Eloisa Castaldo

Investigation of the serotonin transporter regulatory region polymorphism in bulimia nervosa: relationships to harm avoidance, nutritional parameters, and psychiatric comorbidity.

Objective: Genes involved in 5HT transmission have been supposed to contribute to the biologic vulnerability for bulimia nervosa (BN). Because a long (L) and a short (S) variant of the promoter region of the 5HT transporter gene have been identified, we tested whether the 5HTT gene-linked polymorphic region (5HTTLPR) could represent a susceptibility factor for BN and/or could be related to nutritional parameters, harm avoidance personality dimension, and psychiatric comorbidity. Methods: A total of 219 white women (125 bulimics and 94 healthy control subjects) underwent a blood sample collection for 5HTTLPR genotyping and a clinical evaluation assessing comorbidity for axis I and II psychiatric disorders, harm avoidance personality dimension, and body composition (only patients). Results: The distribution of the 5HTTLPR genotypes did not significantly differ between patients and control subjects, although the L allele was significantly more frequent in the former. Bulimic individuals carrying at least one copy of the S allele had significantly lower mean body mass index and body fat mass values and significantly higher mean harm avoidance score than patients with the LL genotype. No significant association was found between the 5HTTLPR genotype and comorbid axis I and II psychiatric disorders. Conclusions: These findings support the view that polymorphic variants of the 5HTT promoter region do not play a part in predisposing to BN, whereas they seem to predispose bulimic individuals to nutritional impairment and increased harm avoidance. ANOVA = analysis of variance; BMI = body mass index; BW = body weight; BN = bulimia nervosa; MINI = Mini International Neuropsychiatric Interview; NS = not significant; 5HT = serotonin; 5HTT = serotonin transporter; 5HTTLPR = serotonin transporter length polymorphic region; SCID-IP = Structured Clinical Interview for DSM IV Axis I disorders–Patient Edition; SCID-II = Structured Clinical Interview for DSM IV Axis II personality disorders; TCI-R = Temperament and Character Inventory Revised.

Neuroendocrine dysregulation of food intake in eating disorders.

Anorexia nervosa (AN) and bulimia nervosa (BN) are psychiatric disorders characterized by abnormal eating behaviors and imbalance of energy homeostasis. Changes of both central and peripheral neuroendocrine substances involved in the modulation of food intake and energy expenditure have been described in acutely ill patients with eating disorders. This review selectively focuses on the most recent findings supporting abnormal changes in the physiology of some peripheral adipokines and gut-secreted peptides, brain-derived neurotrophic factor and endocannabinoids in patients with AN or BN. Literature data do suggest a dysregulation of these neuroendocrine feeding regulators but, at the moment, they do not allow to establish the state or trait-dependent nature of those aberrations. It has been proposed, although not definitively proved, that neuroendocrine alterations, even when secondary to malnutrition and/or to aberrant eating behaviors, might contribute to the genesis and the maintenance of some symptomatic aspects of AN and BN, thus affecting the course and the prognosis of these disorders. Future studies should clarify whether neuroendocrine alterations are part of the genetically transmitted biological vulnerability to eating disorders.

The 196G/A (val66met) polymorphism of the BDNF gene is significantly associated with binge eating behavior in women with bulimia nervosa or binge eating disorder

The brain-derived neurotrophic factor (BDNF) is involved not only in promoting neuronal outgrowth and differentiation, synaptic connectivity and neuronal repair, but also in modulating eating behavior. Since genetic factors likely contribute to the biological vulnerability to bulimia nervosa (BN) and binge eating disorder (BED), we investigated whether the functional 196G/A single nucleotide polymorphism (SNP) of the BDNF gene was associated to BN and/or BED or to some phenotypic aspects of the disordered eating. Two hundred and ten Caucasian women (126 with BN, 84 with BED and 121 healthy controls) participated into the study. No significant differences were found in the frequencies of the 196G/A variants of the BDNF gene among patients with BN or BED and healthy controls. In both BN and BED groups, subjects carrying the 196A/A genotype exhibited a weekly frequency of bingeing and a severity of binge eating (as assessed by the Bulimia Investigation Test Edinburgh) significantly higher than those with the 196A/G and 196G/G genotypes. These results suggest that the 196G/A SNP of the human BDNF gene does not contribute to the genetic susceptibility to BN and BED, but may predispose those patients to a more severe binge eating behavior.

No association of the Arg51Gln and Leu72Met polymorphisms of the ghrelin gene with anorexia nervosa or bulimia nervosa

Genetic factors likely contribute to the biological vulnerability to anorexia nervosa (AN) and bulimia nervosa (BN). We investigated whether the Arg51Gln and/or the Leu72Met gene polymorphisms of the human ghrelin, a peptide involved in the regulation of eating behavior, were associated to AN and/or BN. Two-hundred-ninety-two Caucasian women (114 with BN, 59 with AN and 119 healthy controls) participated into the study. No significant differences were found in the frequencies of the Arg51Gln and the Leu72Met ghrelin gene variants among patients with AN or BN and healthy controls. Moreover, no significant differences emerged in eating-related phenotypic variables between patients carrying the Leu72Met genotype as compared to those with the Leu72Leu genotype. These results suggest that the Arg51Gln and the Leu72Met polymorphisms of the human ghrelin gene do not contribute to the genetic susceptibility to AN and BN.

Association of a functional serotonin transporter gene polymorphism with binge eating disorder

The pathophysiological mechanisms underlying binge eating disorder (BED) are poorly understood. There is evidence that abnormalities in brain serotonin (5HT) play an important role in binge eating behavior, therefore genes involved in 5HT transmission, such as the 5HT transporter (5HTT) gene, may contribute to the biological vulnerability to BED. We examined whether the polymorphism of the promoter of the 5HTT gene, consisting of a long (L) and a short (S) variant, was associated with BED. Seventy‐seven obese or non‐obese women with BED, and 61 normal weight control women were genotyped at the 5HTT gene linked polymorphism (5HTTLPR). Statistical analysis showed that both the LL genotype and the L allele of the 5HTTLPR were significantly more frequent in BED subjects. Moreover, the L allele was associated with a moderate but significant risk to develop BED (OR = 2.01, CI = 1.33–3.57). Although these data should be regarded as preliminary because of the small size of our sample, they suggest that the 5HTTPRL may contribute to the genetic susceptibility to BED.

Leptin functioning in eating disorders.

Leptin is an adipocyte-derived hormone, which is involved predominantly in the long-term regulation of body weight and energy balance by acting as a hunger suppressant signal to the brain. Leptin is also involved in the modulation of reproduction, immune function, physical activity, and some endogenous endocrine axes. Since anorexia nervosa (AN) and bulimia nervosa (BN) are characterized by abnormal eating behaviors, dysregulation of endogenous endocrine axes, alterations of reproductive and immune functions, and increased physical activity, extensive research has been carried out in the last decade in order to ascertain a role of this hormone in the pathophysiology of these syndromes. In this article, we review the available data on leptin physiology in patients with eating disorders. These data support the idea that leptin is not directly involved in the etiology of AN or BN. However, malnutrition-induced alterations in its physiology may contribute to the genesis and/or the maintenance of some clinical manifestations of AN and BN and may have an impact on the prognosis of AN.

Serotonin transporter polymorphism and potential response to SSRIs in bulimia nervosa

Sir—Selective serotonin reuptake inhibitors (SSRIs), alone or in combination with different psychotherapies and/or nutritional counselling, have been proved to reduce binge eating and vomiting frequencies in patients with bulimia nervosa (BN). However, percent reductions in bingeing and purging range from 18 to 87%.1 It has been suggested that the initial capacity, affinity or genotype of proteins involved in the regulation of SSRI action could account for differences in treatment outcome.2 The 5-HT transporter (5-HTT) represents the prime target of SSRIs, and a long (L) and a short (S) variant of the promoter region of the 5-HTT gene, with different transcriptional efficiencies, have been identified.3 The S allele of the 5-HTT gene-linked polymorphic region (5-HTTLPR) has been associated with poorer SSRI response in major depression.2, 4, 5, 6, 7

Melanocortin-4 receptor molecular scanning and pro-opiomelanocortin R236G variant screening in binge eating disorder.

Recently, Branson et al. (2003) found that in a sample of severely obese study participants, all those carrying melanocortin-4 receptor (MC4R) gene mutations fulfilled the DSM-IV criteria for binge eating disorder (BED), suggesting that MC4R variants constitute a genetic vulnerability for BED. This hypothesis has been questioned because most of the MC4R mutations reported by Branson et al. are functionally inactive (Farooqi et al., 2003), and no increased rates of BED have been reported in other groups of MC4R mutation carriers extrapolated from small samples of obese patients in studies where the BED diagnosis was not made according to stringent DSM-IV criteria (Herpetz and Siffert, 2003; Hebebrand et al., 2004). Similarly to MC4R, mutations of the pro-opiomelanocortin (POMC) gene, which encodes for agonist ligands of MC4R, have been reported to confer an inherited susceptibility to obesity and could represent vulnerability factors for the development of BED.