Pharmacogenetic and Neurofunctional Brain Areas Study in Obese Patients With Binge Eating Disorder
Pharmacogenetic and Neurofunctional Brain Areas Study in Obese Patients With Binge Eating Disorder
Adoption, twin and family studies have reported that obesity has a strong heritable component
 and in particular, it has been suggested that BMI in adults is due to genetic influence
 rather than shared family environment. Binge eating in obese patients was described.
 Therefore, it has been proposed that binge eating disorder (BED) may contribute to obesity in
 some individuals.

 Pharmacological studies reported that topiramate plays an important role in the treatment of
 binge eating disorder. It has been observed improvement of co-occurring binge eating disorder
 in patients receiving topiramate for treatment of mood disorders. In addition, topiramate was
 associated with anorexia and weight loss in clinical trials with epilepsy patients. Also,
 topiramate has been demonstrated efficacy in pilot and controlled studies for binge eating
 disorder (BED) associated with obesity. Genetic studies will be important to elucidate the
 mechanism by which putative susceptibility variation in candidate genes influences in
 pharmacological improvement of binge eating disorder in obese patients treated with
 topiramate.

 Connecting drug response with relevant functional DNA variants and differences in brain
 regions represents the ultimate goal for pharmacogenetic research playing an important role
 in advancing this understanding. The use of brain imaging combined with genetics can aid in
 understanding the pathophysiological mechanism of the disease. Additionally, brain imaging
 has the ability to bridge between preclinical research and human pharmacological studies.

 This will be a naturalistic clinical study designed to analyze the effect of genetic variants
 and neurofunctional brain areas associated with food craving in patients with obesity and
 binge eating disorder responders to topiramate.

 Hypothesis: The use of topiramate in obese subjects with binge eating disorder is associated
 with a differential gene variants and different activation brain areas in subjects that
 showed a reduction of food craving and weight lost.
Obesity has been declared the number one illness of the 21st Century in industrialized
 countries, and is reaching epidemic proportions. Adoption, twin and family studies have
 reported that obesity has a strong heritable component and in particular, it has been
 suggested that BMI in adults is due to genetic influence rather than shared family
 environment. Binge eating in obese patients was escribed. Therefore, it has been proposed
 that binge eating disorder (BED) may contribute to obesity in some individuals. Subjects with
 BED are frequently obese. Conversely, BED is often observed in obese populations, especially
 the severely obese. Therefore, these findings suggest that BED is a major public health
 problem and a contributor to the obesity epidemic.

 Evidence from twin studies suggests a significant contribution of genetic factor in binge
 eating. Interestingly, it was reported that relatives of patients with BED displayed a higher
 prevalence of obesity, particularly of severe obesity than relatives of probands without BED.
 Adoption and twin studies have consistently shown that, regardless of the population studied,
 genetic factors play an important role in determining the risk of developing binge eating.

 Pharmacological studies reported that topiramate plays an important role in the treatment of
 binge eating disorder. It has been observed improvement of co-occurring binge eating disorder
 in patients receiving topiramate for treatment of mood disorder. In addition, topiramate was
 associated with anorexia and weight loss in clinical trials with epilepsy patients. Also,
 topiramate has been demonstrated efficacy in pilot and controlled studies for binge eating
 disorder (BED) associated with obesity. A paper review showed that topiramate weigtht loss
 was reported in 21 of 32 studies analyzed.

 Recently, it was approved on 4/6/2012 the use of topiramate in combination with phentermine
 (QNEXA) in the Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee of the
 Food and Drug Administration, as an adjunct to diet and exercise for weight management in
 patients with a body mass index (BMI) equal to or greater than 30 kilograms (kg) per square
 meter or a BMI equal to or greater than 27 kg per square meter if accompanied by
 weight-related co-morbidities.

 Finally, animal studies have shown that stimulation of the lateral hypothalamus by glutamate
 and glutamate agonists, including kainite/AMPA agonists, causes an intense, rapid,
 dose-dependent increase in food intake.

 Topiramate weight loss was reported in 21 of the 32 studies analysed and reached 5% reduction
 of the baseline weight prior treatment in 5 studies. Among the studies analyzed, a frequent
 finding was that the grater weight loss was associated with higher BMI at baseline. Also,
 diabetic patients were related with glycemic control and normalization of blood pressure in
 hypertensive subjects. Topiramate was generally well tolerated and serious adverse events
 were rare. Also, the use of topiramate was reported effective for weight reduction and
 improvement in glycemic control in obese subject with type 2 diabetes treated with metformin
 monotherapy.

 Topiramate, which is approved for use in epilepsy and migraine prophylaxis, has multiple
 sites of action that might contribute to its neurostabilizing effects.

 The mechanism of action of topiramate in BED is unknown. It may act as an appetite
 suppressant or satiety enhancer or somehow influence the reward system acting on appetite,
 and thereby reduce binge eating. Topiramate has not been shown to affect serotoninergic
 neurotransmission. Indeed, it has been shown to attenuate nicotine-induced increases in
 mesolimbic extracellular dopamine and norepinephrine, but not serotonin, release.

 In addition, topiramate antagonizes glutamate receptors. Since glutamate and glutamate
 agonists rapidly elicit intense eating when injected into the lateral hypothalamus of rats,
 topiramate might reduce binge eating through glutamate antagonism. However, the mechanism of
 action of topiramate is unknown. Therefore, it is very important pharmacogenetic and
 neurofunctional brain studies that could help to elucidate the role of topiramate such as a
 new treatment for binge eating disorder associated with obesity in Mexican population.

 Genetic studies will be important to elucidate the mechanism by which putative susceptibility
 variation in candidate genes influences in pharmacological improvement of binge eating
 disorder in obese patients treated with topiramate. DNA variants in coding and regulatory
 regions of genes will be both useful for systematic genome scans, for identifying genes
 associated with drug response, and for examining integrated systems of gene pathways as an
 important step on the route to functional genomics. Initiatives focused on identification of
 gene variants would greatly facilitate postgenomic research on the links between genes,
 brain, behavior, and treatment response.

 Many drug targets (e.g., receptors, transporters, enzymes) that contribute to the
 pharmacodynamics of drug response are not only key players in the regulation of
 neurotransmitter systems but also directly or indirectly modify the development and
 plasticity of neural networks involved in drug effects. There is now considerable evidence
 that variability of epigenetic profiles of genes critical to neurocircuit development and
 function influences drug responses.

 There are a number of different kinds of natural genetic variation that result in functional
 protein differences and affect drug responsiveness. The type of variation that is most
 prevalent in the genome and, arguably, the most relevant to common diseases and complex
 traits is represented by single nucleotide polymorphisms (SNPs).

 There are many ways in which genetic variability, the differences in the sequence of specific
 genes, can lead to variability in drug responsiveness and it is likely that each of these
 mechanisms is involved in determining the effects for example in anticonvulsant drugs. Up to
 now, the focus of pharmacogenetic studies has been on "polymorphic drug metabolism". This
 methodology examines variations in the sequence of genes that code for drug-metabolizing
 enzymes. SNPs have been found to underlie variability in drug-metabolizing capacity and such
 variability is often documented as differences in drug and metabolite profiles between
 patients. It is likely that variation in genes coding for proteins involved in other
 pharmacokinetic processes, including drug absorption, distribution, and excretion, also help
 to determine individual differences in responsiveness although these mechanisms are not as
 well studied regarding genetic influences.

 Another way in which genetic variation plays a role in drug responses depends upon
 polymorphisms in genes that code for proteins involved in drug targets or that mediate drug
 action. These differences in response apply both to therapeutic effects and adverse effects
 so that both efficacy and toxicity may be influenced by individual genetic variation. In the
 future, pharmacogenetic discoveries related to drugs will make individualization of therapy
 even more difficult in the sense that the genetic substrate that mediates efficacy may well
 differ from that mediates toxicity. As such, two different sets of genes and genotypes will
 need to be examined in order to match patients with the most appropriate treatment.

 Differences in response apply both to therapeutic effects and adverse effects so that both
 efficacy and toxicity may be influenced by individual genetic variation.

 In addition, compounds exist with mechanisms of action that either differ from standard drugs
 or are not yet fully characterized. These compounds and their mechanisms will lead eventually
 to the investigation of specific, possibly novel, genes in relation to drug responsiveness.
 Because behavioral traits are the most complex traits of all, response to
 psychopharmacological drugs, which modify behaviour traits, is likely to profit from this
 integration. Moreover, behavioural pharmacogenetics will make a major contribution to
 functional genomics.

 Connecting drug response with relevant functional DNA variants and differences in brain
 regions represents the ultimate goal for pharmacogenetic research playing an important role
 in advancing this understanding. Brain imaging can provide valuable links in understanding
 the potential importance and clarifying the pathophysiological mechanisms that lie between
 associations of genetic variability and clinical response. Analysis of additional
 populations, such as Mexican population, is also necessary to achieve these goals. The use of
 brain imaging combined with genetics can aid in understanding the pathophysiological
 mechanism of the disease. Additionally, brain imaging has the ability to bridge between
 preclinical research and human pharmacological studies.

 This study proposes the collection of samples which will result from this study will form the
 basis with which to identify the genes associated with neurofunctional brain areas involved
 in food craving in obese patients with BED treated with topiramate in Mexican population. The
 pharmacogenetic analysis in obese patients associated with BED will identify gene variants
 associated with the treatment efficacy to topiramate in Mexican population.

 Objective The main objective of this study is to analyze the genetic variants and
 neurofunctional brain areas associated with food craving in obese patients with binge eating
 disorder responders to topiramate treatment.

 Study design:

 This will be a naturalistic clinical study designed to analyze the effect of genetic variants
 and neurofunctional brain areas associated with food craving in patients with obesity and
 binge eating disorder responders to topiramate.
Inclusion Criteria:

 1. Patients of Eating Disorders Clinic with a diagnosis of Bulimia Nervosa, Eating
 Disorders Not Otherwise Specified 3 and 6 with Binge Eating Disorder according to
 research criteria in Diagnostic and Statistical of Mental Disorders, version IV
 revised, who started taking Topiramate.

 2. Probands with diagnosis of obesity (BMI ≥30 kg/m2- 40 kg/m2).

 3. Capable to give written informed consent.

 4. Age of 18 to 50 years at screening.

 5. Maternal and paternal grandparents of Mexican descent.

 6. Probands without psychopharmacological treatment (including anticonvulsants) at least
 4 weeks before inclusion.

 Exclusion Criteria:

 1. Subjects with alcohol or substance abuse or dependence.

 2. Any psychiatric or medical disorder that requires inpatient treatment.

 3. Psychosis or suicidal thoughts.

 4. Abnormal blood chemistry.

 5. Diabetes uncontrolled.

 6. Unstable hypertension or difficult to control (criterion 7 of inclusion section).

 7. Metabolic acidosis.

 8. Narrow-angle glaucoma.

 9. Unstable hypothyroidism or hyperthyroidism.

 10. Unable or unwilling to give a blood sample.

 11. Pace-makers or metal implants that would preclude the functional Magnetic Resonance
 Image scan.

 12. Pregnant or lactating women at screening or positive blood pregnancy test.

 13. Presence of any epileptic disorder.

 14. Subjects unable or unlikely to follow the protocol procedures.