BED (DBT-BED) to CBT is promising but the available data do not favor one treatment over the other. The aim of this study is to evaluate outcome of DBT-BED, compared to a more intensive eating disorders-focused form of cognitive behavior therapy (CBT+), in individuals with BED who are overweight and engage in emotional eating.MethodsSeventy-four obese patients with BED who reported above average levels of emotional eating were quasi-randomly allocated to one of two manualized 20-session group treatments: DBT-BED (n = 41) or CBT+ (n = 33). Intention-to-treat outcome was examined at post-treatment and at 6-month follow-up using general or generalized linear models with multiple imputation.ResultsOverall, greater improvements were observed in CBT+. Differences in number of objective binge eating episodes at end of treatment, and eating disorder psychopathology (EDE-Q Global score) and self-esteem (EDI-3 Low Self-Esteem) at follow-up reached statistical significance with medium effect sizes (Cohen's d between .46 and .59). Of the patients in the DBT group, 69.9% reached clinically significant change at end of the treatment vs 65.0% at follow-up. Although higher, this was not significantly different from the patients in the CBT+ group (52.9% vs 45.8%).ConclusionsThe results of this study show that CBT+ produces better outcomes than the less intensive DBT-BED on several measures. Yet, regardless of the dose-difference, the data suggest that DBT-BED and CBT+ lead to comparable levels of clinically meaningful change in global eating disorder psychopathology. Future recommendations include the need for dose-matched comparisons in a sufficiently powered randomized controlled trial, and the need to determine mediators and moderators of treatment outcome.Trial registrationNederlands Trial Register: NL3982 (NTR4154). Date of registration: 2013 August 28, retrospectively registered.

Project description:Binge eating is a core diagnostic feature of bulimia nervosa, binge eating disorder, anorexia nervosa binge/purge type, and is a common feature of "other specified" and "unspecified" feeding and eating disorders. It has been suggested that specific metacognitive beliefs about food, eating, and binge eating may play a key role in the maintenance of binge eating behaviour. The Eating Beliefs Questionnaire (EBQ-18) provides a brief self-report assessment tool measuring three types of metacognitive beliefs: negative, positive, and permissive beliefs about food and eating. This study aimed to build on past research by validating the factor structure and psychometric properties of the EBQ-18 using both a clinical and non-clinical sample. A sample of 688 participants (n = 498 non-clinical participants, n = 161 participants seeking treatment for an eating disorder, and n = 29 participants seeking treatment for obesity) completed a battery of questionnaires, including the EBQ-18 and other measures of eating disorder symptoms and relevant constructs. A subset of 100 non-clinical participants completed the test battery again after an interval of two-weeks, and 38 clinical participants completed the EBQ-18 before and after receiving psychological treatment for their eating disorder. A confirmatory factor analysis (CFA) was conducted and psychometric properties of this measure were assessed. The results of this study provide support for the three-factor model of the EBQ-18. In addition, the EBQ-18 was found to be a valid and reliable measure, with excellent internal consistency, good test-retest reliability in the non-clinical sample, and also demonstrated evidence of sensitivity to treatment in clinical samples with binge eating pathology. Receiver operating characteristic (ROC) curve analyses were used to identify optimal cut-off scores for the EBQ-18. This study provides valuable information about the utility of the EBQ-18 as a measure for use in both clinical and research settings.

Project description:Distinct environmental and conditioned stimuli influencing ethanol-associated appetitive and consummatory behaviors may jointly contribute to alcohol addiction. To develop an effective translational animal model that illuminates this interaction, daily seeking responses, maintained by alcohol-associated conditioned stimuli (CSs), need to be dissociated from alcohol drinking behavior. For this, we established a procedure whereby alcohol seeking maintained by alcohol-associated CSs is followed by a period during which rats have the opportunity to drink alcohol. This cue-controlled alcohol-seeking procedure was used to compare the effects of naltrexone and GSK1521498, a novel selective μ-opioid receptor antagonist, on both voluntary alcohol-intake and alcohol-seeking behaviors. Rederived alcohol-preferring, alcohol-nonpreferring, and high-alcohol-drinking replicate 1 line of rats (Indiana University) first received 18 sessions of 24 h home cage access to 10% alcohol and water under a 2-bottle choice procedure. They were trained subsequently to respond instrumentally for access to 15% alcohol under a second-order schedule of reinforcement, in which a prolonged period of alcohol-seeking behavior was maintained by contingent presentations of an alcohol-associated CS acting as a conditioned reinforcer. This seeking period was terminated by 20 min of free alcohol drinking access that achieved significant blood alcohol concentrations. The influence of pretreatment with either naltrexone (0.1-1-3 mg/kg) or GSK1521498 (0.1-1-3 mg/kg) before instrumental sessions was measured on both seeking and drinking behaviors, as well as on drinking in the 2-bottle choice procedure. Naltrexone and GSK1521498 dose-dependently reduced both cue-controlled alcohol seeking and alcohol intake in the instrumental context as well as alcohol intake in the choice procedure. However, GSK1521498 showed significantly greater effectiveness than naltrexone, supporting its potential use for promoting abstinence and preventing relapse in alcohol addiction.

Dataset Information

Effects of the mu-opioid receptor antagonist GSK1521498 on hedonic and consummatory eating behaviour: a proof of mechanism study in binge-eating obese subjects.

Publications

Effects of the mu-opioid receptor antagonist GSK1521498 on hedonic and consummatory eating behaviour: a proof of mechanism study in binge-eating obese subjects.

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