Autopsy of a failed trial part 2: Outcomes, challenges, and lessons learnt from the DAISIES trial.

OBJECTIVE: The relative merits of inpatient or day-treatment for adults with anorexia nervosa (AN) are unknown. The DAISIES trial aimed to establish the non-inferiority of a stepped-care day patient treatment (DPT) approach versus inpatient treatment as usual (IP-TAU) for improving body mass index (BMI) at 12 months in adults with AN. The trial was terminated due to poor recruitment. This paper presents outcomes and investigates the reasons behind the trial's failure. METHOD: Fifteen patients with AN (of 53 approached) participated and were followed-up to 6 or 12 months. Summary statistics were calculated due to low sample size, and qualitative data concerning treatment experiences were analysed using thematic analysis. RESULTS: At baseline, participants in both trial arms rated stepped-care DPT as more acceptable. At 12 months, participants' BMIs had increased in both trial arms. Qualitative analysis highlighted valued and challenging aspects of care across settings. Only 6/12 sites opened for recruitment. Among patients approached, the most common reason for declining participation was their treatment preference (n = 12/38). CONCLUSIONS: No conclusions can be drawn concerning the effectiveness of IP-TAU and stepped-care DPT, but the latter was perceived more positively. Patient-related, service-related and systemic factors (COVID-19) contributed to the trial's failure. Lessons learnt can inform future studies.

The clinical effectiveness and cost-effectiveness of a 'stepping into day treatment' approach versus inpatient treatment as usual for anorexia nervosa in adult specialist eating disorder services (DAISIES trial): a study protocol of a randomised controlled multi-centre open-label parallel group non-inferiority trial.

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.

Clinicians' perspectives on supporting individuals with severe anorexia nervosa in specialist eating disorder intensive treatment settings during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has significantly affected intensive treatment settings (i.e., inpatient [IP] and day patient [DP]) in specialist eating disorder services. However, the impact on clinicians working in these services is largely unknown. We therefore explored the perspectives of those supporting individuals with severe anorexia nervosa (AN) in intensive treatment settings during the pandemic. METHODS: Between May 2020 and June 2021, we interviewed clinicians (n = 21) who delivered IP and/or DP treatment to patients with severe AN in four specialist eating disorder services in the United Kingdom. Data relating to experiences during COVID-19 were analysed using reflexive thematic analysis. RESULTS: We identified six themes: Disruptions to Routine Treatment; Introduction of Virtual Treatment; Separation from Treatment, Others and the World; Impact on Recovery; Impact on Staff; and Pressure on Referral Pathways. COVID-19 posed significant challenges to IP and DP services: forcing closures, operating with restrictions and virtual treatment, and impacting delivery of essential treatment components, referral pathways, clinician wellbeing, risk management, and patient isolation and recovery trajectories. Opportunities arose, in particular in DP services offering virtual support. CONCLUSIONS: COVID-19 challenged the continuation of multidisciplinary treatment. The findings underline the necessity for medical, psychological, practical, and nutritional support, as well as carer involvement and fostering social connections to remain at the forefront of intensive treatment for severe AN. They also emphasise the uncertainty surrounding which intensive treatment may be best suited to which patient when, particularly within the context of virtual DP support.

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.

Clinicians' perspectives on supporting individuals with severe anorexia nervosa in specialist eating disorder intensive treatment settings.

BACKGROUND: Admissions to intensive treatment (i.e., inpatient [IP] and/or day patient [DP]) for individuals with severe anorexia nervosa (AN) are common. Growing literature indicates potential risks and benefits of each intensive treatment approach; however, existing research has focused on patient and carer perspectives of these treatments. Also, there is scant empirical evidence available for guiding the parameters of intensive treatments for AN. We therefore explored clinicians' perspectives and experience of supporting adults with severe AN in intensive settings. METHODS: We conducted twenty one semi-structured interviews with clinicians who deliver intensive treatments (i.e., IP and/or DP) for individuals with severe AN across four specialist Eating Disorder Services in the United Kingdom between May 2020 and June 2021. We asked clinicians about their views and experiences of supporting individuals with severe AN in intensive treatment settings and the challenges and opportunities associated with IP and DP treatment. Data were analysed using reflexive thematic analysis supported by NVivo software. RESULTS: Five broad and interrelated themes were identified: (1) Intensive Support; (2) The Severity of Patients' Illnesses; (3) Hope and Recovery; (4) Which Treatment When; (5) Limited Resources; and (6) Carer Burden. We identified various similarities between the two intensive treatment approaches, including the value of intensive and multidisciplinary support and carer involvement, and the challenge of managing complex and unique needs in resource-limited intensive settings. We also found differences in the relationship of treatment to patients' home environments, the necessity of patient motivation, and the management of risk. CONCLUSIONS: Both intensive treatment settings are valued by clinicians; however, there are unique challenges and opportunities for supporting individuals with severe AN within each. Our findings suggest DP treatment may be used as an alternative to IP treatment for individuals with severe AN. However, clear questions remain over which intensive treatment setting is best suited to which patient when and should be the focus of future research.

Some people with anorexia nervosa will need intensive treatment (e.g., inpatient and day patient treatment) during the course of their illness. We interviewed twenty-one clinicians working in Specialist Eating Disorder Services to explore their views on supporting people with severe anorexia nervosa in inpatient and day patient services and about the perceived advantages and disadvantages of these. We analysed the transcripts of these interviews using thematic analysis. We identified similarities between the two intensive treatment approaches. These included the value of intensive and multidisciplinary support, the importance of carer involvement, and the challenge of managing patient's complex and unique needs in services with limited resources. We also found differences between inpatient and day patient treatment. These included how treatment relates to patients' home environments, the importance of patient motivation, and managing risk. Day patient treatment may be an alternative to inpatient treatment for people with severe anorexia nervosa. Future research should investigate which intensive treatment setting is best suited to which patient and when.

Attitudes Surrounding Music of Patients With Anorexia Nervosa: A Survey-Based Mixed-Methods Analysis.

Anorexia nervosa (AN) is one of the main eating disorders. It has the highest mortality of all psychiatric disorders, and the success rates of current therapies are not fully satisfactory. Thus, there is a need for novel interventions. We investigated the attitudes surrounding music of 41 patients with clinically-diagnosed AN as well as their thoughts on the potential therapeutic uses of music using a questionnaire of 50 questions. Free text responses were qualitatively analyzed for reoccurring themes with NVivo 12 software. Yes/no questions and questions of best fit were analyzed using the IBM SPSS Statistics version 25. The most prevalent theme was the positive effect of music. Most patients reported that listening to music evokes varying emotions in them (83%) which may be of positive or negative nature. Similarly, patients associated certain music with particular positive, but also with particular negative memories. A majority of patients stated that music helps to distract them (85%), helps with loneliness (59%) and helps them feel more connected to others (58%). This data indicates that people with AN make nonclinical use of music which seems to elicit positive as well as negative emotions and memories. Patients felt music is beneficial with regard to important aspects of AN, such as emotional problems, loneliness, and relationship difficulties. Most of them would also like to attend music therapy.

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.

Facets of shared decision-making on drug treatment for adults with an eating disorder.

Shared decision-making (SDM) means that clinicians and the patient make decisions about the treatment together. Regarding drug treatment in eating disorders (EDs), such decisions may include psychopharmacological treatment for the ED itself, medications for potential co-morbid psychiatric disorders, pharmacological strategies to alleviate the health consequences of an ED, or 'pro re nata' (PRN) medication which is given in acute care when required. Decisions regarding drug treatment in EDs should be specific in terms of the active pharmacological substance, its dose, its route of administration, and the duration of treatment. Decisions should be made with regard to the specific health risks of patients with EDs and the entire treatment approach, and should take alternative measures, additional therapies, and specific combinations of therapies into account. The differences in the expectations of patients, carers, and clinicians towards drug treatment, the lack of specific suggestions in clinical practice guidelines, and the lack of approved psychopharmacological treatment options make SDM necessary, but also a challenge. However, SDM may be limited due to the patient's impaired insight or limited capacity due to the ED. Thus, the legal framework must be taken into consideration.

Pharmacological interventions for clozapine-induced hypersalivation.

BACKGROUND: Clozapine is widely used for people with schizophrenia. Although agranulocytosis, weight gain, and cardiac problems are serious problems associated with its use, hypersalivation, sometimes of a gross and socially unacceptable quantity, is also common (30-80%). OBJECTIVES: To determine the clinical effects of pharmacological interventions for clozapine-induced hypersalivation. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group Trials Register (March 2007), inspected references of all identified studies for further trials, contacted relevant pharmaceutical companies, drug approval agencies and authors of trials. SELECTION CRITERIA: We included randomised controlled trials comparing pharmacological interventions, at any dose and by any route of administration, for clozapine-induced hypersalivation. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data (homogenous) we calculated relative risk (RR) with 95% confidence intervals (CI) and numbers needed to treat (NNT) on an intention-to-treat basis. We calculated weighted mean difference (WMD) for continuous data. MAIN RESULTS: Of the 15 trials identified, 14 were conducted in China and 14 in hospitals. The quality of reporting was poor with no studies clearly describing allocation concealment and much data were missing or unusable. All results are vulnerable to considerable bias. Most frequently the primary outcome was the diameter of the wet patch on the pillow. Antimuscarinics (astemizole, diphenhydramine, propantheline, doxepin) were the most commonly evaluated drugs. For the outcome of 'no clinically important improvement' astemizole and diphenhydramine were more effective than placebo (astemizole: n=97, 2 RCTs, RR 0.61 CI 0.47 to 0.81 NNT 3 CI 2 to 5; diphenhydramine: n=131, 2 RCTs, RR 0.43 CI 0.31 to 0.58, NNT 2 CI 1.5 to 2.5), but the doses of astemizole used were those that can cause toxicity. Data involving propantheline were heterogeneous (I2= 86.6%), but both studies showed benefit over placebo. Adverse effects were poorly recorded. Of the other interventions, oryzanol (rice bran oil and rice embryo oil extract) showed benefit over the antimuscarinic doxepin in terms of 'no clinically important change' (n=104, 1 RCT, RR 0.45 CI 0.27 to 0.75, NNT 4 CI 2 to 7). The Chinese medicine suo quo wan (comprises spicebush root, Chinese yam and bitter cardamom) showed benefit over doxepin (n=70, 1 RCT, RR 'no clinically important change' 0.31 CI 0.16 to 0.59, NNT 3 CI 1.5 to 3.7). AUTHORS' CONCLUSIONS: There are currently insufficient data to confidently inform clinical practice. The limitations of these studies are plentiful and the risk of bias is high. These trials, however, are invaluable guides for current and future study design. Well conducted randomised trials are possible. Some may be underway. Current practice outside of well designed randomised trials should be clearly justified.