Mimi Israel

Self-destructiveness and serotonin function in bulimia nervosa.

Studies have linked bulimia nervosa (BN) to alterations in brain serotonin (5-hydroxytryptamine: 5-HT) activity and to heightened propensity for parasuicidality and self-injuriousness. The coincidence of self-destructiveness and 5-HT abnormality in BN is of interest, given documentation (in various populations) of an inverse association between 5-HT activity and potential for self-harm. The present study examined the connection between 5-HT status and self-destructiveness in BN. Structured interviews and self-report questionnaires were used to assess 40 bulimic and 21 normal-eater women for: (a) history of parasuicidal or self-injurious acts; and (b) mood and impulse-regulation problems. We then applied tests, presumed to reflect 5-HT function, of serial prolactin (PRL) and cortisol (CORT) responses after oral administration of the partial 5-HT agonist, meta-chlorophenylpiperazine (m-CPP). Relative to non-bulimic women, bulimic women (on average) showed blunting of PRL and CORT following m-CPP. The blunting of neuroendocrine responses was, however, most remarkable in bulimic women with a history of self-destructiveness. These findings suggest that some serotonergic anomalies reported in BN sufferers (i.e. reduced neuroendocrine response after m-CPP) may be most characteristic of individuals in the population showing clear-cut self-destructive potential.

Depression in dialysis patients: a review of psychological factors.

A review of the literature reveals that the incidence and prevalence of depression among dialysis patients is unknown but that estimates may vary from 20 to 50 percent. Diagnostic and methodological problems related to the population are examined and the notion that depression in this population may represent a qualitatively different entity, is evaluated. Finally, several theoretical models of depression are described and their particular relevance to depression among dialysis patients is discussed.

Methylation of the glucocorticoid receptor gene promoter in bulimic women: associations with borderline personality disorder, suicidality, and exposure to childhood abuse.

OBJECTIVE To compare levels of methylation of the glucocorticoid receptor (GR) gene (NR3C1) promoter between women with bulimia nervosa (BN) and women with no eating disorder (ED), and also to explore, in women with BN, the extent to which methylation of the GR gene promoter corresponds to childhood abuse, suicidality, or borderline personality disorder (BPD). METHOD We measured methylation levels in selected NR3C1 promoter regions using DNA obtained from lymphocytes in 64 women with BN (32 selected as having a history of severe childhood abuse and 32 selected as having no such history) and 32 comparison women with no ED or history of childhood abuse. RESULTS Compared to noneating disordered women, women with BN and comorbid BPD (or BN with a history of suicidality) showed significantly more methylation of specific exon 1C sites. There was also a (nonsignificant) result indicative of greater methylation in some 1C sites among women with BN, when compared (as a group) to women with no ED. No parallel effects owing to childhood abuse were observed. DISCUSSION Our findings associate BN (when accompanied by BPD or suicidality) with hypermethylation of certain GR exon 1C promoter sites. We discuss theoretical and clinical implications of our findings.

Methylation of BDNF in women with bulimic eating syndromes: Associations with childhood abuse and borderline personality disorder

DNA methylation allows for the environmental regulation of gene expression and is believed to link environmental stressors to such mental-illness phenotypes as eating disorders. Numerous studies have shown an association between bulimia nervosa (BN) and variations in brain-derived neurotrophic factor (BDNF). BDNF has also been linked to borderline personality disorder (BPD) and to such traits as reward dependence. We examined the extent to which BDNF methylation corresponded to bulimic or normal-eater status, and also to the presence of comorbid borderline personality disorder (BPD) and childhood abuse. Our sample consisted of 64 women with BN and 32 normal-eater (NE) control women. Participants were assessed for eating-disorder symptoms, comorbid psychopathology, and childhood trauma, and then they were required to provide blood samples for methylation analyses. We observed a significant site×group (BN vs. NE) interaction indicating that women with BN showed increases in methylation at specific regions of the BDNF promoter. Furthermore, examining effects of childhood abuse and BPD, we observed significant site×group interactions such that groups composed of individuals with childhood abuse or BPD had particularly high levels of methylation at selected CpG sites. Our findings suggest that BN, especially when co-occurring with childhood abuse or BPD, is associated with a propensity towards elevated methylation at specific BDNF promoter region sites. These findings imply that hypermethylation of the BDNF gene may be related to eating disorder status, developmental stress exposure, and comorbid psychopathology.

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.

Methylation of the dopamine D2 receptor (DRD2) gene promoter in women with a bulimia-spectrum disorder: Associations with borderline personality disorder and exposure to childhood abuse

OBJECTIVE Previous findings indicate that women with Bulimia Nervosa (BN), when compared to women with no eating disorder (NED), tend to display elevated methylation in the promoter region of the DRD2 gene. The preceding would be compatible with evidence of generally reduced dopamine activity in people with BN. However, altered DNA methylation has also been associated with adverse environmental exposures (such as to childhood abuse) and with psychiatric disturbances (such as Borderline Personality Disorder: BPD). In this study, we examined the extent to which DRD2 methylation was associated with the presence or absence of a bulimic eating disorder, to childhood abuse exposure, or to comorbid BPD. METHOD Women with a bulimia-spectrum disorder (BSD) and women with NED were assessed for childhood traumata, eating-disorder symptoms and BPD, and provided blood samples for methylation analyzes. RESULTS BSD and NED groups did not differ as to mean percent DRD2 promoter methylation. However, among the women with a BSD, those with BPD showed small, but significant increases in DRD2 methylation levels compared to women with NED (as indicated by Hochbergs post-hoc tests). Similarly, women with a BSD who reported a history of childhood sexual abuse showed a trend-level elevation of DRD2 methylation compared to our NED group. DISCUSSION Our findings imply that, in people with a BSD, increased methylation of the DRD2 gene promoter may be more strongly characteristic of comorbid psychopathology than it is a global correlate of the eating disorder per se. We discuss theoretical implications of our findings.

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.

DNA methylation in individuals with anorexia nervosa and in matched normal-eater controls: A genome-wide study

OBJECTIVE Evidence associates anorexia nervosa (AN) with epigenetic alterations that could contribute to illness risk or entrenchment. We investigated the extent to which AN is associated with a distinct methylation profile compared to that seen in normal-eater women. METHOD Genome-wide methylation profiles, obtained using DNA from whole blood, were determined in 29 women currently ill with AN (10 with AN-restrictive type, 19 with AN-binge/purge type) and 15 normal-weight, normal-eater control women, using 450 K Illumina bead arrays. RESULTS Regardless of type, AN patients showed higher and less-variable global methylation patterns than controls. False Discovery Rate corrected comparisons identified 14 probes that were hypermethylated in women with AN relative to levels obtained in normal-eater controls, representing genes thought to be associated with histone acetylation, RNA modification, cholesterol storage and lipid transport, and dopamine and glutamate signaling. Age of onset was significantly associated with differential methylation in gene pathways involved in development of the brain and spinal cord, while chronicity of illness was significantly linked to differential methylation in pathways involved with synaptogenesis, neurocognitive deficits, anxiety, altered social functioning, and bowel, kidney, liver and immune function. DISCUSSION Although pre-existing differences cannot be ruled out, our findings are consistent with the idea of secondary alterations in methylation at genomic regions pertaining to social-emotional impairments and physical sequelae that are commonly seen in AN patients. Further investigation is needed to establish the clinical relevance of the affected genes in AN, and, importantly, reversibility of effects observed with nutritional rehabilitation and treatment.