Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation
Sunday, November 10, 2013, 1:00 pm - 5:00 pm
236.03: Effect of lisdexamfetamine in a rat model of binge-eating disorder
Location: Halls B-H
*S. P. VICKERS1, D. J. HEAL1, D. HACKETT2, P. H. HUTSON3; 1Renasci Ltd, Nottingham, United Kingdom; 2Shire Pharmaceuticals Limited, Basingstoke, United Kingdom; 3Shire Develop. Inc, Wayne, PA
Abstract Body: Binge-eating disorder (BED) is a common psychiatric condition, affecting ~2% of the adult population. It occurs approximately equally in women and men and most often in older adults. It manifests as compulsive, excessive consumption of highly palatable foods and may or may not be associated with obesity. Binge eaters frequently experience intense feelings of guilt and anxiety after a binge session, but do not indulge in purging. lisdexamfetamine dimesylate (LDX; Vyvanse®), a novel prodrug that is metabolized to d amfetamine (d-AMF) primarily by red blood cells (Pennick, 2010, Neuropsychiat Dis Treat 6:317) is approved in the USA, Mexico and Europe for ADHD (ages 6-17). It is being clinically evaluated for managing BED in USA. This study compared the acute effects of LDX in rats trained to binge eat chocolate with its active metabolite, d AMF, and with sibutramine (SIB), which is reported to be moderately effective in clinical trials of BED (Wilfley et al, 2008, Am J Psychiat 165:51-58). Forty-four adult, lean, female Wistar rats were housed individually on reversed-phase lighting with free access to standard diet and water. Ground milk chocolate was offered to each rat for 2 hour periods at irregular intervals to establish binge eating. LDX, d AMF and SIB were administered orally. Irregular, limited access to chocolate for ~4 weeks produced reproducible binge eating, but bodyweights were not different from control rats maintained on a standard diet. LDX (0.1-1.5 mg/kg d AMF base) reduced chocolate bingeing by up to 86.1% at the highest dose (p<0.001). The intermediate dose of 0.3 mg/kg, LDX reduced chocolate consumption 40.2% (p<0.001) whilst having no effect on standard diet intake. LDX treatment did not decrease bodyweight compared with the control group given vehicle. d AMF (0.1 1.0 mg/kg d AMF base) decreased chocolate bingeing at 0.5 mg/kg (p<0.01) and 1.0 mg/kg (p<0.001). d AMF did not reduce standard diet consumption, but did reduce bodyweight (p<0.01) at the highest dose. SIB (0.3 5.0 mg/kg) reduced chocolate bingeing (p<0.001 at 1-5 mg/kg); however there were similar reductions of standard diet consumption for all doses (p<0.05-0.01). SIB also produced small bodyweight decreases (p<0.05-0.001 at 1-5 mg/kg). Animals allowed irregular, limited access to chocolate developed robust, intermittent hyperphagia that mirrored BED without the associated obesity. Binge eating was markedly reduced by a single treatment with LDX or its metabolite, d AMF. Unlike SIB, both LDX and d AMF reduced chocolate binge-eating without simultaneously decreasing the consumption of normal diet. These results provide support for use of LDX in the clinical treatment of BED.
Lay Language Summary: Our research provides the first preclinical evidence to support the clinical evaluation of lisdexamfetamine dimesylate as a treatment for binge-eating disorder (BED). Lisdexamfetamine is a d-amfetamine prodrug used to treat attention deficit hyperactivity disorder (ADHD). We established binge-eating in rats by giving them irregular, limited access to a highly palatable food, chocolate. They developed patterns of robust, chocolate bingeing that is analogous to human BED without the development of obesity. Bingeing on chocolate was markedly attenuated by acute treatment with lisdexamfetamine. Importantly, some doses of lisdexamfetamine achieved this outcome without reducing the rats’ consumption of their normal diet. BED is the most common eating disorder in the USA affecting 3.5% of females and 2% of males and it is prevalent in up to 30% of individuals seeking weight loss treatment. There are no approved drugs to treat this serious psychiatric disorder and it is an urgent unmet medical need. Our findings provide robust evidence to support the clinical evaluation of lisdexamfetamine in BED. Moreover, they suggest lisdexamfetamine may be especially beneficial if it also selectively reduces bingeing of palatable foods in humans without adversely affecting normal food consumption. These results have been presented at a small number of other clinical and basic science meetings in 2013, ie NCDEU (Hollywood, Forida), BAP Annual Meeting (Harrogate, UK) and ECNP (Barcelona, Spain). Forty lean, adult, female, Wistar rats were housed individually on reversed-phase lighting with free access to standard diet and water. They were presented with chocolate for 2 hours every few days according to an irregular access schedule to present opportunities for bingeing (ie bouts of intense hyperphagia). This was repeated until animals developed robust and consistent binge eating behaviour that was characterized by significantly increased daily calorie intake in animals that had consumed normally the previous day. Once binge-eating behaviour was established, lisdexamfetamine, d-amfetamine (its active metabolite) and sibutramine (reference comparator) were acutely administered orally. The amounts of chocolate and standard laboratory chow consumed in the 2 hr bingeing sessions were recorded along with bodyweight. The next step in preclinical testing is to determine whether the beneficial effects of lisdexamfetamine are maintained when the compound is administered for prolonged periods. Although BED was not classified in the Diagnostic and Statistical Manual of Mental Disorders as an eating disorder until 2013, it was first described in the 1950s by psychiatrist and researcher, Albert Stunkard, as "Night Eating Syndrome" (NES). The term "Binge Eating Disorder" was coined to describe the same binging-type eating behaviour without the exclusive nocturnal component. BED manifests itself as the compulsive, excessive consumption of highly palatable foods. Binge eaters frequently experience intense feelings of guilt and anxiety after a session. BED frequently occurs together with other psychiatric disorders particularly depression Lisdexamfetamine is a novel d-amfetamine prodrug that is approved in USA for the management of ADHD in children, adolescents and adults. Lisdexamfetamine is not approved for treatment of BED, but it is currently undergoing clinically evaluation for the management of this disorder.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit