Current Drug Targets-CNS & Neurological Disorders - Volume 2, Issue 1, 2003

Disturbances in the functioning of the upper gastrointestinal (GI ) tract have been described in both Anorexia Nervosa (AN) and Bulimia Nervosa (BN). Patients with AN experience substantial delays in gastric emptying as well as constipation. These problems may give rise to significant medical complications and may contribute to increased difficulties with refeeding and weight restoration. Reported GI disturbances in BN include increased gastric capacity, diminished gastric relaxation, delayed gastric emptying, diminished release of cholecystokinin (CCK) and abnormalities of enteric autonomic function, all of which may play a role in perpetuation of the syndrome. This article reviews evidence for the most common disturbances of GI function in AN and BN and discusses potential GI targets for therapeutic intervention.

Anorexia nervosa commonly occurs during adolescence, a critical period for the acquisition of peak bone mass. Osteopenia is an early and serious complication associated with anorexia nervosa. Whether the osteopenia observed in adolescents with anorexia nervosa is reversible is unknown. The possible mechanisms for the osteopenia observed in adolescents with anorexia nervosa are complex and poorly understood. The purpose of this paper is to review a number of the identified factors that influence the attainment of peak bone mass in anorexia nervosa and to examine the best treatment options for optimizing skeletal mineralization in adolescents with anorexia nervosa.

The purpose of this article is to review the psychopharmacology treatment literature for patients with eating disorders including bulimia nervosa, anorexia nervosa and binge eating disorder. The best-developed treatment literature concerns bulimia nervosa, which has been studied now in several dozen pharmacological treatment studies. The agents most commonly used are the antidepressants, with particular focus on the selective serotonin reuptake inhibitors including fluoxetine hydrochloride. These agents clearly impact significantly on the frequency of abnormal eating behaviors such as binge eating and purging. However, subjects treated with these drugs rarely achieve remission. Pharmacotherapy of anorexia nervosa has also traditionally focused on the use of antidepressants and there is some evidence that the use of SSRIs may help in preventing relapse in weight restored patients. Recently interest has developed in the use of atypical neuroleptics to help with the obsessionality and resistance to treatment frequently seen in low weight patients, the most commonly employed agent being olanzapine. Pharmacotherapy of binge-eating disorder is now being intensively investigated. In general medication alone seems inferior to psychotherapy in the short term. Antidepressants can increase the amount of weight loss when combined with psychological treatment and also appear to benefit symptoms such as depression. Further data are needed, but a number of drugs appear promising.

Environmental influences, as well as biological and genetic factors influence risk for eating disorders. Family and twin studies have shown that eating disorders are familial and suggest the influence of genetic factors on their etiology. Positive associations have been observed for some candidate genes that have been studied (such as 5HT2A receptor gene), however, the field has been plagued by nonreplications. In this paper we review the extant association studies of eating disorders.

The eating disorders are severe psychiatric illnesses with significant morbidity and mortality that exhibit statistically significant familial risk and heritability, providing support for a molecular genetic approach toward defining etiological factors. An emerging candidate gene literature has concentrated on serotinergic and dopaminergic candidates. With the financial support of the Price Foundation, a group of investigators initiated an international multi-center collaboration (Price Foundation Collaborative Group) in 1995 to study the genetics of anorexia and bulimia nervosa by collecting and analyzing phenotypes and genotypes of individuals and their relatives affected with eating disorders. The first sample of families collected by this collaborative group, known as the Price Foundation Anorexia Nervosa Affected Relative Pair (AN-ARP) dataset, was ascertained on an proband affected with Anorexia Nervosa (AN), with relative pairs affected with the eating disorders AN, Bulimia Nervosa or Eating Disorders Not Otherwise Specified [1]. Biognosis U.S., Inc. was founded to identify and characterize candidate susceptibility genes for anorexia and bulimia nervosa phenotypes in the Price Foundation eating disorder datasets. During 2000-2001, Biognosis U.S., Inc. developed and implemented a research program with a focus on the analysis of candidate genes nominated by neurochemical characteristics of eating disorder patients [2], serotonergic and dopaminergic candidate gene polymorphisms [3], neuroendocrine regulation of appetite [4], and by a positional hypothesis from a linkage analysis of the AN-ARP dataset [5]. This report reviews the anorexia nervosa candidate gene literature through 2001, the candidate gene research program implemented at Biognosis U.S., Inc. and selected candidate gene findings in the AN-ARP dataset derived from that research program.

Neuropeptides play an important role in the regulation of feeding behavior and obesity. The mechanisms for controlling food intake involve a complicated interplay between peripheral systems (including gustatory stimulation, gastrointestinal peptide secretion, and vagal afferent nerve responses) and central nervous system (CNS) neuropeptides and / or monoamines. These neuronal systems include neuropeptides (CRH, opioids, neuropeptide-Y (NPY) and peptide YY (PYY), vasopressin and oxytocin, CCK, and leptin) and monamines (serotonin, dopamine, norepinephrine). In addition to regulating eating behavior, a number of CNS neuropeptides participate in the regulation of neuroendocrine pathways. Thus, clinical studies have evaluated the possibility that CNS neuropeptide alterations may contribute to dysregulated secretion of the gonadal hormones, cortisol, thyroid hormones and growth hormone in the eating disorders. Most of the neuroendocrine and neuropeptide alterations apparent during symptomatic episodes of AN and BN tend to normalize after recovery. This observation suggests that most of the disturbances are consequences rather than causes of malnutrition, weight loss and / or altered meal patterns. Still, an understanding of these neuropeptide disturbances may shed light on why many people with AN or BN cannot easily “reverse” their illness and even after weight gain and normalized eating patterns, many individuals who have recovered from AN or BN have physiological, behavioral and psychological symptoms that persist for extended periods of time.

Anorexia and Bulimia Nervosa are disorders of unknown etiology that invariably begin during adolescence and near in time to puberty in young women. These disorders are associated with aberrant eating behaviors, body image distortions, impulse and mood disturbances, as well as characteristic temperament and personality traits.It is well known that malnutrition produces changes in neuroendocrine function. More recently, disturbances in neuronal systems have been found to play a role in the modulation of feeding, mood, and impulse control. These neuronal systems include neuropeptides (CRH, opioids, neuropeptide-Y (NPY) and peptide YY (PYY), vasopressin and oxytocin, CCK, and leptin) and monoamines (serotonin, dopamine, norepinephrine). Disturbances of most of these neuronal systems have been found when people are ill with an eating disorder, but it was not certain whether they were a cause or consequence of symptoms. In order to address these questions, a growing number of studies have investigated whether neuromodulatory disturbances persist after recovery. Studies from several centers tend to show altered serotonin activity persists after prolonged normalization of weight, nutrition, and menstrual function, as do anxiety, obsessionality, and perfectionism. While there are fewer data, there may be persistent alterations of dopamine or some neuropeptides in some subjects in a recovered state.The inaccessibility of the central nervous system has made it difficult to understand brain and behavior. In the past decade, new tools, such as brain imaging, have offered the possibility of better characterization of complex neuronal function and behavior. Such studies have tended to consistently find that alterations of brain regions, such as the temporal lobe, occur in people who are ill with anorexia nervosa and appear to persist after some degree of weight gain and recovery. New imaging technology, that marries Positron Emission Tomography (PET) imaging with selective neurotransmitter radioligands, confirms that altered serotonin neuronal pathway activity persists after recovery from an eating disorder and supports the possibility that these psychobiological alterations might contribute to traits, such as increased anxiety or extremes of impulse control, that, in turn, may contribute to a vulnerability to the development of an eating disorder. In summary, studies of pathophysiology are starting to nominate new candidates for treatment leading to the possibility of finding effective treatments for this often chronic or fatal disorder.