Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors.

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Exploring Differences in the Role of Hospitalization on Weight Gain Based on Treatment Type From Randomized Clinical Trials for Adolescent Anorexia Nervosa.

Background: This study explores the impact of weight gain during medical stabilization hospitalization on weight outcomes between three outpatient treatments for adolescent anorexia nervosa (AN): Adolescent Focused Therapy (AFT), Systemic Family Therapy (SyFT), and Family Based Treatment (FBT). Methods: A secondary analysis of weight gain data (N = 215) of adolescents (12-18 years) meeting DSM-IV criteria for AN (exclusive of amenorrhea criteria) who participated in two randomized clinical trials (RCTs) was conducted. Main outcomes examined were changes in weight restoration (≥95% expected body weight or EBW) and differences in weight change attributable to hospital weight gain. Results: Weight gain resulting from hospitalizations did not substantially change weight recovery rates. Hospital weight gain contributed most to overall treatment weight gain in AFT compared to FBT and SyFT. Conclusion: Brief medical stabilization weight gain does not contribute substantially to weight recovery in adolescents with AN who participated in RCTs.

Therapist adherence to family-based treatment for adolescents with anorexia nervosa: A multi-site exploratory study.

OBJECTIVE: This exploratory study is the first to examine family-based treatment (FBT) adherence and association to treatment outcome in the context of a large-scale, multi-centre study for the treatment of adolescents with anorexia nervosa. METHOD: One hundred and ninety recorded FBT sessions from 68 adolescents with anorexia nervosa and their families were recruited across multiple sites (N = 6). Each site provided 1-4 tapes per family over four treatment time points, and each was independently rated for therapist adherence. RESULTS: There were differences in adherence scores within and between sites. ANOVA produced a main effect for site, F(5, 46) = 8.6, p < .001, and phase, F(3, 42) = 12.7, p < .001, with adherence decreasing in later phases. Adherence was not associated to end of treatment percent ideal body weight after controlling for baseline percent ideal body weight (r = .088, p = .48). CONCLUSIONS: Results suggest that FBT can be delivered with adherence in phase one of treatment. Adherence was not associated with treatment outcome as determined using percent ideal body weight.

A randomized controlled trial of group cognitive remediation therapy for anorexia nervosa: Effects on set-shifting tasks for inpatient adults and adolescents.

OBJECTIVE: The aim of this randomized controlled trial with a parallel design was to evaluate the effect of brief, cognitive remediation therapy (CRT) for anorexia nervosa (AN) on set-shifting. METHOD: Two hundred seventy-five inpatient adults and adolescents with AN (mean age = 23.1; SD = 12.7) were randomly assigned (using simple randomization procedures) to either a CRT or control condition. All participants received treatment as usual; however, the CRT condition completed five CRT group sessions in lieu of other group therapies provided on the unit. Set-shifting abilities were evaluated by: (a) neuropsychological measures and (b) experimental cognitive behavior therapy thought records. Blinding of group assignment occurred during baseline assessment and ended following group commencement. RESULTS: Data from 135 CRT and 140 control condition participants were analyzed. On all neuropsychological measures, results revealed no between group condition effects, but did show statistically significant time effects, with medium to large effect sizes. Thought record analysis revealed a significant condition by age interaction effect where adults in the CRT condition generated significantly more alternative thoughts and had stronger believability of alternative thoughts than children, a trend that was not found in the control condition. This yielded moderate to large effect sizes of.0.56 and 0.72, respectively. DISCUSSION: Based on traditional neuropsychological measures, these findings do not suggest a differential effect of CRT for AN in the format applied. However, results suggest that CRT may have some increased beneficial cognitive effect for adults, as compared to children, based on thought record analysis.

An investigation of indirect effects of personality features on anorexia nervosa severity through interoceptive dysfunction in individuals with lifetime anorexia nervosa diagnoses.

OBJECTIVE: This study examined a hypothesized pathway by which interoceptive dysfunction accounted for associations between personality features (harm avoidance, self-directedness, and perfectionism) and anorexia nervosa (AN) severity (indicated by drive for thinness, eating disorder-related preoccupations and rituals, and body mass index). METHOD: The study sample (n = 270, mean age = 28.47, 95.2% female, 98% White/Caucasian) consisted of probands and biological relatives who met DSM-IV criteria for lifetime diagnoses of AN (omitting criterion D, amenorrhea) drawn from the Price Foundation Anorexia Nervosa Affected Relative Pairs Study (AN-ARP). Participants completed measures assessing personality, interoceptive dysfunction, and eating pathology. RESULTS: Associations between personality features of low self-directedness and high perfectionism and indicators of AN severity (drive for thinness and eating disorder-related preoccupations and rituals) were significant, as were the hypothesized indirect pathways through interoceptive dysfunction. Neither harm avoidance nor body mass index was significantly related to other study variables, and the proposed indirect pathways involving these variables were not significant. DISCUSSION: Findings suggest that certain personality features may relate to AN severity, in part, through their associations with interoceptive dysfunction. Future research should examine prospective associations and the value of interventions targeting interoceptive dysfunction for interrupting the link between personality and AN severity.

Associations between dimensions of anorexia nervosa and obsessive-compulsive disorder: An examination of personality and psychological factors in patients with anorexia nervosa.

OBJECTIVE: Anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) are highly comorbid. However, the factors that account for this comorbidity are poorly understood. We examined the core dimensions of AN and OCD and psychological and personality factors shared by both disorders. METHOD: In path analyses (N = 732 women with either current AN or recovered from AN), we examined which factors were uniquely and independently associated with the core dimensions of AN and OCD. We also examined recovery from AN as a moderator. RESULTS: When individuals with AN reported greater concern over mistakes, they endorsed more severity in both AN and OCD core dimensions. These unique associations existed above and beyond all other transdiagnostic personality and psychological factors and regardless of AN recovery status. CONCLUSIONS: Concern over mistakes partially accounts for severity in the core dimensions of both AN and OCD. Concern over mistakes may represent an important target in the aetiology of AN and OCD.

The Anorexia Nervosa Genetics Initiative (ANGI): Overview and methods.

BACKGROUND: Genetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13,000 individuals with AN and ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research. METHODS: ANGI recruited from the United States (US), Australia/New Zealand (ANZ), Sweden (SE), and Denmark (DK). Recruitment was via national registers (SE, DK); treatment centers (US, ANZ, SE, DK); and social and traditional media (US, ANZ, SE). All cases had a lifetime AN diagnosis based on DSM-IV or ICD-10 criteria (excluding amenorrhea). Recruited controls had no lifetime history of disordered eating behaviors. To assess the positive and negative predictive validity of the online eating disorder questionnaire (ED100K-v1), 109 women also completed the Structured Clinical Interview for DSM-IV (SCID), Module H. RESULTS: Blood samples and clinical information were collected from 13,363 individuals with lifetime AN and from controls. Online diagnostic phenotyping was effective and efficient; the validity of the questionnaire was acceptable. CONCLUSIONS: Our multi-pronged recruitment approach was highly effective for rapid recruitment and can be used as a model for efforts by other groups. High online presence of individuals with AN rendered the Internet/social media a remarkably effective recruitment tool in some countries. ANGI has substantially augmented Psychiatric Genomics Consortium AN sample collection. ANGI is a registered clinical trial: clinicaltrials.govNCT01916538; https://clinicaltrials.gov/ct2/show/NCT01916538?cond=Anorexia+Nervosa&draw=1&rank=3.

Are parental self-efficacy and family flexibility mediators of treatment for anorexia nervosa?

OBJECTIVE: Family-based treatment (FBT) for adolescent anorexia nervosa (AN) promotes faster weight restoration when compared to other treatments. However, the mechanisms through which this occurs are not clarified. This study explored the trajectories of parental self-efficacy and perceived family flexibility during FBT and systemic family therapy (SyFT). We also explored whether parental self-efficacy mediates the effects of treatment on weight gain early in treatment. METHOD: 158 adolescents (12-18 years old; 89% girls) and their parents were randomized to FBT or SyFT. Parental self-efficacy as well as adolescents' and parental perceptions of the family's flexibility were collected at baseline and at sessions 2, 4, 6, and 8. RESULTS: Over time, only parents in FBT reported significantly greater self-efficacy. The change in maternal self-efficacy over the first 8 weeks of treatment was a significant mediator of session 10 weight gain. There were no significant group differences in perceived flexibility by session 8. DISCUSSION: Both parents in FBT and mothers in SyFT understand early the need to change their family's rules and roles. However, the specific strategies of FBT appear to mediate early weight gain in AN.

Does family-based treatment reduce the need for hospitalization in adolescent anorexia nervosa?

OBJECTIVE: We examined the timing and number of days of hospitalization during the course of treatment, hospitalization effects on outcome, and predictors and moderators of the use of hospitalization in adolescents with anorexia nervosa (AN). METHOD: Data used in this study were collected from 158 adolescents (ages 12 to 18 years of age) who met DSM-IVTR criteria for AN (exclusive of the amenorrhea criteria) randomized to receive either Family Based Treatment (FBT) or Systemic Family Therapy (SyFT) in a 7 site study. RESULTS: The trajectory of hospital day use is similar in the first 5 weeks irrespective of treatment allocation. However, days of hospitalization continued to increase throughout SyFT but leveled off in FBT after ∼5 weeks of treatment. Early hospitalization was a negative predictor for improvements in percent weight change for both treatment groups (t(1)=2.6, p = 0.011). Co-morbid psychopathology predicted early hospital use in both treatments. Higher levels of eating related obsessions and depression moderated hospitalization rates suggesting that FBT reduces early hospitalization rates compared to SyFT for these subgroups. DISCUSSION: These data support and extend findings from previous studies by identifying patterns of hospital use, and predictors and moderators of treatment effect for early hospitalization use in adolescent AN. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2016; 49:891-894).

Comparison of 2 family therapies for adolescent anorexia nervosa: a randomized parallel trial.

IMPORTANCE: Anorexia nervosa (AN) is a serious disorder with high rates of morbidity and mortality. Family-based treatment (FBT) is an evidence-based therapy for adolescent AN, but less than half of those who receive this approach recover. Hence, it is important to identify other approaches to prevent the development of the chronic form of AN for which there is no known evidence-based treatment. OBJECTIVE: To compare FBT with systemic family therapy (SyFT) for the treatment of adolescent-onset AN. DESIGN, SETTING, AND PARTICIPANTS: Research in Anorexia Nervosa (RIAN) is a 2-group (FBT and SyFT) randomized trial conducted between September 2005 and April 2012. Interviewers were blinded to the treatment condition. A total of 564 adolescents receiving care at 6 outpatient clinics experienced in the treatment of AN were screened. Of these, 262 adolescents did not meet the inclusion criteria and 138 declined to participate; hence, 164 adolescents (aged 12-18 years) of both sexes meeting the criteria for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, AN (except for amenorrhea) were enrolled. Three participants were withdrawn from FBT and 7 were withdrawn from SyFT after serious adverse events occurred. INTERVENTIONS: Two manualized family therapies with 16 one-hour sessions during 9 months. Family-based therapy focuses on the facilitation of weight gain, whereas SyFT addresses general family processes. MAIN OUTCOMES AND MEASURES: The primary outcomes were percentage of ideal body weight (IBW) and remission (≥95% of IBW). The a priori hypothesis was that FBT would result in faster weight gain early in treatment and at the end of treatment (EOT). RESULTS: There were no statistically significant differences between treatment groups for the primary outcome, for eating disorder symptoms or comorbid psychiatric disorders at the EOT or follow-up. Remission rates included FBT, 33.1% at the EOT and 40.7% at follow-up and SyFT, 25.3% and 39.0%, respectively. Family-based therapy led to significantly faster weight gain early in treatment, significantly fewer days in the hospital, and lower treatment costs per patient in remission at the EOT (FBT, $8963; SyFT, $18 005). An exploratory moderator analysis found that SyFT led to greater weight gain than did FBT for participants with more severe obsessive-compulsive symptoms. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that FBT is the preferred treatment for adolescent AN because it is not significantly different from SyFT and leads to similar outcomes at a lower cost than SyFT. Adolescents with more severe obsessive-compulsive symptoms may receive more benefits with SyFT. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00610753.

The role of leptin, melanocortin, and neurotrophin system genes on body weight in anorexia nervosa and bulimia nervosa.

OBJECTIVE: Although low weight is a key factor contributing to the high mortality in anorexia nervosa (AN), it is unclear how AN patients sustain low weight compared with bulimia nervosa (BN) patients with similar psychopathology. Studies of genes involved in appetite and weight regulation in eating disorders have yielded variable findings, in part due to small sample size and clinical heterogeneity. This study: (1) assessed the role of leptin, melanocortin, and neurotrophin genetic variants in conferring risk for AN and BN; and (2) explored the involvement of these genes in body mass index (BMI) variations within AN and BN. METHOD: Our sample consisted of 745 individuals with AN without a history of BN, 245 individuals with BN without a history of AN, and 321 controls. We genotyped 20 markers with known or putative function among genes selected from leptin, melanocortin, and neurotrophin systems. RESULTS: There were no significant differences in allele frequencies among individuals with AN, BN, and controls. AGRP rs13338499 polymorphism was associated with lowest illness-related BMI in those with AN (p = 0.0013), and NTRK2 rs1042571 was associated with highest BMI in those with BN (p = 0.0018). DISCUSSION: To our knowledge, this is the first study to address the issue of clinical heterogeneity in eating disorder genetic research and to explore the role of known or putatively functional markers in genes regulating appetite and weight in individuals with AN and BN. If replicated, our results may serve as an important first step toward gaining a better understanding of weight regulation in eating disorders.

Primary amenorrhea in anorexia nervosa: impact on characteristic masculine and feminine traits.

Animal studies indicate that gonadal hormones at puberty have an effect on the development of masculine and feminine traits. However, it is unknown whether similar processes occur in humans. We examined whether women with anorexia nervosa (AN), who often experience primary amenorrhea, exhibit attenuated feminization in their psychological characteristics in adulthood due to the decrease/absence of gonadal hormones at puberty. Women with AN were compared on a number of psychological characteristics using general linear models on the basis of the presence/absence of primary amenorrhea. Although women with primary amenorrhea exhibited lower anxiety scores than those without primary amenorrhea, in general, results did not provide evidence of attenuated feminization in women with AN with primary amenorrhea. Future research should utilize novel techniques and direct hormone measurement to explore the effects of pubertal gonadal hormones on masculine and feminine traits.

Factors associated with recovery from anorexia nervosa.

Previous studies of prognostic factors of anorexia nervosa (AN) course and recovery have followed clinical populations after treatment discharge. This retrospective study examined the association between prognostic factors--eating disorder features, personality traits, and psychiatric comorbidity--and likelihood of recovery in a large sample of women with AN participating in a multi-site genetic study. The study included 680 women with AN. Recovery was defined as the offset of AN symptoms if the participant experienced at least one year without any eating disorder symptoms of low weight, dieting, binge eating, and inappropriate compensatory behaviors. Participants completed a structured interview about eating disorders features, psychiatric comorbidity, and self-report measures of personality. Survival analysis was applied to model time to recovery from AN. Cox regression models were used to fit associations between predictors and the probability of recovery. In the final model, likelihood of recovery was significantly predicted by the following prognostic factors: vomiting, impulsivity, and trait anxiety. Self-induced vomiting and greater trait anxiety were negative prognostic factors and predicted lower likelihood of recovery. Greater impulsivity was a positive prognostic factor and predicted greater likelihood of recovery. There was a significant interaction between impulsivity and time; the association between impulsivity and likelihood of recovery decreased as duration of AN increased. The anxiolytic function of some AN behaviors may impede recovery for individuals with greater trait anxiety.

Temporal sequence of comorbid alcohol use disorder and anorexia nervosa.

Women with eating disorders have a significantly higher prevalence of substance use disorders than the general population. The goal of the current study was to assess the temporal pattern of comorbid anorexia nervosa (AN) and alcohol use disorder (AUD) and the impact this ordering has on symptomatology and associated features. Women were placed into one of three groups based on the presence or absence of comorbid AUD and the order of AN and AUD onset in those with both disorders: (1) AN Only, (2) AN First, and (3) AUD First. The groups were compared on psychological symptoms and personality characteristics often associated with AN, AUD, or both using general linear models. Twenty-one percent of women (n=161) with AN reported a history of AUD with 115 reporting AN onset first and 35 reporting AUD onset first. Women with binge-eating and/or purging type AN were significantly more likely to have AUD. In general, differences were found only between women with AN Only and women with AN and AUD regardless of order of emergence. Women with AN and AUD had higher impulsivity scores and higher prevalence of depression and borderline personality disorder than women with AN Only. Women with AN First scored higher on traits commonly associated with AN, whereas women with comorbid AN and AUD displayed elevations in traits more commonly associated with AUD. Results do not indicate a distinct pattern of symptomatology in comorbid AN and AUD based on the temporal sequence of the disorders.

An examination of early childhood perfectionism across anorexia nervosa subtypes.

OBJECTIVE: To examine childhood perfectionism in anorexia nervosa (AN) restricting (RAN), purging (PAN), and binge eating with or without purging (BAN) subtypes. METHOD: The EATATE, a retrospective assessment of childhood perfectionism, and the eating disorder inventory (EDI-2) were administered to 728 AN participants. RESULTS: EATATE responses revealed general childhood perfectionism, 22.3% of 333 with RAN, 29.2% of 220 with PAN, and 24.8% of 116 with BAN; school work perfectionism, 31.2% with RAN, 30.4% with PAN, and 24.8% with BAN; childhood order and symmetry, 18.7% with RAN, 21.7% with PAN, and 17.8% with BAN; and global childhood rigidity, 42.6% with RAN, 48.3% with PAN and 48.1% with BAN. Perfectionism preceded the onset of AN in all subtypes. Significant associations between EDI-2 drive for thinness and body dissatisfaction were present with four EATATE subscales. DISCUSSION: Global childhood rigidity was the predominate feature that preceded all AN subtypes. This may be a risk factor for AN.

Understanding the association of impulsivity, obsessions, and compulsions with binge eating and purging behaviours in anorexia nervosa.

OBJECTIVE: To further refine our understanding of impulsivity, obsessions, and compulsions in anorexia nervosa (AN) by isolating which behaviours--binge eating, purging, or both--are associated with these features. METHODS: We conducted regression analyses with binge eating, purging, and the interaction of binge eating with purging as individual predictors of scores for impulsivity, obsessions, and compulsions in two samples of women with AN (n = 1373). RESULTS: Purging, but not binge eating, was associated with higher scores on impulsivity, obsessions, and compulsions. Purging was also associated with worst eating rituals and with worst eating preoccupations. CONCLUSION: Our results suggest that purging, compared with binge eating, may be a stronger correlate of impulsivity, obsessions, and compulsions in AN.

Challenges in conducting a multi-site randomized clinical trial comparing treatments for adolescent anorexia nervosa.

OBJECTIVE: To describe obstacles in the implementation of a controlled treatment trial of adolescent anorexia nervosa (AN). METHOD: The original aim was to enter 240 participants with AN to one of four cells: Behavioral family therapy (BFT) plus fluoxetine; BFT plus placebo; systems family therapy (SFT) plus fluoxetine; SFT plus placebo. RESULTS: Recruitment was delayed pending a satisfactory resolution concerning participant safety. After 6 months of recruitment it became clear that the medication was associated with poor recruitment leading to a study redesign resulting in a comparison of two types of family therapy with a projected sample size of 160. One site was unable to recruit and was replaced. DISCUSSION: Problems with the delineation of safety procedures, recruitment, re-design of the study, and replacement of a site, were the main elements resulting in a 1-year delay. Suggestions are made for overcoming such problems in future AN trials.