Blake Woodside

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.

Comparison of 2 Family Therapies for Adolescent Anorexia Nervosa: A Randomized Parallel Trial

IMPORTANCE Anorexia nervosa (AN) is a serious disorder with high rates of morbidity and mortality. Family-based treatment (FBT) is an evidence-based therapy for adolescent AN, but less than half of those who receive this approach recover. Hence, it is important to identify other approaches to prevent the development of the chronic form of AN for which there is no known evidence-based treatment. OBJECTIVE To compare FBT with systemic family therapy (SyFT) for the treatment of adolescent-onset AN. DESIGN, SETTING, AND PARTICIPANTS Research in Anorexia Nervosa (RIAN) is a 2-group (FBT and SyFT) randomized trial conducted between September 2005 and April 2012. Interviewers were blinded to the treatment condition. A total of 564 adolescents receiving care at 6 outpatient clinics experienced in the treatment of AN were screened. Of these, 262 adolescents did not meet the inclusion criteria and 138 declined to participate; hence, 164 adolescents (aged 12-18 years) of both sexes meeting the criteria for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, AN (except for amenorrhea) were enrolled. Three participants were withdrawn from FBT and 7 were withdrawn from SyFT after serious adverse events occurred. INTERVENTIONS Two manualized family therapies with 16 one-hour sessions during 9 months. Family-based therapy focuses on the facilitation of weight gain, whereas SyFT addresses general family processes. MAIN OUTCOMES AND MEASURES The primary outcomes were percentage of ideal body weight (IBW) and remission (≥95% of IBW). The a priori hypothesis was that FBT would result in faster weight gain early in treatment and at the end of treatment (EOT). RESULTS There were no statistically significant differences between treatment groups for the primary outcome, for eating disorder symptoms or comorbid psychiatric disorders at the EOT or follow-up. Remission rates included FBT, 33.1% at the EOT and 40.7% at follow-up and SyFT, 25.3% and 39.0%, respectively. Family-based therapy led to significantly faster weight gain early in treatment, significantly fewer days in the hospital, and lower treatment costs per patient in remission at the EOT (FBT,

Unanticipated Rapid Remission of Refractory Bulimia Nervosa, during High-Dose Repetitive Transcranial Magnetic Stimulation of the Dorsomedial Prefrontal Cortex: A Case Report.

8963; SyFT,

Reductions in Cortico-Striatal Hyperconnectivity Accompany Successful Treatment of Obsessive-Compulsive Disorder with Dorsomedial Prefrontal rTMS

18 005). An exploratory moderator analysis found that SyFT led to greater weight gain than did FBT for participants with more severe obsessive-compulsive symptoms. CONCLUSIONS AND RELEVANCE The findings of this study suggest that FBT is the preferred treatment for adolescent AN because it is not significantly different from SyFT and leads to similar outcomes at a lower cost than SyFT. Adolescents with more severe obsessive-compulsive symptoms may receive more benefits with SyFT. TRIAL REGISTRATION clinicaltrials.gov Identifier NCT00610753.

Challenges in Conducting A Multi-Site Randomized Clinical Trial Comparing Treatments for Adolescent Anorexia Nervosa

A woman with severe, refractory bulimia nervosa (BN) underwent treatment for comorbid depression using repetitive transcranial magnetic stimulation (rTMS) of the dorsomedial prefrontal cortex (DMPFC) using a novel technique. Unexpectedly, she showed a rapid, dramatic remission from BN. For 5 months pre-treatment, she had reported two 5-h binge-purge episodes per day. After rTMS session 2 the episodes stopped entirely for 1 week; after session 10 there were no further recurrences. Depression scores improved more gradually to remission at session 10. Full remission from depression and binge-eating/purging episodes was sustained more than 2 months after treatment completion. In neuroimaging studies, the DMPFC is important in impulse control, and is underactive in BN. DMPFC–rTMS may have enhanced the patient’s ability to deploy previously acquired strategies to avoid binge-eating and purging via a reduction in her impulsivity. A larger sham-controlled trial of DMPFC–rTMS for binge-eating and purging behavior may be warranted.

Increases in frontostriatal connectivity are associated with response to dorsomedial repetitive transcranial magnetic stimulation in refractory binge/purge behaviors

Obsessive-compulsive disorder (OCD) is a disabling illness with high rates of nonresponse to conventional treatments. OCD pathophysiology is believed to involve abnormalities in cortico-striatal-thalamic-cortical circuits through regions such as dorsomedial prefrontal cortex (dmPFC) and ventral striatum. These regions may constitute therapeutic targets for neuromodulation treatments, such as repetitive transcranial magnetic stimulation (rTMS). However, the neurobiological predictors and correlates of successful rTMS treatment for OCD are unclear. Here, we used resting-state functional magnetic resonance imaging (fMRI) to identify neural predictors and correlates of response to 20–30 sessions of bilateral 10 Hz dmPFC-rTMS in 20 treatment-resistant OCD patients, with 40 healthy controls as baseline comparators. A region of interest in the dmPFC was used to generate whole-brain functional connectivity maps pre-treatment and post treatment. Ten of 20 patients met the response criteria (⩾50% improvement on Yale-Brown Obsessive-Compulsive Scale, YBOCS); response to dmPFC-rTMS was sharply bimodal. dmPFC-rTMS responders had higher dmPFC-ventral striatal connectivity at baseline. The degree of reduction in this connectivity, from pre- to post-treatment, correlated to the degree of YBOCS symptomatic improvement. Baseline clinical and psychometric data did not predict treatment response. In summary, reductions in fronto-striatal hyperconnectivity were associated with treatment response to dmPFC-rTMS in OCD. This finding is consistent with previous fMRI studies of deep brain stimulation in OCD, but opposite to previous reports on mechanisms of dmPFC-rTMS in major depression. fMRI could prove useful in predicting the response to dmPFC-rTMS in OCD.

MATCHING PATIENT VARIABLES TO TREATMENT INTENSITY: The Continuum of Care

OBJECTIVE To describe obstacles in the implementation of a controlled treatment trial of adolescent anorexia nervosa (AN). METHOD The original aim was to enter 240 participants with AN to one of four cells: Behavioral family therapy (BFT) plus fluoxetine; BFT plus placebo; systems family therapy (SFT) plus fluoxetine; SFT plus placebo. RESULTS Recruitment was delayed pending a satisfactory resolution concerning participant safety. After 6 months of recruitment it became clear that the medication was associated with poor recruitment leading to a study redesign resulting in a comparison of two types of family therapy with a projected sample size of 160. One site was unable to recruit and was replaced. DISCUSSION Problems with the delineation of safety procedures, recruitment, re-design of the study, and replacement of a site, were the main elements resulting in a 1-year delay. Suggestions are made for overcoming such problems in future AN trials.

Navigating the transition from pediatric to adult eating disorder programs: Perspectives of service providers

Background Conventional treatments for eating disorders are associated with poor response rates and frequent relapse. Novel treatments are needed, in combination with markers to characterize and predict treatment response. Here, resting-state functional magnetic resonance imaging (rs-fMRI) was used to identify predictors and correlates of response to repetitive transcranial magnetic stimulation (rTMS) of the dorsomedial prefrontal cortex (dmPFC) at 10 Hz for eating disorders with refractory binge/purge symptomatology. Methods 28 subjects with anorexia nervosa, binge−purge subtype or bulimia nervosa underwent 20–30 sessions of 10 Hz dmPFC rTMS. rs-fMRI data were collected before and after rTMS. Subjects were stratified into responder and nonresponder groups using a criterion of ≥50% reduction in weekly binge/purge frequency. Neural predictors and correlates of response were identified using seed-based functional connectivity (FC), using the dmPFC and adjacent dorsal anterior cingulate cortex (dACC) as regions of interest. Results 16 of 28 subjects met response criteria. Treatment responders had lower baseline FC from dmPFC to lateral orbitofrontal cortex and right posterior insula, and from dACC to right posterior insula and hippocampus. Responders had low baseline FC from the dACC to the ventral striatum and anterior insula; this connectivity increased over treatment. However, in nonresponders, frontostriatal FC was high at baseline, and dmPFC-rTMS suppressed FC in association with symptomatic worsening. Conclusions Enhanced frontostriatal connectivity was associated with responders to dmPFC-rTMS for binge/purge behavior. rTMS caused paradoxical suppression of frontostriatal connectivity in nonresponders. rs-fMRI could prove critical for optimizing stimulation parameters in a future sham-controlled trial of rTMS in disordered eating.

Targeting Neural Endophenotypes of Eating Disorders with Non-invasive Brain Stimulation

This article has reviewed what is currently known regarding the relationship between specific patient variables and treatment response in AN, BN, and BED. Matching patient variables to treatment intensity remains an important and fruitful area for future research. There is a need for established guidelines for clinicians regarding the choice of the appropriateness of treatment settings and type of interventions delivered in those settings. These guidelines should be evidence based, with clear clinical indicators for each of the recognized eating disorders and their subclinical variants.

Does family-based treatment reduce the need for hospitalization in adolescent anorexia nervosa?

OBJECTIVE This study aims to conduct qualitative research on the perspectives of service providers regarding the transition process from pediatric to adult specialized eating disorder tertiary care programs. METHOD Two focus groups with a diverse group of clinicians in pediatric and adult eating disorder programs and five qualitative interviews with clinicians in the community were conducted. RESULTS Three themes were identified as challenges during the transition process: (1) illness related factors (ambivalence and denial); (2) the interruption of normative adolescent developmental processes by the illness; and, (3) the impact of decreased parental involvement in the adult compared to pediatric eating disorder programs. DISCUSSION These themes were compared with empirical evidence on other chronic mental or physical health concerns for the purpose of identifying ways to facilitate a more successful service transition for young adults with anorexia nervosa. Future research and clinical implications are delineated.