An experimental antagonist of the mu-opioid receptor in the brain has been found to reduce appetite, especially for sweet and fatty foods, in obese people with binge-eating disorder.
This finding was reported by Hisham Ziauddeen, a doctoral student in psychiatry at the University of Cambridge in England, and colleagues online November 13, 2012, in Molecular Psychiatry.
Previous studies have found that between 25 percent and 50 percent of people with binge-eating disorder seeking weight-loss treatment are obese. Since there is a paucity of effective and safe pharmacological treatments for binge eating and/or obesity and since the mu-opioid receptor has been implicated in binge eating, Ziauddeen and his team decided to see what effects an antagonist of the mu-opioid receptor might have on binge eating and weight in obese binge eaters.
Sixty-three obese binge eaters were randomized to three groups for a 28-day period. One group received 2 mg/day of an experimental mu-opioid receptor antagonist called GSK1521498. A second group received 5 mg/day of the experimental antagonist, and the third group received a placebo.
Compared with the placebo group, the 2 mg/day antagonist group experienced no significant changes in eating behavior or weight. However, the 5 mg/day group did show a change. Subjects in that group experienced a significant reduction in hedonic responses to sweetened dairy products and reduced their caloric intake, especially of high-fat desserts, during unrestricted buffet dining.
Moreover, the antagonist was found to be safe according to the Profile of Mood States–Brief, the Beck’s Anxiety and Depression Inventory, the Columbia Suicide Severity Rating Scale, cardiovascular parameters, liver-function tests, and standard lab measures. The antagonist was also generally well tolerated, although diarrhea and abdominal discomfort tended to be more commonly reported by the antagonist groups than by the placebo group.
But the effects of the 5 mg/day antagonist on eating behavior did not translate into weight reduction. One possible explanation for this, the researchers suggested, is that it might have taken longer than 28 days for the antagonist’s influence on eating behavior to bring about weight loss. Another possibility, they noted, is that outside of the lab experiments, subjects could eat whatever they wanted.
In any event, even though “the study did not show drug effects on body weight in the sample as a whole, the pharmacogenetic analyses showed that patients with the less-common form of the opioid receptor gene did have significantly greater weight reduction,” Ziauddeen told Psychiatric News. “As far as we know, this is the first time it has been shown that genetic variation in the opioid receptor gene can modify a drug’s effects on body weight.”
Also intriguingly, he pointed out, “the same genetic variant can modify the effects of similar opioid-receptor-antagonist drugs used in the treatment of alcohol dependence.” So in the future, he said, it might be possible to personalize treatments for binge eating and alcohol dependence based on individual differences in the mu-opioid receptor gene. Indeed, he and his colleagues “are currently in the process of examining the role of mu-opioid antagonism on eating behavior…in genetically stratified groups.”
These are “provocative” findings and “a promising area for future research, including determining whether these findings will lead to useful clinical applications,” B. Timothy Walsh, M.D., a professor of pediatric psychopharmacology at Columbia University and chair of the DSM-5 Feeding and Eating Disorders Work Group, said in an interview.
The study was funded by GlaxoSmithKline as part of the Academic Discovery Performance Unit program with the University of Cambridge. “This novel initiative is a joint academia-industry collaboration pioneered here in Cambridge to optimize the early development of new therapeutic agents,” Ziauddeen said. ■