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1.  Anorexia nervosa trios: behavioral profiles of individuals with anorexianervosa and their parents 
Psychological medicine  2008;39(3):451-461.
Background
Anorexia nervosa (AN) is associated with behavioral traits that predate the onset of AN and persist after recovery. We identified patterns of behavioral traits in AN trios (proband plus two biological parents).
Method
A total of 433 complete trios were collected in the Price Foundation Genetic Study of AN using standardized instruments for eating disorder (ED) symptoms, anxiety, perfectionism, and temperament. We used latent profile analysis and ANOVA to identify and validate patterns of behavioral traits.
Results
We distinguished three classes with medium to large effect sizes by mothers’ and probands’ drive for thinness, body dissatisfaction, perfectionism, neuroticism, trait anxiety, and harm avoidance. Fathers did not differ significantly across classes. Classes were distinguished by degree of symptomatology rather than qualitative differences. Class 1 (~33 %) comprised low symptom probands and mothers with scores in the healthy range. Class 2 (~43 %) included probands with marked elevations in drive for thinness, body dissatisfaction, neuroticism, trait anxiety, and harm avoidance and mothers with mild anxious/perfectionistic traits. Class 3 (~24 %) included probands and mothers with elevations on ED and anxious/perfectionistic traits. Mother–daughter symptom severity was related in classes 1 and 3 only. Trio profiles did not differ significantly by proband clinical status or subtype.
Conclusions
A key finding is the importance of mother and daughter traits in the identification of temperament and personality patterns in families affected by AN. Mother–daughter pairs with severe ED and anxious/perfectionistic traits may represent a more homogeneous and familial variant of AN that could be of value in genetic studies.
doi:10.1017/S0033291708003826
PMCID: PMC3714180  PMID: 18578898
Anorexia nervosa; eating disorder; genetics; temperament
2.  Association Study of 182 Candidate Genes in Anorexia Nervosa 
We performed association studies with 5,151 SNPs that were judged as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN) based on location under reported linkage peaks, previous results in the literature (182 candidate genes), brain expression, biological plausibility, and estrogen responsivity. We employed a case–control design that tested each SNP individually as well as haplotypes derived from these SNPs in 1,085 case individuals with AN diagnoses and 677 control individuals. We also performed separate association analyses using three increasingly restrictive case definitions for AN: all individuals with any subtype of AN (All AN: n = 1,085); individuals with AN with no binge eating behavior (AN with No Binge Eating: n = 687); and individuals with the restricting subtype of AN (Restricting AN: n = 421). After accounting for multiple comparisons, there were no statistically significant associations for any individual SNP or haplotype block with any definition of illness. These results underscore the importance of large samples to yield appropriate power to detect genotypic differences in individuals with AN and also motivate complementary approaches involving Genome-Wide Association (GWA) studies, Copy Number Variation (CNV) analyses, sequencing-based rare variant discovery assays, and pathway-based analysis in order to make up for deficiencies in traditional candidate gene approaches to AN.
doi:10.1002/ajmg.b.31082
PMCID: PMC2963154  PMID: 20468064
single nucleotide polymorphisms; probands; anorexia nervosa; bulimia nervosa
3.  Linkage analysis of anorexia and bulimia nervosa cohorts using selected behavioral phenotypes as quantitative traits or covariates 
To increase the likelihood of finding genetic variation conferring liability to eating disorders, we measured over 100 attributes thought to be related to liability to eating disorders on affected individuals from multiplex families and two cohorts: one recruited through a proband with anorexia nervosa (AN; AN cohort); the other recruited through a proband with bulimia nervosa (BN; BN cohort). By a multilayer decision process based on expert evaluation and statistical analysis, six traits were selected for linkage analysis (1): obsessionality (OBS), age at menarche (MENAR) and anxiety (ANX) for quantitative trait locus (QTL) linkage analysis; and lifetime minimum Body Mass Index (BMI), concern over mistakes (CM) and food-related obsessions (OBF) for covariate-based linkage analysis. The BN cohort produced the largest linkage signals: for QTL linkage analysis, four suggestive signals: (for MENAR, at 10p13; for ANX, at 1q31.1, 4q35.2, and 8q13.1); for covariate-based linkage analyses, both significant and suggestive linkages (for BMI, one significant [4q21.1] and three suggestive [3p23, 10p13, 5p15.3]; for CM, two significant [16p13.3, 14q21.1] and three suggestive [4p15.33, 8q11.23, 10p11.21]; and for OBF, one significant [14q21.1] and five suggestive [4p16.1, 10p13.1, 8q11.23, 16p13.3, 18p11.31]). Results from the AN cohort were far less compelling: for QTL linkage analysis, two suggestive signals (for OBS at 6q21 and for ANX at 9p21.3); for covariate-based linkage analysis, five suggestive signals (for BMI at 4q13.1, for CM at 11p11.2 and 17q25.1, and for OBF at 17q25.1 and 15q26.2). Overlap between the two cohorts was minimal for substantial linkage signals.
doi:10.1002/ajmg.b.30226
PMCID: PMC2590774  PMID: 16152574
Complex disease; endophenotype; liability; mixture model; regression
4.  Heightened Fear of Uncertainty in Anorexia and Bulimia Nervosa 
Objective
To test whether intolerance of uncertainty (IU) is related to eating disorder (ED) pathology.
Method
Thirty individuals with anorexia nervosa (AN), 19 with bulimia nervosa (BN) and 28 healthy control women (CW) completed the Intolerance of Uncertainty Scale (IUS).
Results
AN and BN groups showed higher IU compared to CW. In AN and BN, Harm Avoidance and Depression scores were positively correlated with IU. In AN but not BN, IU was related positively to Drive for Thinness and Body Dissatisfaction.
Conclusion
Elevated IU is associated with AN and BN. Anxious traits may be inherent in EDs and IU could be a developmental factor contributing to anxiety, mood and ED behavior in AN and BN.
doi:10.1002/eat.20929
PMCID: PMC3140557  PMID: 21495057
5.  Anorexia nervosa 
Clinical Evidence  2011;2011:1011.
Introduction
Anorexia nervosa is characterised by a low body mass index (BMI), fear of gaining weight, denial of current low weight and its impact on health, and amenorrhoea. Estimated prevalence is highest in teenage girls, and up to 0.7% of this age group may be affected. While most people with anorexia nervosa recover completely or partially, about 5% die of the condition, and 20% develop a chronic eating disorder. Young women with anorexia nervosa are at increased risk of bone fractures later in life.
Methods and outcomes
We conducted a systematic review, and aimed to answer the following clinical questions: What are the effects of treatments in anorexia nervosa? What are the effects of interventions to prevent or treat complications of anorexia nervosa? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 40 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: atypical antipsychotic drugs, benzodiazepines, cyproheptadine, inpatient/outpatient treatment setting, oestrogen treatment (HRT or oral contraceptives), older-generation antipsychotic drugs, psychotherapy, refeeding, selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants.
Key Points
Anorexia nervosa is characterised by a low body mass index (BMI), fear of gaining weight, denial of current low weight and its impact on health, and amenorrhoea. Estimated prevalence is highest in teenage girls, and the condition may affect up to 0.7% of this group.Anorexia nervosa is related to family, sociocultural, genetic, and other biological factors. Psychiatric and personality disorders such as depression, anxiety disorders, obsessive compulsive disorder, and perfectionism are commonly found in people who have anorexia nervosa.Most people with anorexia nervosa recover completely or partially, but about 5% die from the condition and 20% develop a chronic eating disorder.Young women with anorexia nervosa are at increased risk of fractures later in life.Population assessment indicates that risks to fertility may be overstated in those who reach a healthy BMI, but children born to mothers who have recovered from anorexia nervosa seem to have lower birth weights.
There is no strong RCT evidence that any treatments work well for anorexia nervosa. However, there is a gradual accumulation of evidence suggesting that early intervention is effective. Increasing evidence suggests that working with the family may also interrupt the development of a persistent form of the illness, when this work begins early in the disease.
Evidence on the benefits of psychotherapy is unclear.
Refeeding is a necessary and effective component of treatment, but is not sufficient alone. Very limited evidence from a quasi-experimental study suggests that a lenient approach to refeeding is as effective and more acceptable compared with a more strict approach.Refeeding may be as effective in an outpatient setting as during hospital admission.Nasogastric refeeding has been used to speed up weight gain in inpatient observational studies, although it is rarely studied in RCTs. Very limited RCT evidence suggests that adding nasogastric feeding to oral nutrition can increase weight gain and reduce relapse in the short term more than oral nutrition alone, but these gains are not maintained at 1 year post-discharge. Given ethical and medical concerns with tube feeding, this approach is encouraged with caution.Nutritional supplements, including zinc, have only limited evidence for their effectiveness, and additional evaluations of these measures are warranted.
We don't know whether inpatient or outpatient treatment is more effective in people with anorexia nervosa.
Limited evidence from small RCTs has not shown significant weight gain from SSRIs or tricyclic antidepressants, some of which may cause serious adverse effects. Tricyclic antidepressants may cause drowsiness, dry mouth, blurred vision, and a prolonged QT interval in people who have anorexia nervosa. SSRIs have not been shown to be beneficial, but the evidence remains very limited; in the 4 RCTs we found, conclusions were limited because of small trial size and high rates of withdrawal.
Older-generation antipsychotic drugs may prolong the QT interval, increasing the risk of ventricular tachycardia, torsades de pointes, and sudden death. Atypical antipsychotics have been evaluated for their potential role in reducing agitation and anxiety related to refeeding, as well as for potentially increasing appetite. Increasing observational data (case series) have suggested that they may decrease obsessiveness and agitation. However, further evidence from large, well-conducted RCTs is necessary to draw reliable conclusions. Newer atypical antipsychotics, in particular olanzapine, do not seem to be associated with the same cardiac risks as older-generation antipsychotic drugs, but the known association between olanzapine and weight gain may impact compliance in people with anorexia nervosa. However, further research needs to be done.
We found insufficient RCT evidence assessing benzodiazepines or cyproheptadine for treating anorexia nervosa.
Oestrogen treatment has been hypothesised to reduce the negative effects on bone mineral density associated with anorexia nervosa. However, three small RCTs have failed to demonstrate clinically relevant changes in bone mineral density after treatment with oestrogen either HRT or oral contraceptives), and these results are supported by 2-year longitudinal data, which found similar lack of improvement.
PMCID: PMC3275304  PMID: 21481284
6.  Evidence for the role of EPHX2 gene variants in anorexia nervosa 
Molecular Psychiatry  2013;19(6):724-732.
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.
doi:10.1038/mp.2013.91
PMCID: PMC3852189  PMID: 23999524
anorexia nervosa; EPHX2; genomics; hyperlipidemia; pooling; sequencing
7.  Evidence For The Role Of EPHX2 Gene Variants In Anorexia Nervosa 
Molecular psychiatry  2013;19(6):724-732.
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). Since 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 females and males (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.
doi:10.1038/mp.2013.91
PMCID: PMC3852189  PMID: 23999524
genomics; sequencing; hyperlipidemia; pooling; EPHX2; anorexia nervosa
8.  Anorexia nervosa 
Clinical Evidence  2009;2009:1011.
Introduction
Anorexia nervosa is characterised by a low body mass index (BMI), fear of gaining weight, denial of current low weight and its impact on health, and amenorrhoea. Estimated prevalence is highest in teenage girls, and up to 0.7% of this age group may be affected. While most people with anorexia nervosa recover completely or partially, about 5% die of the condition, and 20% develop a chronic eating disorder. Young women with anorexia nervosa are at increased risk of bone fractures later in life.
Methods and outcomes
We conducted a systematic review which aimed to answer the following clinical questions: What are the effects of treatments for anorexia nervosa? What are the effects of interventions to prevent or treat complications of anorexia nervosa? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 40 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: anxiolytic drugs, cyproheptadine, inpatient/outpatient treatment setting, oestrogen treatment, psychotherapy, refeeding, selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants.
Key Points
Anorexia nervosa is characterised by a low BMI, fear of gaining weight, denial of current low weight and its impact on health, and amenorrhoea. Estimated prevalence is highest in teenage girls, and may affect up to 0.7% of this group.Anorexia nervosa is related to family, sociocultural, genetic, and other biological factors. Psychiatric and personality disorders such as depression, anxiety disorders, obsessive compulsive disorder, and perfectionism, are commonly found in people who have anorexia nervosa.Most people with anorexia nervosa recover completely or partially, but about 5% die from the condition and 20% develop a chronic eating disorder.Young women with anorexia nervosa are at increased risk of fractures later in life.
There is no strong research evidence that any treatments work well for anorexia nervosa. However, there is a gradual accumulation of evidence which suggests that early intervention is effective. Working with the family may also interrupt the development of a persistent form of the illness.
Evidence on the benefits of psychotherapy is unclear.
Refeeding is a necessary and effective component of treatment, but is not sufficient alone. Very limited evidence from a quasi-experimental study suggests that a lenient approach to refeeding is as effective and more acceptable compared with a more strict approach.Refeeding may be as effective in an outpatient setting as during hospital admission.Nasogastric feeding is rarely required and can lead to problems due to hypophosphataemia.Nutritional supplements, including zinc, have only limited evidence for their effectiveness, and additional evaluation of these measures are warranted.
Limited evidence from small RCTs has not shown significant weight gain from SSRIs or tricyclic antidepressants, some of which may cause serious adverse effects. Tricyclic antidepressants may cause drowsiness, dry mouth, blurred vision, and a prolonged QT interval in people who have anorexia nervosa. SSRIs have not been shown to be beneficial, but the evidence remains very limited; in the four RCTs we found, conclusions were limited due to small trial size and high withdrawal rates.
Anxiolytic drugs (mainly older generation antipsychotic drugs) may prolong the QT interval, increasing the risk of ventricular tachycardia, torsades de pointes, and sudden death. Atypical antipsychotics have been evaluated for their potential role in reducing agitation and anxiety related to refeeding, as well as for potentially increasing appetite. Weak observational evidence has suggested that they may decrease obsessiveness and agitation. However, we found no RCTs of sufficient quality on the effects of atypical antipsychotics, and further evidence from large, well-conducted RCTs is necessary to draw reliable conclusions. Some atypical antipsychotics do not appear to be associated with the same cardiac risks as older-generation antipsychotic drugs. However, further research needs to be done.
We found insufficient evidence assessing cyproheptadine for treating anorexia nervosa.
Oestrogen treatment has been hypothesized to reduce the negative effects on bone mineral density associated with anorexia nervosa. However, three small RCTs have failed to demonstrate significant changes in bone mineral density after treatment with oestrogen.
PMCID: PMC2907776  PMID: 19445758
9.  Food motivation circuitry hypoactivation related to hedonic and nonhedonic aspects of hunger and satiety in women with active anorexia nervosa and weight-restored women with anorexia nervosa 
Background
Previous studies have provided evidence of food motivation circuitry dysfunction in individuals with anorexia nervosa. However, methodological limitations present challenges to the development of a cohesive neurobiological model of anorexia nervosa. Our goal was to investigate the neural circuitry of appetite dysregulation across states of hunger and satiety in active and weight-restored phases of anorexia nervosa using robust methodology to advance our understanding of potential neural circuitry abnormalities related to hedonic and nonhedonic state and trait.
Methods
We scanned women with active anorexia nervosa, weight-restored women with anorexia nervosa and healthy-weight controls on a 3-T Siemens magnetic resonance scanner while they viewed images of high- and low-calorie foods and objects before (premeal) and after (postmeal) eating a 400 kcal meal.
Results
We enrolled 12 women with active disease, 10 weight-restored women with anorexia nervosa and 11 controls in our study. Compared with controls, both weight-restored women and those with active disease demonstrated hypoactivity premeal in the hypothalamus, amygdala and anterior insula in response to high-calorie foods (v. objects). Postmeal, hypoactivation in the anterior insula persisted in women with active disease. Percent signal change in the anterior insula was positively correlated with food stimuli ratings and hedonic and nonhedonic appetite ratings in controls, but not women with active disease.
Limitations
Our findings are limited by a relatively small sample size, which prevented the use of an analysis of variance model and exploration of interaction effects, although our substantial effect sizes of between-group differences suggest adequate power for our statistical analysis approach. Participants taking psychotropic medications were included.
Conclusion
Our data provide evidence of potential state and trait hypoactivations in food motivation regions involved in the assessment of food’s reward value and integration of these with interoceptive signalling of one’s internal state of well-being, with important relations between brain activity and homeostatic and hedonic aspects of appetite. Our findings give novel evidence of disruption in neurobiological circuits and stress the importance of examining both state and trait characteristics in the investigation of brain phenotypes in individuals with anorexia nervosa.
doi:10.1503/jpn.110156
PMCID: PMC3447131  PMID: 22498079
10.  Cardiac abnormalities in young women with anorexia nervosa. 
British Heart Journal  1994;71(3):287-292.
OBJECTIVE--To identify the characteristics of cardiac involvement in the self-induced starvation phase of anorexia nervosa. METHODS--Doppler echocardiographic indices of left ventricular geometry, function, and filling were examined in 21 white women (mean (SD) 22 (5) years) with anorexia nervosa according to the DSMIII (Diagnostic and Statistical Manual of Mental Disorders) criteria, 19 women (23 (2) years) of normal weight, and 22 constitutionally thin women (21 (4) years) with body mass index < 20. RESULTS--13 patients (62%) had abnormalities of mitral valve motion compared with one normal weight woman and two thin women (p < 0.001) v both control groups). Left ventricular chamber dimension and mass were significantly less in women with anorexia nervosa than in either the women of normal weight or the thin women, even after standardisation for body size or after controlling for blood pressure. There were no substantial changes in left ventricular shape. Midwall shortening as a percentage of the values predicted from end systolic stress was significantly lower in the starving patients than in women of normal weight: when endocardial shortening was used as the index this difference was overestimated. The cardiac index was also significantly reduced in anorexia nervosa because of a low stroke index and heart rate. The total peripheral resistance was significantly higher in starving patients than in both control groups. The left atrial dimension was significantly smaller in anorexia than in the women of normal weight and the thin women, independently of body size. The transmitral flow velocity E/A ratio was significantly higher in anorexia than in both the control groups because of the reduction of peak velocity A. When data from all three groups were pooled the flow velocity E/A ratio was inversely related to left atrial dimension (r = -0.43, p < 0.0001) and cardiac output (r = -0.64, p < 0.0001) independently of body size. CONCLUSIONS--Anorexia nervosa caused demonstrable abnormalities of mitral valve motion and reduced left ventricular mass and filling associated with systolic dysfunction.
PMCID: PMC483668  PMID: 8142200
11.  What can we learn from the history of male anorexia nervosa? 
The eating disorders literature has focussed on females and little is known of the male experience. The overall image this has generated suggests a young woman in conflict with socio-cultural pressures which associate thinness with beauty. Historical studies have examined anorexia nervosa from an entirely female focus while ignoring how diagnostic categories have shaped approaches to the male body. This paper will track the case of the male with anorexia nervosa through changing theories of causation and treatment approaches, from when the condition first emerged in 1873 to the present. In doing so, we gain a valuable new insight into how anorexia nervosa has been historically gendered and the far-reaching implications this has had for diagnosis and treatment of the male sufferer.
Similarities between the sexes helped to establish male anorexia as a distinct category. However, this shifted focus away from important differences, which have yet unexplored implications in the assessment, diagnosis and management of disordered eating. Throughout history, there has been constant pressure to give a precise definition to anorexia nervosa, despite being fraught with medical uncertainties. This has resulted in inevitably harmful generalisations rooted in the dominant epidemiology. This paper reveals that anorexia nervosa is a truly global phenomenon which cannot be adequately constructed through exclusive studies of the female. There is consequently a pressing need to address the dearth of research examining eating disorders in males.
doi:10.1186/s40337-014-0036-9
PMCID: PMC4323236  PMID: 25671131
Anorexia nervosa; Eating disorder; History of psychiatry
12.  A genome-wide association study of anorexia nervosa 
Boraska, Vesna | Franklin, Christopher S | Floyd, James AB | Thornton, Laura M | Huckins, Laura M | Southam, Lorraine | Rayner, N William | Tachmazidou, Ioanna | Klump, Kelly L | Treasure, Janet | Lewis, Cathryn M | Schmidt, Ulrike | Tozzi, Federica | Kiezebrink, Kirsty | Hebebrand, Johannes | Gorwood, Philip | Adan, Roger AH | Kas, Martien JH | Favaro, Angela | Santonastaso, Paolo | Fernández-Aranda, Fernando | Gratacos, Monica | Rybakowski, Filip | Dmitrzak-Weglarz, Monika | Kaprio, Jaakko | Keski-Rahkonen, Anna | Raevuori, Anu | Van Furth, Eric F | Slof-Op t Landt, Margarita CT | Hudson, James I | Reichborn-Kjennerud, Ted | Knudsen, Gun Peggy S | Monteleone, Palmiero | Kaplan, Allan S | Karwautz, Andreas | Hakonarson, Hakon | Berrettini, Wade H | Guo, Yiran | Li, Dong | Schork, Nicholas J. | Komaki, Gen | Ando, Tetsuya | Inoko, Hidetoshi | Esko, Tõnu | Fischer, Krista | Männik, Katrin | Metspalu, Andres | Baker, Jessica H | Cone, Roger D | Dackor, Jennifer | DeSocio, Janiece E | Hilliard, Christopher E | O’Toole, Julie K | Pantel, Jacques | Szatkiewicz, Jin P | Taico, Chrysecolla | Zerwas, Stephanie | Trace, Sara E | Davis, Oliver SP | Helder, Sietske | Bühren, Katharina | Burghardt, Roland | de Zwaan, Martina | Egberts, Karin | Ehrlich, Stefan | Herpertz-Dahlmann, Beate | Herzog, Wolfgang | Imgart, Hartmut | Scherag, André | Scherag, Susann | Zipfel, Stephan | Boni, Claudette | Ramoz, Nicolas | Versini, Audrey | Brandys, Marek K | Danner, Unna N | de Kovel, Carolien | Hendriks, Judith | Koeleman, Bobby PC | Ophoff, Roel A | Strengman, Eric | van Elburg, Annemarie A | Bruson, Alice | Clementi, Maurizio | Degortes, Daniela | Forzan, Monica | Tenconi, Elena | Docampo, Elisa | Escaramís, Geòrgia | Jiménez-Murcia, Susana | Lissowska, Jolanta | Rajewski, Andrzej | Szeszenia-Dabrowska, Neonila | Slopien, Agnieszka | Hauser, Joanna | Karhunen, Leila | Meulenbelt, Ingrid | Slagboom, P Eline | Tortorella, Alfonso | Maj, Mario | Dedoussis, George | Dikeos, Dimitris | Gonidakis, Fragiskos | Tziouvas, Konstantinos | Tsitsika, Artemis | Papezova, Hana | Slachtova, Lenka | Martaskova, Debora | Kennedy, James L. | Levitan, Robert D. | Yilmaz, Zeynep | Huemer, Julia | Koubek, Doris | Merl, Elisabeth | Wagner, Gudrun | Lichtenstein, Paul | Breen, Gerome | Cohen-Woods, Sarah | Farmer, Anne | McGuffin, Peter | Cichon, Sven | Giegling, Ina | Herms, Stefan | Rujescu, Dan | Schreiber, Stefan | Wichmann, H-Erich | Dina, Christian | Sladek, Rob | Gambaro, Giovanni | Soranzo, Nicole | Julia, Antonio | Marsal, Sara | Rabionet, Raquel | Gaborieau, Valerie | Dick, Danielle M | Palotie, Aarno | Ripatti, Samuli | Widén, Elisabeth | Andreassen, Ole A | Espeseth, Thomas | Lundervold, Astri | Reinvang, Ivar | Steen, Vidar M | Le Hellard, Stephanie | Mattingsdal, Morten | Ntalla, Ioanna | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Navratilova, Marie | Gallinger, Steven | Pinto, Dalila | Scherer, Stephen | Aschauer, Harald | Carlberg, Laura | Schosser, Alexandra | Alfredsson, Lars | Ding, Bo | Klareskog, Lars | Padyukov, Leonid | Finan, Chris | Kalsi, Gursharan | Roberts, Marion | Logan, Darren W | Peltonen, Leena | Ritchie, Graham RS | Barrett, Jeffrey C | Estivill, Xavier | Hinney, Anke | Sullivan, Patrick F | Collier, David A | Zeggini, Eleftheria | Bulik, Cynthia M
Molecular psychiatry  2010;16(9):10.1038/mp.2010.107.
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 2,907 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 datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 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 to 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 that 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.
doi:10.1038/mp.2010.107
PMCID: PMC3859494  PMID: 21079607
anorexia nervosa; eating disorders; GWAS; genome-wide association study; body mass index; metabolic
13.  A genome-wide association study of anorexia nervosa 
Boraska, Vesna | Franklin, Christopher S | Floyd, James AB | Thornton, Laura M | Huckins, Laura M | Southam, Lorraine | Rayner, N William | Tachmazidou, Ioanna | Klump, Kelly L | Treasure, Janet | Lewis, Cathryn M | Schmidt, Ulrike | Tozzi, Federica | Kiezebrink, Kirsty | Hebebrand, Johannes | Gorwood, Philip | Adan, Roger AH | Kas, Martien JH | Favaro, Angela | Santonastaso, Paolo | Fernández-Aranda, Fernando | Gratacos, Monica | Rybakowski, Filip | Dmitrzak-Weglarz, Monika | Kaprio, Jaakko | Keski-Rahkonen, Anna | Raevuori, Anu | Van Furth, Eric F | Landt, Margarita CT Slof-Op t | Hudson, James I | Reichborn-Kjennerud, Ted | Knudsen, Gun Peggy S | Monteleone, Palmiero | Kaplan, Allan S | Karwautz, Andreas | Hakonarson, Hakon | Berrettini, Wade H | Guo, Yiran | Li, Dong | Schork, Nicholas J. | Komaki, Gen | Ando, Tetsuya | Inoko, Hidetoshi | Esko, Tõnu | Fischer, Krista | Männik, Katrin | Metspalu, Andres | Baker, Jessica H | Cone, Roger D | Dackor, Jennifer | DeSocio, Janiece E | Hilliard, Christopher E | O'Toole, Julie K | Pantel, Jacques | Szatkiewicz, Jin P | Taico, Chrysecolla | Zerwas, Stephanie | Trace, Sara E | Davis, Oliver SP | Helder, Sietske | Bühren, Katharina | Burghardt, Roland | de Zwaan, Martina | Egberts, Karin | Ehrlich, Stefan | Herpertz-Dahlmann, Beate | Herzog, Wolfgang | Imgart, Hartmut | Scherag, André | Scherag, Susann | Zipfel, Stephan | Boni, Claudette | Ramoz, Nicolas | Versini, Audrey | Brandys, Marek K | Danner, Unna N | de Kovel, Carolien | Hendriks, Judith | Koeleman, Bobby PC | Ophoff, Roel A | Strengman, Eric | van Elburg, Annemarie A | Bruson, Alice | Clementi, Maurizio | Degortes, Daniela | Forzan, Monica | Tenconi, Elena | Docampo, Elisa | Escaramís, Geòrgia | Jiménez-Murcia, Susana | Lissowska, Jolanta | Rajewski, Andrzej | Szeszenia-Dabrowska, Neonila | Slopien, Agnieszka | Hauser, Joanna | Karhunen, Leila | Meulenbelt, Ingrid | Slagboom, P Eline | Tortorella, Alfonso | Maj, Mario | Dedoussis, George | Dikeos, Dimitris | Gonidakis, Fragiskos | Tziouvas, Konstantinos | Tsitsika, Artemis | Papezova, Hana | Slachtova, Lenka | Martaskova, Debora | Kennedy, James L. | Levitan, Robert D. | Yilmaz, Zeynep | Huemer, Julia | Koubek, Doris | Merl, Elisabeth | Wagner, Gudrun | Lichtenstein, Paul | Breen, Gerome | Cohen-Woods, Sarah | Farmer, Anne | McGuffin, Peter | Cichon, Sven | Giegling, Ina | Herms, Stefan | Rujescu, Dan | Schreiber, Stefan | Wichmann, H-Erich | Dina, Christian | Sladek, Rob | Gambaro, Giovanni | Soranzo, Nicole | Julia, Antonio | Marsal, Sara | Rabionet, Raquel | Gaborieau, Valerie | Dick, Danielle M | Palotie, Aarno | Ripatti, Samuli | Widén, Elisabeth | Andreassen, Ole A | Espeseth, Thomas | Lundervold, Astri | Reinvang, Ivar | Steen, Vidar M | Le Hellard, Stephanie | Mattingsdal, Morten | Ntalla, Ioanna | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Navratilova, Marie | Gallinger, Steven | Pinto, Dalila | Scherer, Stephen | Aschauer, Harald | Carlberg, Laura | Schosser, Alexandra | Alfredsson, Lars | Ding, Bo | Klareskog, Lars | Padyukov, Leonid | Finan, Chris | Kalsi, Gursharan | Roberts, Marion | Logan, Darren W | Peltonen, Leena | Ritchie, Graham RS | Barrett, Jeffrey C | Estivill, Xavier | Hinney, Anke | Sullivan, Patrick F | Collier, David A | Zeggini, Eleftheria | Bulik, Cynthia M
Molecular psychiatry  2014;19(10):1085-1094.
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 2,907 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 datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 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 to 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 that 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.
doi:10.1038/mp.2013.187
PMCID: PMC4325090  PMID: 24514567
anorexia nervosa; eating disorders; GWAS; genome-wide association study; body mass index; metabolic
14.  Childhood Anxiety Associated with Low BMI in Women with Anorexia Nervosa 
Behaviour research and therapy  2009;48(1):60-67.
Objective
Extremely low body mass index (BMI) values are associated with increased risk for death and poor long-term prognosis in individuals with AN. The present study explores childhood personality characteristics that could be associated with the ability to attain an extremely low BMI.
Methods
Participants were 326 women from the Genetics of Anorexia Nervosa (GAN) Study who completed the Structured Interview for Anorexia Nervosa and Bulimic Syndromes and whose mother completed the Child Behavioral Check List and/or Revised Dimensions of Temperament Survey.
Results
Children who were described as having greater fear or anxiety by their mothers attained lower BMIs during AN (p <0.02). Path analysis in the GAN and a validation sample, Price Foundation Anorexia Nervosa Trios Study, confirmed the relation between early childhood anxiety, caloric restriction, qualitative food item restriction, excessive exercise, and low BMI. Path analysis also confirmed a relation between childhood anxiety and caloric restriction, which mediated the relation between childhood anxiety and low BMI in the GAN sample only.
Conclusion
Fearful or anxious behavior as a child was associated with the attainment of low BMI in AN and childhood anxiety was associated with caloric restriction. Measures of anxiety and factors associated with anxiety-proneness in childhood may index children at risk for restrictive behaviors and extremely low BMIs in AN.
doi:10.1016/j.brat.2009.09.009
PMCID: PMC2812624  PMID: 19822312
Anorexia Nervosa; Anxiety; Body Mass Index
15.  Trait-level and momentary correlates of bulimia nervosa with a history of anorexia nervosa 
Objective
Some investigators have suggested subtyping bulimia nervosa (BN) by anorexia nervosa (AN) history. We examined trait-level and momentary eating-related and psychosocial factors in BN with and without an AN history.
Method
Interview, questionnaire, and ecological momentary assessment data of eating-related and psychological symptoms were collected from 122 women with BN, including 43 with (BN+) and 79 without an AN history (BN−).
Results
Body mass index (kg/m2) was lower in BN+ than BN− (p=.001). Groups did not differ on trait-level anxiety, shape/weight concerns, psychiatric comorbidity, or dietary restraint; or on momentary anxiety, dietary restriction, binge eating, purging, or exercise frequency, or affective patterns surrounding binge/purge behaviors. Negative affect increased prior to exercise and decreased thereafter in BN+ but not BN−, although groups did not statistically differ.
Discussion
Results do not support formally subtyping BN by AN history. Exercise in BN+ may modulate negative affect, which could have important treatment implications.
doi:10.1002/eat.22054
PMCID: PMC3570735  PMID: 22987478
eating disorders; bulimia nervosa; history of anorexia nervosa; subtyping; classification; exercise
16.  Psychological and weight-related characteristics of patients with anorexia nervosa-restricting type who later develop bulimia nervosa 
Background
Patients with anorexia nervosa-restricting type (AN-R) sometimes develop accompanying bulimic symptoms or the full syndrome of bulimia nervosa (BN). If clinicians could predict who might change into the bulimic sub-type or BN, preventative steps could be taken. Therefore, we investigated anthropometric and psychological factors possibly associated with such changes.
Method
All participants were from a study by the Japanese Genetic Research Group for Eating Disorders. Of 80 patients initially diagnosed with AN-R, 22 changed to the AN-Binge Eating/Purging Type (AN-BP) and 14 to BN for some period of time. The remaining 44 patients remained AN-R only from the onset to the investigation period. Variables compared by ANOVA included anthropometric measures, personality traits such as Multiple Perfectionism Scale scores and Temperament and Character Inventory scores, and Beck Depression Inventory-II scores.
Results
In comparison with AN-R only patients, those who developed BN had significantly higher current BMI (p < 0.05) and maximum BMI in the past (p < 0.05). They also scored significantly higher for the psychological characteristic of parental criticism (p < 0.05) and lower in self-directedness (p < 0.05), which confirms previous reports, but these differences disappeared when the depression score was used as a co-variant. No significant differences were obtained for personality traits or depression among the AN-R only patients irrespective of their duration of illness.
Conclusion
The present findings suggest a tendency toward obesity among patients who cross over from AN-R to BN. Low self-directedness and high parental criticism may be associated with the development of BN by patients with AN-R, although the differences may also be associated with depression.
doi:10.1186/1751-0759-2-5
PMCID: PMC2275291  PMID: 18267038
17.  Assessing the Heritability of Anorexia Nervosa Symptoms Using a Marginal Maximal Likelihood Approach 
Psychological medicine  2008;39(3):463-473.
Background
Assessment of eating disorders at the symptom level can facilitate the refinement of phenotypes. We examined genetic and environmental contributions to liability to anorexia nervosa (AN) symptoms in a population-based twin sample using a genetic common pathway model.
Method
Participants were from the Norwegian Institute of Public Health Twin Panel and included all female monozygotic (n = 448 complete pairs and 4 singletons) and dizygotic (n = 263 complete pairs and 4 singletons) twins who completed the Composite International Diagnostic Interview assessing DSM-IV axis I and ICD-10 criteria. Responses to items assessing AN symptoms were included in a model fitted using marginal maximum likelihood.
Results
Heritability of the overall AN diagnosis was moderate (a2 = .22, 95% CI: 0.0; .50), whereas heritabilities of the specific items varied. Heritability estimates for weight loss items were moderate (a2 estimates ranged from .31 to .34) and items assessing weight concern when at a low weight were smaller (ranging from .18 to .29). Additive genetic factors contributed little to the variance of amenorrhea, which was most strongly influenced by unshared environment (a2 =.16; e2 = .71).
Conclusions
AN symptoms are differentially heritable. Specific criteria such as those related to body weight and weight loss history represent more biologically driven potential endophenotypes or liability indices. Results regarding weight concern differ somewhat from those of previous studies, which highlights the importance of assessing genetic and environmental influences on variance of traits within specific subgroups of interest.
doi:10.1017/S0033291708003310
PMCID: PMC2640444  PMID: 18485259
18.  Constitutional Thinness and Anorexia Nervosa: A Possible Misdiagnosis? 
Clinical and biological aspects of restrictive anorexia nervosa (R-AN) are well documented. More than 10,000 articles since 1911 and more than 600 in 2013 have addressed R-AN psychiatric, somatic, and biological aspects. Genetic background, ineffectiveness of appetite regulating hormones on refeeding process, bone loss, and place of amenorrhea in the definition are widely discussed and reviewed. Oppositely, constitutional thinness (CT) is an almost unknown entity. Only 32 articles have been published on this topic since 1953. Similar symptoms associating low body mass index, low fat, and bone mass are reported in both CT and R-AN subjects. Conversely, menses are preserved in CT women and almost the entire hormonal profile is normal, except for leptin and PYY. The aim of the present review is to alert the clinician on the confusing clinical presentation of these two situations, a potential source of misdiagnosis, especially since R-AN definition has changed in DSM5.
doi:10.3389/fendo.2014.00175
PMCID: PMC4202249  PMID: 25368605
anorexia nervosa; constitutional thinness; phenotyping; DSM IV; DSM5
19.  Selection of eating-disorder phenotypes for linkage analysis 
Vulnerability to anorexia nervosa (AN) and bulimia nervosa (BN) arise from the interplay of genetic and environmental factors. To explore the genetic contribution, we measured over 100 psychiatric, personality and temperament phenotypes of individuals with eating disorders from 154 multiplex families accessed through an AN proband (AN cohort) and 244 multiplex families accessed through a BN proband (BN cohort). To select a parsimonious subset of these attributes for linkage analysis, we subjected the variables to a multilayer decision process based on expert evaluation and statistical analysis. Criteria for trait choice included relevance to eating disorders pathology, published evidence for heritability, and results from our data. Based on these criteria, we chose six traits to analyze for linkage. Obsessionality, Age-at-Menarche, and a composite Anxiety measure displayed features of heritable quantitative traits, such as normal distribution and familial correlation, and thus appeared ideal for quantitative trait locus (QTL) linkage analysis. By contrast, some families showed highly concordant and extreme values for three variables — lifetime minimum Body Mass Index (lowest BMI attained during the course of illness), concern over mistakes, and food-related obsessions — whereas others did not. These distributions are consistent with a mixture of populations, and thus the variables were matched with covariate linkage analysis. Linkage results appear in a subsequent report. Our report lays out a systematic roadmap for utilizing a rich set of phenotypes for genetic analyses, including the selection of linkage methods paired to those phenotypes.
doi:10.1002/ajmg.b.30227
PMCID: PMC2560991  PMID: 16152575
Complex disease; endophenotype; liability; clinical judgment; covariate selection; mixture model; regression
20.  Anorexia Nervosa and Body Fat Distribution: A Systematic Review 
Nutrients  2014;6(9):3895-3912.
The aim of this paper was to conduct a systematic review of body fat distribution before and after partial and complete weight restoration in individuals with anorexia nervosa. Literature searches, study selection, method development and quality appraisal were performed independently by two authors, and data was synthesized using a narrative approach. Twenty studies met the inclusion criteria and were consequently analyzed. The review had five main findings. First, during anorexia nervosa adolescent females lose more central body fat, while adult females more peripheral fat. Second, partial weight restoration leads to greater fat mass deposition in the trunk region than other body regions in adolescent females. Third, after short-term weight restoration, whether partial or complete, adults show a central adiposity phenotype with respect to healthy age-matched controls. Fourth, central fat distribution is associated with increased insulin resistance, but does not adversely affect eating disorder psychopathology or cause psychological distress in female adults. Fifth, the abnormal central fat distribution seems to normalize after long-term maintenance of complete weight restoration, indicating that preferential central distribution of body fat is a transitory phenomenon. However, a discrepancy in the findings has been noted, especially between adolescents and adults; besides age and gender, these appear to be related to differences in the methodology and time of body composition assessments. The PROSPERO Registry—Anorexia Nervosa and Body Fat Distribution: A Systematic Review (CRD42014008738).
doi:10.3390/nu6093895
PMCID: PMC4179194  PMID: 25251296
anorexia nervosa; eating disorders; body composition; body fat percentage; body fat redistribution; adipose tissue distribution
21.  Differential Methylation of the Oxytocin Receptor Gene in Patients with Anorexia Nervosa: A Pilot Study 
PLoS ONE  2014;9(2):e88673.
Background and Aim
Recent studies in patients with anorexia nervosa suggest that oxytocin may be involved in the pathophysiology of anorexia nervosa. We examined whether there was evidence of variation in methylation status of the oxytocin receptor (OXTR) gene in patients with anorexia nervosa that might account for these findings.
Methods
We analyzed the methylation status of the CpG sites in a region from the exon 1 to the MT2 regions of the OXTR gene in buccal cells from 15 patients and 36 healthy women using bisulfite sequencing. We further examined whether methylation status was associated with markers of illness severity or form.
Results
We identified six CpG sites with significant differences in average methylation levels between the patient and control groups. Among the six differentially methylated CpG sites, five showed higher than average methylation levels in patients than those in the control group (64.9–88.8% vs. 6.6–45.0%). The methylation levels of these five CpG sites were negatively associated with body mass index (BMI). BMI, eating disorders psychopathology, and anxiety were identified in a regression analysis as factors affecting the methylation levels of these CpG sites with more variation accounted for by BMI.
Conclusions
Epigenetic misregulation of the OXTR gene may be implicated in anorexia nervosa, which may either be a mechanism linking environmental adversity to risk or may be a secondary consequence of the illness.
doi:10.1371/journal.pone.0088673
PMCID: PMC3921190  PMID: 24523928
22.  The Genetics of Anorexia Nervosa: Current Findings and Future Perspectives 
Anorexia nervosa is a perplexing illness with the highest mortality rate of any psychiatric disease. In this paper, we review the genetic research on anorexia nervosa (AN). Family studies have demonstrated that anorexia nervosa is familial, and twin studies have indicated that additive genetic factors contribute to the familial aggregation. Molecular genetic research, including genomewide linkage and case control association studies, have not been successful in identifying DNA variants that are unequivocally involved in the etiology of AN. We provide a critical appraisal of these studies and discuss methodological issues that may be implicated in conflicting results. Furthermore, we discuss issues relevant to genetic research such as the importance of phenotypic refinement, the use of endophenotypes, and the implications for nosology and genetic analysis. Finally, the future of genetic research for AN is discussed in terms of genomewide association studies (GWAS) and the need for establishing large samples.
PMCID: PMC2828778  PMID: 20191112
twin; linkage; molecular genetics; anorexia nervosa
23.  Do girls with anorexia nervosa have elevated autistic traits? 
Molecular Autism  2013;4:24.
Background
Patients with anorexia may have elevated autistic traits. In this study, we tested test whether patients with anorexia nervosa (anorexia) have an elevated score on a dimensional measure of autistic traits, the Autism Spectrum Quotient (AQ), as well as on trait measures relevant to the autism spectrum: the Empathy Quotient (EQ), and the Systemizing Quotient (SQ).
Methods
Two groups were tested: (1) female adolescents with anorexia: n = 66, aged 12 to 18 years; and (2) female adolescents without anorexia: n =1,609, aged 12 to 18 years. Both groups were tested using the AQ, EQ, and SQ, via the parent-report adolescent versions for patients aged 12 to 15 years old, and the self-report adult versions for patients aged over 16 years.
Results
As predicted, the patients with anorexia had a higher AQ and SQ. Their EQ score was reduced, but only for the parent-report version in the younger age group. Using EQ-SQ scores to calculate ‘cognitive types’, patients with anorexia were more likely to show the Type S profile (systemizing (S) better than empathy (E)), compared with typical females.
Conclusions
Females with anorexia have elevated autistic traits. Clinicians should consider if a focus on autistic traits might be helpful in the assessment and treatment of anorexia. Future research needs to establish if these results reflect traits or states associated with anorexia.
doi:10.1186/2040-2392-4-24
PMCID: PMC3735388  PMID: 23915495
Autistic traits; Anorexia; Autism spectrum conditions; Broader autism phenotype
24.  The relation of weight suppression and body mass index to symptomatology and treatment response in anorexia nervosa 
Journal of abnormal psychology  2013;122(3):694-708.
Weight suppression, the difference between highest past weight and current weight, is a robust predictor of clinical characteristics of bulimia nervosa; however, the influence of weight suppression in anorexia nervosa (AN) has been little studied, and no study to date has investigated the ways in which the relevance of weight suppression in AN may depend upon an individual’s current body mass index (BMI). The present study investigated weight suppression, BMI, and their interaction as cross-sectional and prospective predictors of psychological symptoms and weight in AN. Women with AN completed depression (Beck Depression Inventory-II) and eating disorder symptomatology measures (Eating Disorder Examination Questionnaire and Eating Disorders Inventory-3) at residential treatment admission (N = 350) and discharge (N = 238). Weight suppression and BMI were weakly correlated (r = −.22). At admission, BMI was positively correlated with all symptom measures except Restraint and depression scores. Weight suppression was also independently positively correlated with all measures except Weight Concern and Body Dissatisfaction subscale scores. In analyses examining discharge scores (including admission values as covariates), the admission weight suppression X BMI interaction consistently predicted post-treatment psychopathology. Controlling for weight gain in treatment and age, higher admission weight suppression predicted lower discharge scores (less symptom endorsement) among those with lower BMIs; among those with higher BMIs, higher weight suppression predicted higher discharge scores. These results are the first to demonstrate that absolute and relative weight status are joint indicators of AN severity and prognosis. These findings may have major implications for conceptualization and treatment of AN.
doi:10.1037/a0033930
PMCID: PMC4096540  PMID: 24016010
Anorexia nervosa; weight suppression; treatment; outcome
25.  Impact of Physiologic Estrogen Replacement on Anxiety Symptoms, Body Shape Perception and Eating Attitudes in Adolescent Girls with Anorexia Nervosa: Data from a Randomized Controlled Trial 
The Journal of clinical psychiatry  2013;74(8):e765-e771.
Objectives
Anorexia nervosa (AN) is characterized by low weight, aberrant eating attitudes, body image distortion and hypogonadism. Anxiety is a common co-morbid condition. Estrogen replacement reduces anxiety in animal models, and reported variations in food intake across the menstrual cycle may be related to gonadal steroid levels. The impact of estrogen replacement on anxiety, eating attitudes, and body image has not been reported in AN. We hypothesized that physiologic estrogen replacement would ameliorate anxiety and improve eating attitudes, without affecting body image in AN.
Methods
Girls with AN (DSM-IV) 13–18 yo were randomized to transdermal estradiol (100-mcg twice weekly) with cyclic progesterone (AN-E+) or placebo patches and pills (AN-E−) for 18-months, between 2002 and 2010. The Spielberger’s State-Trait Anxiety Inventory for Children (STAIC), the Eating Disorders Inventory II (EDI II), and the Body Shape Questionnaire (BSQ-34) were administered. 72 girls completed these at baseline (38 AN-E+ and 34 AN-E−), and 37 at 18-months (20 AN-E+ and 17 AN-E−). The primary outcome measure was the change in these scores over 18-months.
Results
Estrogen replacement caused a decrease in STAIC-trait scores (−3.05±1.22 vs. 2.07±1.73, p=0.02), without impacting STAI-state scores (−1.11±2.17 vs. 0.20±1.42, p=0.64). There was no effect of estrogen replacement on EDI II or BSQ-34 scores. BMI changes did not differ between groups, and effects of estrogen replacement on STAIC-trait scores persisted after controlling for BMI changes (p=0.03). There was an inverse association between serum estradiol changes and changes in STAIC-trait scores (r=−0.66, p=0.001).
Conclusions
Estrogen replacement improved trait anxiety (the tendency to experience anxiety), but did not impact eating attitudes or body shape perception.
doi:10.4088/JCP.13m08365
PMCID: PMC4017248  PMID: 24021517
Estrogen; anxiety; eating behavior; body shape; anorexia nervosa; adolescents

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