Association between MC4R rs17782313 polymorphism and overeating behaviors.

BACKGROUND/OBJECTIVES: Melanocortins have a crucial role in appetite and weight regulation. Although the melanocortin 4 receptor (MC4R) gene has been repeatedly linked to obesity and antipsychotic-induced weight gain, the mechanism behind how it leads to this effect in still undetermined. The goal of this study was to conduct an in-depth and sophisticated analysis of MC4R polymorphisms, body mass index (BMI), eating behavior and depressed mood. SUBJECTS/METHODS: We genotyped 328 individuals of European ancestry on the following MC4R markers based on the relevant literature on obesity and antipsychotic-induced weight gain: rs571312, rs17782313, rs489693, rs11872992, and rs8087522. Height and weight were measured, and information on depressed mood and overeating behaviors was obtained during the in-person assessment. RESULTS: BMI was associated with rs17782313 C allele; however, this finding did not survive correction for multiple testing (P = 0.018). Although rs17782313 was significantly associated with depressed mood and overeating behaviors, tests of indirect effects indicated that emotional eating and food cravings, rather than depressed mood, uniquely accounted for the effect of this marker and BMI (n = 152). CONCLUSIONS: To our knowledge, this is the first study to investigate the link between MC4R rs17782313, mood and overeating behavior, as well as to demonstrate possible mechanisms behind MC4R's influence on body weight. If replicated in a larger sample, these results may have important clinical implications, including potential for the use of MC4R agonists in the treatment of obesity and disordered eating.

Evidence for the role of EPHX2 gene variants in anorexia nervosa.

Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric conditions with likely rare and common genetic and environmental determinants. To identify genetic variants associated with AN, we pursued a series of sequencing and genotyping studies focusing on the coding regions and upstream sequence of 152 candidate genes in a total of 1205 AN cases and 1948 controls. We identified individual variant associations in the Estrogen Receptor-ß (ESR2) gene, as well as a set of rare and common variants in the Epoxide Hydrolase 2 (EPHX2) gene, in an initial sequencing study of 261 early-onset severe AN cases and 73 controls (P=0.0004). The association of EPHX2 variants was further delineated in: (1) a pooling-based replication study involving an additional 500 AN patients and 500 controls (replication set P=0.00000016); (2) single-locus studies in a cohort of 386 previously genotyped broadly defined AN cases and 295 female population controls from the Bogalusa Heart Study (BHS) and a cohort of 58 individuals with self-reported eating disturbances and 851 controls (combined smallest single locus P<0.01). As EPHX2 is known to influence cholesterol metabolism, and AN is often associated with elevated cholesterol levels, we also investigated the association of EPHX2 variants and longitudinal body mass index (BMI) and cholesterol in BHS female and male subjects (N=229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (P<0.01). These findings suggest a novel association of gene variants within EPHX2 to susceptibility to AN and provide a foundation for future study of this important yet poorly understood condition.

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 role of depression and childhood trauma on cortisol suppression in women with bulimia nervosa: a pilot study.

OBJECTIVE: Although some studies have shown cortisol nonsuppression following dexamethasone suppression test (DST) in current bulimia nervosa (BN), no study has looked at HPA axis abnormalities in behaviorally recovered BN patients. The purpose of this pilot study is to explore the role of current vs behaviorally recovered BN, as well as depression and childhood trauma in cortisol suppression in BN. METHODS: A 0.5 mg DST was performed on 21 patients with behaviorally recovered BN, 9 women with current BN and 14 controls. BN group also completed the Hamilton Depression Rating Scale and Childhood Trauma Questionnaire. RESULTS: There were no differences between the three groups in cortisol suppression, and BMI was not associated with cortisol levels following DST. Within the BN group, depression was significantly associated with afternoon cortisol nonsuppression (p=0.005). DISCUSSION: As researchers look for more accurate ways to identify biological phenotypes of BN, presence of comorbid depression may help explain differences in cortisol suppression.

Opiates, overeating and obesity: a psychogenetic analysis.

OBJECTIVE: This study provides an original perspective on the associations among endogenous opiates, overeating and obesity. The aim was to assess whether variability in the OPRM1 gene, as assessed by seven single-nucleotide polymorphisms, relates to individual differences in the preference for sweet and fatty foods. We also anticipated that these food preferences would be positively associated with binge eating, hedonic eating and emotionally driven eating-patterns of overeating that would, in turn, predict higher body mass index (BMI). DESIGN: Analysis of variance procedures examined genotype differences in food preferences; bivariate correlation coefficients examined the relationships among food preferences and the overeating variables; and a regression analysis tested the combined influences of the overeating variables on BMI. DNA was extracted from whole blood for the genotyping, and measures of food preferences and eating behaviours were obtained from well-validated self-report questionnaires. SUBJECTS: Participants were 300 healthy adult men and women recruited from the community. RESULTS: All the predicted associations were supported by statistically significant results. In particular, the G/G genotype group of the functional A118G marker of the OPRM1 gene reported higher preferences for sweet and fatty foods compared with the other two groups. Food preferences were also related to all overeating measures, which in turn accounted for a substantial proportion of the variance in BMI. CONCLUSIONS: Our findings suggest that some of the diversity in the preference for highly palatable foods can be explained by genotypic differences in the regulation of mu opioid receptors. The associations reported in this paper are important from a public-health perspective because of the abuse potential of sweet-fat foods and their strong relationship with obesity.

Olanzapine versus placebo for out-patients with anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is a serious psychiatric illness associated with significant morbidity and mortality. There is little empirical support for specific treatments and new approaches are sorely needed. This two-site study aimed to determine whether olanzapine is superior to placebo in increasing body mass index (BMI) and improving psychological symptoms in out-patients with AN. METHOD: A total of 23 individuals with AN were randomly assigned in double-blind fashion to receive olanzapine or placebo for 8 weeks together with medication management sessions that emphasized compliance. Weight, other physical assessments and measures of psychopathology were collected. RESULTS: End-of-treatment BMI, with initial BMI as a covariate, was significantly greater in the group receiving olanzapine [F(1, 20)=6.64, p=0.018]. Psychological symptoms improved in both groups, but there were no statistically significant group differences. Of the 23 participants, 17 (74%) completed the 8-week trial. Participants tolerated the medication well with sedation being the only frequent side effect and no adverse metabolic effects were noted. CONCLUSIONS: This small study suggests that olanzapine is generally well tolerated by, and may provide more benefit than placebo for out-patients with AN. Further study is indicated to determine whether olanzapine may affect psychological symptoms in addition to BMI.

Is season of birth related to disordered eating and personality in women with eating disorders?

We assessed the relation between season of birth and eating disorder symptoms and personality characteristics in a sample of 880 women with eating disorders and 580 controls from two Price Foundation Studies. Eating disorder symptoms were assessed using the Structured Interview of Anorexic and Bulimic Disorders and the Structured Clinical Interview for DSM-IV. Personality traits were assessed using the Temperament and Character Inventory and the Frost Multidimensional Perfectionism Scale. Date of birth was obtained from a sociodemographic questionnaire. No significant differences were observed 1) in season of birth across eating disorder subtypes and controls; nor 2) for any clinical or personality variables and season of birth. We found no evidence of season of birth variation in eating disorders symptoms or personality traits. Contributing to previous conflicting findings, the present results do not support a season of birth hypothesis for eating disorders.

The slippery slope: prediction of successful weight maintenance in anorexia nervosa.

BACKGROUND: Previous research has found that many patients with anorexia nervosa (AN) are unable to maintain normal weight after weight restoration. The objective of this study was to identify variables that predicted successful weight maintenance among weight-restored AN patients. METHOD: Ninety-three patients with AN treated at two sites (Toronto and New York) through in-patient or partial hospitalization achieved a minimally normal weight and were then randomly assigned to receive fluoxetine or placebo along with cognitive behavioral therapy (CBT) for 1 year. Clinical, demographic and psychometric variables were assessed after weight restoration prior to randomization and putative predictors of successful weight maintenance at 6 and 12 months were examined. RESULTS: The most powerful predictors of weight maintenance at 6 and 12 months following weight restoration were pre-randomization body mass index (BMI) and the rate of weight loss in the first 28 days following randomization. Higher BMI and lower rate of weight loss were associated with greater likelihood of maintaining a normal BMI at 6 and 12 months. An additional predictor of weight maintenance was site; patients in Toronto fared better than those in New York. CONCLUSIONS: This study found that the best predictors of weight maintenance in weight-restored AN patients over 6 and 12 months were the level of weight restoration at the conclusion of acute treatment and the avoidance of weight loss immediately following intensive treatment. These results suggest that outcome might be improved by achieving a higher BMI during structured treatment programs and on preventing weight loss immediately following discharge from such programs.

The serotonin-1Dbeta receptor gene and severity of obsessive-compulsive disorder in women with bulimia nervosa.

BACKGROUND: There is significant evidence that eating disorders have an important biological overlap with obsessive-compulsive disorder (OCD), though the specific mediators of this relationship remain unclear. Recent evidence suggests that the G861C polymorphism of the 5HT-1Dbeta receptor gene and the G allele in particular may play a role in OCD. We thus hypothesized that, among a heterogenous group of probands with bulimia nervosa (BN), this same G allele might predict the presence and/or severity of OCD pathology. METHODS: 165 consecutive female probands with BN were genotyped for the G861C polymorphism of the 5HT-1Dbeta receptor gene. Rates of full syndrome OCD, partial syndrome OCD and no OCD were compared across the three genotypic groups defined by this polymorphism. RESULTS: 45 out of 165 BN probands (27.3%) had either full or partial syndrome OCD. In the full sample, there was a significant difference in the distribution of the three diagnostic groups by genotype (chi2=10.07, df=4, p=.039). The G861C polymorphism did not strongly predict which probands had any vs. no OCD pathology. However, among the 45 probands with OCD symptoms, the G861C polymorphism did strongly differentiate full syndrome vs. partial syndrome OCD (chi2=9.26, df=2, p=.01; odds ratio for full syndrome OCD with GG genotype=7.69, 95% CI=1.45-40.9). DISCUSSION: In women with BN, the G861C polymorphism of the 5HT-1Dbeta gene does not appear to be associated with the generation of OCD symptoms; however, it might directly or indirectly be associated with a modulatory effect on syndrome severity in probands otherwise predisposed to OCD. While preliminary and in need of replication in other samples, this is the first association study to suggest how a particular gene might influence OCD pathology in an eating disorder population.

Hormonal and subjective responses to intravenous meta-chlorophenylpiperazine in bulimia nervosa.

BACKGROUND: Several lines of evidence point to serotonergic abnormalities in patients with bulimia nervosa (BN). Our goal was to further examine central serotonergic function in bulimic patients using neuroendocrine and subjective responses to the postsynaptic serotonin receptor agonist meta-chlorophenylpiperazine (mCPP). METHOD: Using a double-blind, randomized, placebo-controlled design, we assessed neuroendocrine and subjective responses to intravenous mCPP (0.1 mg/kg) and placebo in 16 patients with BN, free of medication, and 14 normal control subjects. Plasma prolactin and cortisol levels were used as neuroendocrine measures, whereas subjective responses were measured using a visual analog scale of 10 different mood states. RESULTS: Compared with controls, the BN group exhibited blunted prolactin and net cortisol responses following mCPP challenge. Subjective responses, while preliminary, also differed between groups on items related to anxiety, calmness, and altered self-awareness. CONCLUSION: Evidence of dysfunction at or downstream of central serotonergic receptors in BN confirms and extends findings of prior research.

Hormonal and subjective responses to intravenous m-chlorophenylpiperazine in women with seasonal affective disorder.

BACKGROUND: There is emerging evidence of serotonergic dysfunction in patients with seasonal affective disorder (SAD). We examined central serotonergic function in female patients with SAD (fall-winter pattern) by means of neuroendocrine and subjective responses to the postsynaptic serotonin receptor agonist m-chlorophenylpiperazine. METHODS: Using a double-blind, randomized, placebo-controlled design, we assessed neuroendocrine and subjective responses to m-chlorophenylpiperazine (0.1 mg/kg intravenously) and placebo in 14 unmedicated female patients with SAD in the depressed state and 15 female normal controls. All testing was done in the fall-winter months and during the follicular phase of the menstrual cycle. Plasma prolactin and cortisol levels were used as neuroendocrine measures, while subjective responses were assessed by means of visual analog scales of 10 mood states. RESULTS: On the basis of net responses to m-chlorophenylpiperazine (placebo effects subtracted from drug effects), patients with SAD exhibited blunted prolactin responses and less sadness than normal controls in response to the drug. When order of presentation of drug and placebo was taken into consideration, altered "calm" and "high" responses were also found in the patient group. CONCLUSION: Evidence of dysfunction at or downstream to central serotonergic receptors in female patients with SAD confirms and extends findings from previous research.

Polymorphism of the serotonin 5-HT1B receptor gene (HTR1B) associated with minimum lifetime body mass index in women with bulimia nervosa.

BACKGROUND: Preclinical research has shown that the serotonin-1B receptor has important modulatory effects on feeding behavior and thus body weight. In the current study, we examined whether genetic variation of the serotonin-1B receptor was associated with minimum and maximum lifetime body mass indices (BMIs) in a sample of women with bulimia nervosa (BN). METHODS: Ninety-eight women with BN were genotyped based on the G861C polymorphism of the serotonin-1B receptor gene (HTR1B). Minimum and maximum lifetime BMIs were compared across the three genotypic groups using analysis of variance. RESULTS: There was a highly significant difference in minimum lifetime BMI across the three genotypic groups (p =.001). Both the G/C and C/C genotypes were associated with significantly lower minimum lifetime BMIs than was the G/G genotype. Maximum lifetime BMI was not significantly different across groups. These results were not attributable to different lifetime rates of anorexia nervosa across the three genotypic groups. CONCLUSIONS: These preliminary findings suggest a possible association between HTR1B genetic polymorphism and minimum lifetime BMI in women with BN. These findings may shed light on why, in response to dieting, some BN patients achieve lower BMIs, whereas others have a natural limitation to their weight loss. Pending replication in a larger sample, these findings point to a possible genetic factor of fundamental importance to the BN population.

A Golgi study of hypothalamic transplants in young and old host rats.

The supraoptic nucleus of the F344 rat shows an age-related dendritic regression. In order to determine whether this previously observed dendritic regression may have been related to extrinsic (to the cell) hormonal, neurotoxic, or other circulating factors unique to the hypothalamus of older brains, we conducted a quantitative Golgi study of F344 embryonic anterior hypothalamic transplants into the third ventricle of young adult (5 months) and older (25 months) male F344 rats. Three months following transplantation there were no qualitative effects of host age on neuronal morphology, nor were there quantitative effects on transplant size, dendritic length or branching frequency within the transplanted tissue. These results suggest that either (a) there were no age-related changes in factors in the host brain which were sufficient to significantly affect dendritic extent or, (b) intrinsic connections or other properties within the transplant may be important in moderating the effect of the milieu of the aged brain on the transplanted tissue.

Rate and prediction of relapse in bulimia nervosa.

OBJECTIVE: The purpose of this study was to provide an estimate of the rate of relapse in patients with bulimia nervosa and to attempt to identify indexes of functioning before or after treatment that predicted subsequent relapse. METHOD: The subjects were 48 female patients with bulimia nervosa who achieved symptom control while attending a specialized day hospital treatment program for eating disorders. The subjects were assessed before treatment, after treatment, and at a 2-year follow-up interview with respect to their eating symptoms and psychosocial functioning. RESULTS: A relapse rate of 31% was observed during the 2-year follow-up period, and the vast majority of relapses occurred within the first 6 months after treatment. The strongest predictors of relapse were younger age, higher vomiting frequency, and a higher score on the bulimia subscale of the 26-item Eating Attitudes Test before treatment and higher vomiting frequency and a higher score on the interpersonal distrust subscale of the Eating Disorder Inventory at the end of treatment. Measures of binge eating frequency, self-esteem, depression, and social adjustment were not significant predictors of relapse. CONCLUSIONS: Vomiting frequency, even at subthreshold levels, appears to be an important prognostic indicator and may be one of the best barometers of residual symptoms in these patients.

The differentiation of vomiting/weight loss as a conversion disorder from anorexia nervosa.

The authors studied patients with weight loss and vomiting, distinguishing by means of objective criteria those who had what they feel is a conversion disorder from those with anorexia nervosa. The group of patients with conversion disorder were quite different from those with anorexia nervosa and could be considered as suffering from less pervasive psychological deficits. Medical and psychotherapeutic intervention must take into account the differences between these two groups for treatment to achieve maximal benefit.

Carbamazepine in the treatment of bulimia.

Of six bulimic outpatients who completed a double-blind crossover trial with carbamazepine, one patient, who had a history suggestive of bipolar disorder, responded dramatically with cessation of binge eating. This supports a possible link in some patients between bulimia and affective illness.

Bulimia nervosa in a Canadian community sample: prevalence and comparison of subgroups.

OBJECTIVE: Previous epidemiological studies of bulimia nervosa have generated differing estimates of the incidence and prevalence of the disorder. These differences are attributable, in part, to varying definitions of the illness and a range of methodologies. The authors sought to define the prevalence of bulimia nervosa in a nonclinical community sample, examine the clinical significance of DSM-III-R threshold criteria, and examine comorbidity. METHOD: Subjects across Ontario (N = 8,116) were assessed with a structured interview, the World Health Organization Composite International Diagnostic Interview, with specific questions added for bulimia nervosa. Subjects who met DSM-III-R criteria for bulimia nervosa were compared with those who were missing only the frequency criterion (two or more binge-eating episodes per week for 3 months). RESULTS: In this sample, the lifetime prevalence of bulimia nervosa was 1.1% for female subjects and 0.1% for male subjects. The subjects with full- and partial-syndrome bulimia nervosa showed significant vulnerability for mood and anxiety disorders. Lifetime rates of alcohol dependence were high in the full-syndrome group. Rates of parental psychopathologies were high in both bulimic groups but tended to be higher in the subjects with full-syndrome bulimia nervosa. Both bulimic groups were significantly more likely to experience childhood sexual abuse than a normal female comparison group. CONCLUSIONS: This study confirms other prevalence estimates of bulimia nervosa and its comorbid diagnoses from studies that were based on sound methodologies. It also points to the arbitrary aspects of the frequency of binge eating as a diagnostic threshold criterion for the disorder.

Comparisons of men with full or partial eating disorders, men without eating disorders, and women with eating disorders in the community.

OBJECTIVE: The authors compared 62 men who met all or most of the DSM-III-R criteria for eating disorders with 212 women who had similar eating disorders and 3,769 men who had no eating disorders on a wide variety of clinical and historical variables. METHOD: The groups of subjects were derived from a community epidemiologic survey performed in the province of Ontario that used the World Health Organization's Composite International Diagnostic Interview. RESULTS: Men with eating disorders were very similar to women with eating disorders on most variables. Men with eating disorders showed higher rates of psychiatric comorbidity and more psychosocial morbidity than men without eating disorders. CONCLUSIONS: These results confirm the clinical similarities between men with eating disorders and women with eating disorders. They also reveal that both groups suffer similar psychosocial morbidity. Men with eating disorders show a wide range of differences from men without eating disorders; the extent to which these differences are effects of the illness or possible risk factors for the occurrence of these illnesses in men is not clear.

Childhood inattention and dysphoria and adult obesity associated with the dopamine D4 receptor gene in overeating women with seasonal affective disorder.

There is significant evidence that altered dopamine activity plays a role in seasonal affective disorder (SAD). The current study examined three separate genetic hypotheses for SAD related to the 7-repeat allele (7R) of the dopamine-4 receptor gene (DRD4), a variant associated with decreased affinity for dopamine. We examined the possible contribution of 7R to the overall expression of SAD, attention deficit disorder (ADD) comorbidity, and body weight regulation. As part of an ongoing genetic study of increased eating behavior and mood in female subjects, 108 women with winter SAD and carbohydrate craving/weight gain were administered the Wender-Utah Rating Scale to measure childhood ADD symptomatology, and a questionnaire to assess maximal lifetime body mass index (BMI). To test for an association between 7R and the categorical diagnosis of SAD, the transmission disequilibrium test (TDT) was used in a subsample of probands providing familial DNA. Standard parametric tests were used to compare childhood ADD symptoms and maximal lifetime BMI across the two genotypic groups defined by the presence or absence of 7R. The TDT found no initial evidence for an association between 7R and the categorical diagnosis of SAD. However, 7R carriers reported significantly greater inattention and dysphoria in childhood (p=0.01 and 0.001, respectively) and a higher maximal lifetime BMI (p=0.007) than did probands without this allele. Furthermore, excluding probands with extreme obesity (maximal BMI >40), a strong correlation was found linking childhood inattentive symptoms and maximal lifetime BMI (r=0.35, p=0.001). In overeating women with SAD, the 7R allele of DRD4 may be associated with a unique developmental trajectory characterized by attentional deficits and dysphoria in childhood and mild to moderate obesity in adulthood. This developmental course may reflect different manifestations of the same underlying vulnerability related to central dopamine dysfunction. Given the possibility of population stratification when studying genotype/phenotype relationships, future use of genomic controls and replication of our findings in other overeating and/or ADD populations are needed to confirm these initial results.

Chronic obstructive pulmonary disease: rehabilitation program with continuation on an outpatient basis.

A total of 187 patients with chronic obstructive pulmonary disease (COPD) were treated in a rehabilitation program, initially as inpatients and then scheduled to continue 6 months or more in an outpatient clinic. The mean age was 61 (range, 28-76 years). Changes shown by participants in the outpatient program were compared to those shown by the nonparticipants. For both groups, the mortality rates were similar to published figures, and were strongly related to the levels of forced expiratory volume/sec (FEV 1.0). The FEV 1.0 declined significantly within one year in both groups. Psychologic test scores were unchanged. There was a sharp increase in unemployment. Although rehabilitative therapy must be continued, high priority should be given to early detection of COPD in patients who have airway obstruction but are otherwise asymptomatic. Possibly, at that stage, the elimination of cigarette smoking may slow the process.