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Abstract Background The OPEN feasibility trial testing olanzapine in anorexia nervosa (AN) in young people (YP) was not successful due to poor recruitment. This study aims to understand clinicians’ views and experiences of using olanzapine in AN and the challenges in implementing the trial in National Health Service (NHS) clinical settings. Methods We conducted qualitative interviews with eating disorders (ED) clinicians involved with the study (n = 11). Framework analysis was applied to qualitative data to identify barriers and facilitators to recruitment and study implementation. A web-based semi-structured Qualtrics survey was administered to ED clinicians (n = 24). Findings from the survey were used to corroborate and expand on the information derived from qualitative interviews. Results Qualitative analysis identified four main themes: (1) Acknowledging Service User (SU) / Family Concerns, (2) Prioritising person-centred care, (3) Limited Service Capacity and (4) Study eligibility criteria. Subthemes are outlined accordingly. Clinicians appeared confident addressing SU concerns around olanzapine in clinical discussions, but timing was critical, and olanzapine was considered one aspect of treatment that needed to align with their holistic approach. Service pressures restricted opportunities for recruitment and the ability to offer regular review. At the same time, some YP were ineligible for the trial, as they were already taking olanzapine, or needed to be prescribed it more promptly than the study procedures allowed. Survey findings underlined confidence in prescribing and informing on olanzapine, the various possible benefits of olanzapine besides weight gain, and the importance of therapeutic alliances and informed consent. Both data sets highlight the need for further evidence on long-term safety, side effects and efficacy of olanzapine use for AN. Where clinical service capacity is at a premium, research implementation is not prioritised, particularly in intensive clinical settings. Conclusions Findings provide first-hand insight into individual and systemic challenges with research implementation in the NHS, which need to be considered when designing future clinical research studies. We emphasise a person-centred approach when discussing olanzapine to consider a holistic recovery from AN beyond weight-gain as an isolated outcome for improvement.

Abstract Introduction Although there have been qualitative meta-syntheses on experiences of eating disorders treatments, there is a paucity of syntheses specifically examining the perspectives and experiences of eating disorders treatments (ED) in East Asia (EA). Such synthesis could facilitate a better understanding of culture-specific perspectives and experiences. This review complements a quantitative scoping review published on ED treatments in EA (Yim & Schmidt, 2023), where most interventions reviewed focused on cognitive behavioural therapy (CBT) and internet interventions. The present meta-synthesis summarises stakeholders’ views on treatments and to synthesise clinical and research recommendations. Method A systematic search of five databases and a citation search were conducted to identify relevant studies and data were analysed using thematic synthesis. Out of the 301 studies found, a total of 12 papers were included in the analysis. Results A diverse range of treatments, such as family therapy, paediatric/psychiatric inpatient care, CBT, and counselling, were discussed. Three overarching themes were identified: Delineating Physical and Psychological Recovery; ‘I am not alone in this battle’; and Barriers to Change. The themes further delve into the various obstacles to recovery, including financial concerns and limited access to professionals and services. Culture-specific factors include family obligations and promoting family harmony. Balancing interdependence and independence from one’s family, as well as understanding family body ideals versus broader societal body ideals, are important considerations in ED interventions. Discussion Some themes paralleled other qualitative syntheses, highlighting improved family relationships, perceived authoritarianism in treatments, and financial barriers. The review extends beyond the previous findings, revealing nuanced factors like family roles, cultural values, and norms. Clinical recommendations include incorporating family context in treatment and considering cultural influences on body image ideals. Capacity building through telemedicine and increased training is essential for advancing ED treatment in East Asia. Continued research is needed to better understand and treat people affected by ED in EA.

Abstract Background Eating disorders are complex difficulties that impact the individual, their supporters and society. Increasing numbers are being admitted to intensive treatment settings (e.g., for inpatient treatment, day-patient treatment or acute medical treatment). The lived experience perspectives of what helps and hinders eating disorder recovery during intensive treatment is an emerging area of interest. This review aims to explore patients’ perspectives of what helps and hinders recovery in these contexts. Methods A systematic review was conducted to identify studies using qualitative methods to explore patients’ experiences of intensive treatment for an eating disorder. Article quality was assessed using the Critical Appraisal Skill Programme (CASP) checklist and thematic synthesis was used to analyse the primary research and develop overarching analytical themes. Results Thirty articles met inclusion criteria and were included in this review. The methodological quality was mostly good. Thematic synthesis generated six main themes; collaborative care supports recovery; a safe and terrifying environment; negotiating identity; supporting mind and body; the need for specialist support; and the value of close others. The included articles focused predominantly on specialist inpatient care and were from eight different countries. One clear limitation was that ethnicity data were not reported in 22 out of the 30 studies. When ethnicity data were reported, participants predominantly identified as white. Conclusions This review identifies that a person-centred, biopsychosocial approach is necessary throughout all stages of eating disorder treatment, with support from a sufficiently resourced and adequately trained multidisciplinary team. Improving physical health remains fundamental to eating disorder recovery, though psychological support is also essential to understand what causes and maintains the eating disorder and to facilitate a shift away from an eating disorder dominated identity. Carers and peers who instil hope and offer empathy and validation are valuable additional sources of support. Future research should explore what works best for whom and why, evaluating patient and carer focused psychological interventions and dietetic support during intensive treatment. Future research should also explore the long-term effects of, at times, coercive and distressing treatment practices and determine how to mitigate against potential iatrogenic harm.

Abstract Background Multi-family Therapy (MFT) is being increasingly used in specialist eating disorder services internationally. Despite evidence of its efficacy, little is understood about the treatment mechanisms and what specifically promotes change. This study aimed to understand clinician perspectives on how change occurs during MFT. Methods Clinicians with (a) 5 or more years’ experience facilitating MFT and (b) who had facilitated a minimum of two MFT groups were eligible for this study. Two individual interviews and four semi-structured focus groups were conducted online. Recordings were transcribed verbatim and analysed using reflexive thematic analysis. Results Twelve clinicians (five systemic/family psychotherapists, five clinical psychologists, and two consultant child and adolescent psychiatrists) from six different specialist services in the UK participated. Four main inter-connected themes describing how change is perceived to occur were generated; (1) Intensity and immediacy, (2) Flexibility, (3) New ideas and channels of learning and (4) Containment. Conclusions Current data matches closely with young person and parent experiences of MFT and intensive day treatment and how they perceive change to occur. Quantitative data are now needed to evaluate the impact of these factors on outcome. Plain English Summary Multi-family Therapy (MFT) is being increasingly used in specialist eating disorder services internationally. While there is evidence that it is helpful, little is understood about how the treatment works and what specifically promotes change. This study aimed to understand how clinician believe change to occur during MFT for young people and their family members. Clinicians with (a) five or more years’ experience facilitating MFT and (b) who had facilitated a minimum of two MFT groups were eligible for this study. Two individual interviews and four semi-structured focus groups were conducted online. Recordings were written out word-for-word and analysed using reflexive thematic analysis, a commonly used method for analysing this type of data. Twelve clinicians (five systemic/family psychotherapists, five clinical psychologists, and two consultant child and adolescent psychiatrists) from six different specialist services in the UK participated. Four related themes describing how change is perceived to occur were generated; (1) Intensity and immediacy, (2) Flexibility, (3) New ideas and channels of learning and (4) Containment. Current data matches closely with young person and parent experiences of MFT and intensive day treatment and how they perceive change to occur. These factors now need to be tested in future research.

Abstract 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 (‘Ōura 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.

Abstract Background The First Episode Rapid Early Intervention for Eating Disorders (FREED) service has been shown to reduce the wait for care and improve clinical outcomes in initial evaluations. These findings led to the national scaling of FREED in England. To support this scaling, we conducted a mixed method evaluation of the perceptions and experiences of clinicians in the early phases of scaling. The Normalisation Process Theory (NPT) was used as a conceptual lens to understand if and how FREED becomes embedded in routine practice. Methods The convergent mixed method evaluation included 21 semi-structured interviews with clinicians from early adopter sites and 211 surveys administered to clinicians before, immediately after and 3 months after the FREED training. The interview guide and survey included questions evaluating attitudes towards early intervention for eating disorders (EDs) and NPT mechanisms. Interview data were analysed using an inductive thematic analysis. The NPT was applied to the inductively derived themes to evaluate if and how NPT domains impacted the implementation. Survey data were analysed using multilevel growth models. Results Six themes and 15 subthemes captured barriers and facilitators to implementation at the patient, clinician, service, intervention, implementation and wider system levels. These interacted with the NPT mechanisms to facilitate or hinder the embedding of FREED. Overall, clinicians were enthusiastic and positive towards early intervention for EDs and FREED, largely because of the expectation of improved patient outcomes. This was a considerable driver in the uptake and implementation of FREED. Clinicians also had reservations about capacity and the potential impact on other patients, which, at times, was a barrier for its use. The FREED training led to significant improvements in positive attitudes and NPT mechanisms that were largely maintained at the 3-month follow-up. However, negative attitudes did not significantly improve following training. Conclusions Positive attitudes towards early intervention for EDs increased enthusiasm and engagement with the model. Features of the model and its implementation were effective at developing adopter commitment and capabilities. However, there were aspects of the model and its implementation which require attention in the future (e.g., capacity and the potential impact on the wider service).

Abstract Background Family therapy for anorexia nervosa (FT-AN) is the first line recommended treatment for child and adolescent anorexia nervosa. Despite evidence of its efficacy, little is understood about the treatment mechanisms. This study aimed to understand how young people who have received FT-AN perceive change to occur across treatment. Method Fifteen adolescents (age 12–18 years) completed individual semi-structured interviews online. Recordings were transcribed verbatim and analysed using reflexive thematic analysis. Results Four inter-connected themes describing the process of change during treatment were generated; (1) relationships as the vehicle for change, (2) an awakening, (3) through, not around – no way out, (4) the life beyond. Conclusions Current data match relatively closely with theoretical models of FT-AN and emphasise the importance of building trust with all family members, including the young person. Additionally, supporting the family to create a trusting context in which there is a sense that the only way out of the illness is by going through it (rather than avoiding it) is critical. Empirical investigation of each of the described mechanisms is needed.

Abstract Background In a feasibility randomised controlled trial in people with overweight/obesity with and without binge eating disorder (BED) symptoms, we assessed eight weekly sessions of attention bias modification training (ABMT) and mindfulness training (MT) versus waiting list (WL) and explored potential mechanisms. Methods 45 participants were randomly allocated to one of three trial arms. Primary outcomes were recruitment, retention and treatment adherence rates. Secondary outcomes included measures of eating behaviour, mood, attention and treatment acceptability. Assessments were conducted at baseline, post-intervention (week 8), and follow-up (week 12). Results Participant retention at follow-up was 84.5% across groups. Session completion rates in the laboratory were 87% for ABMT and 94% for MT, but home practice was much poorer for ABMT. Changes in BMI and body composition were small between groups and there was a medium size BMI reduction in the MT group at follow-up. Effect sizes of eating disorder symptom changes were not greater for either intervention group compared to WL, but favoured ABMT compared to MT. Hedonic hunger and mindful eating scores favoured MT compared to ABMT and WL. ABMT reduced attention biases towards high-calorie food cues, which correlated with lower objective binge eating days at post-intervention. No significant changes were observed in the MT, or WL conditions. Conclusions Both ABMT and MT have potential value as adjuncts in the treatment of obesity and BED, and a larger clinical trial appears feasible and indicated. Trial registration: ISRCTN Registry, ISRCTN15745838. Registered on 22 May 2018.

Plain English summary Individuals with eating disorders (EDs) have an increased risk for developing osteoporosis and suffering fractures. To better understand this problem, we conducted a systematic review and meta-analysis comparing bone mineral density (BMD) of females with EDs with that of healthy people without an ED. We also tried to identify key factors linked with reduced bone mass in EDs. We included studies reporting BMD of individuals with anorexia nervosa (AN), bulimia nervosa (BN), binge-eating (BED) or other non-specified ED (OSFED), and of healthy controls. We found that people with AN had overall lower BMD than controls and also in the spine, hip, and femur. In people with BN, there was lower BMD overall and in the spine, but that must be only in those who previously had AN. In people with OSFED, BMD was lower in the spine. Having a low BMI, low fat mass, low lean mass and not having menstrual periods seem to negatively affect BMD. Therefore, this systematic review supports the idea that people with current or past AN, irrespective of their current ED diagnosis, should have their bone health assessed. For early identification of those most at risk, body composition measurements, current menstrual status, duration of amenorrhoea and presence or absence of a history of AN should be considered in clinical practice.

Abstract Background Due to scarce resources and high demand, priority setting in mental health services is necessary and inevitable. To date, no study has examined priority setting in eating disorder (ED) services specifically. Here, we evaluate the level of consensus and perceived relative importance of factors used to determine patient prioritisation in ED services, amongst clinicians and individuals with lived experience (LE) of an ED. Methods A three round Delphi study and a ranking task were used to determine the level of consensus and importance. Consensus was defined as > 80% agreement or disagreement. Items that reached consensus for agreement were ranked in order of importance from most to least important. Participants were 50 ED clinicians and 60 LE individuals. Participant retention across rounds 2, 3, and 4 were 92%, 85%, and 79%, respectively. Results Over three iterative rounds, a total of 87 statements about patient prioritisation were rated on a 5-point Likert-scale of agreement. Twenty-three items reached consensus in the clinician panel and 20 items reached consensus in the LE panel. The pattern of responding was broadly similar across the panels. The three most important items in both panels were medical risk, overall severity, and physical health deteriorating quickly. Clinicians tended to place greater emphasis on physical risk and early intervention whereas the LE panel focused more on mental health and quality of life. Conclusions Eating disorder services tend to prioritise patients based upon medical risk and severity, and then by the order in which patients are referred. Our findings align in some respects with what is observed in services, but diverge in others (e.g., prioritising on quality of life), providing important novel insights into clinician and LE opinions on waiting list prioritisation in EDs. More research is warranted to validate these findings using multi-criterion decision techniques and observational methods. We hope these findings provide a foundation for future research and encourage evidence-based conversations around priority setting in ED services.

Plain English Summary People with anorexia nervosa often have difficulty thinking flexibly and in terms of the big picture. We investigated whether these thinking styles (1) change over treatment, (2) influence response to treatment, or (3) predict whether people gain weight or overcome the eating disorder. We found that people were able to think more flexibly after treatment. We also found that people who had more difficulty seeing the big picture prior to treatment had a more rapid decrease in eating disorder symptoms and clinical impairment in treatment. Thinking styles did not predict whether people gained weight early in treatment or overcame the eating disorder. Our findings suggest that the detail-focused thinking style commonly observed among people with anorexia nervosa can be both a vulnerability and a strength.

Abstract Background Anorexia nervosa (AN) is a serious and disabling mental disorder with a high disease burden. In a proportion of cases, intensive hospital-based treatments, i.e. inpatient or day patient treatment, are required, with day patient treatment often being used as a ‘step-down’ treatment after a period of inpatient treatment. Demand for such treatment approaches has seen a sharp rise. Despite this, the relative merits of these approaches for patients, their families, and the NHS and wider society are relatively unknown. This paper describes the rationale for, and protocol of, a two-arm multi-centre open-label parallel group non-inferiority randomised controlled trial, evaluating the effectiveness and cost-effectiveness of these two intensive treatments for adults with severe AN: inpatient treatment as usual and a stepped care day patient approach (the combination of day patient treatment with the option of initial inpatient treatment for medical stabilisation). The main aim of this trial is to establish whether, in adults with severe AN, a stepped care day patient approach is non-inferior to inpatient treatment as usual in relation to improving body mass index (BMI) at 12 months post-randomisation. Methods 386 patients with a Diagnostic and Statistical Manual 5th edition diagnosis of severe AN or related disorder, with a BMI of ≤16 kg/m2 and in need of intensive treatment will be randomly allocated to either inpatient treatment as usual or a stepped care day patient approach. Patients in both groups will receive treatment until they reach a healthy weight or get as close to this point as possible. Assessments will be conducted at baseline (prior to randomisation), and at 6 and 12 months post-randomisation, with additional monthly symptom monitoring. The primary outcome will be BMI at the 12-month post-randomisation assessment. Other outcomes will include psychosocial adjustment; treatment motivation, expectations and experiences; cost-effectiveness; and carer burden. Discussion The results of this study will provide a rigorous evaluation of two intensive treatment approaches which will inform future national and international treatment guidelines and service provision. Trial registration ISRCTN ISRCTN10166784 . Registered 28 February 2020. ISRCTN is a primary registry of the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) network and includes all items from the WHO Trial Registration Data Set.

Plain English summary The COVID-19 pandemic has significantly affected eating disorder inpatient and day patient treatment. However, the impact of the pandemic on clinicians working in these settings is largely unknown. We interviewed twenty-one clinicians working in specialist inpatient and day patient eating disorder services to explore their views on supporting people with severe anorexia nervosa during the pandemic. We analysed the transcripts using thematic analysis. We identified that COVID-19 posed significant challenges for intensive treatment settings, forcing the closure or merging of eating disorder services, the delivery of treatment under restrictions, and the introduction of virtual treatment. These changes challenged the delivery of multidisciplinary treatment for people with severe anorexia nervosa and impacted referral pathways, clinicians’ wellbeing, risk management, and patients’ isolation and recovery trajectories. We also identified some opportunities as a result of the pandemic, in particular in day patient services offering virtual support. These opportunities included more accessible treatment for patients and their families, more individualised treatment, and the chance for treatment innovation and creativity.

Plain English summary Patients with a severe form of anorexia nervosa (AN) are often treated as inpatients. Many of them benefit from this acute treatment. Unfortunately, a significant number of patients experience relapse after discharge. This problem could be addressed by specific treatments directly following inpatient therapy, so called aftercare interventions, which are tailored to patients’ needs in this treatment period. This review looks at studies which have investigated the efficacy of aftercare interventions for patients with AN directly after inpatient treatment. We included any studies which compared a novel aftercare intervention to a control treatment and where patients were randomly assigned to either of these treatments, as this procedure is considered to reduce bias. We found seven studies that investigated different aftercare intervention approaches, including medication, guided self-help and psychotherapy, and three ongoing studies. Based on the very limited evidence so far, no clear recommendations can be made favoring a specific approach for post-inpatient aftercare in adult patients with AN. The review shows that it should be a priority to increase uptake of aftercare interventions and to reduce dropout rates. This could be achieved by a better tailoring of interventions to patient needs and the integration of patient perspectives in intervention design. More studies are needed to find interventions which allow patients with AN to maintain treatment gains after intensive inpatient treatment.

Plain English summary Repetitive transcranial magnetic stimulation (rTMS) is a novel treatment option for people with severe enduring anorexia nervosa (SE-AN). However, little is known about the neurobiological effects of this treatment. This study explored the effect of rTMS treatment on regional cerebral blood flow (CBF) and whether any observed changes in CBF are associated with changes in clinical outcomes in people with SE-AN. Participants completed arterial spin labelling (ASL) functional magnetic resonance imaging (fMRI) before and after receiving 20 sessions (over 4 weeks) of real or sham rTMS. We found a greater reduction in amygdala CBF following real rTMS compared to sham rTMS. Participants with the greatest rTMS-related reduction in amygdala CBF showed the greatest sustained weight gain at an 18-month follow-up. Higher baseline CBF in the insula predicted greater weight gain during treatment and at a 4-month follow-up. This suggests that CBF (as measured by ASL fMRI) may be a marker of rTMS treatment response in this patient group. Future rTMS studies in AN should use longitudinal neuroimaging to further explore the neurobiological changes related to rTMS treatment.

Plain English summary Treatments for Anorexia Nervosa (AN) are somewhat effective, but there is room for improvement. A core struggle for individuals with Anorexia Nervosa is managing emotions especially in a social context. One of the leading treatments for AN - MANTRA – was adapted to be delivered in a group to provide opportunities for individuals to practice experiencing and managing emotions amongst others. We hoped that being in a group could help tackle the shame and isolation that many people with AN endure. Patients seemed to find value in this approach and there are early signs that it may support people on their journey of recovery from Anorexia Nervosa.

Abstract Introduction Multi-family therapy (MFT) is a recommended treatment for adolescent anorexia nervosa internationally. Despite recent significant advances in single-family therapy, the evidence base for MFT remains relatively small. Several individual and family factors have been associated with poorer outcomes in single-family therapy, many of which may be addressed or ameliorated by MFT if delivered early in treatment. This trial aims to determine the feasibility and acceptability of adding a five-day multi-family therapy group to the early stages of family therapy for anorexia nervosa. Secondary objectives are to explore effect size changes in key individual and family factors across treatment. Methods This feasibility trial will use a randomised controlled design. Sixty adolescents (age 10–17 inclusive) with anorexia nervosa or atypical anorexia nervosa and their parents will be recruited from a community-based specialist eating disorder service in London, UK. Participants will be randomly allocated to receive six months of eating disorder focussed family therapy with a five-day MFT group (experimental group) or without (control group). Block randomisation will be conducted by the King’s Clinical Trials Unit and researchers will be blind to participants’ intervention allocation. Feasibility, acceptability and secondary outcomes measures will be collected at baseline, post-MFT, end of treatment, six-month and 12-month follow-up. Feasibility and acceptability will be assessed according to trial sign-up rates, retention, measure completion rates and satisfaction. Secondary outcomes include physical health improvements, changes in psychiatric symptoms, emotion regulation and reflective function capacity, expressed emotion, parental difficulties and therapeutic alliance. Descriptive data and exploration analysis of trends and effect sizes will be reported upon at trial completion. Discussion The five-day MFT program developed for this study is novel, brief and more accessible than previous MFT models. The inclusion of a data collection point during treatment and follow-up will allow for an investigation of trends during and after treatment. This will allow exploration and comparison of future potential mediators and moderators of MFT and FT-AN outcomes and how these may differ between treatments. Trial registration ISRCTN registry; ISRCTN93437752 , on 27 January 2021.

Abstract Background A major barrier to long-term recovery from anorexia nervosa (AN) are early and frequent relapses after inpatient treatment. There is an urgent need for enhanced continuity of specialized care involving effective aftercare interventions and relapse prevention strategies in order to improve the long-term outcome for patients with AN. Methods SUSTAIN is a multi-center, prospective, randomized-controlled trial investigating the efficacy of a novel post-inpatient aftercare intervention for patients with AN as compared to optimized treatment-as-usual (TAU-O). The SUSTAIN aftercare intervention is based on the cognitive-interpersonal maintenance model of AN and specifically tailored to achieve sustained recovery in AN following inpatient treatment. The SUSTAIN aftercare intervention comprises 20 treatment sessions over eight months and will be predominantly delivered via videoconference to overcome discontinuity of care. TAU-O refers to routine outpatient psychotherapy as generally offered in the German health care system. A total number of 190 patients receiving inpatient or day-hospital treatment for AN will be randomized and assessed over a 14-month period following randomization including a 6 months follow-up. Minimum Body Mass Index (BMI) is 15 kg/m2 at trial inclusion. The primary efficacy endpoint is the change in BMI between baseline (T0) and end of treatment (T2) adjusted for baseline BMI. Key secondary outcomes comprise eating disorder and general psychopathology, quality of life, proportion of relapse and of weight restoration, and cost-effectiveness. Discussion The results of the present trial will provide evidence if the novel aftercare intervention fosters sustained recovery in patients affected by severe courses of AN. Trial registration The SUSTAIN trial was prospectively registered on November 18, 2020, under the registration number DRKS00023372 at the German Clinical Trials Register ( https://www.drks.de/drks_web/ ) which is an acknowledged primary register of the World Health Organization ( http://apps.who.int/trialsearch/ ). Protocol version: 1.2.

Abstract Background The treatment of anorexia nervosa (AN) is often challenging due to medical complications as well as high relapse and mortality rates. Studies about effective treatment options for people with AN are particularly scarce in the adolescent population. This paper is a study protocol for a multi-center cohort study assessing the feasibility, acceptability and efficacy of a new, manualized treatment program, the “Maudsley Model of Anorexia Nervosa Treatment for Adolescents and Young Adults” (MANTRa) compared to psychotherapeutic treatment as usual (TAU). Methods/design One hundred patients between 13 and 21 years who meet the inclusion criteria will receive 24 to 34 individual weekly MANTRa therapy sessions or weekly TAU sessions. Primary outcome variables will be BMI and eating disorder psychopathology 12 months after baseline. Further changes in central coherence, cognitive flexibility, emotion recognition, comorbid psychopathology (e.g. depression, obsessive-compulsive and anxiety disorders, non-suicidal self-injury), personality factors and therapeutic alliance will be assessed. Discussion This multi-center study will examine the utility of the treatment program MANTRa for adolescents with AN and, therefore enhances the current knowledge about potential treatments for this patient group. Trial registration ClinicalTrials.gov Identifier: NCT03535714 . Registered: 24/05/2018 (retrospectively registered, still recruiting).

Abstract Background Most psychiatric disorders have their onset in childhood or adolescence, and if not fully treated have the potential for causing life-long psycho-social and physical sequelae. Effective psychotherapeutic and medication treatments exist, but a significant proportion of children and young people do not make a full recovery. Thus, novel, safe, brain-based alternatives or adjuncts to conventional treatments are needed. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are non-invasive brain stimulation (NIBS) techniques which have shown clinical benefits in adult psychiatric conditions. However, in children and young people their efficacy is not well established. The objective of this study will be to systematically evaluate the evidence on clinical effects of NIBS in children and young people with psychiatric disorders, assessing disorder-specific symptoms, mood and neurocognitive functions. Methods We designed and registered a study protocol for a systematic review. We will include randomised and non-randomised controlled trials and observational studies (e.g. cohort, case-control, case series) assessing the effects of NIBS in children and young people (aged ≤ 24 years old) for psychiatric disorders. The primary outcome will be reduction of disorder-specific symptoms. Secondary outcomes will include effects on mood and cognition. A comprehensive search from database inception onwards will be conducted in MEDLINE, EMBASE and PsycINFO. Grey literature will be identified through searching multiple clinical trial registries. Two reviewers will independently screen all citations, full-text articles and abstract data. The methodological quality of the studies will be appraised using appropriate tools. We will provide a narrative synthesis of the evidence and according to heterogeneity will conduct an appropriate meta-analysis. Additional analyses will be conducted to explore the potential sources of heterogeneity. Discussion This systematic review will provide a broad and comprehensive evaluation of the evidence on clinical effects of NIBS in children and young people with psychiatric disorders. Our findings will be reported according to the PRISMA guidelines and will be of interest to multiple audiences (including patients, researchers, healthcare professionals and policy-makers). Results will be published in a peer-reviewed journal. Systematic review registration PROSPERO CRD42019158957

Abstract Background Gene amplification of MET, which encodes for the receptor tyrosine kinase c-MET, occurs in a variety of human cancers. High c-MET levels often correlate with poor cancer prognosis. Interleukin-like EMT inducer (ILEI) is also overexpressed in many cancers and is associated with metastasis and poor survival. The gene for ILEI, FAM3C, is located close to MET on chromosome 7q31 in an amplification “hotspot”, but it is unclear whether FAMC3 amplification contributes to elevated ILEI expression in cancer. In this study we have investigated FAMC3 copy number gain in different cancers and its potential connection to MET amplifications. Methods FAMC3 and MET copy numbers were investigated in various cancer samples and 200 cancer cell lines. Copy numbers of the two genes were correlated with mRNA levels, with relapse-free survival in lung cancer patient samples as well as with clinicopathological parameters in primary samples from 49 advanced stage colorectal cancer patients. ILEI knock-down and c-MET inhibition effects on proliferation and invasiveness of five cancer cell lines and growth of xenograft tumors in mice were then investigated. Results FAMC3 was amplified in strict association with MET amplification in several human cancers and cancer cell lines. Increased FAM3C and MET copy numbers were tightly linked and correlated with increased gene expression and poor survival in human lung cancer and with extramural invasion in colorectal carcinoma. Stable ILEI shRNA knock-down did not influence proliferation or sensitivity towards c-MET-inhibitor induced proliferation arrest in cancer cells, but impaired both c-MET-independent and -dependent cancer cell invasion. c-MET inhibition reduced ILEI secretion, and shRNA mediated ILEI knock-down prevented c-MET-signaling induced elevated expression and secretion of matrix metalloproteinase (MMP)-2 and MMP-9. Combination of ILEI knock-down and c-MET-inhibition significantly reduced the invasive outgrowth of NCI-H441 and NCI-H1993 lung tumor xenografts by inhibiting proliferation, MMP expression and E-cadherin membrane localization. Conclusions These novel findings suggest MET amplifications are often in reality MET-FAM3C co-amplifications with tight functional cooperation. Therefore, the clinical relevance of this frequent cancer amplification hotspot, so far dedicated purely to c-MET function, should be re-evaluated to include ILEI as a target in the therapy of c-MET-amplified human carcinomas.

Abstract Background Eating disorders (EDs) typically start during adolescence or emerging adulthood, periods of intense biopsychosocial development. FREED (First Episode Rapid Early Intervention for EDs) is a service model and care pathway providing rapid access to developmentally-informed care for emerging adults with EDs. FREED is associated with reduced duration of untreated eating disorder and improved clinical outcomes, but patients’ experiences of treatment have yet to be assessed. Objective This study aimed to assess emerging adults’ experiences of receiving treatment through FREED. Method This study triangulated qualitative data on participants’ experiences of FREED treatment from questionnaires and semi-structured interviews. Participants were 106 emerging adults (aged 16–25; illness duration

Abstract Background Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment option for people with severe, enduring anorexia nervosa (SE-AN). As depression is often comorbid with AN, antidepressant medication is commonly prescribed to this patient group. Concurrent antidepressant medications may affect the rTMS treatment response. Therefore, in a secondary analysis of data from a feasibility trial, we explored the effect of antidepressant medication on responses to rTMS in people with SE-AN. Methods Twenty-six participants with SE-AN received 20 sessions (over 4 weeks) of neuronavigated high-frequency real rTMS to the left dorsolateral prefrontal cortex. Eating disorder (ED) and general psychopathology symptoms were assessed at baseline, post-treatment and at a 4-month follow-up. Results Participants taking antidepressants (n = 16) for the duration of the rTMS treatment had a greater reduction in ED symptoms at the 4-month follow-up, compared to those not taking antidepressants (n = 10). Antidepressant status was not however associated with significant changes in mood outcomes. Conclusions In people with SE-AN receiving rTMS treatment, preliminary findings suggest a potential synergistic effect of antidepressant medication in reducing ED symptomatology. There was however no associated reduction in affective symptoms i.e., the effect does not seem to be related to changes in mood. The sample in this exploratory study was small and heterogenous. However, the preliminary results provide a basis for hypothesis generation for future studies.

Abstract Background Eating disorders (EDs) typically have their onset during adolescence or the transition to adulthood. Emerging adulthood (~ 18–25 years) is a developmental phase which conceptually overlaps with adolescence but also has unique characteristics (e.g. increased independence). Emerging adults tend to come to ED services later in illness than adolescents, and emerging adulthood’s unique characteristics may contribute to such delays. Objective This study aimed to explore attitudes towards ED symptoms, and their implications for help-seeking, amongst emerging adults receiving ED treatment through FREED, an early intervention care pathway. Method Participants were 14 emerging adults (mean age 20.9 years; SD = 2.0), all currently receiving specialist treatment for a first-episode, recent-onset (

Abstract Background Recent research has identified several cognitive biases in patients with eating disorders, such as a tendency to interpret ambiguous information about one’s own body in a negative way. The so-called “negative interpretation bias” is considered to be a key factor in maintaining maladaptive cognitions and behaviors in eating disorders. Studies on modification of the negative interpretation bias in eating disorders have yielded mixed results. This randomized controlled pilot study examined whether a specially adapted, computerized version of the Scrambled Sentences Task modifies negative interpretation bias in women with elevated body dissatisfaction. Methods The sample consisted of 40 normal-weight women with elevated body dissatisfaction, randomly assigned either to an intervention or a no-intervention control group (each n = 20). The intervention group received six sessions (within two weeks) of a newly-developed interpretation bias modification training that involved unscrambling positively valenced, body image-related sentences. The control group received no intervention. In both groups, body image-related negative interpretation bias (main outcome), trait body dissatisfaction and thin-ideal cue reactivity were assessed at baseline and two weeks later. Additionally, in the intervention condition, the trajectory of expected reductions in the thin-ideal internalization was measured during each training session. Results In both conditions, body image-related negative interpretation bias and trait body dissatisfaction decreased significantly from pre- to post-assessment; however, a specific effect imparted by the interpretation bias modification training was not found. Groups did not differ in thin-ideal cue reactivity. In the intervention group, thin-ideal internalization decreased significantly over the training sessions. Conclusions The findings do not support use of body image-related interpretation bias modification in its current form in the treatment of body dissatisfaction. Further research involving different versions of the training and clinical samples is warranted.

Abstract Background Antipsychotic drug-induced weight gain puts individuals with schizophrenia at increased cardiometabolic risk. As a potential intervention for this problem, we describe the theoretical background and a protocol for a feasibility randomised controlled trial (RCT) of approach bias modification (ABM) training combined with real versus sham (placebo) transcranial direct current stimulation (tDCS). The primary aim of this trial is to obtain information that will guide decision making and protocol development in relation to a future large-scale RCT of ABM and tDCS in this group of participants. Second, the study will assess the preliminary efficacy of ABM + tDCS in reducing food cravings in people who take antipsychotic medication. Methods Thirty adults with a DSM-V diagnosis of schizophrenia or schizoaffective disorder treated with anti-psychotic medication will be randomly allocated to receive five sessions that will combine ABM and real or sham tDCS, in a parallel group design. In this feasibility study, a broad range of outcome variables will be examined. Measures will include food craving, psychopathology (e.g. symptoms of schizophrenia and depression), neuropsychological processes (such as attentional bias and impulsiveness), and the tolerability and acceptability of tDCS. The feasibility of conducting a large-scale RCT of ABM + tDCS and appropriateness of tDCS as a treatment for antipsychotic drug-induced weight gain will be evaluated by assessment of recruitment and retention rates, acceptability of random allocation, blinding success (allocation concealment), completion of treatment sessions and research assessments (baseline, post-treatment and follow-up). Discussion The effect sizes generated and other findings from this trial will inform a future large-scale RCT with respect to decisions on primary outcome measures and other aspects of protocol development. In addition, results from this study will provide a preliminary indication of the efficacy of ABM + tDCS treatment for antipsychotic drug-induced weight gain. Trial registration ISRCTN Registry, ISRCTN13280178 . Registered on 16 October 2018.

Abstract Treatment outcomes in anorexia nervosa (AN) remain suboptimal, evidencing the need for better and more targeted treatments. Whilst the aetiology of AN is complex, cognitive processes such as attention bias (AB) have been proposed to contribute to maintaining food restriction behaviour. Attention bias modification raining (ABMT) has been investigated in other eating disorders (EDs) such as binge eating disorder (BED) as a means of modifying AB for food and of changing eating behaviour. Promising findings have been reported, but the mechanisms underlying ABMT are poorly understood. We hypothesise that in AN, ABMT has the potential to modify maladaptive eating behaviours related to anxiety around food and eating and propose two mechanistic models; (1) ABMT increases general attentional control (which will improve control over disorder-relevant thoughts) or (2) ABMT promotes stimulus re-evaluation. In this second case, the effects of ABMT might arise via changes in the subjective value of food stimuli (i.e. reward processing) or via habituation, with both resulting in a reduced threat response. Investigating the clinical potential of ABMT in AN holds the promise of a novel, evidence-based adjunctive treatment approach. Importantly, understanding ABMT’s underlying mechanisms will help tailor treatment protocols and improve understanding of the cognitive characteristics of AN and other EDs.

Abstract Background Obesity is a highly prevalent condition with multiple adverse health consequences. Widely available first-line treatments for obesity, such as dietary and other lifestyle interventions, typically have only short-term effects. Thus, new treatment approaches are needed. Novel interventions such as Attention Bias Modification Training (ABMT) and mindfulness-based interventions focus on modifying different maladaptive cognitive patterns typically present in people with obesity (e.g. attention bias to food cues); however, their mechanisms of action remain largely unknown. We describe the theoretical basis and the rationale for a study protocol of a feasibility randomised controlled trial (RCT) comparing two attention trainings (ABMT vs Mindfulness Training [MT]) in people with overweight or obesity. The aim of this study is to inform the development of a large-scale RCT in relation to acceptability and attendance rates and to identify preliminary evidence for the interventions’ clinical efficacy and potential underlying mechanisms. Design Forty-five adults who are either overweight or obese (minimum body mass index of 25 kg/m2) will be randomly allocated to receive eight sessions over eight weeks of either computerised ABMT or MT or be on a waiting list. Clinical and cognitive outcomes will be assessed at baseline, post-treatment (8 weeks) and follow-up (12 weeks post-randomisation). These include mood, body composition and attention biases. Credibility and acceptability of the trainings will be assessed using questionnaires, and recruitment and retention rates will be recorded. Discussion Findings will inform the feasibility of developing a large-scale RCT that takes into consideration effect sizes for primary outcome measures and the acceptability of the design. The study will also provide preliminary evidence on the clinical efficacy of two different attention trainings for people with obesity and associated underlying mechanisms. Trial registration ISRCTN Registry, ISRCTN15745838. Registered on 22 May 2018.

Abstract Background Outpatient treatment studies of anorexia nervosa (AN) are notoriously hard to conduct given the ambivalence of the patient group and high drop-out rates. It is therefore not surprising that previous meta-analyses of pharmacological and psychological treatments for outpatient treatment of adult AN have proved to be inconclusive. Network meta-analysis (NMA) has the potential to overcome the limitations of pairwise meta-analysis, as this approach can compare multiple treatments using both direct comparisons of interventions within randomized controlled trials (RCTs) and indirect comparisons across trials based on a common comparator. To date there is no published example of this approach with eating disorders and the current study provides a protocol which will use NMA to advance knowledge about what outpatient therapy works best for which patients with AN by conducting both direct and indirect comparisons of different treatments and the moderating variables. Methods Searches of electronic data bases will be supplemented with manual searches for published, unpublished and ongoing RCTs in international registries, and clinical trials registries of regulatory agencies and pharmaceutical companies. Two reviewers will independently extract the data and where possible we will access individual data in order to examine moderators of treatment. Two primary outcomes will be selected: changes to body mass index and changes to global eating disorder psychopathology. The secondary outcome is the total number of patients who, at 12-month post-randomization, attained over the previous 28 day period: (i) BMI > 18.5, and (ii) global eating disorder psychopathology to within 1 SD of community norms. We will also provide a statistical evaluation of consistency, the agreement between direct and indirect evidence. Results Descriptive statistics across all eligible trials will be provided along with a network diagram, where the size of the nodes will reflect the amount of evidence accumulated for each treatment. We will use a contribution matrix that describes the percentage contribution of each direct meta-analysis to the entire body of evidence. Discussion Findings will make a major contribution to the literature by summarising individual data across rapidly accumulating outpatient trials of AN using state of the art NMA methodology. Trial registration PROSPERO registration number: CRD42017064429