Kenneth R. Bruce

Phenotypes, Endophenotypes, and Genotypes in Bulimia Spectrum Eating Disorders

Objectives: To review the main phenomenological variants observed among bulimia spectrum syndromes and the factors believed to act etiologically for them and also to generate an etiologic model that accommodates known heterogeneities within the population suffering bulimic syndromes. Method: Defining bulimic syndromes broadly, we address threshold and subthreshold forms of bulimia nervosa (BN) and also the provisional or newly proposed diagnoses of binge eating disorder (BED) and purging disorder (PD). We review evidence bearing on the validity of these diagnostic entities and on the place of sociocultural, family-developmental, neurobiological, and genetic factors in a multidimensional etiologic model for these classifications. Results: Available data validate certain bulimic phenotypes and subphenotypes that are characterized by such traits as impulsivity or affective instability. Findings associate subphenotypic, or trait-based, variations with putative endophenotypes, such as reduced serotonin transporter activity, and with candidate genotypes affecting the serotonin system; the data also indicate intriguing correspondences between gene–environment interactions and subphenotypic variations along such dimensions as novelty seeking. Conclusions: Bulimic syndromes sometimes reflect a primary disruption of controls over mood, impulses, and appetite in individuals showing marked psychopathology; at other times, they reflect a more circumscribed erosion of appetitive controls in relatively intact individuals, following prolonged dieting. We argue that dimensional perspectives involving careful attention to comorbid personality traits and symptoms are needed to accommodate existing heterogeneities within the population suffering from bulimia and to characterize the etiologic roles of familial-developmental, neurobiological, and genetic variables (and of interactions among these variables) in bulimic syndromes.

Treatment Implications of Axis-II Comorbidity in Eating Disorders

In this article, we review the clinical research on the implications of comorbid personality disorders (PDs), pathological personality traits, and the expression and response to treatment of those with eating disorders (EDs) (i.e., anorexia and bulimia nervosa, and binge eating disorder). Obsessive-compulsive PDs and related traits, such as perfectionism and rigidity, appear to be clear-cut risk and maintenance factors for anorexia nervosa. In bulimia nervosa, trait impulsivity seems to be related to early termination from therapy and, according to at least some indices, poorer responses to treatment. Dramatic-Erratic PD features, generally more characteristic of binge-purge ED variants, clearly predict a protracted course for general psychiatric symptoms, but may have less prognostic value for eating symptoms. Recent guidelines from two influential bodies—the American Psychiatric Association (APA, 2000) and the United Kingdom’s National Institute for Clinical Excellence (NICE, 2004)—both include the concept that “trait-oriented” interventions, targeting personality-linked components like perfectionism, affective instability, impulsivity, and interpersonal disturbances, may optimize treatment effects. In general, the literature supports the recommendation that clinicians should apply well-validated, symptom-focused therapies for the EDs; in addition, clinicians may wish to incorporate trait-focused interventions in patients in whom personality pathology contributes to suboptimal response.

Childhood emotional abuse and eating symptoms in bulimic disorders: An examination of possible mediating variables

OBJECTIVE We sought to estimate prevalences of childhood emotional abuse (CEA) in bulimic and normal-eater control groups, and to replicate previous findings linking CEA to severity of eating symptoms in BN. We also examined potential mediators of the link between CEA and disordered eating. METHOD Women diagnosed with a bulimic disorder (n = 176) and normal-eater women (n = 139) were assessed for childhood traumata, eating-disorder (ED) symptoms and psychopathological characteristics (ineffectiveness, perfectionism, depression, and affective instability) thought to be potential mediators of interest. RESULTS CEA was more prevalent in the bulimic than in the nonbulimic group, and predicted severity of some eating-symptom indices. Ineffectiveness and affective instability both mediated relationships between CEA and selected ED symptoms. DISCUSSION We found CEA to predict eating pathology through mediating effects of ineffectiveness and affective instability. CEA might influence severity of ED symptoms by impacting an individuals self-esteem and capacity for affect regulation.

Association of the promoter polymorphism -1438G/A of the 5-HT2A receptor gene with behavioral impulsiveness and serotonin function in women with bulimia nervosa

Separate lines of research suggest that the functional alterations in the serotonin (5‐HT) 2A receptor are associated with 5‐HT tone, behavioral impulsiveness, and bulimia nervosa (BN). We explored the effect of allelic variations within the 5‐HT2A receptor gene promoter polymorphism −1438G/A on trait impulsiveness and serotonin function in women with BN. Participants included women with BN having the A allele (i.e., AA homozygotes and AG heterozygotes, BNA+, N = 21); women with BN but without the A allele (i.e., GG homozygotes, BNGG, N = 12), and normal eater control women having the A allele (NEA+, N = 19) or without the A allele (NEGG; N = 9). The women were assessed for psychopathological tendencies and eating disorder symptoms, and provided blood samples for measurement of serial prolactin responses following oral administration of the post‐synaptic partial 5‐HT agonist meta‐chlorophenylpiperazine (m‐CPP). The BNGG group had higher scores than the other groups on self‐report measures of non‐planning and overall impulsiveness and had blunted prolactin response following m‐CPP. The bulimic groups did not differ from each other on current eating symptoms or on frequencies of other Axis I mental disorders. Findings indicate that women with BN who are GG homozygotes on the −1438G/A promoter polymorphism are characterized by increased impulsiveness and lower sensitivity to post‐synaptic serotonin activation. These findings implicate the GG genotype in the co‐aggregation of impulsive behaviors and alterations of post‐synaptic 5‐HT functioning in women with BN.

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” (LG and LA) 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 × 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 LG 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.

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 [3H]paroxetine binding, eating symptoms and psychopathology. The BN-R group showed normal-range scores on eating and psychopathological symptoms, but reductions in density (Bmax) of binding sites for paroxetine similar to those obtained in the actively ill women. Both BN groups had substantially lower Bmax 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.

Bulimia nervosa with co-morbid avoidant personality disorder: behavioural characteristics and serotonergic function

BACKGROUND Separate lines of research link lowered serotonin tone to interpersonal submissiveness and bulimia nervosa (BN). We explored the impact of co-morbid avoidant personality disorder (APD), as a proxy for submissiveness, on behavioural inhibition and serotonin function in women with BN. METHOD Participants included women with BN with co-morbid APD (BNA +, N = 13); women with BN but without APD (BNA-, N = 23), and control women with neither BN nor APD (N = 23). The women were assessed for psychopathological tendencies and eating disorder symptoms, and participated in a computerized laboratory task that measured behavioural inhibition and disinhibition. Participants also provided blood samples for measurement of serial prolactin responses following oral administration of the partial 5-HT agonist meta-chlorophenylpiperazine (m-CPP). RESULTS The BNA+ group had higher scores than the other groups on self-report measures of submissiveness, social avoidance, restricted emotional expression, affective instability and self-harming behaviours. Compared with the other groups, the BNA+ group tended to be more inhibited under cues for punishment on the computerized task and to have blunted prolactin response following m-CPP. The bulimic groups did not differ from each other on current eating symptoms or on frequencies of other mental disorders. CONCLUSIONS Findings indicate that women with BN and co-morbid APD may be characterized by interpersonal submissiveness and avoidance, affective instability, self-harm, behavioural inhibition in response to threat and lower sensitivity to serotonergic activation. These findings may indicate common, serotonergic factors, associated with social submissiveness, behavioural inhibition to threat and BN.

Autonomous motivation: a predictor of treatment outcome in bulimia-spectrum eating disorders.

UNLABELLED Individuals with eating disorders are said to be highly ambivalent towards change and thus have difficulty maintaining a commitment to, and motivation for, treatment. Self-Determination Theory postulates that autonomous motivation for therapy exists when individuals view their participation as freely chosen. OBJECTIVE The present study was designed to ascertain whether or not autonomous motivation was associated with treatment response in individuals with bulimia-spectrum eating disorders (BSED). METHOD One hundred and fifty-five women with DSM-IV-TR BSED participated in multimodal group therapy and completed measures to assess motivation, eating and comorbid symptoms. RESULTS Hierarchical multiple regression analyses demonstrated that higher levels of autonomous motivation at pretreatment predicted lower post-treatment scores on measures of eating preoccupations (shape, weight and eating concerns), binge eating, anxiety/depression, relationship to self and others and impulsivity. DISCUSSION These results indicate that autonomous motivation may be an important predictor of outcome following treatment for BSED.

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.

Reduced platelet [3H]paroxetine binding in anorexia nervosa: Relationship to eating symptoms and personality pathology

Alterations in serotonin function have been implicated in both anorexia and bulimia nervosa, and previous studies suggest associations between serotonin function and variations in pathological personality traits. Women meeting DSM-IV criteria for anorexia nervosa (AN, 16 with the restricting subtype and 14 with the binge-purge subtype) and 49 healthy control women (CW) provided blood samples for analyses of platelet [(3)H]paroxetine binding. Participants also filled out questionnaires tapping eating disorder symptoms, depression, and personality pathology. Compared with CW, women with restricting and binge-purge AN had significantly lower levels of paroxetine binding (respectively: 1012 + 487 vs. 560 + 253 vs. 618 + 217 fmol/mg protein). Simple correlation analyses showed that, within AN but not within controls, paroxetine binding was inversely related to dieting preoccupations, affective instability, anxiousness, compulsivity, restricted expression and social avoidance but independent of age, body mass index, depression, and other eating symptoms. Findings suggest that reduced peripheral serotonin transporter density in AN relates to increased dieting preoccupations, affective instability and anxiousness-fearfulness.