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.

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.

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.

Valproate in the treatment of acute mania. A placebo-controlled study.

We conducted a placebo-controlled, double-blind study of valproate, a drug originally developed as an antiepileptic, in 36 patients with acute manic episodes who had previously failed to respond to or to tolerate lithium carbonate. Treatment duration was 7 to 21 days, with no other psychotropic medications permitted except lorazepam up to 4 mg/d during the first 10 days of treatment. Serum valproate concentrations were measured three times weekly; an unblinded investigator then adjusted dosage to produce serum concentrations between 50 and 100 mg/L. Valproate proved superior to placebo in alleviating manic symptoms. The 17 patients randomized to active drug demonstrated a median 54% decrease in scores on the Young Mania Rating Scale as compared with a median 5.0% decrease among the 19 patients receiving placebo. On the 100-point Global Assessment Scale of overall psychiatric functioning, patients receiving valproate improved by a median of 20 points as compared with a zero-point change with placebo. Significant differences also emerged on the Brief Psychiatric Rating Scale and in the number of supplemental doses of lorazepam required by the patients in each group. Substantial antimanic effects appeared within 1 to 4 days of achieving therapeutic serum valproate concentrations. Adverse effects were infrequent, with no adverse effect appearing significantly more frequently with valproate than with placebo. We conclude that valproate represents a useful new drug for the treatment of manic patients.

Electroencephalographic sleep in mania.

Electroencephalographic (EEG) sleep patterns were examined in nine unmedicated patients meeting DSM-III-R criteria for a current manic episode (four men and five women) for two to four consecutive nights. Compared with age- and sex-matched normal control subjects, manic patients exhibited significantly decreased total recording period, decreased time spent asleep, increased time awake in the last two hours of recording, shortened rapid eye movement (REM) latency, increased REM activity, and increased REM density. These results suggest that mania is associated with marked disturbances of sleep continuity and REM measures. Sleep continuity and REM sleep abnormalities of a similar nature and degree have been reported in major depression and psychotic depression. Thus, it is possible that various forms of affective disorders and psychotic disorders have pathophysiologic mechanisms in common.

The validity of DSM-III borderline personality disorder. A phenomenologic, family history, treatment response, and long-term follow-up study.

To test the validity of the DSM-III diagnosis of borderline personality disorder (BPD), we examined the phenomenology, family history, treatment response, and four-to-seven-year long-term outcome of a cohort of 33 patients meeting DSM-III criteria for BPD. We found that (1) BPD could be distinguished readily from DSM-III schizophrenia; (2) BPD did not appear to represent "borderline affective disorder," although many patients displayed BPD and major affective disorder concomitantly; and (3) BPD could not be distinguished on any of the indices from histrionic and antisocial personality disorders.

Abnormal results of dexamethasone suppression tests in nondepressed patients with diabetes mellitus.

To investigate the specificity of the dexamethasone suppression test (DST) for the diagnosis of major depression in patients with diabetes mellitus, we administered 1 mg of dexamethasone to 30 nondepressed diabetics and to 58 normal controls at 11 PM. Diabetic subjects received hemoglobin A1 (Hb A1) determinations, the Hamilton Rating Scale for Depression (HRSD), and five to eight blood glucose determinations during the 48 hours surrounding the DST. Results demonstrated a significantly higher rate of nonsuppression (plasma cortisol level, greater than or equal to 5 micrograms/dL) at 4 PM the following day among diabetics (43%) than among controls (7%) but no difference between these groups in the rate of nonsuppression at 8 AM. Plasma cortisol level at 4 PM correlated with Hb A1 level but not with duration of illness, HRSD score, mean blood glucose level, or maximum blood glucose excursion. These results suggest that the results of the DST used as a diagnostic test for major depression must be interpreted with caution in patients with diabetes.

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.

Polysomnographic characteristics of young manic patients. Comparison with unipolar depressed patients and normal control subjects.

Although sleep disturbance is a prominent feature of mania, its polysomnographic (PSG) features have received little study. To investigate more systematically the PSG characteristics of sleep in mania, all-night PSG evaluations were performed for two to four consecutive nights in 19 young manic patients (age range, 18 to 36 years), 19 age-matched patients with major depression, and 19 age-matched normal control subjects. Manic and depressed patients displayed nearly identical profiles of PSG abnormalities compared with normal control subjects, including disturbed sleep continuity, increased percentage of stage 1 sleep, shortened rapid eye movement latency, and increased rapid eye movement density. These results are similar to those reported in previous studies of major depression, and they are consistent with the possibility that the sleep disturbance in mania and major depression is caused by the same mechanism.

Familial hyperkalemic periodic paralysis and bipolar disorder: a linkage and treatment study.

Familial hyperkalemic periodic paralysis and bipolar disorder are both hereditary disorders, characterized by episodes of illness separated by periods of remission, and possibly related to abnormalities in cellular ion transport. Recently we discovered a patient who suffered from both illnesses, as did his mother and grandmother. However, a detailed investigation of the pedigree suggested that these two disorders are not linked genetically. Furthermore, a placebo-controlled double-blind trial of lithium carbonate in this patient found lithium ineffective in preventing the attacks of paralysis, in contrast to another recent study which found lithium effective in hypermagnesemic periodic paralysis.

Sleep EEG in bulimia.

To evaluate the sleep electroencephalogram (EEG) characteristics of bulimia, all-night sleep EEGs were performed on 11 women meeting DSM-III criteria for bulimia. Comparison groups consisted of young women outpatients with major depression (n = 44) and young normal women (n = 20). The sleep EEGs of the bulimic patients were largely indistinguishable from those of the normal controls, except for a trend toward increased rapid eye movement (REM) density in the first REM period among the bulimic subjects. No differences in any sleep EEG measure were observed between bulimic patients with major depression and those without affective disorder. By contrast, the outpatients with major depression displayed marked sleep continuity disturbances, as well as significantly increased REM intensity and REM density, as compared to normal controls. Implications of these results with respect to the hypothesis that bulimia is related to major affective disorder are discussed.

Good sleep, bad sleep: a meta-analysis of polysomnographic measures in insomnia, depression, and narcolepsy.

Primary insomnia, major depression, and narcolepsy are usually considered to be separate disorders, distinguished by different polysomnographic profiles. But do polysomnographic data provide adequate evidence to segregate the three disorders, or might they display fundamentally the same sleep disturbance, differing only in degree? To test the viability of these two alternate hypotheses, the authors performed a meta-analysis of controlled polysomnographic studies of these disorders. A summary measure of degree of sleep disturbance was constructed from five variables: wakefulness after sleep onset, percentage of stage 1 sleep, percentage of stage 3 + 4 sleep, rapid eye movement (REM) latency, and REM density. The results of available studies for each variable were combined using a weighted average of effect sizes. An overall "sleep disturbance index" was then calculated by combining the estimates for the five above listed variables. On both the individual measures and especially on the summary index, insomnia, depression, and narcolepsy were arrayed on a simple continuum of progressively more severe sleep disturbance--congruent with the clinical observation that these disorders display progressively more disturbed sleep. These findings suggest that sleep can be disturbed in only a limited number of ways: in evaluating sleep architecture, it may not be possible to elaborate much beyond a single axis of good-to-bad sleep. Thus, polysomnographic measures may not provide adequate evidence to classify insomnia, depression, and narcolepsy as separate entities.

Is childhood sexual abuse a risk factor for bulimia nervosa?

OBJECTIVE: It is of considerable theoretical and clinical importance to assess whether childhood sexual abuse is a risk factor for the development of bulimia nervosa. The authors reviewed the scientific literature bearing on this issue. METHOD: Since prospective studies on this question have not been done, they assessed 1) controlled retrospective studies comparing the prevalence of childhood sexual abuse among bulimic and control groups, 2) uncontrolled retrospective studies of the prevalence of childhood sexual abuse in samples of 10 or more bulimic subjects, and 3) studies of the prevalence of childhood sexual abuse in the general population, which were chosen to match as closely as possible in methodology the available studies of bulimia nervosa (i.e., in geographic location, age and ethnicity of subjects, interview method, and criteria for defining childhood sexual abuse). RESULTS: Controlled studies generally did not find that bulimic patients show a significantly higher prevalence of childhood sexual abuse than control groups, especially when allowance is made for possible methodologic effects. Furthermore, neither controlled nor uncontrolled studies of bulimia nervosa found higher rates of childhood sexual abuse than were found in studies of the general population that used comparable methods. When it is taken into consideration that several methodologic factors might have exaggerated the rates of childhood sexual abuse among subjects with bulimia nervosa relative to rates in the general population, the absence of actual observed differences becomes particularly striking. CONCLUSIONS: Current evidence does support the hypothesis that childhood sexual abuse is a risk factor for bulimia nervosa.

Affective spectrum disorder: does antidepressant response identify a family of disorders with a common pathophysiology?

Response to pharmacologic treatments may identify groups of disorders with a common pathophysiology. The authors applied a treatment-response model, based on four classes of antidepressants (tricyclic types, monoamine oxidase inhibitors, serotonin uptake inhibitors, and atypical agents), to the medical literature. The model identified eight disorders that may share a pathophysiologic abnormality: major depression, bulimia, panic disorder, obsessive-compulsive disorder, attention deficit disorder with hyperactivity, cataplexy, migraine, and irritable bowel syndrome. Phenomenologic and family studies support this grouping. If the model is validated, this family of disorders, which the authors term "affective spectrum disorder," would represent one of the most prevalent diseases in the population.

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.

Eating disorders in college men.

OBJECTIVE: This study was designed to assess the characteristics of men with eating disorders in the community. METHOD: The authors recruited 25 men meeting DSM-IV criteria for eating disorders and 25 comparison men through advertisements in college newspapers. A second comparison group comprised 33 women with bulimia nervosa who were recruited and interviewed with virtually identical methods. RESULTS: The men with eating disorders closely resembled the women with eating disorders but differed sharply from the comparison men in phenomenology of illness, rates of comorbid psychiatric disorders, and dissatisfaction with body image. Homosexuality did not appear to be a common feature of men with eating disorders in the community. Childhood physical and sexual abuse appeared slightly more common among the eating-disordered men than among the comparison men. CONCLUSIONS: Eating disorders, although less common in men than in women, appear to display strikingly similar features in affected individuals of the two genders.

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.

Undiagnosed vomiting in an older woman: unsuspected bulimia.

Bulimia, believed to occur primarily in young women, is rarely suspected in older individuals. The authors report on a 56-year-old woman with rapid cycling bipolar disorder, whose unexplained vomiting proved attributable to bulimia.

Anorexia nervosa and bulimia among 300 suburban women shoppers.

Of 300 female shoppers who responded to a questionnaire on anorexia nervosa and bulimia, 0.7% reported a history of anorexia nervosa and 10.3% reported a history of bulimia. The data support the belief that these disorders may be increasing in prevalence.