Brain connectome modularity in weight-restored anorexia nervosa and body dysmorphic disorder.

BACKGROUND: Anorexia nervosa (AN) and body dysmorphic disorder (BDD) frequently co-occur, and have several overlapping phenomenological features. Little is known about their shared neurobiology. The aim of the study was to compare modular organization of brain structural connectivity. METHOD: We acquired diffusion-weighted magnetic resonance imaging data on unmedicated individuals with BDD (n = 29), weight-restored AN (n = 24) and healthy controls (HC) (n = 31). We constructed connectivity matrices using whole-brain white matter tractography, and compared modular structures across groups. RESULTS: AN showed abnormal modularity involving frontal, basal ganglia and posterior cingulate nodes. There was a trend in BDD for similar abnormalities, but no significant differences compared with AN. In AN, poor insight correlated with longer path length in right caudal anterior cingulate and right posterior cingulate. CONCLUSIONS: Abnormal network organization patterns in AN, partially shared with BDD, may have implications for understanding integration between reward and habit/ritual formation, as well as conflict monitoring/error detection.

The influence of comorbid disorders on the episodicity of bipolar disorder in youth.

OBJECTIVE: Bipolar disorder (BP) frequently co-occurs with other psychiatric disorders. We examine whether course of anxiety disorders (ANX), attention deficit hyperactivity disorder (ADHD), disruptive behavior disorders (DBD), and substance use disorders (SUD) influence likelihood of recovery and recurrence of depression and mania in BP youth. METHOD: Weekly ratings of psychiatric disorder intensity were obtained from 413 participants of the Course and Outcome of BP Youth project, followed for an average of 7.75 years. Multiple-event Cox proportional hazards regression analyses examined worsening of comorbid disorders as predictors of mood episode recovery and recurrence. RESULTS: Increased severity in ANX and SUD predicted longer time to recovery and less time to next depressive episode, and less time to next manic episode. Multivariate models with ANX and SUD found that significant effects of ANX remained, but SUD only predicted longer time to depression recovery. Increased severity of ADHD and DBD predicted shorter time to recurrence for depressive and manic episodes. CONCLUSION: There are significant time-varying relationships between the course of comorbid disorders and episodicity of depression and mania in BP youth. Worsening of comorbid conditions may present as a precursor to mood episode recurrence or warn of mood episode protraction.

Anorexia nervosa and body dysmorphic disorder are associated with abnormalities in processing visual information.

BACKGROUND: Anorexia nervosa (AN) and body dysmorphic disorder (BDD) are characterized by distorted body image and are frequently co-morbid with each other, although their relationship remains little studied. While there is evidence of abnormalities in visual and visuospatial processing in both disorders, no study has directly compared the two. We used two complementary modalities--event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI)--to test for abnormal activity associated with early visual signaling. METHOD: We acquired fMRI and ERP data in separate sessions from 15 unmedicated individuals in each of three groups (weight-restored AN, BDD, and healthy controls) while they viewed images of faces and houses of different spatial frequencies. We used joint independent component analyses to compare activity in visual systems. RESULTS: AN and BDD groups demonstrated similar hypoactivity in early secondary visual processing regions and the dorsal visual stream when viewing low spatial frequency faces, linked to the N170 component, as well as in early secondary visual processing regions when viewing low spatial frequency houses, linked to the P100 component. Additionally, the BDD group exhibited hyperactivity in fusiform cortex when viewing high spatial frequency houses, linked to the N170 component. Greater activity in this component was associated with lower attractiveness ratings of faces. CONCLUSIONS: Results provide preliminary evidence of similar abnormal spatiotemporal activation in AN and BDD for configural/holistic information for appearance- and non-appearance-related stimuli. This suggests a common phenotype of abnormal early visual system functioning, which may contribute to perceptual distortions.

Functional connectivity for face processing in individuals with body dysmorphic disorder and anorexia nervosa.

BACKGROUND: Body dysmorphic disorder (BDD) and anorexia nervosa (AN) are both characterized by distorted perception of appearance. Previous studies in BDD suggest abnormalities in visual processing of own and others' faces, but no study has examined visual processing of faces in AN, nor directly compared the two disorders in this respect. METHOD: We collected functional magnetic resonance imaging data on 60 individuals of equivalent age and gender in each of three groups--20 BDD, 20 weight-restored AN, and 20 healthy controls (HC)--while they viewed images of others' faces that contained only high or low spatial frequency information (HSF or LSF). We tested hypotheses about functional connectivity within specialized sub-networks for HSF and LSF visual processing, using psychophysiological interaction analyses. RESULTS: The BDD group demonstrated increased functional connectivity compared to HC between left anterior occipital face area and right fusiform face area (FFA) for LSF faces, which was associated with symptom severity. Both BDD and AN groups had increased connectivity compared to HC between FFA and precuneous/posterior cingulate gyrus for LSF faces, and decreased connectivity between FFA and insula. In addition, we found that LSF connectivity between FFA and posterior cingulate gyrus was significantly associated with thoughts about own appearance in AN. CONCLUSIONS: Results suggest similar abnormal functional connectivity within higher-order systems for face processing in BDD and AN, but distinct abnormal connectivity patterns within occipito-temporal visual networks. Findings may have implications for understanding relationships between these disorders, and the pathophysiology underlying perceptual distortions.

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.

Borderline personality disorder in transition age youth with bipolar disorder.

OBJECTIVE: To determine the longitudinal impact of borderline personality disorder (BPD) on the course and outcome of bipolar disorder (BP) in a pediatric BP sample. METHOD: Participants (N = 271) and parents from the Course and Outcome of Bipolar Youth (COBY) study were administered structured clinical interviews and self-reports on average every 8.7 months over a mean of 93 months starting at age 13.0 ± 3.1 years. The structured interview for DSM-IV personality disorders (SIDP-IV) was administered at the first follow-up after age 18 to assess for symptoms of BPD. BPD operationalized at the disorder, factor, and symptom level, was examined as a predictor of poor clinical course of BP using all years of follow-up data. RESULTS: The number of BPD symptoms was significantly associated with poor clinical course of BP, above and beyond BP characteristics. Affective dysregulation was most strongly associated with poor course at the factor level; the individual symptoms most strongly associated with poor course were dissociation/stress-related paranoid ideation, impulsivity, and affective instability. CONCLUSION: BPD severity adds significantly to the burden of BP illness and is significantly associated with a more chronic and severe course and outcome beyond what can be attributable to BP characteristics.

Testing anxiety and reward processing in anorexia nervosa as predictors of longitudinal clinical outcomes.

Anorexia nervosa (AN) is a psychiatric disorder with a tenuous longitudinal course marked by a high risk of relapse. Previous studies suggest that aberrant threat perception and reward processing operate in many with AN, and may produce obstacles to treatment engagement; therefore, these could potentially represent predictors for longitudinal clinical outcomes. In this study, anxiety and reward symptoms, behaviors, and neural circuit connectivity were measured in intensively treated AN-restrictive subtype patients (n = 33) and healthy controls (n = 31). Participants underwent an fMRI experiment using a monetary reward task in combination with either overlapping individually tailored anxiety-provoking words or neutral words. Behavioral/psychometric measures consisted of reaction times on the monetary reward task and self-ratings on anxiety symptoms at study entry. We tested multimodal, multivariate models based on neural, behavioral, and psychometric measures of reward and anxiety to predict physiological (Body Mass Index; BMI) and psychological (eating disorder symptom severity) longitudinal outcomes in AN over six months. Our results indicated that higher anxiety symptom psychometric scores significantly predicted BMI reductions at follow-up. Untreated anxiety after intensive treatment could put individuals with AN at heightened risk for weight loss. This represents a potentially modifiable risk factor that could be targeted more aggressively to help reduce the chance of future clinical worsening.

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.

Bipolar illness in adolescents with major depression: clinical, genetic, and psychopharmacologic predictors in a three- to four-year prospective follow-up investigation.

Sixty adolescents, aged 13 to 16 years, hospitalized for major depression were studied prospectively, for three to four years to determine the utility of clinical, genetic, and pharmacologic response variables in predicting a bipolar course of illness. Bipolar outcome was observed in 20% of the cohort. Statistical analyses showed that bipolarity was predicted by (1) a depressive symptom cluster comprising rapid symptom onset, psychomotor retardation, and mood-congruent psychotic features; (2) a "loading" of affective disorder in the family pedigree, a family history of bipolar illness, and the presence of illness in three successive generations of the pedigree; and (3) pharmacologically induced hypomania. All predictors were shown to have high specificity for bipolar outcome, whereas pharmacologic hypomania and symptom cluster permitted the highest confidence of prediction, 100% and 80%, respectively. Even in juvenile depression, careful attention to clinical and biologic variables may aid in the predictive differentiation of meaningful diagnostic subtypes.

Reliability of psychiatric diagnosis in hospitalized adolescents. Interrater agreement using DSM-III.

To determine the reliability of psychiatric diagnosis in hospitalized adolescents, 95 consecutively admitted patients were diagnosed independently by two experienced clinicians using DSM-III criteria. Diagnostic judgments were based on joint interview of the patient via a structured mental-status examination, nursing observations, and referral materials. Concordance was analyzed by the kappa coefficient. A total of 13 DSM-III categories were used to classify this cohort, with the majority of categories representing traditional syndromes of functional psychopathology. There was complete agreement between the raters for more than three fourths of the patients. Levels of agreement for the categories of schizophrenia and major affective disorder were similar to values obtained in recent studies of adult patients. The results are discussed in relation to historical conceptions of adolescent psychopathology.

A controlled family study of anorexia nervosa and bulimia nervosa: psychiatric disorders in first-degree relatives and effects of proband comorbidity.

BACKGROUND: We used contemporary family-epidemiological methods to examine patterns of comorbidity and familial aggregation of psychiatric disorders for anorexia and bulimia nervosa. METHODS: Direct interviews and blind best-estimate diagnostic procedures were used with diagnostically "pure" groups of probands with eating disorders and a matched control group. Lifetime prevalence rates of eating disorders, mood disorders, substance use disorders, anxiety disorders, and selected personality disorders were determined in female probands with restricting anorexia nervosa (n=26) or bulimia nervosa (n=47), control women (n=44), and first-degree biological relatives (n=460). RESULTS: Relatives of anorexic and bulimic probands had increased risk of clinically subthreshold forms of an eating disorder, major depressive disorder, and obsessive-compulsive disorder. Familial aggregation of major depressive disorder and obsessive-compulsive disorder was independent of that of anorexia nervosa and bulimia nervosa. These relatives also had increased risk of other anxiety disorders, but the mode of familial transmission was not clear-cut. The risk of substance dependence was elevated among relatives of bulimic probands compared with relatives of anorexic probands, and familial aggregation was independent of that of bulimia nervosa. The risk of obsessive-compulsive personality disorder was elevated only among relatives of anorexic probands, and there was evidence that these 2 disorders may have shared familial risk factors. CONCLUSIONS: There may be a common familial vulnerability for anorexia nervosa and bulimia nervosa. Major depressive disorder, obsessive-compulsive disorder, and substance dependence are not likely to share a common cause with eating disorders. However, obsessional personality traits may be a specific familial risk factor for anorexia nervosa.

Adrenal steroid responses to continuous intravenous adrenocorticotropin infusion compared to bolus injection in normal volunteers.

We compared the adrenal steroid responses after synthetic ACTH-(1-24) (Cosyntropin) administration given by either continuous iv infusion or bolus injection in 11 normal women and 6 normal men. Each subject received 250 micrograms Cosyntropin as a bolus iv injection on 1 occasion and as a continuous 2-h iv infusion on another occasion, in random order. There was a 1-week interval between the studies. We measured the plasma levels of cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, progesterone, pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, delta 5-androstenediol, androstenedione, and testosterone by RIA 15 and 0 min before and 30, 45, 60, and 120 min after administering ACTH. The steroid concentrations and their increments, ratios, or areas above baseline did not differ significantly between the bolus injection and the continuous infusion. Thus, at the dose of 250 micrograms, a bolus ACTH injection stimulates adrenal steroid secretion as effectively as a 2-h continuous ACTH infusion.

Serotonin neuronal function and selective serotonin reuptake inhibitor treatment in anorexia and bulimia nervosa.

Anorexia nervosa (AN) and bulimia nervosa (BN) are disorders characterized by aberrant patterns of feeding behavior and weight regulation, and disturbances in attitudes toward weight and shape and the perception of body shape. Emerging data support the possibility that substantial biologic and genetic vulnerabilities contribute to the pathogenesis of AN and BN. Multiple neuroendocrine and neurotransmitter abnormalities have been documented in AN and BN, but for the most part, these disturbances are state-related and tend to normalize after symptom remission and weight restoration; however, elevated concentrations of 5-hydroxyindoleacetic acid in the cerebrospinal fluid after recovery suggest that altered serotonin activity in AN and BN is a trait-related characteristic. Elevated serotonin activity is consistent with behaviors found after recovery from AN and BN, such as obsessionality with symmetry and exactness, harm avoidance, perfectionism, and behavioral over control. In BN, serotonergic modulating antidepressant medications suppress symptoms independently of their antidepressant effects. Selective serotonin reuptake inhibitors (SSRIs) are not useful when AN subjects are malnourished and under-weight; however, when given after weight restoration, fluoxetine may significantly reduce the extremely high rate of relapse normally seen in AN. Nonresponse to SSRI medication in ill AN subjects could be a consequence of an inadequate supply of nutrients, which are essential to normal serotonin synthesis and function. These data raise the possibility that a disturbance of serotonin activity may create a vulnerability for the expression of a cluster of symptoms that are common to both AN and BN and that nutritional factors may affect SSRI response in depression, obsessive-compulsive disorder, or other conditions characterized by disturbances in serotonergic pathways.

New directions in treatment research of anorexia and bulimia nervosa.

Although considerable progress has been made in the understanding and treatment of anorexia and bulimia nervosa, a substantial proportion of people with these disorders have a limited response to treatment. Treatment strategies used in eating disorders have tended to be adopted from therapies that were devised to treat other psychiatric illnesses. Recent studies suggest that eating disorders are independently transmitted familial liabilities with a unique pathophysiology. These new findings raise the possibility that an improved understanding of the pathogenesis of eating disorders will generate more specific and effective psychotherapies and pharmacologic interventions.

Effects of electroconvulsive therapy in adolescents with severe endogenous depression resistant to pharmacotherapy.

BACKGROUND: This open, prospective study examined the effects of electroconvulsive therapy (ECT) in 10 adolescents with primary, endogenous, psychotic depression who were resistant to antidepressant pharmacotherapy. METHODS: Change in symptom severity from baseline was assessed weekly with Hamilton Depression Rating Scale (HDRS) ratings, and outcome was measured additionally at 1 month, and again at 1 year, post-ECT. RESULTS: All but 1 patient demonstrated dramatic improvement, with statistically significant decreases in mean HDRS score detected after the first week of treatment. All responders maintained the benefits of their treatment. CONCLUSIONS: The results provide evidence of the clinical effectiveness of ECT in adolescents with phenomenological characteristics shown to be predictive of ECT response in adults.

A search for susceptibility loci for anorexia nervosa: methods and sample description.

BACKGROUND: Eating disorders have not traditionally been viewed as heritable illnesses; however, recent family and twin studies lend credence to the potential role of genetic transmission. The Price Foundation funded an international, multisite study to identify genetic factors contributing to the pathogenesis of anorexia nervosa (AN) by recruiting affective relative pairs. This article is an overview of study methods and the clinical characteristics of the sample. METHODS: All probands met modified DSM-IV criteria for AN; all affected first, second, and third degree relatives met DSM-IV criteria for AN, bulimia nervosa (BN), or eating disorder not otherwise specified (NOS). Probands and affected relatives were assessed diagnostically with the Structured Interview for Anorexia and Bulimia. DNA was collected from probands, affected relatives and a subset of their biological parents. RESULTS: Assessments were obtained from 196 probands and 237 affected relatives, over 98% of whom are of Caucasian ancestry. Overall, there were 229 relative pairs who were informative for linkage analysis. Of the proband-relative pairs, 63% were AN-AN, 20% were AN-BN, and 16% were AN-NOS. For family-based association analyses, DNA has been collected from both biological parents of 159 eating-disordered subjects. Few significant differences in demographic characteristics were found between proband and relative groups. CONCLUSIONS: The present study represents the first large-scale molecular genetic investigation of AN. Our successful recruitment of over 500 subjects, consisting of affected probands, affected relatives, and their biological parents, will provide the basis to investigate genetic transmission of eating disorders via a genome scan and assessment of candidate genes.

Relapse following discontinuation of lithium maintenance therapy in adolescents with bipolar I illness: a naturalistic study.

The authors conducted an 18-month naturalistic prospective follow-up study of 37 adolescents whose bipolar I illness had been stabilized with lithium carbonate during inpatient hospitalization. Thirteen of the patients discontinued prophylactic lithium therapy shortly after discharge. The relapse rate of bipolar illness in these 13 patients was nearly three times higher than the rate in patients who continued lithium prophylaxis without interruption. Early relapse among lithium-treated patients was associated with a greater risk of relapsing again. The authors discuss the theoretical and clinical implications of these findings.

Controlled family study of anorexia nervosa and bulimia nervosa: evidence of shared liability and transmission of partial syndromes.

OBJECTIVE: Lifetime rates of full and partial anorexia nervosa and bulimia nervosa were determined in first-degree relatives of diagnostically pure proband groups and relatives of matched, never-ill comparison subjects. METHOD: Rates of each eating disorder were obtained for 1,831 relatives of 504 probands on the basis of personal structured clinical interviews and family history. Best-estimate diagnoses based on all available information were rendered without knowledge of proband status and pedigree identity. Only definite and probable diagnoses were considered. RESULTS: Whereas anorexia nervosa was rare in families of the comparison subjects, full and partial syndromes of anorexia nervosa aggregated in female relatives of both anorexic and bulimic probands. For the full syndrome of anorexia nervosa, the relative risks were 11.3 and 12.3 in female relatives of anorexic and bulimic probands, respectively. Bulimia nervosa was more common than anorexia nervosa in female relatives of comparison subjects, but it, too, aggregated in the families of ill probands; the corresponding relative risks for bulimia nervosa were 4.2 and 4.4 for female relatives of anorexic and bulimic probands, respectively. When partial syndromes of anorexia nervosa and bulimia nervosa were considered, relative risks fell by one-half in each group of ill probands. CONCLUSIONS: Both anorexia nervosa and bulimia nervosa are familial. Their cross-transmission in families suggests a common, or shared, familial diathesis. The additional observation that familial aggregation and cross-transmission extend to milder phenotypes suggests the validity of their inclusion in a continuum of familial liability.

Perfectionism in anorexia nervosa: variation by clinical subtype, obsessionality, and pathological eating behavior.

OBJECTIVE: The purpose of this study was to examine the role of perfectionism as a phenotypic trait in anorexia nervosa and its relevance across clinical subtypes of this illness. METHOD: The Multidimensional Perfectionism Scale and the perfectionism subscale of the Eating Disorder Inventory were administered to 322 women with a history of anorexia nervosa who were participating in an international, multicenter genetic study of anorexia nervosa. All participants were additionally interviewed with the Yale-Brown Obsessive Compulsive Scale and the Yale-Brown-Cornell Eating Disorder Scale. Mean differences on dependent measures among women with anorexia nervosa and comparison subjects were examined by using generalized estimating equations. RESULTS: Persons who had had anorexia nervosa had significantly higher total scores on the Multidimensional Perfectionism Scale than did the healthy comparison subjects. In addition, scores of the anorexia subjects on the Eating Disorder Inventory-2 perfectionism subscale exceeded Eating Disorder Inventory-2 normative data. For the anorexia nervosa participants, the total score on the Multidimensional Perfectionism Scale and the Eating Disorder Inventory-2 perfectionism subscale score were highly correlated. Total score on the Multidimensional Perfectionism Scale was also significantly related to the total score and the motivation-for-change subscale score of the Yale-Brown-Cornell Eating Disorder Scale. CONCLUSIONS: These data show that perfectionism is a robust, discriminating characteristic of anorexia nervosa. Perfectionism is likely to be one of a cluster of phenotypic trait variables associated with a genetic diathesis for anorexia nervosa.

Decreased anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment in children with bipolar disorder.

This project was designed to compare differences in brain proton spectra between children and adolescents with bipolar disorder (BPD) and gender and age-matched normal controls, and to measure changes in myo-inositol levels following lithium therapy, utilizing in vivo proton magnetic resonance spectroscopy (1H MRS). A single voxel (2x2x2 cm3) was placed in brain anterior cingulate cortex for acquisition of the 1H spectra at baseline and after acute (7 days) lithium administration in 11 children (mean age 11.4 years) diagnosed with BPD, and in 11 normal controls. Acute lithium treatment was associated with a significant reduction in the myo-inositol/creatine ratio. This decrement was also significant in lithium-responders when analyzed separate from non-responders. Compared to normal controls, BPD subjects showed a trend towards a higher myo-inositol/creatine during the manic phase. These preliminary data provide evidence that a significant reduction in anterior cingulate myo-inositol magnetic resonance may occur after lithium treatment, especially among responders. Follow-up studies involving a larger sample may allow us to confirm whether changes in myo-inositol associated with acute lithium therapy persist in long-term clinical response of patients with and without lithium compliance.