Laura M. Thornton

Exaggerated 5-HT1A but Normal 5-HT2A Receptor Activity in Individuals Ill with Anorexia Nervosa

BACKGROUND Many studies have found disturbances of serotonin (5-HT) activity in anorexia nervosa (AN). Because little is known about 5-HT receptor function in AN, positron emission tomography (PET) imaging with 5-HT receptor-specific radioligands was used to characterize 5-HT1A and 5-HT2A receptors. METHODS Fifteen women ill with AN (ILL AN) were compared with 29 healthy control women (CW); PET and [11C]WAY100635 were used to assess binding potential (BP) of the 5-HT1A receptor, and [18F]altanserin was used to assess postsynaptic 5-HT2A receptor BP. [15O] water and PET were used to assess cerebral blood flow. RESULTS The ILL AN women had a highly significant (30%-70%) increase in [11C]WAY100635 BP in prefrontal and lateral orbital frontal regions, mesial and lateral temporal lobes, parietal cortex, and dorsal raphe nuclei compared with CW. The [18F]altanserin BP was normal in ILL AN but was positively and significantly related to harm avoidance in suprapragenual cingulate, frontal, and parietal regions. Cerebral blood flow was normal in ILL AN women. CONCLUSIONS Increased activity of 5-HT1A receptor activity may help explain poor response to 5-HT medication in ILL AN. This study extends data suggesting that 5-HT function, and, specifically, the 5-HT2A receptor, is related to anxiety in AN.

Significant Linkage on Chromosome 10p in Families with Bulimia Nervosa

Bulimia nervosa (BN) is strongly familial, and additive genetic effects appear to contribute substantially to the observed familiality. In turn, behavioral components of BN, such as self-induced vomiting, are reliably measured and heritable. To identify regions of the genome harboring genetic variants conferring susceptibility to BN, we conducted a linkage analysis of multiplex families with eating disorders that were identified through a proband with BN. Linkage analysis of the entire sample of 308 families yielded a double peak, with the highest nonparametric multipoint maximum LOD score (MLS), of 2.92, on chromosome 10. Given the high heritability of self-induced vomiting and the reliability with which it can be measured, we performed linkage analysis in a subset (n=133) of families in which at least two affected relatives reported a symptom pattern that included self-induced vomiting. The highest MLS (3.39) observed was on chromosome 10, between markers D10S1430 and D10S1423. These results provide evidence of the presence of a susceptibility locus for BN on chromosome 10p. Using simulations, we demonstrate that both of these scores, 2.92 and 3.39, meet the widely accepted criterion for genomewide significance. Another region on 14q meets the criterion for genomewide suggestive linkage, with MLSs of 1.97 (full sample) and 1.75 (subset) at 62 centimorgans from p-ter.

Impulse control disorders in women with eating disorders.

We compared symptom patterns, severity of illness, and comorbidity in individuals with eating disorders with and without impulse control disorders (ICD), and documented the temporal pattern of illness onset. Lifetime ICD were present in 16.6% of 709 women with a history of eating disorders. The most common syndromes were compulsive buying disorder and kleptomania. ICD occurred more in individuals with binge eating subtypes, and were associated with significantly greater use of laxatives, diuretics, appetite suppressants and fasting, and with greater body image disturbance, higher harm avoidance, neuroticism, cognitive impulsivity, and lower self-directedness. In addition, individuals with ICD were more likely to have obsessive-compulsive disorder, any anxiety disorder, specific phobia, depression, cluster B personality disorder, avoidant personality disorder, and to use psychoactive substances. Among those with ICD, 62% reported the ICD predated the eating disorder and 45% reported the onset of both disorders within the same 3-year window. The presence of a lifetime ICD appears to be limited to eating disorders marked by binge eating and to be associated with worse eating-related psychopathology, more pathological personality traits, and more frequent comorbid Axis I and II conditions. Untreated ICD may complicate recovery from eating disorders.

Suicide attempts in anorexia nervosa.

Objective: To explore prevalence and patterns of suicidal attempts in persons with anorexia nervosa (AN). Methods: Participants were the first 432 persons (22 male, 410 female) enrolled in the NIH funded Genetics of Anorexia Nervosa Collaborative Study. All participants had current or lifetime AN. The participants ranged in age from 16 to 76 (mean = 30.4, SD = 11.3). Suicidal behavior and intent was assessed via the Diagnostic Interview for Genetic Studies. We compared frequency and severity of attempts across diagnostic subtypes and comorbidity, and personality features associated with the presence of suicide attempts in persons with AN. Results: About 16.9% of those with AN attempted suicide. Significantly fewer persons with the restricting subtype (7.4%) reported at least one attempt than those with purging AN (26.1%), AN with binge eating (29.3%), and a mixed picture of AN and bulimia nervosa (21.2%). After controlling for major depression, suicide attempts were associated with substance abuse, impulsive behaviors and traits, Cluster B personality disorders, panic disorder, and post-traumatic stress disorder as well as low self-directedness and eating disorder severity. Conclusions: Suicide attempts in AN are not uncommon, are frequently associated with the intention to die, occur less frequently in persons with the restricting subtype of the illness, and after controlling for depression are associated with a constellation of behaviors and traits associated with behavioral and affective dyscontrol. AN = anorexia nervosa; BN = bulimia nervosa; RAN = restricting anorexia nervosa; PAN = purging anorexia nervosa; AN(B) = binging anorexia nervosa; EDNOS = eating disorder not otherwise specified; ANBN = lifetime history of both AN and BN.

Understanding the relation between anorexia nervosa and bulimia nervosa in a Swedish national twin sample.

BACKGROUND We present a bivariate twin analysis of anorexia nervosa and bulimia nervosa to determine the extent to which shared genetic and environmental factors contribute to liability to these disorders. METHOD Focusing on females from the Swedish Twin study of Adults: Genes and Environment (n = 7000), we calculated heritability estimates for narrow and broad anorexia nervosa and bulimia nervosa and estimated their genetic correlation. RESULTS In the full model, the heritability estimate for narrow anorexia nervosa (AN) was (a(2) = .57; 95% confidence interval [CI]: .00-.81) and for narrow bulimia nervosa (BN) (a(2) = .62; 95% CI: .08-.70), with the remaining variance accounted for by unique environmental factors. Shared environmental factors estimates were (c(2) = .00; 95% CI: .00-.67) for AN and (c(2) = .00; 95% CI: .00-.40) for BN. Moderate additive genetic (.46) and unique environmental (.42) correlations between AN and BN were observed. Heritability estimates for broad AN were lower (a(2) = .29; 95% CI: .04-.43) than for narrow AN, but estimates for broad BN were similar to narrow BN. The genetic correlation for broad AN and BN was .79, and the unique environmental correlation was .44. CONCLUSIONS We highlight the contribution of additive genetic factors to both narrow and broad AN and BN and demonstrate a moderate overlap of both genetic and unique environmental factors that influence the two conditions. Common concurrent and sequential comorbidity of AN and BN can in part be accounted for by shared genetic and environmental influences on liability although independent factors also operative.

Patterns of co-morbidity of eating disorders and substance use in Swedish females

BACKGROUND Little is known about the association of eating disorder subtypes across multiple categories of substance use in population-based samples. We examined the association between eating disorders and substance use in a large population-based sample. METHOD Female participants (n=13 297) were from the Swedish Twin Registry [Lichtenstein et al., Twin Research and Human Genetics (2006) 9, 875-882]. Substance use was examined in four defined groups - (1) anorexia nervosa (AN); (2) bulimia nervosa (BN); (3) AN and BN (ANBN); and (4) binge eating disorder (BED) as well as a referent group without eating disorder (no ED). Secondary analyses examined differences between restricting AN (RAN) and binge and/or purge AN (ANBP). RESULTS In general, eating disorders were associated with greater substance use relative to the referent. The AN group had significantly increased odds for all illicit drugs. Significant differences emerged across the RAN and ANBP groups for alcohol abuse/dependence, diet pills, stimulants, and polysubstance use with greater use in the ANBP group. Across eating disorder groups, (1) the BN and ANBN groups were more likely to report alcohol abuse/dependence relative to the AN group, (2) the ANBN group was more likely to report diet pill use relative to the AN, BN and BED groups, and (3) the BN group was more likely to report diet pill use relative to the no ED, AN and BED groups. CONCLUSIONS Eating disorders are associated with a range of substance use behaviors. Improved understanding of how they mutually influence risk could enhance understanding of etiology and prevention.

SEXUAL FUNCTIONING IN WOMEN WITH EATING DISORDERS

OBJECTIVE To describe sexual functioning in women with eating disorders. METHOD We assessed physical intimacy, libido, sexual anxiety, partner status, and sexual relationships in 242 women from the International Price Foundation Genetic Studies relative to normative data. RESULTS Intercourse (55.3%), having a partner (52.7%), decreased sexual desire (66.9%), and increased sexual anxiety (59.2%) were common. Women with restricting and purging anorexia nervosa had a higher prevalence of loss of libido than women with bulimia nervosa and eating disorder not otherwise specified (75%, 74.6%, 39%, and 45.4%, respectively). Absence of sexual relationships was associated with lower minimum lifetime body mass index (BMI) and earlier age of onset; loss of libido with lower lifetime BMI, higher interoceptive awareness and trait anxiety; and sexual anxiety with lower lifetime BMI, higher harm avoidance and ineffectiveness. Sexual dysfunction in eating disorders was higher than in the normative sample. DISCUSSION Sexual dysfunction is common across eating disorders subtypes. Low BMI is associated with loss of libido, sexual anxiety, and avoidance of sexual relationships.

Influence of overanxious disorder of childhood on the expression of anorexia nervosa

OBJECTIVE Childhood anxiety often precedes the onset of anorexia nervosa (AN) and may mark a liability to the emergence of an eating disorder for some women. This study investigates the prevalence of overanxious disorder (OAD) among women with AN and explores how OAD impacts AN symptoms and personality traits. METHOD Participants were 637 women with AN who completed an eating disorders history, the Structured Clinical Interview for DSM-IV Axis I Disorders, and assessments for childhood anxiety, eating disorder attitudes, and associated personality traits. RESULTS Of 249 women (39.1%) reporting a history of OAD, 235 (94.4%) met criteria for OAD before meeting criteria for AN. In comparison to those without OAD, women with AN and OAD self-reported more extreme personality traits and attitudes and they engaged in more compensatory behaviors. CONCLUSION Among individuals with AN, those entering AN on a pathway via OAD present with more severe eating disorder pathology.

Association Study of 182 Candidate Genes in Anorexia Nervosa

We performed association studies with 5,151 SNPs that were judged as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN) based on location under reported linkage peaks, previous results in the literature (182 candidate genes), brain expression, biological plausibility, and estrogen responsivity. We employed a case–control design that tested each SNP individually as well as haplotypes derived from these SNPs in 1,085 case individuals with AN diagnoses and 677 control individuals. We also performed separate association analyses using three increasingly restrictive case definitions for AN: all individuals with any subtype of AN (All AN: n = 1,085); individuals with AN with no binge eating behavior (AN with No Binge Eating: n = 687); and individuals with the restricting subtype of AN (Restricting AN: n = 421). After accounting for multiple comparisons, there were no statistically significant associations for any individual SNP or haplotype block with any definition of illness. These results underscore the importance of large samples to yield appropriate power to detect genotypic differences in individuals with AN and also motivate complementary approaches involving Genome‐Wide Association (GWA) studies, Copy Number Variation (CNV) analyses, sequencing‐based rare variant discovery assays, and pathway‐based analysis in order to make up for deficiencies in traditional candidate gene approaches to AN.

Symptom profile of major depressive disorder in women with eating disorders

Objective: Based on the well-documented association between eating disorders (EDs) and affective disorders, the patterns of comorbidity of EDs and major depressive disorder (MDD) were investigated. The temporal relation between EDs and MDD onset was analyzed to determine differences in the course and nature of MDD when experienced prior to versus after the onset of the ED. Method: Lifetime MDD and depressive symptoms were assessed in 1371 women with a history of ED. The prevalence of MDD was first explored across ED subtypes, and ages of onset of MDD and EDs were compared. Depressive symptoms were examined in individuals who developed MDD before and after ED onset. Results: The lifetime prevalence of MDD was 72.9%. Among those with lifetime MDD (n =963), 34.5% reported MDD onset before the onset of ED. Those who experienced MDD first reported greater psychomotor agitation (OR =1.53; 95%CI =1.14–2.06), and thoughts of own death (but not suicide attempts or ideation; OR =1.73; 95%CI =1.31–2.30). Among individuals who had MDD before ED, 26.5% had the MDD onset during the year before the onset of ED; 67% of individuals had the onset of both disorders within the same 3 year window. Conclusion: Clinicians treating individuals with new-onset ED or MDD should remain vigilant for the emergence of additional psychopathology, especially during the initial 3 year window following the onset of the first disorder.