A systematic review and secondary data analysis of the interactions between the serotonin transporter 5-HTTLPR polymorphism and environmental and psychological factors in eating disorders.

OBJECTIVES: To summarize and synthesize the growing gene x environment (GxE) research investigating the promoter region of the serotonin transporter gene (5-HTTLPR) in the eating disorders (ED) field, and overcome the common limitation of low sample size, by undertaking a systematic review followed by a secondary data meta-analysis of studies identified by the review. METHOD: A systematic review of articles using PsycINFO, PubMed, and EMBASE was undertaken to identify studies investigating the interaction between 5-HTTLPR and an environmental or psychological factor, with an ED-related outcome variable. Seven studies were identified by the systematic review, with complete data sets of five community (n = 1750, 64.5% female) and two clinical (n = 426, 100% female) samples combined to perform four secondary-data analyses: 5-HTTLPR x Traumatic Life Events to predict ED status (n = 909), 5-HTTLPR x Sexual and Physical Abuse to predict bulimic symptoms (n = 1097), 5-HTTLPR x Depression to predict bulimic symptoms (n = 1256), and 5-HTTLPR x Impulsiveness to predict disordered eating (n = 1149). RESULTS: Under a multiplicative model, the low function (s) allele of 5-HTTLPR interacted with traumatic life events and experiencing both sexual and physical abuse (but not only one) to predict increased likelihood of an ED and bulimic symptoms, respectively. However, under an additive model there was also an interaction between sexual and physical abuse considered independently and 5-HTTLPR, and no interaction with traumatic life events. No other GxE interactions were significant. CONCLUSION: Early promising results should be followed-up with continued cross-institutional collaboration in order to achieve the large sample sizes necessary for genetic research.

Effects of acute alcohol intoxication on eating-related urges among women with bulimia nervosa.

OBJECTIVE: To investigate the effects of acute alcohol intoxication on eating-related urges among women with bulimia nervosa (BN). METHOD: Participants included women with BN or normal-weight eating disorder NOS with regular binge/purge symptoms (N = 13), and normal-eater control women (N = 17). Tested individually, the women reported on their mood state as well as on urges to binge eat and engage in various compensatory behaviors, prior to consuming alcohol, and again at 60 and 180 min following the consumption of 1.0 ml kg(-1) alcohol. RESULTS: Both groups reported feeling less clearheaded after drinking, as well as initial subjective mood stimulation followed by subsequent mood lowering. In addition, BN participants reported reductions in their urges to binge eat, exercise compulsively, and restrict food intake following alcohol consumption-the urge to purge was not significantly affected. DISCUSSION: Among women with BN, alcohol consumption appeared to reduce select eating-related urges with concomitant reductions in attention or concentration.

Contributions of the glucocorticoid receptor polymorphism (Bcl1) and childhood abuse to risk of bulimia nervosa.

This study evaluated the hypothesis that traumatic stress can increase risk of bulimia nervosa (BN) in individuals who are genetically disposed towards lower modulation of physiological stress reactions. We explored the extent to which childhood abuse (physical or sexual), variants of a main glucocorticoid receptor (GR) polymorphism (Bcl1), or their interaction, differentiated women with and without BN. Women seeking treatment for BN (N=129) and non-eating-disordered comparison women (N=98) provided blood samples for assays of the Bcl1 polymorphism, and completed structured interviews assessing eating symptoms, psychiatric symptoms and childhood abuse. Compared to normal-eaters, bulimic women were significantly more likely to carry the low-function Bcl1 C allele (CC or CG genotypes), to report a history of childhood abuse and, more importantly, to be positive for both factors. We interpret our findings as indicating that traumatic stress, when impacting individuals disposed to lower GR modulation, can be etiological for BN.

Molecular-genetic correlates of self-harming behaviors in eating-disordered women: findings from a combined Canadian-German sample.

Across populations, findings suggest that rates of self-mutilation, suicidal acts, and other self-harming behaviors (SHBs) may be influenced by polymorphisms that code for activity of the serotonin transporter (e.g., 5HTTLPR) and the enzyme, monoamine oxidase A (e.g., MAOAuVNTR). SHBs being common in patients with Eating Disorders (EDs), we evaluated (in a large sample of eating-disordered women) relationships between triallelic 5HTTLPR and MAOAuVNTR variants, on the one hand, and SHBs, on the other. We had 399 eating-disordered women report on eating symptoms and lifetime history of SHBs, and provide blood samples for genotyping. Individuals carrying high-function MAOAuVNTR alleles reported a history of SHBs about twice as often as did carriers of low-function alleles. We obtained no comparable main effect of 5HTTLPR, or MAOAuVNTR×5HTTLPR interaction effect. Genetic variations did not predict severity of eating symptoms. As in other populations, our findings link the MAOAuVNTR high-function alleles with increased risk of self-directed harm in bulimic females. We discuss theoretical and clinical ramifications of our results.

Trait-defined eating-disorder subtypes and history of childhood abuse.

OBJECTIVE: In participants with eating disorders (EDs), prior physical or sexual abuse has been associated with increased likelihood of impulsivity and affective instability. However, previous studies among participants with eating disorders have not systematically explored relationships between empirically derived, personality-trait-based classes, on the one hand, and likelihood of exposure to either childhood sexual or physical abuse, on the other. METHOD: We assessed multiple psychopathological traits, eating symptoms, and history of abuse in 185 women with an ED and 93 with no ED. RESULTS: A latent class analysis, conducted using psychopathological-trait measures, yielded latent classes of participants with eating disorders fitting the descriptors "dissocial/impulsive," "inhibited/compulsive," and "low psychopathology." ED was generally associated with increased risk of childhood sexual abuse, but the dissocial/impulsive characteristic corresponded with a unique likelihood of physical abuse and especially high rates of sexual abuse. DISCUSSION: Observed associations between different forms of childhood abuse and trait-defined ED variants help inform models on the development of eating disorders and of psychopathological traits that often accompany them.

Association of trait-defined, eating-disorder sub-phenotypes with (biallelic and triallelic) 5HTTLPR variations.

CONTEXT: Efforts to classify eating-disordered individuals based on concurrent personality traits have consistently converged on a typology encompassing "over-regulated", "dysregulated", and "low psychopathology" subgroups. In various populations, evidence has associated personality variations of an "over-regulated/dysregulated" type with differences on serotonin-system indices, and specifically, with different loadings of serotonin transporter promoter regulatory region polymorphism (5HTTLPR) genotypes and alleles. We explored the extent to which an empirical, trait-defined typology of eating-disordered individuals coincided systematically with variations in 5HTTLPR, assayed using biallelic and triallelic models. METHOD: We tested 185 women with a DSM-IV eating disorder (108 with Bulimia Nervosa, 17 Anorexia Nervosa, and 60 an Eating Disorder Not Otherwise Specified) and 93 with no eating disorder on measures reflecting psychopathological traits and 5HTTLPR (biallelic and triallelic) genotypes and alleles. RESULTS: The highest-function, triallelic (L(A)/L(A)) genotype occurred significantly more frequently among eating-disordered individuals than among controls. However, a more fine-grained analysis suggested that this association was attributable to the fact that, among eating-disordered participants, those displaying an "Inhibited/Compulsive" profile (derived using latent class analysis) were more likely than those of a "Dissocial/Impulsive" or a "Low Psychopathology" group to carry the triallelic 5HTTLPR gain-of-function L(A) allele and to be L(A)/L(A) homozygotes. DISCUSSION: This study's empirically derived classes coincide with interpretable differences on genetic indices-associating an "Inhibited/Compulsive" group with 5HTTLPR gain-of-function genotypes (and alleles) that have elsewhere been linked to trait compulsivity. The findings, furthermore, suggest that 5HTTLPR, by influencing personality-trait manifestations may, in turn, influence eating-disorder risk and symptom expression.

Relevance of the 5-HTTLPR polymorphism and childhood abuse to increased psychiatric comorbidity in women with bulimia-spectrum disorders.

OBJECTIVE: Individuals with bulimia nervosa have been shown to display heterogeneous profiles of comorbid psychiatric disturbance, possibly due to varying degrees of genetic and environmental vulnerability. Using information about comorbid psychiatric disturbances, we developed an empirically based classification of individuals with bulimia-spectrum disorders, and then explored whether or not the resulting phenotypes corresponded to variations in the serotonin transporter promoter polymorphism (5-HTTLPR) and exposure to childhood abuse. METHOD: Eighty-nine women aged 17 to 49 years with DSM-IV bulimia-spectrum disorders completed questionnaires assessing eating and general psychopathologic symptoms, participated in interviews assessing Axis I disorders and childhood abuse, and provided blood samples for genotyping. Data on lifetime Axis I disorders were analyzed using latent class analysis, and resulting classes were compared on eating and psychopathologic symptoms, 5-HTTLPR genotype, and childhood abuse. The study was conducted from June 2002 to October 2006. RESULTS: The analysis yielded a model with 2 classes: a first class labeled low comorbidity (N = 59, 66%), characterized by a high likelihood of major depressive disorder, and another class labeled high comorbidity (N = 30, 34%), characterized by a high likelihood of major depressive disorder, anxiety disorder, and substance-use disorders. The high-comorbidity class displayed significantly higher dieting preoccupations and conduct problems, and showed a greater likelihood of carrying the 5-HTTLPR S allele and of childhood abuse than did the low-comorbidity class. CONCLUSIONS: The present results are consistent with previous findings identifying a subgroup of individuals with bulimia characterized by high psychiatric comorbidity and suggest that the 5-HTTLPR polymorphism and childhood trauma may both be pertinent to explaining the presence of greater psychiatric comorbidity in bulimia-spectrum disorders.

Dissocial behavior, the 5HTTLPR polymorphism, and maltreatment in women with bulimic syndromes.

We recently reported that, among bulimic women, previously abused carriers of the 5HTTLPR S allele showed special propensities towards novelty seeking (implying recklessness or impulsivity) and interpersonal insecurity. We subsequently re-analyzed our data, to examine the bearing of the 5HTTLPR polymorphism and prior sexual or physical maltreatment upon validated, higher-order personality-traits. Ninety women with bulimic syndromes were genotyped for 5HTTLPR "short" (S) and "long" (L(G) and L(A)) alleles, and then assessed for eating symptoms, history of sexual or physical abuse, and the higher-order personality traits Emotional Dysregulation, Dissocial Behavior, Inhibition, and Compulsivity. With a classification based on a biallelic model of 5HTTLPR (i.e., presence or absence of at least one S-allele copy), multiple regression indicated a significant proportion of variance in Dissocial Behavior to be explained by an abuse x genotype interaction-greater psychopathology occurring in abused S-allele carriers. A parallel analysis applying a triallelic model of 5HTTLPR (i.e., presence or absence of at least one copy of presumably low-function S or L(G) alleles) produced a similar pattern, but no statistically significant effect. The finding that bulimic 5HTTLPR S-allele carriers who are previously abused display elevations on Dissocial Behavior corroborates previous observations concerning phenomenological correlates of traumatic stress in 5HTTLPR S allele carriers. (c) 2007 Wiley-Liss, Inc.

Serotonin-system polymorphisms (5-HTTLPR and -1438G/A) and responses of patients with bulimic syndromes to multimodal treatments.

BACKGROUND: We tested the hypothesis that individuals carrying low-function alleles of the serotonin transporter (5-HTTLPR) and 5-HT(2A) receptor gene (-1438G/A) promoter polymorphisms would show relatively poor treatment responses on indices of bulimic and concurrent symptoms. METHOD: Participants included 111 women with bulimia-spectrum eating disorders (DSM-IV-TR criteria), 98 of whom were followed through 4- to 8-month spans of specialized multimodal treatment to enable examination of relationships between genotypes and prospective changes in eating and general psychiatric symptoms. Given a hierarchically structured dataset and a desire to control for effects of variations in adjunctive pharmacotherapy, individual therapy, group therapy, or day treatment, we used multilevel modeling techniques. The study was conducted between October 2001 and May 2007. RESULTS: After effects of treatments were removed, 5-HTTLPR low-function allele carriers showed smaller treatment reductions in binge eating (p < .01) and in anxiety and depression (p < .05), whereas low-function -1438G/A G carriers showed smaller reductions in binge eating (p < .01) and impulsivity (p < .05). CONCLUSIONS: This study documents an expected association between poorer bulimia-treatment response and low-function alleles of 5-HTTLPR and -1438G/A--and suggests that such effects cannot be attributed to mediating influences of medication or psychotherapy responsiveness alone. A better understanding of hereditary, serotonin-mediated factors affecting bulimic individuals' progress during therapy may facilitate the development of more effective treatments.

The 5HTTLPR polymorphism, prior maltreatment and dramatic-erratic personality manifestations in women with bulimic syndromes.

BACKGROUND: Low-function alleles of the serotonin transporter promoter polymorphism (5HTTLPR) have been linked to various psychopathological entities, especially in individuals exposed to prior stressors. In women with bulimic syndromes, we explored associations with personality pathology of 5HTTLPR and prior sexual or physical maltreatment. METHODS: Ninety-two women with bulimic syndromes were genotyped for 5HTTLPR short (S) and long (L(G) and L(A)) alleles and were then assessed for eating symptoms, dimensional personality disturbances, history of sexual or physical abuse and borderline personality disorder (BPD). RESULTS: With a classification based on a biallelic model of 5HTTLPR (i.e., presence or absence of at least 1 S-allele copy), multiple regression analyses indicated significant proportions of variance in stimulus seeking and insecure attachment to be explained by abuse x genotype interaction effects, with greater psychopathology always occurring in S-allele carriers who had been abused. Likewise, a logistic regression analysis linked BPD to significant main effects of genotype and abuse. Analyses that aggregated carriers according to a triallelic model of 5HTTLPR (i.e., presence or absence of at least 1 copy of a presumably low-function S or LG allele) produced similar patterns but no statistically significant effects. CONCLUSIONS: Traits such as sensation seeking and insecure attachment are, on average, elevated in 5HTTLPR S-allele carriers with bulimic syndromes who report prior physical or sexual maltreatment. These results add to the literature associating pronounced psychopathological manifestations, with conjoint effects of stress and the 5HTTLPR polymorphism.

Impulsivity in women with eating disorders: problem of response inhibition, planning, or attention?

OBJECTIVE: Impulsivity is generally believed to be more characteristic of individuals with bulimic than with restrictive eating disorders (EDs). However, studies have not exhaustively explored the association between EDs and various component dimensions of the impulsivity construct. METHOD: We conducted a multidimensional assessment of impulsivity in 84 women with bulimia nervosa (BN), 37 with anorexia nervosa (AN: 19 restricters and 18 bingers-purgers), and 61 normal-control participants. To assess multiple components of impulsivity, participants completed a battery of self-report questionnaires and a performance test. RESULTS: Compared with normal-control participants, all ED groups showed attentional problems. However, only women suffering BN or AN-binge purge subtype showed elevations on motoric forms of impulsivity, whereas women with BN were the only group to report tendencies toward reckless behavior. CONCLUSION: These findings suggest that binge-eating behavior coincides with problems of response inhibition, whereas a risk-taking attitude may be a unique characteristic of individuals with BN.

Intrafamilial correspondences on platelet [3H-]paroxetine-binding indices in bulimic probands and their unaffected first-degree relatives.

Reduced brain serotonin (5-hydroxytryptamine: 5-HT) transporter activity has been associated with susceptibility to various forms of psychopathology, including bulimia nervosa (BN) and related syndromes characterized by appetitive or behavioural dysregulation. We applied density (Bmax) of platelet [3H-]paroxetine binding as a proxy for central 5-HT reuptake activity in two groups of women (33 with BN-spectrum disorders and 19 with no apparent eating or psychiatric disorders), most of these individuals' mothers (31 and 18, respectively), and a small sampling of their sisters (seven and eight, respectively). Hierarchical linear modeling techniques were used to account for nesting of individuals within families and diagnostic groupings. Bulimic probands, their mothers, and their sisters all displayed significantly lower density (Bmax) of platelet-paroxetine binding than did 'control' probands, mothers, or sisters-even when relatives showing apparent eating or psychiatric disturbances were excluded. In addition, in bulimic probands and mothers, significant within-family correlations were obtained on Bmax. These findings imply a heritable trait (or endophenotype), linked to 5-HT activity, and carried by BN sufferers and their first-degree relatives (even when asymptomatic). We propose that, under conducive circumstances, such a trait may increase risk of binge-eating behavior, or associated symptoms of affective or behavioral dysregulation.

Mood- and restraint-based antecedents to binge episodes in bulimia nervosa: possible influences of the serotonin system.

BACKGROUND: In bulimic syndromes, binge episodes are thought to be caused by dietary restraint and negative moods. However, as central serotonin (5-hydroxytryptamine: 5-HT) mechanisms regulate appetite and mood, the 5-HT system could be implicated in diet- and mood-based binge antecedents. METHOD: We used hand-held computers to obtain repeated "online" measurements of eating behaviors, moods, and self-concepts in 21 women with bulimic syndromes, and modeled 5-HT system activity with a measure of platelet [3H]paroxetine-binding density. RESULTS: Mood and self-concept ratings were found to be worse before binge episodes (than at other moments), and cognitive restraint was increased. After binges, mood and self-concept deteriorated further, and thoughts of dieting became more intense. Intriguingly, lower paroxetine-binding density predicted poorer mood and self-concept before a binge, larger post-binge decrements in mood and self-concept, and larger post-binge increases in dietary restraint. CONCLUSIONS: Paroxetine binding thus seemed to reflect processes that impacted upon mood-related antecedents to binge episodes, and consequences implicating mood and dietary restraint.

Reduced density of platelet-binding sites for [3H]paroxetine in remitted bulimic women.

Findings show brain serotonin (5-hydroxytryptamine (5-HT)) activity to be altered in individuals who have had bulimia nervosa (BN), even after substantial remission of symptoms. Such findings could reflect persistent sequelae due to BN, or a vulnerability 'trait' that exists independently of active eating-disorder manifestations. We compared women with full-blown BN (BN; n=22), BN in remission (BN-R; n=11), and no eating or psychiatric disturbances (n=22) on measures of platelet [(3)H]paroxetine binding, eating symptoms and psychopathology. The BN-R group showed normal-range scores on eating and psychopathological symptoms, but reductions in density (B(max)) of binding sites for paroxetine similar to those obtained in the actively ill women. Both BN groups had substantially lower B(max) than did healthy controls. Our results corroborate other findings indicating recovered BN patients to have anomalous 5-HT functioning. While such effects could represent a lasting 'injury' to the system, reported covariations between personality traits and 5-HT indices in BN encourage us to favor the argument that some alterations of 5-HT activity (in this case, consistent with reduced transporter activity) represent a 'trait' associated with the risk of developing BN and/or associated psychopathology.