A genome-wide association study was carried out in 1020 case subjects with recurrent early-onset major depressive disorder (MDD) (onset before age 31) and 1636 control subjects screened to exclude lifetime MDD. Subjects were genotyped with the Affymetrix 6.0 platform. After extensive quality control procedures, 671 424 autosomal single nucleotide polymorphisms (SNPs) and 25 068 X chromosome SNPs with minor allele frequency greater than 1% were available for analysis. An additional 1 892 186 HapMap II SNPs were analyzed based on imputed genotypic data. Single-SNP logistic regression trend tests were computed, with correction for ancestry-informative principal component scores. No genome-wide significant evidence for association was observed, assuming that nominal P <5 × 10 −8 approximates a 5% genome-wide significance threshold. The strongest evidence for association was observed on chromosome 18q22.1 (rs17077540, P =1.83 × 10 −7 ) in a region that has produced some evidence for linkage to bipolar-I or -II disorder in several studies, within an mRNA detected in human brain tissue (BC053410) and approximately 75 kb upstream of DSEL . Comparing these results with those of a meta-analysis of three MDD GWAS data sets reported in a companion article, we note that among the strongest signals observed in the GenRED sample, the meta-analysis provided the greatest support (although not at a genome-wide significant level) for association of MDD to SNPs within SP4 , a brain-specific transcription factor. Larger samples will be required to confirm the hypothesis of association between MDD (and particularly the recurrent early-onset subtype) and common SNPs.

BACKGROUNDSome investigators fear that dieting may precipitate binge eating and other adverse behavioral consequences.OBJECTIVEThe objective of the study was to examine whether dieting would elicit binge eating and mood disturbance in individuals free of these complications before treatment.DESIGNA total of 123 obese women were randomly assigned to 1) a 1000 kcal/d diet that included 4 servings/d of a liquid meal replacement (MR); 2) a 1200-1500 kcal/d balanced deficit diet (BDD) of conventional foods; or 3) a nondieting (ND) approach that discouraged energy restriction. All women attended weekly group sessions for 20 wk and biweekly sessions from week 20 to week 40.RESULTSAt week 20, participants in the MR, BDD, and ND groups lost 12.1 +/- 6.7%, 7.8 +/- 6.0%, and 0.1 +/- 2.4% of initial weight, respectively (P < 0.001). During the first 20 wk, there were no significant differences among groups in the number of persons who had objective binge episodes or in reports of hunger or dietary disinhibition. Symptoms of depression decreased significantly more (P < 0.001) in the MR and BDD groups than in ND participants. At week 28, significantly more (P < 0.003) cases of binge eating were observed in MR participants than in the 2 other groups. No differences, however, were observed between groups at weeks 40 or 65 (a follow-up visit). At no time did any participant meet criteria for binge-eating disorder.CONCLUSIONConcerns about possible adverse behavioral consequences of dieting should not dissuade primary care providers from recommending modest energy restriction to obese individuals.

A genome scan was performed on the first phase sample of the Genetics of Recurrent Early-Onset Depression (GenRED) project. The sample consisted of 297 informative families containing 415 independent affected sibling pairs (ASPs), or, counting all possible pairs, 685 informative affected relative pairs (555 ASPs and 130 other pair types). Affected cases had recurrent major depressive disorder (MDD) with onset before age 31 years for probands or age 41 years for other affected relatives; the mean age at onset was 18.5 years, and the mean number of depressive episodes was 7.3. The Center for Inherited Disease Research genotyped 389 microsatellite markers (mean spacing of 9.3 cM). The primary linkage analysis considered allele sharing in all possible affected relative pairs with the use of the Z(lr) statistic computed by the ALLEGRO program. A secondary logistic regression analysis considered the effect of the sex of the pair as a covariate. Genomewide significant linkage was observed on chromosome 15q25.3-26.2 (Zlr=4.14, equivalent LOD = 3.73, empirical genomewide P=.023). The linkage was not sex specific. No other suggestive or significant results were observed in the primary analysis. The secondary analysis produced three regions of suggestive linkage, but these results should be interpreted cautiously because they depended primarily on the small subsample of 42 male-male pairs. Chromosome 15q25.3-26.2 deserves further study as a candidate region for susceptibility to MDD.

Caregivers of persons with severe mental illness often experience a significant burden in coping with patients' symptoms. Several factors have been hypothesized to mediate the impact of caring for a mentally ill relative, including cognitive appraisal, coping strategies, and social support. The present study examined the relationships between these factors, and subjective burden and well-being in caregivers of persons with a severe mental illness. Higher levels of subjective burden were related to (1) greater perceived frequency of positive and negative symptom behaviors, (2) a tendency to use problem-focused oriented coping for dealing with negative symptom behaviors, and (3) a tendency not to use problem-solving oriented coping for dealing with positive symptom behaviors. Well-being was also related to lower perceived frequency of positive symptom behaviors and social support, but not to coping style. The implications of the findings for interventions designed to reduce caregiver subjective burden are discussed. (C) 1998 Elsevier Science B.V. All rights reserved.

Objective: The goal of this study was to identify chromosomal regions likely to contain schizophrenia susceptibility genes. Method: A genomewide map of 310 microsatellite DNA markers with average spacing of 11 centimorgans was genotyped in 269 individuals-126 of them with schizophrenia-related psychoses-from 43 pedigrees. Nonparametric linkage analysis was used to assess the pattern of allele sharing at each marker locus relative to the presence of disease. Results: Nonparametric linkage scores did not reach a genomewide level of statistical significance for any marker. There were five chromosomal regions in which empirically derived p values reached nominal levels of significance at eight marker locations. There were p values less than 0.01 at chromosomes 2q (with the peak value in this region at D2S410) and 10q (D10S1239), and there were p values less than 0.05 at chromosomes 4q (D4S2623), 9q (D9S257), and 11q (D11S2002). Conclusions: The results do not support the hypothesis that a single gene causes a large increase in the risk of schizophrenia. The sample (like most others being studied for psychiatric disorders) has limited power to detect genes of small effect or those that are determinants of risk in a small proportion of families. All of the most positive results could be due to chance, or some could reflect weak linkage (genes of small effect). Multicenter studies may be useful in the effort to identify chromosomal regions most likely to contain schizophrenia susceptibility genes.

OBJECTIVE The study compared the burden that specific problem behaviors of patients with schizophrenia or bipolar disorder placed on relatives and evaluated the accuracy of mental health professionals' judgment of the burden. METHODS A questionnaire was developed to assess the burden of 20 common problem behaviors associated with manic, positive, and negative symptoms. The questionnaire was given to 48 relatives of patients with schizophrenia or bipolar disorder. In addition, 39 mental health professionals completed separate questionnaires indicating the amount of burden they believed relatives experienced due to these behaviors. RESULTS Relatives of patients with bipolar disorder rated manic symptoms as more burdensome than did relatives of patients with schizophrenia, but relatives of patients in the two groups did not differ in their ratings of burden associated with positive or negative symptoms. Professionals' perceptions of the burden associated with manic symptoms were relatively accurate, but they tended to underestimate the burden of positive and negative symptoms experienced by relative of patients with bipolar disorder. CONCLUSIONS Psychiatric diagnosis may be of limited value in understanding the burden relatives experience due to specific psychiatric symptoms. Professionals are encouraged to assess the burden that is associated with specific problem behaviors regardless of psychiatric diagnosis.

OBJECTIVE The purpose of this study was 1) to replicate previous work indicating that antidepressant medication is superior to placebo in the treatment of bulimia nervosa and 2) to assess the long-term efficacy of this form of treatment. METHOD Eighty patients entered a three-phase treatment protocol. An 8-week double-blind initiation phase was used to compare the effects of desipramine and placebo. Patients who responded satisfactorily to desipramine entered a 16-week maintenance phase. Patients who remained well were then randomly assigned to either desipramine or placebo for 6 additional months (discontinuation phase). The primary outcome measure was binge frequency, which was assessed weekly by self-report diaries. RESULTS In the initiation phase the superiority of desipramine over placebo in reducing binge frequency was demonstrated. Patients treated with desipramine had a mean reduction in binge frequency of 47% at termination, whereas patients taking placebo experienced a mean increase of 7%. Less than half of the patients treated with desipramine met the criteria for entering the maintenance phase, and 29% of the patients entering that phase relapsed in the following 4 months. There were not enough patients in the discontinuation phase to permit clear conclusions about the need for continued antidepressant medication after 6 months of treatment. CONCLUSIONS The study documents a beneficial effect of desipramine in the treatment of bulimia nervosa when compared to placebo. However, limited improvement and considerable relapse with continued treatment suggest serious limitations to the long-term efficacy of a single antidepressant trial in treating bulimia nervosa.

We performed lactate infusions in 18 bulimic patients and 11 normal controls. On the basis of blind ratings, bulimic patients appeared to react to the infusion with greater anxiety than controls. The frequency of lactate-induced panic, per se, was lower in bulimic patients than rates reported for panic disorder patients. However, it would be premature to conclude that bulimia is not a heterogeneous syndrome which includes a group of patients who panic with lactate.

To examine the efficacy of the monoamine oxidase inhibitor phenelzine sulfate in the treatment of bulimia, a double-blind, placebo-controlled trial was conducted. In 50 women who completed the trial, phenelzine was significantly superior to placebo in the reduction of binge frequency (64% vs 5%), in the fraction of patients who had ceased bingeing at the end of the trial (35% vs 4%), and in several measures of psychological state. The superiority of phenelzine over placebo was not confined to a depressed subgroup of patients. Although no patient experienced a hypertensive crisis during the study, other side effects of phenelzine were problematic and limit the usefulness of phenelzine in this population.

It is clear that patients with anorexia nervosa and bulimia have disturbances of mood, and it is likely that the mood disturbances bear an important relationship to the disturbances of eating behavior. We have as many questions, however, about the relationship between mood and eating behavior in these syndromes as we have answers. Although patients with anorexia nervosa and bulimia are frequently depressed, they fail to exhibit many of the biological characteristics of typical depressive illness, suggesting that these eating disorders are probably not simply variants of depression. Patients with bulimia appear to binge in response to dysphoric emotional states and to derive some transient relief from their bingeing. But it is unclear what facet or facets of the binge produce the alteration in emotional state, and thereby may serve to reinforce the behavior. A more detailed examination of this issue may significantly advance our understanding of the relationship between mood and food in eating disorders.

A 1-mg dexamethasone suppression test (DST) was carried out in 66 women with bulimia and in 26 age- and sex-matched controls. Blood samples were obtained at 4 PM on the day following dexamethasone ingestion, and levels of cortisol and of dexamethasone in the plasma were measured. Thirty-two percent of the patients vs only 7% of the controls had plasma cortisol levels of 140 nmol/L (5 micrograms/dL) or greater following the DST (a positive DST). The plasma levels of dexamethasone varied substantially, and there was a significant inverse relationship between the plasma level of cortisol and that of dexamethasone. Patients with positive DST results had lower levels of plasma dexamethasone than did those with negative DST results, and the mean plasma level of dexamethasone was lower in the bulimic group than in the control group. These results suggest that factors other than a disturbance of hypothalamic-pituitary-adrenal activity may contribute to positive DST results in bulimia.

Thirty normal weight women with bulimia completed a double-blind, placebo-controlled trial of phenelzine sulfate. The results demonstrate a significant therapeutic advantage for phenelzine over placebo. Preliminary data suggest that phenelzine may be of benefit even to non-depressed patients with bulimia.

C-Peptide is secreted from pancreatic beta cells in equimolar concentrations with insulin. Unlike insulin, C-peptide is largely metabolized by the kidney, with 5%-10% of it excreted in the urine. Timed urine collections for C-peptide reflect prehepatic insulin production. We collected 24h urines in four consecutive six hour aliquots from 32 healthy, ambulatory children (ages 2 to 21 years) on normal diets. C-peptide (by RIA) and creatinine levels were measured on all 6 hour aliqots and on each 24h specimen. Mean C-peptide excretion in micrograms (ug) is listed in the table: Weight was more highly correlated with 24h C-peptide excretion than was age (0.535 vs 0.339), and accounted for 29% of the total variance. When controlled for weight in a multiple regression analysis, age was not a significant predictor. Significant correlation (0.835) existed between C-peptide excretion in the 3AM-9AM and the 24h urines. We conclude that weight can predict C-peptide excretion, which when measured on 1st AM urines can be used to screen for endogenous insulin production.

Previous studies have suggested that increased activity in endogenous opiate systems can lead to suppression of LH secretion in certain normal and patho- logical states. Increased food intake has also been linked to increased en- dogenous opiate activity. We hypothesized that in some women with the syndrome of bulimia there is an increase in endogenous opiate system activ- ity which contributes both to a suppression of LH secretion and to an in- creased drive to eat. We tested the endocrine aspect of this hypothesis by determining the effect of naloxone on LH secretion in nine amenorrheic or oligomenorrheic women with bulimia. Naloxone failed to increase LH in five underweight women with bulimia and anorexia nervosa. There was a slight increase in LH secretion during naloxone infusion in two of four women of normal weight with bulimia.

In recent years several lines of evidence have emerged suggesting that eating disorders in general, and bulimia in particular, are in some way linked to affective illness. However, there are few data on the frequency of affective syndromes among patients who have anorexia nervosa or bulimia. This report describes the results of semistructured interviews using the Schedule for Affective Disorders and Schizophrenia (SADS) to evaluate the frequency of the current and lifetime diagnoses of affective illness among 50 female patients meeting DSM-III criteria for bulimia. Seventy percent of the patients had, at some time during their lives, met Research Diagnostic Criteria (RDC) for an episode of major depression and 88% had met RDC at some time during their lives for some affective disturbance. The implications of this high frequency of affective disturbance among patients with bulimia are discussed.

Nineteen (35%) of 55 women with bulimia failed to exhibit cortisol suppression after dexamethasone administration. Although there was no statistically significant difference between suppressors and nonsuppressors on any clinical variable, there was a higher frequency of major depression among nonsuppressors.

Twenty bulimic women of normal weight participated in a double-blind trial studying the effects of a monoamine oxidase inhibitor (MAOI). Nine women received phenelzine sulfate and 11 received placebo. Although phenelzine's side effects were a problem, the phenelzine-treated patients reported significantly fewer binges per week and had a lower Eating Attitudes Test score. Five of the nine phenelzine-treated patients ceased binging entirely and the other four reduced their binge frequency by at least 50%; none of the 11 placebo-treated patients stopped binging and only two reduced their binge frequency by 50% or more. These data demonstrate that phenelzine is significantly more effective than placebo in the treatment of bulimic women of normal weight and suggest a place for MAOIs in the treatment of bulimic patients capable of maintaining a tyramine-free diet.