Restrictive Anorexia Nervosa Research Articles

Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations

Eating disorders (ED), such as anorexia nervosa (AN) and bulimia nervosa (BN), are complex psychiatric disorders where different genetic and environmental factors are involved. Several lines of evidence support that brain-derived neurotrophic factor (BDNF) plays an essential role in eating behaviour and that alterations on this neurotrophic system participates in the susceptibility to both AN and BN. Accordingly, intraventricular administration of BDNF in rats determines food starvation and body weight loss, while BDNF or its specific receptor NTRK2 knockout mice develop obesity and hyperphagia. Case-control studies also suggest a BDNF contribution in the aetiology of ED: we have previously reported a strong association between the Met66 variant within the BDNF gene, restricting AN (ANR) and minimum body mass index (minBMI) in a Spanish sample, and a positive association between the Val66Met and -270C/T BDNF SNPs and ED in six different European populations. To replicate these results, avoiding population stratification effects, we recruited 453 ED trios from eight European centres and performed a family-based association study. Both haplotype relative risk (HRR) and haplotype-based haplotype relative risk (HHRR) methods showed a positive association between the Met66 allele and ANR. Consistently, we also observed an effect of the Met66 variant on low minBMI and a preferential transmission of the -270C/Met66 haplotype to the affected ANR offspring. These results support the involvement of BDNF in eating behaviour and further suggest its participation in the genetic susceptibility to ED, mainly ANR and low minBMI.

The Relationship Between Temperament and Impulsive Behaviors in Eating Disordered Subjects

To date, few studies have examined the personality characteristics and clinical predictors of impulsive behaviors in eating disorders (ED). The aim of this work was to study the prevalence of a wide range of impulsive behaviors in a sample of 554 ED subjects and to examine the predictors of these behaviors. Subjects were diagnosed according to DSM-IV criteria as having anorexia nervosa restricting type (ANR; n = 183), anorexia nervosa binge eating/purging type (ANBP; n = 65), bulimia nervosa purging type (BNP; n = 244), and bulimia nervosa nonpurging type (BNNP; n = 62). Nine different types of impulsive behaviors were assessed in these groups. About 55% of the whole sample reported at least one type of impulsive behavior, 35% more than one, and about 13% more than three. According to findings, impulsive and multi-impulsive subjects are characterized by the presence of purging behavior and by specific temperamental features such as high levels of novelty seeking and low persistence. The prediction of impulsive behavior is further improved by considering the presence of a history of childhood abuse, maternal psychiatric morbidity, and some specific psychological symptoms such as maturity fears, perfectionism, depression, and obsessive-compulsive symptoms. The presence of impulsive behavior appears to be associated with overall higher levels of psychiatric symptomatology and eating psychopathology, thus indicating that they are an important feature to be considered in the assessment and treatment of ED.

Attachment Predicts Treatment Completion in an Eating Disorders Partial Hospital Program Among Women With Anorexia Nervosa

The goal of this study was to examine if attachment theory can provide a framework for understanding treatment completion in an eating disorders partial hospital program among women with anorexia nervosa (AN). Attachment was measured using the Attachment Styles Questionnaire (Feeney, Noller, & Hanrahan, 1994). As hypothesized, self-reports of high avoidant attachment predicted noncompletion of treatment for those with AN binge-purge subtype (ANB). However, this relationship did not emerge for those with AN restricting subtype (ANR). Also as hypothesized, self-reports of high anxious attachment predicted completing treatment for those with ANB but not for those with ANR. For completers with ANB and ANR, the program was helpful in increasing body weight and lowering drive for thinness, body dissatisfaction, interpersonal problems, and depression. Attachment avoidance, characterized by devaluing one's need for relationships, may be a contraindication for group-based partial hospital treatment of ANB. Attachment anxiety, characterized by high preoccupation with relationships, may facilitate remaining in treatment for those with ANB.

Epistatic interaction between the monoamine oxidase A and serotonin transporter genes in anorexia nervosa

The serotonin (5-HT) and norepinephrine (NE) systems are likely involved in the aetiology of anorexia nervosa (AN) as sufferers are premorbidly anxious. Specifically, we hypothesize that genes encoding proteins, which clear 5-HT and NE from the synapse, are prime candidates for affecting susceptibility to AN. Supporting our hypothesis, we earlier showed that the NE transporter (NET) and monoamine oxidase A (MAOA) genes appear to contribute additively to increased risk of developing restricting AN (AN-R). With regard to the MAOA gene, a sequence variant that increases MAOA activity and has suggested association with the anxiety condition, panic disorder was preferentially transmitted from parents to affected children. Here we provide evidence in support of interaction between the MAOA and serotonin transporter (SERT) genes in 114 AN nuclear families (patient with AN plus biological parents). A SERT gene genotype with no apparent individual effect on risk and known to be associated with anxiety is preferentially transmitted to children with AN (chi2 trend=9.457, 1 df, P=0.0021) and AN-R alone (chi2 trend=7.477, 1 df, P=0.0063) when the 'more active' MAOA gene variant is also transmitted. The increased risk of developing the disorder is up to eight times greater than the risk imposed by the MAOA gene variant alone--an example of synergistic epistatic interaction. If independently replicated, our findings to date suggest that we may have identified three genes affecting susceptibility to AN, particularly AN-R: the MAOA, SERT, and NET genes.

QT Interval and QT Dispersion in Eating Disorders

Background: Eating disorders are thought to be risk factors for cardiac sudden death secondary to arrhythmia. Results in previous studies on QT interval and QT dispersion, markers of fatal arrhythmia, have been inconsistent. Methods: We prospectively examined 179 female eating disorder patients, being over 18 years old and diagnosed according to the DSM-IV criteria between January 1995 and December 2002, and 52 healthy women. Patients with abnormal plasma electrolytes or taking medications that might influence the electrocardiogram (ECG) were excluded from the study. QT intervals were corrected for heart rate using Bazett’s formula and the nomogram method, which is more reliable at extremely low heart rates than Bazett’s formula. QT dispersion was measured as the difference between the longest and shortest QT intervals. QT intervals and QT dispersion in each patient group were compared with those in the control group. Results: The 164 eligible patients consisted of 43 patients with anorexia nervosa restricting type, 35 with anorexia nervosa binge eating/purging type, 63 with bulimia nervosa purging type, and 23 with bulimia nervosa nonpurging type. There was no significant difference in age between eating disorder patients and controls. QT interval and QT dispersion were significantly longer in all eating disorder subtypes than in the control group. QT interval and QT dispersion were significantly correlated with the rate of body weight loss in bulimia nervosa. Conclusions: QT interval and QT dispersion were prolonged in both anorexia nervosa and bulimia nervosa. Examination of ECG in eating disorder patients without extremely low body weight also appears to be clinically important.

Affective temperament in the eating disorders.

In this study, we investigate the affective temperamental characteristics in a sample of ED (eating disorder) patients. 49 ED patients diagnosed by the SCID (Structured Clinical Interview for DSM-IV), were divided into two groups on the basis of the presence or absence of Binge Eating (restricting-anorexia nervosa [R-AN]= 16; Binge Eaters= 33). All patients were administered the TEMPS-I (Temperament Evaluation Memphis Pisa Semistructured - Interview), to assess affective temperament. A third group of controls (N= 1010), derived from a study with the TEMPS-I on normal subjects, was included for comparison. A full affective temperament was not found in patients of the restricting group. By contrast 24% of the binge eating group had a full affective temperament of one of three types. Comparing the three temperaments for the three groups, only cyclothymic temperament proved to be significant, with higher levels in the binge eating group (p<0.01). In this study, people with R-AN do not show a full affective temperament. However, people with binge eating, had depressive and hyperthymic temperament, and displayed higher level of cyclothymic temperament than the normal population. The findings of this study add to a growing literature on temperament in people with ED; particularly, they add to the view that may be various paths leading to R-AN, and these may differ from those of binge eating.

Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations.

Several genes with an essential role in the regulation of eating behavior and body weight are considered candidates involved in the etiology of eating disorders (ED), but no relevant susceptibility genes with a major effect on anorexia nervosa (AN) or bulimia nervosa (BN) have been identified. Brain-derived neurotrophic factor (BDNF) has been implicated in the regulation of food intake and body weight in rodents. We previously reported a strong association of the Met66 allele of the Val66Met BDNF variant with restricting AN (ANR) and low minimum body mass index in Spanish patients. Another single nucleotide polymorphism located in the promoter region of the BDNF gene (-270C>T) showed lack of association with any ED phenotype. In order to replicate these findings in a larger sample, we performed a case-control study in 1142 Caucasian patients with ED consecutively recruited in six different centers from five European countries (France, Germany, Italy, Spain and UK) participating in the 'Factors in Healthy Eating' project. We have found that the Met66 variant is strongly associated to all ED subtypes (AN, ANR, binge-eating/purging AN and BN), and that the -270C BDNF variant has an effect on BN and late age at onset of weight loss. These are the first two variants associated with the pathophysiology of ED in different populations and support a role for BDNF in the susceptibility to aberrant eating behaviors.

Stability of personality traits in patients who received intensive treatment for a severe eating disorder.

A longitudinal prospective design with four assessments was used to examine the stability of personality traits and their relation to recovery in patients with restrictive anorexia nervosa (N=35), bingeing/purging anorexia nervosa (N=37), bulimia nervosa (N=47), and eating disorder not otherwise specified (N=27). Recovery is associated with changes in personality traits in the direction of healthy control women. Recovered patients still show higher harm avoidance and higher persistence than healthy control women. These temperament factors seem to be a vulnerability factor for developing an eating disorder. Novelty seeking seems to define the type of eating disorder one is prone to develop. The character dimensions contribute the most to recovery. High self-directedness contributes to a favorable prognosis of bulimic symptomatology, whereas high cooperativeness contributes to an unfavorable prognosis in patients with anorexia nervosa.

Personality-related characteristics in restricting versus binging and purging eating disordered patients

The current study sought to examine differences in personality-related characteristics between restricting anorexia nervosa (RAN), binging/purging anorexia (BPAN), and purging bulimia nervosa (BN) patients. Scores on the Temperament and Character Inventory (TCI) and on the Dutch Eating Behaviour Questionnaire (DEBQ) were compared for 166 RAN, 78 BPAN, and 151 BN patients. Bingers/purgers showed a higher score for restrained, external and emotional eating and a lower score for a subscale of “self-directedness” compared to patients who never binge and purge. Personality differences were most marked between RAN and BN patients, while personality characteristics of BPAN patients tended to be similar to those of BN patients. BN patients showed higher scores on “novelty seeking” and the subscales “exploratory excitability,” “impulsivity,” and “extravagance,” and lower scores on “self-directedness,” compared to restricting patients. Moreover RAN patients also showed higher scores on subscales of character dimensions, compared to BN patients. The higher the scores on novelty seeking, the lower the scores on several character scales, which has important implications for the reinforcement of behavior and the treatment of eating disorders.

Association study of cannabinoid receptor gene (CNR1) alleles and anorexia nervosa: differences between restricting and binging/purging subtypes.

Anorexia nervosa (AN) is a severe and disabling psychiatric disorder, characterized by profound weight loss and body image disturbance. Family and twin studies indicate a significant genetic contribution to this disorder although no genetic mutation has yet been identified. The endocannabinoid system has recently been implicated in many physiological functions including appetite regulation. We, therefore, undertook a family based study to test the hypothesis whether a polymorphism of the CNR1 gene, which encodes human CB1 receptor, a subclass of the central cannabinoid receptor, contributes to the susceptibility to AN. Fifty two families (parents with one or two affected siblings) were genotyped for the (AAT) trinucleotide repeat of CNR1 gene. Using the haplotype relative risk (HRR) method, the distribution of alleles transmitted to the patients was not found to be significantly different from the non-transmitted parental alleles. However, upon dividing the samples to restricting and binging/purging subtypes of AN, the extended transmission disequilibrium test (ETDT) revealed that there is preferential transmission of different alleles in each of the subtypes. The 14 repeat allele was preferentially transmitted in the binging/purging AN group (P = 0.05) but not in the restricting AN group, whereas the 13 repeat allele was preferentially transmitted in the restricting AN group (almost significant, P = 0.07) but not in the binging/purging AN group. Our study suggests that restricting AN and binging/purging AN may be associated with different alleles of the CNR1 gene.

Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type.

Several lines of evidence support a role for brain-derived neurotrophic factor (BDNF) alterations in the etiology of eating disorders (EDs). BDNF heterozygous knockout mice show alterations in eating behavior, increased body weight and adipocyte hypertrophy. BDNF also regulates the synaptic efficiency through the modulation of key neurotransmitter systems previously known to be involved in ED. These findings, together with the fact that this neurotrophin is expressed in the hypothalamus nuclei associated with weight regulation and feeding control, led us to propose BDNF as a candidate gene for ED. To investigate the possible involvement of this neurotrophin in eating behavior, we screened the BDNF gene in 95 ED patients and identified four sequence variants. Two of them, -374A/T and -256G/A, were found in two patients with anorexia nervosa (AN) and consisted of single-nucleotide mutations within the 5' untranslated region (5'UTR). The other two polymorphisms resulted in a C to T transition located at the 5'UTR of the BDNF gene and an amino-acid substitution within the BDNF precursor protein (Val66Met). We performed a case-control study for these two Single-nucleotide polymorphisms in a sample of 143 ED patients and 112 unrelated controls and found a strong association of restricting AN (ANR) with the Met allele of the Val66Met BDNF polymorphism (2p=0.002). There was also evidence for a significant effect of this sequence variant on the minimum body mass index (MBMI) (2p=0.006). These results suggest that the BDNF Met66 variant may be a susceptibility factor to ED, mainly to ANR and low MBMI.

Recovery and chronicity in anorexia nervosa: brain activity associated with differential outcomes

Background The course of anorexia nervosa varies from rapid recovery to a chronic debilitating illness. This study aimed to identify functional neural correlates associated with differential outcomes. Methods Brain reactions to food and emotional visual stimuli were measured with functional magnetic resonance imaging in nine women who had long-term recovery from restricting anorexia nervosa. These were compared with age- and education-matched groups of eight women chronically ill with restricting anorexia nervosa and nine healthy control women. Results In response to food stimuli, increased medial prefrontal and anterior cingulate activation, as well as a lack of activity in the inferior parietal lobule, differentiated the recovered group from the healthy control subjects. Increased activation of the right lateral prefrontal, apical prefrontal, and dorsal anterior cingulate cortices differentiated these recovered subjects from chronically ill patients. Group differences were specific to food stimuli, whereas processing of emotional stimuli did not differ between groups. Conclusions Separate neural correlates underlie trait and state characteristics of anorexia nervosa. The medial prefrontal response to disease-specific stimuli may be related to trait vulnerability. Lateral and apical prefrontal involvement is associated with a good outcome.

Depression influences the EDI scores in anorexia nervosa patients

Aim. – To study the influence of the severity of depression on the eating disorder’s inventory (EDI) scores in anorexia nervosa (AN) patients. Method. – We compared by variance analysis the EDI scores from three groups of AN patients: 55 patients having a major depression (as assessed by a Beck’s depression inventory (BDI) ≥ 16); 77 patients having a less severe depression (BDI < 16); 32 patients with mild or non-existent depression (BDI ≤ 7) and the EDI scores from a control group of 29 French healthy young women. Results. – Higher EDI scores were elicited in the more severely depressed AN patients than in the less- or non-depressed AN patients ( P < 0.01). In non-depressed AN patients, none of the scores was different from those of the control group. This was particularly true for the scores “Slimness wish”, “bulimia”, “body image dissatisfaction”, “perfectionism” and “fear of maturity”. The non-depressed restrictive AN patients had no score which differ from healthy controls. Discussion. – The present results suggested that the EDI scores are clearly influenced by the severity of depression. Among the psychopathological and behavioural traits assessed with the EDI, only a few were not related to depressive symptoms: “feeling of inefficiency” and “distrust in interpersonal relations”.

Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa.

Serotonergic and opioidergic neurotransmitter system alterations have been observed in people with eating disorders; the genes for the serotonin 1D receptor (HTR1D) and the opioid delta receptor (OPRD1) are found on chr1p36.3-34.3, a region identified by our group in a linkage analysis of anorexia nervosa (AN). These candidate genes were evaluated for sequence variation and for linkage and association of this sequence variation to AN in family and case : control data sets. Resequencing of the HTR1D locus and a portion of the OPRD1 locus identified novel SNPs and confirmed existing SNPs. Genotype assay development and genotyping of nine SNPs (four at HTR1D and five at OPRD1) was performed on 191 unrelated individuals fulfilling DSM-IV criteria (w/o amenorrhea criterion) for AN, 442 relatives of AN probands and 98 psychiatrically screened controls. Linkage analysis of these candidate gene SNPs with 33 microsatellite markers in families including relative pairs concordantly affected with restricting AN (N=37) substantially increased the evidence for linkage of this region to restricting AN to an NPL score of 3.91. Statistically significant genotypic, allelic, and haplotypic association to AN in the case : control design was observed at HTR1D and OPRD1 with effect sizes for individual SNPs of 2.63 (95% CI=1.21-5.75) for HTR1D and 1.61 (95% CI=1.11-2.44) for OPRD1. Using genotype data on parents and AN probands, three SNPs at HTR1D were found to exhibit significant transmission disequilibrium (P&<0.05). The combined statistical genetic evidence suggests that HTR1D and OPRD1 or linked genes may be involved in the etiology of AN.

Obsessions and compulsions in anorexia nervosa subtypes.

Obsession and compulsions in anorexia nervosa (AN) patients are often confused with the preoccupations and rituals that are characteristic of obsessive-compulsive disorder (OCD). We examined the type and frequency of characteristic OCD obsessions and compulsions in a large sample of AN patients. In personal interviews with 324 AN patients, we assessed lifetime histories of eating disorder symptomatology and obsessive-compulsive behaviors with valid semistructured interviews. Checklist category sums on the Yale-Brown Obsessive Compulsive Scale were compared between AN and OCD subjects using generalized estimating equations. Lifetime obsessions and compulsions occurred in 68% of the AN restricting type and in 79.1% of the AN binge/purge type. The AN subgroups did not differ from OCD controls in frequency of obsessions in the symmetry and somatic categories or in the compulsion categories of ordering and hoarding. In all other categories, the AN subgroups had a significantly lower frequency compared with the OCD controls. Some common phenotype characteristics shared by most AN and OCD patients suggest these disorders may share common brain behavioral pathways. However, the lack of complete overlap indicates they most likely have different loci of pathology within those pathways.

Temperament and character of Japanese eating disorder patients.

Previous studies consistently reported a link between bulimic behaviors and high Novelty Seeking (NS), as measured by the Temperament and Character Inventory (TCI). However, it remains unclear whether this relationship is universal and occurs in different environments. Subjects of the present study consisted of 66 patients with anorexia nervosa restricting type (AN-R), 59 patients with anorexia nervosa binge eating/ purging type (AN-BP), 101 patients with bulimia nervosa purging type (BN), and 75 controls. NS score in AN-R patients was significantly lower than that in controls, although NS in BN patients did not differ from that in controls. The temperament of AN-R patients seems to be universal, even in different environments. Conversely, something other than temperament might be important in the development of bulimia nervosa in Japan.

Insulinogenic index at 15 min as a marker of nutritional rehabilitation in anorexia nervosa

Insulin responses to the oral-glucose-tolerance test (OGTT) in anorexia nervosa (AN) are related to body weight and show various patterns. Although weight gain is a key indicator of a successful nutritional program, it is not a sufficiently accurate index for assessing nutritional status, especially in the periods of marked fear of obesity, because patients often manipulate body weight measurements. The aim of this study was to determine the relation between insulin metabolism during the early phase of the OGTT and progress (weekly weight gain) during nutritional rehabilitation. Forty-eight inpatients with AN (25 AN restricting type and 23 AN bulimic type) underwent the OGTT, with additional blood sampling at 15 min, when energy intake reached 6694 kJ/d (1600 kcal/d). Thirteen healthy volunteers were also studied. To evaluate early-phase insulin metabolism, we calculated the insulinogenic index after 15 (II(15 min)) and 30 min. On the basis of weekly changes in body weight, the AN participants were divided into good (> or =0.5 kg) and poor (<0.5 kg) responders. Among the AN patients, 48% were poor responders. Analysis of variance showed significant differences in the II(15 min) values (P = 0.0005) and showed that II(15 min) values for good responders were significantly higher than those for the other groups. These findings suggest that a lack of progress in weight gain is frequently observed in AN and that II(15 min) values may be a useful marker with which to assess the weekly progress during nutritional rehabilitation.

Modest familial aggregation of eating disorders in restrictive anorexia nervosa with adolescent onset in a Romanian sample

The study of the familial psychopathology in relatives of restrictive anorexia nervosa (AN) probands whose diagnosis was verified during a long-term follow-up was aimed at determining behavioural phenotypes with which AN could share the genetic liability. A total of 185 first degree relatives of 68 restrictive AN patients with adolescent onset followed up for 5 to 18 years and 198 first degree relatives of 68 normal women were investigated. DSM-III-R criteria were used. The lifetime rate of clinical AN was 1% and the rate of any eating disorders was 2% in female proband relatives versus 0 in control relatives. No case of bulimia nervosa (BN) was found in proband relatives. The heritability of AN was low (0.18) when only the full-blown AN was considered in relatives and modest (0.36) when also a case of subthreshold AN was added. There were significantly higher rates of anxiety disorders (14.6%) and unipolar major depression (8.3%) in female proband relatives and "schizo"-spectrum disorders (8.3%) and alcoholism (13.1%) in male proband relatives compared to relatives of controls. Restrictive AN might share partial liability with phenotypes expressing emotional restraint and anxiety. A sex effect of the heterotypically affected relative on the vulnerability for AN was suggested.

Subjective family image in anorexia nervosa and bulimia nervosa in adolescence: a controlled study

The family environments of patients with eating disorders have been studied extensively in recent decades. The "Subjective Family Image Test" is an instrument developed especially to measure differential perceptions by family members. Assessments of subjective family image in families of adolescents by means of this test have been carried out in only a few samples. We aimed first to investigate subjective perceptions by adolescents of their family relations in a larger clinical sample of female adolescents (n = 118) suffering from anorexia nervosa of either subtype or from bulimia nervosa and to compare these perceptions with those of healthy controls (n = 96). Second we investigated intra-familial differences in perception. The main findings were that bulimia nervosa patients perceived lower individual autonomy and lower emotional connectedness than all other groups, the adolescents with bulimia perceived significantly lower autonomy and emotional connectedness within the family than their fathers, and the restrictive anorexia nervosa patients perceived higher connectedness than their fathers. The relevance of these findings for understanding family dynamics are discussed.

Effectiveness of multidisciplinary team approach and prognosis of inpatients with eating disorders

Multidisciplinary team approach to eating disorders (ED) mainly utilizing behavior therapy including cognitive, group and family therapy has been implemented in our hospital. In order to assess usefulness of our treatment, we investigated the long-term (more than 4 years after discharge) prognosis of the 68 inpatients with ED consisting of restrictive anorexia nervosa (AN) (AN-R), AN with binge-eating/purge (AN-BP) and bulimia nervosa (BN) by using newly developed checklist for ED in Japan. We defined the score and five outcome criteria. We found that 51.5% ( n=35) of the patients was excellent, 17.9% ( n=12) was much improved, 11.9% ( n=8) was symptomatic and 11.9% ( n=8) poor and 7.4% ( n=5) had died. AN-R had the youngest average age at admission, shortest duration of illness and smallest body mass index at admission. Around 84% of AN-R patients had reached the level of excellent or much improved outcome, though only around 61% of AN-BP patients and 50% of BN patients showed excellent or much improved outcome. In conclusion, the present findings indicate that our treatment is effective for ED patients, especially AN-R. However, in order to improve the effectiveness of treatment for AN-BP and BN, we should further develop every system of the treatment strategy.