A genome-wide association study of anorexia nervosa.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

The contribution of familial internalizing and externalizing liability factors to borderline personality disorder.

BACKGROUND: Individuals with borderline personality disorder (BPD) frequently display co-morbid mental disorders. These disorders include 'internalizing' disorders (such as major depressive disorder and anxiety disorders) and 'externalizing' disorders (such as substance use disorders and antisocial personality disorder). It is hypothesized that these disorders may arise from latent 'internalizing' and 'externalizing' liability factors. Factor analytic studies suggest that internalizing and externalizing factors both contribute to BPD, but the extent to which such contributions are familial is unknown. METHOD: Participants were 368 probands (132 with BPD; 134 without BPD; and 102 with major depressive disorder) and 885 siblings and parents of probands. Participants were administered the Diagnostic Interview for DSM-IV Personality Disorders, the Revised Diagnostic Interview for Borderlines, and the Structured Clinical Interview for DSM-IV. RESULTS: On confirmatory factor analysis of within-person associations of disorders, BPD loaded moderately on internalizing (factor loading 0.53, S.E. = 0.10, p < 0.001) and externalizing latent variables (0.48, S.E. = 0.10, p < 0.001). Within-family associations were assessed using structural equation models of familial and non-familial factors for BPD, internalizing disorders, and externalizing disorders. In a Cholesky decomposition model, 84% (S.E. = 17%, p < 0.001) of the association of BPD with internalizing and externalizing factors was accounted for by familial contributions. CONCLUSIONS: Familial internalizing and externalizing liability factors are both associated with, and therefore may mutually contribute to, BPD. These familial contributions account largely for the pattern of co-morbidity between BPD and internalizing and externalizing disorders.

A comparative analysis of role attainment and impairment in binge-eating disorder and bulimia nervosa: results from the WHO World Mental Health Surveys.

Background. Cross-national population data from the WHO World Mental Health surveys are used to compare role attainments and role impairments associated with binge-eating disorder (BED) and bulimia nervosa (BN). Methods. Community surveys assessed 23 000 adults across 12 countries for BED, BN and ten other DSM-IV mental disorders using the WHO Composite International Diagnostic Interview. Age-of-onset was assessed retrospectively. Ten physical disorders were assessed using standard conditions checklists. Analyses examined reciprocal time-lagged associations of eating disorders (EDs) with education, associations of early-onset (i.e., prior to completing education) EDs with subsequent adult role attainments and cross-sectional associations of current EDs with days of role impairment. Results. BED and BN predicted significantly increased education (females). Student status predicted increased risk of subsequent BED and BN (females). Early-onset BED predicted reduced odds of current (at time of interview) marriage (females) and reduced odds of current employment (males). Early-onset BN predicted increased odds of current work disability (females and males). Current BED and BN were both associated with significantly increased days of role impairment (females and males). Significant BED and BN effects on adult role attainments and impairments were explained by controls for comorbid disorders. Conclusions. Effects of BED on role attainments and impairments are comparable with those of BN. The most plausible interpretation of the fact that these associations are explained by comorbid disorders is that causal effects of EDs are mediated through secondary disorders. Controlled treatment effectiveness studies are needed to trace out long-term effects of BED-BN on secondary disorders.

Fitting ACE structural equation models to case-control family data.

Investigators interested in whether a disease aggregates in families often collect case-control family data, which consist of disease status and covariate information for members of families selected via case or control probands. Here, we focus on the use of case-control family data to investigate the relative contributions to the disease of additive genetic effects (A), shared family environment (C), and unique environment (E). We describe an ACE model for binary family data; this structural equation model, which has been described previously, combines a general-family extension of the classic ACE twin model with a (possibly covariate-specific) liability-threshold model for binary outcomes. We then introduce our contribution, a likelihood-based approach to fitting the model to singly ascertained case-control family data. The approach, which involves conditioning on the proband's disease status and also setting prevalence equal to a prespecified value that can be estimated from the data, makes it possible to obtain valid estimates of the A, C, and E variance components from case-control (rather than only from population-based) family data. In fact, simulation experiments suggest that our approach to fitting yields approximately unbiased estimates of the A, C, and E variance components, provided that certain commonly made assumptions hold. Further, when our approach is used to fit the ACE model to Austrian case-control family data on depression, the resulting estimate of heritability is very similar to those from previous analyses of twin data.

Attributes of long-term heavy cannabis users: a case-control study.

BACKGROUND: Although cannabis is the most widely used illicit drug in the United States, few recent American studies have examined the attributes of long-term heavy cannabis users. METHOD: Using a case-control design, we obtained psychological and demographic measures on 108 individuals, age 30-55, who had smoked cannabis a mean of 18000 times and a minimum of 5000 times in their lives. We compared these heavy users to 72 age-matched control subjects who had smoked at least once, but no more than 50 times in their lives. RESULTS: We found no significant differences between the two groups on reported levels of income and education in their families of origin. However, the heavy users themselves reported significantly lower educational attainment (P < 0.001) and income (P = 0.003) than the controls, even after adjustment for a large number of potentially confounding variables. When asked to rate the subjective effects of cannabis on their cognition, memory, career, social life, physical health and mental health, large majorities of heavy users (66-90%) reported a 'negative effect'. On several measures of quality of life, heavy users also reported significantly lower levels of satisfaction than controls. CONCLUSION: Both objective and self-report measures suggest numerous negative features associated with long-term heavy cannabis use. Thus, it seems important to understand why heavy users continue to smoke regularly for years, despite acknowledging these negative effects. Such an understanding may guide the development of strategies to treat cannabis dependence.

Family study of the aggregation of eating disorders and mood disorders.

BACKGROUND: Family studies have suggested that eating disorders and mood disorders may coaggregate in families. To study further this question, data from a family interview study of probands with and without major depressive disorder was examined. METHOD: A bivariate proband predictive logistic regression model was applied to data from a family interview study, conducted in Innsbruck, Austria, of probands with (N = 64) and without (N = 58) major depressive disorder, together with 330 of their first-degree relatives. RESULTS: The estimated odds ratio (OR) for the familial aggregation of eating disorders (anorexia nervosa, bulimia nervosa and binge-eating disorder) was 7.0 (95 % CI 1.4, 28; P = 0.006); the OR for the familial aggregation of mood disorders (major depression and bipolar disorder) was 2.2 (0.92, 5.4; P = 0.076); and for the familial coaggregation of eating disorders with mood disorders the OR was 2.2 (1.1, 4.6; P = 0.035). CONCLUSIONS: The familial coaggregation of eating disorders with mood disorders was significant and of the same magnitude as the aggregation of mood disorders alone--suggesting that eating disorders and mood disorders have common familial causal factors.

Neuropsychological performance in long-term cannabis users.

BACKGROUND: Although cannabis is the most widely used illicit drug in the United States, its long-term cognitive effects remain inadequately studied. METHODS: We recruited individuals aged 30 to 55 years in 3 groups: (1) 63 current heavy users who had smoked cannabis at least 5000 times in their lives and who were smoking daily at study entry; (2) 45 former heavy users who had also smoked at least 5000 times but fewer than 12 times in the last 3 months; and (3) 72 control subjects who had smoked no more than 50 times in their lives. Subjects underwent a 28-day washout from cannabis use, monitored by observed urine samples. On days 0, 1, 7, and 28, we administered a neuropsychological test battery to assess general intellectual function, abstraction ability, sustained attention, verbal fluency, and ability to learn and recall new verbal and visuospatial information. Test results were analyzed by repeated-measures regression analysis, adjusting for potentially confounding variables. RESULTS: At days 0, 1, and 7, current heavy users scored significantly below control subjects on recall of word lists, and this deficit was associated with users' urinary 11-nor-9-carboxy-Delta9-tetrahydrocannabinol concentrations at study entry. By day 28, however, there were virtually no significant differences among the groups on any of the test results, and no significant associations between cumulative lifetime cannabis use and test scores. CONCLUSION: Some cognitive deficits appear detectable at least 7 days after heavy cannabis use but appear reversible and related to recent cannabis exposure rather than irreversible and related to cumulative lifetime use.

Why do young women diet? The roles of body fat, body perception, and body ideal.

BACKGROUND: To assess the relative roles of body fat, body perception, and body ideals as motivations for dieting in college women. METHOD: We compared 45 college women who reported having dieted with 32 who had not, using a novel computerized test of body image called the somatomorphic matrix. RESULTS: As expected, the difference in body fat between subjects' "perceived body" and "ideal body" was significantly greater in dieters than in nondieters (p < .001). Remarkably, however, this difference remained highly significant even after adjusting for the subjects' actual measured body fat (p = .002). Further analysis revealed that this difference persisted, not because dieters had unrealistic ideals of thinness, but because they had distorted perceptions of their fatness. CONCLUSION: Distorted body image perception, a potentially treatable condition, may play an unexpectedly large role in motivating young women to diet.

Standards for informed consent in recovered memory therapy.

Malpractice suits against therapists for either instilling or recovering false memories of sexual abuse have increased in the last few years and some of the awards have been large. Failure to give informed consent, that is, failing to inform patients concerning the risk of recovering false memories, is one of the main allegations increasingly made against therapists in recovered memory cases. In the landmark case on informed consent, Canterbury v. Spence fashioned a standard of disclosure that focused on how material the potential warnings were to the patient's decision and specifically stated the standard would be set by the law, not by the profession. The court ruled that the "risk or cluster of risks" must be disclosed to the patient in a manner that meets the patient's "informational needs." A review of relevant literature shows that a substantial body of information existed by the early 1990s that warned psychotherapists about the risk of false reports of sexual and physical abuse. This article concludes that the "risk or cluster of risks" that must be disclosed to a patient recovering repressed memories in psychotherapy should have included warnings about recovering false memories.

Canadian and American psychiatrists' attitudes toward dissociative disorders diagnoses.

OBJECTIVE: To compare the opinions of Canadian psychiatrists regarding dissociative disorder diagnoses with those of previously surveyed American psychiatrists. METHOD: We sent a 1-page questionnaire to a stratified representative sample of 550 Canadian psychiatrists. RESULTS: Eighty percent of Canadian psychiatrists responded. Fewer than one-third replied that dissociative amnesia and dissociative identity disorder should be included without reservations in the DSM-IV; fewer than 1 in 7 felt that the validity of these diagnoses was supported by strong scientific evidence. French- and English-speaking Canadians had similar opinions. Overall, Canadians were significantly less accepting than Americans. CONCLUSION: Both Canadian and American psychiatrists show little consensus regarding the diagnostic status or scientific validity of dissociative amnesia and dissociative identity disorder.

Over-the-counter drug use in gymnasiums: an underrecognized substance abuse problem?

OBJECTIVE: Many individuals, attempting to gain muscle or lose fat, use 'dietary supplements'. Though widely available over the counter or by mail order in America and Europe, some of these 'supplements' are actually potent drugs such as androstenedione and ephedrine. We sought to estimate the prevalence of these forms of drug use in American gymnasiums. METHODS: We distributed anonymous questionnaires to 511 clients entering five gymnasiums, asking about use of both supplements and anabolic steroids. RESULTS: Among men, 18% reported use of androstenedione and/or other adrenal hormones, 25% reported ephedrine use, and 5% reported anabolic steroid use within the last 3 years; among women these rates were 3, 13 and 0%. Extrapolating from these figures to the United States as a whole, we estimated that possibly 1.5 million American gymnasium clients have used adrenal hormones and 2.8 million have used ephedrine within the last 3 years. CONCLUSIONS: Millions of men and women are currently using potent drugs, widely sold over the counter as 'supplements', despite their known adverse effects, unknown long-term risks, and possible potential for causing abuse or dependence.

A computationally simple test of homogeneity of odds ratios for twin data.

It is of interest to compare measures of association of binary traits among samples of bivariate data. One example is the comparison of association within a sample of monozygotic (MZ) twins to that within a sample of dizygotic (DZ) twins. A larger association in the MZ twins suggests that the trait of interest may have a genetic component. The Bivariate data in this example are binary traits for the twins in each pair. Another example is the comparison of a measure of Hardy-Weinberg disequilibrium across several populations. The bivariate data in this example are the two alleles comprising the genotype of interest. We propose using derived logistic regression equations from the full exponential model for the bivariate outcomes to test for homogeneity. We adjust for correlation among outcomes via generalized estimating equations. This modeling approach allows for adjustment for individual-level and pair-level covariates and thereby allows for testing for gene x environment interactions. Further, we extend the model to allow for simultaneous analysis of two diseases, which allows for testing for a genetic component to the coaggregation of two diseases. In contrast to approaches proposed by previous authors, no special software is required; our approach can be easily implemented in standard software packages. We compare our results to those of other methods proposed in the literature for data from the Vietnam Era Twins Study. We apply our methods also to the Anqing Twin Study and to data on major depression and generalized anxiety disorder from the Virginia Twin Register.

Multivariate logistic regression for familial aggregation of two disorders. I. Development of models and methods.

The question of whether two disorders cluster together, or coaggregate, within families often arises. This paper considers how to analyze familial aggregation of two disorders and presents two multivariate logistic regression methods that model both disorder outcomes simultaneously. The first, a proband predictive model, predicts a relative's outcomes (the presence or absence of each of the two disorders) by using the proband's disorder status. The second, a family predictive model derived from the quadratic exponential model, predicts a family member's outcomes by using all of the remaining family members' disorder statuses. The models are more realistic, flexible, and powerful than univariate models. Methods for estimation and testing account for the correlation of outcomes among family members and can be implemented by using commercial software.

Multivariate logistic regression for familial aggregation of two disorders. II. Analysis of studies of eating and mood disorders.

Family studies have suggested that eating disorders and mood disorders may coaggregate within families. Previous studies, however, have been limited by use of univariate modeling techniques and failure to account for the correlation of observations within families. To provide a more efficient analysis and to illustrate multivariate logistic regression models for familial aggregation of two disorders, the authors analyzed pooled data from two previously published family studies (conducted in Massachusetts in 1984-1986 and 1986-1987) by using multivariate proband predictive and family predictive models. Both models demonstrated a significant familial aggregation of mood disorders and familial coaggregation of eating and mood disorders. The magnitude of the coaggregation between eating and mood disorders was similar to that of the aggregation of mood disorders. Similar results were obtained with alternative models, including a traditional univariate proband predictive model. In comparison with the univariate model, the multivariate models provided greater flexibility, improved precision, and wider generality for interpreting aggregation effects.

Muscle dysmorphia in male weightlifters: a case-control study.

OBJECTIVE: Muscle dysmorphia is a form of body dysmorphic disorder in which individuals develop a pathological preoccupation with their muscularity. METHOD: The authors interviewed 24 men with muscle dysmorphia and 30 normal comparison weightlifters, recruited from gymnasiums in the Boston area, using a battery of demographic, psychiatric, and physical measures. RESULTS: The men with muscle dysmorphia differed significantly from the normal comparison weightlifters on numerous measures, including body dissatisfaction, eating attitudes, prevalence of anabolic steroid use, and lifetime prevalence of DSM-IV mood, anxiety, and eating disorders. The men with muscle dysmorphia frequently described shame, embarrassment, and impairment of social and occupational functioning in association with their condition. By contrast, normal weightlifters displayed little pathology. Indeed, in an a posteriori analysis, the normal weightlifters proved closely comparable to a group of male college students recruited as a normal comparison group in an earlier study. CONCLUSIONS: Muscle dysmorphia appears to be a valid diagnostic entity, possibly related to a larger group of disorders, and is associated with striking and stereotypical features. Men with muscle dysmorphia differ sharply from normal weightlifters, most of whom display little psychopathology. Further research is necessary to characterize the nosology and potential treatment of this syndrome.

Body image perception among men in three countries.

OBJECTIVE: The authors tested the hypothesis that men in modern Western societies would desire to have a much leaner and more muscular body than the body they actually had or perceived themselves to have. METHOD: The height, weight, and body fat of college-aged men in Austria (N=54), France (N=65), and the United States (N=81) were measured. Using the somatomorphic matrix, a computerized test devised by the authors, the men chose the body image that they felt represented 1) their own body, 2) the body they ideally would like to have, 3) the body of an average man of their age, and 4) the male body they believed was preferred by women. The men's actual fat and muscularity was compared with that of the four images chosen. RESULTS: Only slight demographic and physical differences were found among the three groups of men. Modest differences were found between the men's measured fat and the fat of the images chosen. However, measures of muscularity produced large and highly significant differences. In all three countries, men chose a ideal body that was a mean of about 28 lb (13 kg) more muscular than themselves and estimated that women preferred a male body about 30 lb (14 kg) more muscular than themselves. In a pilot study, however, the authors found that actual women preferred an ordinary male body without added muscle. CONCLUSIONS: The wide discrepancy between men's actual muscularity and their body ideals may help explain the apparent rise in disorders such as muscle dysmorphia and anabolic steroid abuse.

Placebo-controlled trial of sertraline in the treatment of binge eating disorder.

OBJECTIVE: The authors' goal was to assess the efficacy of sertraline in the treatment of binge eating disorder. METHOD: Thirty-four outpatients with DSM-IV binge eating disorder were randomly assigned to receive either sertraline (N=18) or placebo (N=16) in a 6-week, double-blind, flexible-dose (50-200 mg) study. Except for response level, outcome measures were analyzed by random regression methods, with treatment-by-time interaction as the effect measure. RESULTS: Compared with placebo, sertraline was associated with a significantly greater rate of reduction in the frequency of binges, clinical global severity, and body mass index as well as a significantly greater rate of increase in clinical global improvement. Patients receiving sertraline who completed the study demonstrated a higher level of response, although the effect was not significant. CONCLUSIONS: In a 6-week trial, sertraline was effective and well tolerated in the treatment of binge eating disorder.

MDMA ("Ecstasy") abuse and high-risk sexual behaviors among 169 gay and bisexual men.

OBJECTIVE: The authors explored the association between abuse of 3, 4-methylenedioxymethamphetamine (MDMA, or "Ecstasy") and high-risk sexual behaviors among gay and bisexual men. METHOD: An anonymous questionnaire was completed by 169 gay and bisexual men at three New York City dance clubs. The questionnaire covered demographic indices, use of MDMA and other drugs, and history of high-risk sexual behaviors. RESULTS: About one-third of the respondents reported MDMA use at least monthly. MDMA use was strongly and significantly associated with a history of recent unprotected anal intercourse. This association remained equally strong even after controlling for age, ethnicity, and all other forms of drug use, including alcohol. CONCLUSIONS: MDMA abuse, and its strong association with high-risk sexual behaviors, appears to represent important unexplored public health problems among some gay or bisexual men.

Effects of supraphysiologic doses of testosterone on mood and aggression in normal men: a randomized controlled trial.

BACKGROUND: Field studies of illicit anabolic-androgenic steroid users suggest that some develop manic or aggressive reactions to these drugs-a potential public health problem. However, controlled laboratory evaluations of these effects remain limited. METHODS: In a randomized, placebo-controlled, crossover trial, we administered testosterone cypionate for 6 weeks in doses rising to 600 mg/wk and placebo for 6 weeks, separated by 6 weeks of no treatment, to 56 men aged 20 to 50 years. Psychiatric outcome measures included the Young Mania Rating Scale (YMRS), the Point Subtraction Aggression Paradigm (a computerized provocation test of aggression), the Aggression Questionnaire of Buss and Perry, the Symptom Checklist-90-R, daily diaries of manic and depressive symptoms, and similar weekly diaries completed by a "significant other" who knew the participant well. RESULTS: Testosterone treatment significantly increased manic scores on the YMRS (P = .002), manic scores on daily diaries (P = .003), visual analog ratings of liking the drug effect (P = .008), and aggressive responses on the Point Subtraction Aggression Paradigm (P = .03). Drug response was highly variable: of 50 participants who received 600 mg/wk of testosterone cypionate, 42 (84%) exhibited minimal psychiatric effects (maximum YMRS score, <10), 6 (12%) became mildly hypomanic (YMRS score, 10-19), and 2 (4%) became markedly hypomanic (YMRS score, > or =20). The 8 "responders" and 42 "nonresponders" did not differ significantly on baseline demographic, psychological, laboratory, or physiological measures. CONCLUSIONS: Testosterone administration, 600 mg/wk increased ratings of manic symptoms in normal men. This effect, however, was not uniform across individuals; most showed little psychological change, whereas a few developed prominent effects. The mechanism of these variable reactions remains unclear.