Characterising illness stages and recovery trajectories of eating disorders in young people via remote measurement technology (STORY): a multi-centre prospective cohort study protocol.

BACKGROUND: Eating disorders (EDs) are serious, often chronic, conditions associated with pronounced morbidity, mortality, and dysfunction increasingly affecting young people worldwide. Illness progression, stages and recovery trajectories of EDs are still poorly characterised. The STORY study dynamically and longitudinally assesses young people with different EDs (restricting; bingeing/bulimic presentations) and illness durations (earlier; later stages) compared to healthy controls. Remote measurement technology (RMT) with active and passive sensing is used to advance understanding of the heterogeneity of earlier and more progressed clinical presentations and predictors of recovery or relapse. METHODS: STORY follows 720 young people aged 16-25 with EDs and 120 healthy controls for 12 months. Online self-report questionnaires regularly assess ED symptoms, psychiatric comorbidities, quality of life, and socioeconomic environment. Additional ongoing monitoring using multi-parametric RMT via smartphones and wearable smart rings ('Oura ring') unobtrusively measures individuals' daily behaviour and physiology (e.g., Bluetooth connections, sleep, autonomic arousal). A subgroup of participants completes additional in-person cognitive and neuroimaging assessments at study-baseline and after 12 months. DISCUSSION: By leveraging these large-scale longitudinal data from participants across ED diagnoses and illness durations, the STORY study seeks to elucidate potential biopsychosocial predictors of outcome, their interplay with developmental and socioemotional changes, and barriers and facilitators of recovery. STORY holds the promise of providing actionable findings that can be translated into clinical practice by informing the development of both early intervention and personalised treatment that is tailored to illness stage and individual circumstances, ultimately disrupting the long-term burden of EDs on individuals and their families.

A randomised controlled feasibility trial of intermittent theta burst stimulation with an open longer-term follow-up for young people with persistent anorexia nervosa (RaISE): Study protocol.

OBJECTIVE: We present the protocol of a feasibility randomised controlled trial (RCT) of intermittent theta burst stimulation (iTBS) for young people with anorexia nervosa (AN). Effective first-line psychological therapies exist for young people with AN, but little is known about how to treat those who do not respond. Non-invasive neuromodulation, such as iTBS, could address unmet treatment needs by targeting neurocircuitry associated with the development and/or maintenance of AN. DESIGN: Sixty-six young people (aged 13-30 years) with persistent AN will be randomly allocated to receive 20 sessions of real or sham iTBS over the left dorsolateral prefrontal cortex in addition to their usual treatment. Outcomes will be measured at baseline, post-treatment (1-month post-randomisation) and 4-months post-randomisation (when unblinding will occur). Additional open follow-ups will be conducted at 12- and 24-months post-randomisation. The primary feasibility outcome is the proportion of participants retained in the study at 4-months. Secondary outcomes include AN symptomatology, other psychopathology, quality of life, service utilisation, neurocognitive processes, and neuroimaging measures. DISCUSSION: Findings will inform the development of a future large-scale RCT. They will also provide exploratory data on treatment efficacy, and neural and neurocognitive predictors and correlates of treatment response to iTBS in AN.

Novel treatments for anorexia nervosa: Insights from neuroplasticity research.

OBJECTIVE: Treatment for anorexia nervosa (AN) remains challenging; there are no approved psychopharmacological interventions and psychotherapeutic strategies have variable efficacy. The investigation of evidence-based treatments has so far been compounded by an underdeveloped understanding into the neurobiological changes associated with the acute stages of AN. There is converging evidence of deficiencies in neuroplasticity in AN. METHOD: This paper provides an overview of neuroimaging, neuropsychological, molecular and qualitative findings relating to neuroplasticity in AN, translating these findings to the identification of novel biological and psychotherapeutic strategies. RESULTS: Novel psychopharmacological approaches that may ameliorate deficiencies in neuroplasticity include medications such as ketamine, psilocybin and human recombinant leptin. Anti-inflammatory medications and brain-derived neurotrophic factor mimetics may emerge as potential treatments following further research. Psychotherapeutic strategies that may target neuroplastic deficiencies, as well as having wider effects on identity, include imagery rescripting, memory specificity training, cognitive remediation therapy, exposure therapies, narrative therapies, cultural interventions (e.g. music and arts therapies) and yoga/mindfulness-based interventions. CONCLUSIONS: Treatments specifically targeted towards mitigating the neurobiological sequalae of AN are warranted, and emerging neurobiological and neuropsychological research utilising longitudinal designs and large sample sizes, as well as initial feasibility studies, are necessitated to bolster translational efforts.

Reply to Skokou, M. Comment on "Keeler et al. Ketamine as a Treatment for Anorexia Nervosa: A Narrative Review. Nutrients 2021, 13, 4158".

In response to our narrative review, which suggested the use of the glutamatergic n-methyl-D-aspartate (NMDA) receptor antagonist ketamine as a potential treatment for anorexia nervosa (AN) [...].

The experiential perspectives of siblings and partners caring for a loved one with an eating disorder in the UK.

BACKGROUND: Caring for a loved one with an eating disorder typically comes with a multitude of challenges, yet siblings and partners are often overlooked. It is important to understand if current clinical guidance for supporting carers are effective and being utilised for these groups, to help meet their needs. AIMS: To identify the experiential perspectives of siblings and partners of a loved one with an eating disorder compared with guidance for improving the adequacy of support provided to carers published by Beat and Academy for Eating Disorders. METHOD: Three online focus groups were held for ten siblings and five partners from across the UK (12 females and three males). Carers had experience of caring for a loved one with anorexia nervosa (13 carers) or bulimia nervosa (two carers), across a range of therapeutic settings. Focus group transcriptions were analysed with thematic analysis. RESULTS: Four key themes were identified: (a) role-specific needs, (b) challenges encountered by siblings and partners, (c) generic needs and helpful strategies or approaches, and (d) accounts of service provision and family support. CONCLUSIONS: Overall, the majority of experiences reported by siblings and partners did not meet the published guidance. Consequently, clinical practice recommendations were identified for services, alongside the charity sector, to take a proactive approach in detecting difficulties, providing skills training and emotional/practical support, adapting/tailoring peer support groups and supporting online facilitation. Our findings part-informed the design of our national online survey on loved ones' experiences of care in eating disorders.

Ketamine as a Treatment for Anorexia Nervosa: A Narrative Review.

Anorexia nervosa (AN) is a highly complex disorder to treat, especially in severe and enduring cases. Whilst the precise aetiology of the disorder is uncertain, malnutrition and weight loss can contribute to reductions in grey and white matter of the brain, impairments in neuroplasticity and neurogenesis and difficulties with cognitive flexibility, memory and learning. Depression is highly comorbid in AN and may be a barrier to recovery. However, traditional antidepressants are often ineffective in alleviating depressive symptoms in underweight patients with AN. There is an urgent need for new treatment approaches for AN. This review gives a conceptual overview for the treatment of AN with ketamine. Ketamine has rapid antidepressant effects, which are hypothesised to occur via increases in glutamate, with sequelae including increased neuroplasticity, neurogenesis and synaptogenesis. This article provides an overview of the use of ketamine for common psychiatric comorbidities of AN and discusses particular safety concerns and side effects. Potential avenues for future research and specific methodological considerations are explored. Overall, there appears to be ample theoretical background, via several potential mechanisms, that warrant the exploration of ketamine as a treatment for adults with AN.

Perspectives on psychedelic treatment and research in eating disorders: a web-based questionnaire study of people with eating disorders.

Approximately 1.25 million people in the UK suffer from an eating disorder, yet the treatment options show limited efficacy, warranting the need for novel approaches. This study aimed to investigate the perspectives of people with eating disorders on the use of complementary therapies and psychedelic research and treatment. Two hundred participants with eating disorders took part in this web survey study. The majority of participants (70%) had used a complementary treatment to manage their eating disorder. Participants believed that psychedelic research was worthwhile in the context of a moderate level of concern. The most popular solutions to meet these concerns included providing education around psychedelics and their effects and use in psychiatry and experiencing endorsement from professionals in the area. Moreover, participant responses emphasized the need for a safe, monitored environment and the patient-therapist rapport in the context of psychedelic treatment. The findings are explored concerning future trials of psychedelics as a treatment for eating disorders.

Fear conditioning in women with anorexia nervosa and healthy controls: A preliminary study.

Anorexia nervosa is characterized by anxiety-driven behaviors, such as food avoidance and distressing persistent thoughts about weight gain and body image. The present study used a classical fear conditioning procedure to test the processes of fear acquisition and generalization, extinction, and renewal in patients with anorexia nervosa and healthy controls. An app-based fear conditioning procedure was administered remotely to 64 patients and 60 healthy controls, over two sessions. A human female scream served as the unconditioned stimulus (US) and two neutral shapes were used as either the paired conditioned stimulus (danger cue; CS+) or the unpaired conditioned stimulus (safe cue; CS-). Patients with anorexia nervosa reported greater threat expectancy in response to the danger cue during the extinction and renewal phases and overall higher levels of negative affect throughout the task, compared with controls. Future research is warranted to replicate these findings and highlight the role that anxiety plays in explaining fear conditioning responses in patients with anorexia nervosa. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Length of stay for anorexia nervosa: Systematic review and meta-analysis.

OBJECTIVE: Evidence regarding global trends in length of stay for patients with anorexia nervosa is limited. The aim of this study is to conduct a meta-analysis examining the length of stay for anorexia nervosa patients globally, and to investigate moderators of the variance. METHOD: Medline, EMBASE and PsycINFO were searched for studies published up to January 2019. Two independent reviewers assessed the eligibility of each report based on predefined inclusion criteria. A meta-analysis was performed to calculate a pooled mean length of stay using the random-effects model. Subgroup analyses and meta-regression were conducted to explore potential sources of heterogeneity between studies. RESULTS: Of 305 abstracts reviewed, 71 studies met the inclusion criteria, generating 111 datasets. The pooled mean length of stay (95% confidence interval) was 76.3 days (73.3, 79.4) using the random-effects model, with marked variation across countries and time. Heterogeneity between studies was explained by age and admission body mass index. CONCLUSIONS: This meta-analysis found that although clinical features do contribute to length of admissions for anorexia nervosa, there are also global and temporal variations. Future research should provide an in-depth analysis of why and how this variation exists and what the impact is on the well-being of people with anorexia nervosa.

Pharmacological treatment of eating disorders, comorbid mental health problems, malnutrition and physical health consequences.

The pharmacological treatment of patients with an eating disorder (ED) often includes medications to treat their ED, comorbid mental health problems, malnutrition and the physical health problems resulting from it. The currently approved pharmacological treatment options for EDs are limited to fluoxetine for bulimia nervosa (BN) and - in some countries - lisdexamfetamine for binge eating disorder (BED). Thus, there are no approved pharmacological options for anorexia nervosa (AN), even though study results for olanzapine and dronabinol are promising. Topiramate might be an additional future option for the treatment of BN and BED. Selective serotonin reuptake inhibitors (SSRI), mirtazapine and bupropion could be considered for the treatment of comorbid unipolar depression. However, AN and BN are contraindications for bupropion. For ED patients with a manic episode, we recommend olanzapine in AN and risperidone in BN and BED; whereas for bipolar depression, olanzapine (plus fluoxetine) seems appropriate in AN and lamotrigine in BN and BED. Acute anxiety or suicidality may warrant benzodiazepine treatment with lorazepam. Proton-pump inhibitors, gastroprokinetic drugs, laxatives and hormones can alleviate certain physical health problems caused by EDs. Therapeutic drug monitoring, pharmacogenomic testing, a more restrictive use of "pro re nata" (PRN) medication, an interdisciplinary treatment approach, shared decision making (SDM) and the formulation of common treatment goals by the patients, their family or carers and clinicians could improve treatment success and safety. Novel genetic, immunological, microbiome and brain imaging research as well as new pharmacological developments like the use of psychedelics, stimulants, novel monoaminergic drugs, hormone analogues and drugs which enhance the effects of psychotherapy may extend our therapeutic options in the near future.

Common etiological architecture underlying reward responsiveness, externally driven eating behaviors, and BMI in childhood: findings from the Gemini twin cohort.

BACKGROUND: Studies have reported that impulsivity predicts childhood BMI and that the association is mediated by eating behaviors. One aspect of impulsivity-potentially crucial in the obesity context-is reward responsiveness, which may predispose to responsiveness to palatable food cues. The behavioral susceptibility theory hypothesizes that genetic susceptibility to obesity operates partly via genetically determined differences in appetite regulation. Reward responsiveness may therefore be one of the neuro-endophenotypes that mediates genetic susceptibility to obesity. OBJECTIVE: To test whether reward responsiveness, eating behaviors, and child BMI share common genetic architecture. METHODS: We examined reward responsiveness, eating behaviors, and BMI in 5-year-old children from Gemini, a UK birth cohort of 2402 twin pairs born in 2007. All measures were collected by parent report. Reward responsiveness was derived from the Behavioral Approach System. Compulsion to eat and eating for pleasure was measured with the "food responsiveness" scale of the Child Eating Behavior Questionnaire. Wanting to eat in response to environmental food cues was measured with the "external eating" scale of the Dutch Eating Behavior Questionnaire. Maximum-likelihood structural equation modeling was used to establish underlying common genetic and environmental influences. RESULTS: There were significant positive phenotypic correlations between all traits except for reward responsiveness and BMI. Genetic factors explained the majority of the association between food responsiveness and external eating (74%, 95% CI: 61, 87), whereas common shared environmental factors explained the majority of the associations between reward responsiveness with both food responsiveness (55%, 95% CI: 20, 90) and external eating (70%, 95% CI: 39, 100). CONCLUSIONS: Our study demonstrates the importance of common environmental factors in the shared etiology between reward responsiveness and childhood eating behaviors. However, the common etiology underlying both reward responsiveness and BMI is unclear, as there was no phenotypic correlation between reward responsiveness and BMI at this age. Further longitudinal research needs to detangle this complex relationship throughout development.

A Meta-Analysis of Dropout and Metabolic Effects of Antipsychotics in Anorexia Nervosa.

BACKGROUND: Second-generation antipsychotics are often used off-label in the treatment of anorexia nervosa (AN) across the clinical spectrum. Patients with anorexia nervosa often cite concerns about metabolic effects, such as weight gain, as reasons for their reluctance to start or continue second-generation antipsychotics. Improving our understanding of the metabolic effect patients experience and reasons underlying their disinclination will enable us to build rapport and guide our clinical decisions. We therefore aimed to conduct a comprehensive review of dropouts, metabolic effects, and patient-reported outcomes associated with second-generation antipsychotic in people with AN. METHOD: EMBASE, Medline, and PsycINFO were searched for all relevant studies published until 2019, and retrieved studies were assessed for eligibility as per predefined inclusion criteria. A random-effects meta-analysis was conducted to assess overall dropout rates. RESULTS: Of 983 citations retrieved, 21 studies met the inclusion criteria for the systematic review and 10 studies had appropriate data for meta-analysis. Using the random effects model, the pooled dropout rate in the intervention arm (95% confidence interval) from psychopharmacological trials was 28% (19 to 38%) in people with AN. Personal reasons or factors associated with study were commonest reason for dropout, not adverse events or metabolic effects as hypothesized. CONCLUSION: Compared to personal reasons, drug-related factors such as side effects seem to play a lesser role for the discontinuation of antipsychotic treatment under trial conditions. This suggests an urgent need to consider and fully examine potential individual and patient-related factors that influence dropout rates in psychopharmacological trials and treatment compliance in clinical settings.

Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank.

Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8 × 10-7 versus rg = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10-4). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.

A major role for common genetic variation in anxiety disorders.

Anxiety disorders are common, complex psychiatric disorders with twin heritabilities of 30-60%. We conducted a genome-wide association study of Lifetime Anxiety Disorder (ncase = 25 453, ncontrol = 58 113) and an additional analysis of Current Anxiety Symptoms (ncase = 19 012, ncontrol = 58 113). The liability scale common variant heritability estimate for Lifetime Anxiety Disorder was 26%, and for Current Anxiety Symptoms was 31%. Five novel genome-wide significant loci were identified including an intergenic region on chromosome 9 that has previously been associated with neuroticism, and a locus overlapping the BDNF receptor gene, NTRK2. Anxiety showed significant positive genetic correlations with depression and insomnia as well as coronary artery disease, mirroring findings from epidemiological studies. We conclude that common genetic variation accounts for a substantive proportion of the genetic architecture underlying anxiety.

Genetic Overlap Between Type 2 Diabetes and Depression in a Sri Lankan Population Twin Sample.

OBJECTIVE: Results from twin studies examining the genetic overlap between type 2 diabetes and depression are currently inconclusive. This question has not been addressed in non-Western populations. We aimed to examine whether there are common genetic factors between type 2 diabetes and depression in a Sri Lankan population using genetic model-fitting analysis. METHOD: The Colombo Twin and Singleton Study-Phase 2 consists of 2019 singletons, and 842 monozygotic and 578 dizygotic twin pairs. The primary outcomes were self-reported type 2 diabetes diagnosis and Beck Depression Inventory scores. Standard bivariate twin models were fitted to estimate the genetic and environmental (co)variance of type 2 diabetes and depression. RESULTS: In the best-fitting model, the phenotypic correlation between type 2 diabetes and depression was significant in female individuals only (r = 0.15 [0.08-0.21]). This association was primarily attributed to a significant genetic correlation between the traits (rA = 0.53 [0.19-0.98]). CONCLUSIONS: In female individuals, but not male individuals, we found a significant genetic overlap between type 2 diabetes and depression in the context of a modest phenotypic correlation.

An illustration of collaborative care with a focus on the role of fathers in Maudsley Anorexia Nervosa Treatment for Adults (MANTRA).

The aim of this case study is to illustrate the importance of collaborative care as part of Maudsley Anorexia Nervosa Treatment for Adults (MANTRA). Mothers are often at the foreground of providing support within the family. However, fathers have the potential to play a profound role. In this paper, we describe a patient with anorexia nervosa treated with the MANTRA. The formulation of this case included autistic spectrum traits in both the father and daughter leading to social isolation. We describe how the family members were engaged into treatment and how paternal support was used to promote social connection and an improved quality of life in the daughter. Some details of the case have been altered to maintain confidentiality.

The association between emotional eating and depressive symptoms: a population-based twin study in Sri Lanka.

This study investigated the genetic and environmental contributions to emotional overeating (EOE) and depressive symptoms, and their covariation, in a Sri-Lankan population, using genetic model-fitting analysis. In total, 3957 twins and singletons in the Colombo Twin and Singleton Study-Phase 2 rated their EOE behaviour and depressive symptoms, which were significantly associated (men: r = 0.11, 95% confidence interval (CI) 0.06-0.16, women: r = 0.12, 95% CI 0.07-0.16). Non-shared environmental factors explained the majority of variance in men (EOE e2 = 87%, 95% CI 78-95%; depressive symptoms e2 = 72%, 95% CI 61-83%) and women (EOE e2 = 76%, 95% CI 68-83%; depressive symptoms e2 = 64%, 95% CI 55-74%). Genetic factors were more important for EOE in women (h2 = 21%, 95% CI 4-32%) than men (h2 = 9%, 95% CI 0-20%). Shared-environmental factors were more important for depressive symptoms in men (c2 = 25%, 95% CI 10-36%) than women (c2 = 9%, 95% CI 0-35%). Non-shared environmental factors explained the overlap between depressive symptoms and EOE in women but not in men. Results differed from high-income populations, highlighting the need for behavioural genetic research in global populations.

Task-sharing interventions for patients with anorexia nervosa or their carers: a systematic evaluation of the literature and meta-analysis of outcomes.

The eating disorder clinical and scientific community advocates for the use of a shared approach to healthcare that actively involves patients and carers. A systematic review of the literature on guided self-help or self-help in anorexia nervosa (targeting either the individual affected by the illness or their carers) and meta-analyses of studies using randomised controlled designs for the evaluation of the outcomes: (1) drop-out from end-of-treatment assessment, (2) body mass index (BMI), (3) anxiety, (4) depression and (5) quality of life, were undertaken. Guided self-help was directed to patients in 15 studies and to carers in seven studies. The interventions were based on a variety of theoretical models, used different formats (books and digital materials), and were delivered by individuals with a range of experiences and expertise (e.g. individuals with lived experience of the illness, graduate students, or clinically trained professionals). Guided self-help was associated with significantly lower drop-out from the completion of end-of-treatment assessments compared to a control condition. There was an improvement in carers' wellbeing from skill-sharing interventions. Guided self-help may facilitate patients' treatment engagement and also improve carers' wellbeing.