Longitudinal changes in brain-derived neurotrophic factor (BDNF) but not cytokines contribute to hippocampal recovery in anorexia nervosa above increases in body mass index.

BACKGROUND: Physical sequelae of anorexia nervosa (AN) include a marked reduction in whole brain volume and subcortical structures such as the hippocampus. Previous research has indicated aberrant levels of inflammatory markers and growth factors in AN, which in other populations have been shown to influence hippocampal integrity. METHODS: Here we investigated the influence of concentrations of two pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6]) and brain-derived neurotrophic factor (BDNF) on the whole hippocampal volume, as well as the volumes of three regions (the hippocampal body, head, and tail) and 18 subfields bilaterally. Investigations occurred both cross-sectionally between acutely underweight adolescent/young adult females with AN (acAN; n = 82) and people recovered from AN (recAN; n = 20), each independently pairwise age-matched with healthy controls (HC), and longitudinally in acAN after partial renourishment (n = 58). Hippocampal subfield volumes were quantified using FreeSurfer. Concentrations of molecular factors were analyzed in linear models with hippocampal (subfield) volumes as the dependent variable. RESULTS: Cross-sectionally, there was no evidence for an association between IL-6, TNF-α, or BDNF and between-group differences in hippocampal subfield volumes. Longitudinally, increasing concentrations of BDNF were positively associated with longitudinal increases in bilateral global hippocampal volumes after controlling for age, age2, estimated total intracranial volume, and increases in body mass index (BMI). CONCLUSIONS: These findings suggest that increases in BDNF may contribute to global hippocampal recovery over and above increases in BMI during renourishment. Investigations into treatments targeted toward increasing BDNF in AN may be warranted.

Olanzapine for young PEople with aNorexia nervosa (OPEN): A protocol for an open-label feasibility study.

INTRODUCTION: Antipsychotics are routinely prescribed off-label for anorexia nervosa (AN) despite limited evidence. This article presents a protocol of a study aiming to assess the feasibility of a future definitive trial on olanzapine in young people with AN. METHODS AND ANALYSIS: In an open-label, one-armed feasibility study, 55 patients with AN or atypical AN, aged 12-24, receiving outpatient, inpatient or day-care treatment who are considered for olanzapine treatment will be recruited from NHS sites based in England. Assessments will be conducted at screening, baseline and at 8-, 16 weeks, 6- and 12 months. Primary feasibility parameters will be proportions of patients who agree to take olanzapine and who adhere to treatment and complete study assessments. Qualitative methods will be used to explore acceptability of the intervention and study design. Secondary feasibility parameters will be changes in body mass index, psychopathology, side effects, health-related quality of life, carer burden and proportion of participants who would enrol in a future randomised controlled trial. The study is funded by the National Institute for Health Research via Health Technology Assessment programme. DISCUSSION: Olanzapine for young PEople with aNorexia nervosa will inform a future randomised controlled trial on the efficacy and safety of prescribing olanzapine in young people with AN.

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 effect of a low-calorie diet on depressive symptoms in individuals with overweight or obesity: a systematic review and meta-analysis of interventional studies.

BACKGROUND: Individuals with overweight or obesity are at a high risk for so-called 'atypical' or immunometabolic depression, with associated neurovegetative symptoms including overeating, fatigue, weight gain, and a poor metabolic profile evidenced e.g. by dyslipidemia or hyperglycemia. Research has generated preliminary evidence for a low-calorie diet (LCD) in reducing depressive symptoms. The aim of the current systematic review and meta-analysis is to examine this evidence to determine whether a LCD reduces depressive symptoms in people with overweight or obesity. METHODS: Eligible studies were identified through PubMed, ISI Web of Science, and PsycINFO until August 2023. Standardized mean differences (SMDs) were derived using random-effects meta-analyses for (1) pre-post LCD comparisons of depression outcomes, and (2) LCD v. no-diet-control group comparisons of depression outcomes. RESULTS: A total of 25 studies were included in the pre-post meta-analysis, finding that depression scores were significantly lower following a LCD (SMD = -0.47), which was not significantly moderated by the addition of exercise or behavioral therapy as a non-diet adjunct. Meta-regressions indicated that a higher baseline BMI and greater weight reduction were associated with a greater reduction in depression scores. The intervention-control meta-analysis (n = 4) found that overweight or obese participants adhering to a LCD showed a nominally lower depression score compared with those given no intervention (SMD = -0.29). CONCLUSIONS: There is evidence that LCDs may reduce depressive symptoms in people with overweight or obesity in the short term. Future well-controlled intervention studies, including a non-active control group, and longer-term follow-ups, are warranted in order to make more definitive conclusions.

Medical morbidity and risk of general hospital admission associated with concurrent anorexia nervosa and COVID-19: An observational study.

OBJECTIVE: Investigate medical morbidity and risk of general hospital admission for patients with concurrent coronavirus disease 2019 (COVID-19) and anorexia nervosa (AN) who have not received severe acute respiratory syndrome coronavirus 2 vaccination. METHODS: United Kingdom eating disorders clinicians contributed to a database of patients with an eating disorder and COVID-19. We used this to investigate demography, symptoms, hospitalization, treatment, and outcomes for those with AN. RESULTS: We describe data for 49 patients (median age 21.5 years [interquartile range 17.0-33.5], 46 female) including 36 adults and 13 under-18-year-olds. Three (6.1% [95% confidence interval 1.3%-17.9]) were admitted to a general hospital. For this sample, the expected age-standardized hospital admission rate per COVID-19 case (based on the general population of England) was 2.6% and therefore not significantly different to the hospitalization rate we observed. Three (including two of those admitted to hospital) contracted pneumonia. One had severe pneumonia and was admitted to an intensive care unit. No deaths or use of mechanical ventilation were recorded. DISCUSSION: To our knowledge, this represents the first study investigating medical morbidity or frequency of hospitalization for patients with COVID-19 and AN. We did not find evidence that patients with AN are at increased risk of severe COVID-19. PUBLIC SIGNIFICANCE: Medical morbidity and risk of hospitalization associated with concurrent COVID-19 and anorexia nervosa (AN) had not, to our knowledge, been studied before. We used a database of patients with eating disorders and COVID-19 (to which United Kingdom clinicians had contributed) to investigate presentation, treatment, outcomes, and COVID-19 severity for those with AN and COVID-19. We did not find evidence that patients with AN are at increased risk of severe COVID-19.

The negative relationship of dietary inflammatory index and sleeping quality in obese and overweight women.

Background and aims: Substantial evidence have linked low grade inflammation with the pathophysiology of chronic diseases and psychological impairment. An integral component underlying the link is pro-inflammatory diet. While sleeping is another significant contributor, few studies have addressed the relationship between the sleep quality and inflammatory cascade with the dietary quality as a moderator. The current study assesses the relation between inflammatory potential of the diet and sleep quality in Iranian obese and overweight women. Method: A total of 219 obese and overweight adult women were enrolled in this cross-sectional study. A standard 147-item food-frequency-questionnaire was used to record the dietary intakes; then, the dietary inflammatosry index (DII) was derived from the result-consolidated questionnaires. Pittsburgh Sleep Quality Index (PSQI) was utilized to withdraw the sleep quality and quantity. Results: The mean (±standard deviation) age, body mass index, and PSQI of individuals were 36.49 (8.38) years, 31.04 (4.31) kg/m2, and 5.78(3.55), respectively. Patients in the highest DII quartile were the ones with the higher consumption of pro-inflammatory food, and, ~58% of participants who were in the higher quartile had a sleep disturbance status. Results revealed an inverse relationship between sleep quality and DII in the crude model (ß=-0.17, p=0.01) as well as full-adjusted model (ß=0.24, p<0.001), such that women with higher DII had the poorest sleep quality. Conclusion: Based on the present observational study, obese and overweight females with higher adherence of the anti-inflammatory diet may have better sleeping status.

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.

Autopsy of a failed trial part 1: A qualitative investigation of clinician's views on and experiences of the implementation of the DAISIES trial in UK-based intensive eating disorder services.

OBJECTIVE: The DAISIES trial, comparing inpatient and stepped-care day patient treatment for adults with severe anorexia nervosa was prematurely terminated in March 2022 due to poor recruitment. This qualitative study seeks to understand the difficulties faced during the trial by investigating stakeholders' views on and experiences of its implementation. METHOD: Semi-structured interview and focus group transcripts, and trial management and oversight group meeting minutes from May 2020-June 2022 were analysed using thematic analysis. Participants were 47 clinicians and co-investigators involved with the DAISIES trial. The Non-Adoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework was applied to the interpretive themes to classify barriers and facilitators to implementation. RESULTS: Five themes were identified: incompatible participation interests; changing standard practice; concerns around clinical management; systemic capacity and capability issues; and Covid-19 disrupting implementation. Applying the NASSS framework indicated the greatest implementation challenges to arise with the adopters (e.g. patients, clinicians), the organisational systems (e.g. service capacity), and the wider socio-political context (e.g. Covid-19 closing services). CONCLUSIONS: Our findings emphasise the top-down impact of systemic-level research implementation challenges. The impact of the Covid-19 pandemic accentuated pre-existing organisational barriers to trial implementation within intensive eating disorder services, further limiting the capacity for research.

[Therapy of Food Refusal and Anorexia Nervosa in German-Language Psychiatry Textbooks of the Past 200 Years]. / Die Therapie der Nahrungsverweigerung und der Anorexia nervosa in deutschsprachigen Psychiatrie-Lehrbüchern der vergangenen 200 Jahre.

The aim of this study was to describe how the therapy of anorexia nervosa (AN) and food refusal have been discussed in leading textbooks used in German-speaking academic psychiatry over the past 200 years. For this purpose, 18 textbooks of important school psychiatrists were selected. These were analyzed in a structured way to determine the content of the subject taught at universities in German-speaking countries at a given period. We found that AN was not taught as a distinct disorder until the end of the 20th century, although great attention had been paid to food refusal as a symptom and manifold therapeutic concepts had been developed much earlier. Whereas at the beginning of the 19th century forced feeding using feeding tubes was established, in the following years pharmacotherapies and special diets were developed. It is noteworthy that since the beginnings of academic psychiatry, some early forms of psychotherapy have been developed; for instance, special kinds of behavior were recommended when dealing with the patient, as the therapist was supposed to serve as a role model to encourage patients to eat. Treatment of food refusal by means of structured psychotherapeutic approaches were not established before AN was generally accepted as a distinct disease entity. The understanding of etiological factors that might lead to AN as well as potential psychotherapeutic interventions have changed fundamentally over the past decades.

Cytokines and Water Distribution in Anorexia Nervosa.

In patients with anorexia nervosa (AN), decreased intracellular (ICW), extracellular (ECW), and total body water (TBW) as well as changes in serum cytokine concentrations have been reported. In this exploratory study, we measured body composition and serum cytokine levels in patients with AN (n = 27) and healthy controls (HCs; n = 13). Eating disorder symptom severity was assessed using the Eating Disorder Examination-Questionnaire (EDE-Q). Body composition was determined by bioimpedance analysis (BIA) which provided information on ICW, ECW, and TBW. Following blood collection, 27 cytokines and chemokines were quantified using multiplex ELISA-based technology: Eotaxin, Eotaxin-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon- (IFN-) γ, interleukin- (IL-) 1α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, interferon γ-induced protein- (IP-) 10, macrophage inflammatory protein- (MIP-) 1α, MIP-1ß, monocyte chemoattractant protein- (MCP-) 1, MCP-4, thymus and activation-regulated chemokine (TARC), TNF-α, and TNF-ß. ICW, ECW, and TBW volumes were significantly lower in patients with AN than in HCs. In the whole sample, GM-CSF, MCP-4, and IL-4 were positively, whereas IFN-γ, IL-6, and IL-10 were negatively associated with all three parameters of body water. In AN participants, we found a statistically significant negative correlation of IL-10 with ICW, ECW, and TBW. Our results suggest an interaction between body water and the cytokine system. Underlying mechanisms are unclear but may involve a loss of water from the gut, kidneys, or skin due to AN-associated inflammatory processes.

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.

A longitudinal analysis of cytokines in anorexia nervosa.

OBJECTIVE: Inflammation has been proposed to have a pathophysiological role in anorexia nervosa (AN) and to contribute to the maintenance of the disorder. Longitudinal cytokine research in AN has focused on only a few pro-inflammatory cytokines. We assessed a broad range of cytokines over time in people undergoing specialised treatment for AN. METHOD: We measured serum concentrations of 27 cytokines in people with AN (n = 23). Body mass index (BMI), eating disorder (ED) symptoms and general psychopathology were assessed and blood samples were collected within four weeks of the commencement of specialised ED treatment (baseline) and at 12- and 24-week follow-ups. RESULTS: Both BMI and ED symptoms improved over the assessment period. Linear mixed models showed that log IL-6 decreased between baseline and week 12 assessments. By week 12, log IL-6 values were comparable to levels in healthy individuals. Log IL-7 increased from week 12 to week 24. DISCUSSION: Initially elevated IL-6 serum concentrations appear to 'normalize' during the first 3-months of specialised treatment for AN and this co-occurs with improvements in ED symptoms. Therefore, IL-6 has the potential to be a state biomarker for AN.

Suicide attempts requiring hospitalization in patients with eating disorders: A retrospective cohort study.

OBJECTIVE: Suicide attempts requiring hospitalization are known to be common in patients who are diagnosed with eating disorders. Attempting suicide is a major indicator for those at risk of completed suicide. Both the specific eating disorder diagnosis and the influence of psychiatric comorbidities on suicide attempts requiring hospitalization were investigated, with demographic and socioeconomic variables as confounders, over a 10-year observation period from January 2007 to March 2017. METHODS: Anonymized health-record data from the South London and Maudsley NHS Foundation Trust (SLaM) were retrieved through the Clinical Record Interactive Search (CRIS) data resource; this is linked to national Hospital Episode Statistics (HES) data. These data include all diagnoses for inpatient admissions. Hazard ratios, with 95% confidence intervals (CIs), were calculated from cox regression analyses and the effects of a number of confounders were estimated by performing multivariable analyses. RESULTS: In total, 4,895 patients were diagnosed with anorexia nervosa (AN), bulimia nervosa (BN), or eating disorder otherwise not specified (EDNOS). Of these, 331 (6.7%) had attempted suicide requiring hospitalization and 21 (0.04%) completed suicide. The eating disorder category associated with the highest risk of a suicide attempt was AN (HR: 1.43, 95%CI: 1.08-1.89, p = .01). The risk was significantly increased further if the patient had a comorbid diagnosis of personality disorder, depression, bipolar affective disorder, and substance misuse. DISCUSSION: Suicide attempts requiring hospitalization have a high incidence rate among patients with eating disorders, and the risk is significantly increased in AN. Comorbid psychiatric illness and suicidal ideation should be carefully assessed in all eating disorder patients.

Effects of IL-6 Signaling Pathway Inhibition on Weight and BMI: A Systematic Review and Meta-Analysis.

Inhibitors of the IL-6 signaling pathway, such as tocilizumab, are frequently administered for the treatment of immune diseases, e.g., rheumatoid arthritis and multicentric Castleman's disease. The aim of this systematic review and meta-analysis was to ascertain the effects of IL-6 pathway inhibitors on weight and body mass index (BMI). Using PRISMA guidelines, we systematically reviewed relevant articles from three databases (PubMed, OVID, EMBASE). A random effects model was used to estimate standardized mean change (SMCC). Ten studies with a total of 1531 patients were included in the meta-analysis for weight and ten studies with a total of 1537 patients were included in the BMI meta-analysis. The most commonly administered IL-6 pathway inhibitor was tocilizumab. IL-6 pathway inhibitors were associated with increases in weight (SMCC = 0.09, p = 0.016, 95% CI [0.03, 0.14]) and BMI (SMCC = 0.10, p = 0.0001, 95% CI [0.05, 0.15]). These findings suggest that the IL-6 pathway is involved in weight regulation. Modulating IL-6 signaling may be a potential future therapeutic avenue used as an adjunct for the treatment of disorders associated with weight changes, such as cancer cachexia and anorexia nervosa.

A Systematic Review of Scientific Studies on the Effects of Music in People with or at Risk for Eating Disorders.

BACKGROUND: The prevalence of the three main eating disorders (EDs) anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorder (BED) is increasing, and a growing number of patients with EDs is seeking professional help. Thus, there is a need for additional treatment strategies in EDs. The aim of this review was to summarize the literature on the benefits and risks of music as well as the evidence for its therapeutic application in people with EDs. METHODS: Following the PRISMA guidelines, we performed a systematic literature review on scientific studies on the effect of music in people with or at risk for EDs using PubMed and the Web of Science database. The search terms used were: "music", "music therapy", "eating disorders", "anorexia nervosa", "bulimia nervosa" and "binge eating disorder". RESULTS: 16 out of 119 identified and screened articles qualified as scientific studies involving a total of 3,792 participants. They reported on the use of music or music therapy in individuals with or at risk of AN and BN, but not BED. In inpatients with AN, listening to classical music was beneficial to food consumption. Singing in a group reduced post-prandial anxiety in AN inpatients and outpatients. Vodcasts which also included positive visual or autobiographical stimuli helped BN patients with anxiety and body image perception. Songwriting and sessions with a Body Monochord helped with the processing of therapeutically relevant topics in AN. Watching music videos, however, reinforced body dissatisfaction, drive for thinness, bodyweight concerns, preoccupation with physical appearance in pre-teenage and teenage girls, and drive for muscularity in adolescent boys. CONCLUSIONS: These findings suggest that the therapeutic application of music may be beneficial in patients with AN and BN. However, the availability of studies with a rigorous randomized controlled trial (RCT) design is scarce.

Phosphatidylcholine Containing Long Chain Omega-3 Fatty Acids: a Treatment Adjunct for Patients with Anorexia Nervosa?

BACKGROUND: Anorexia nervosa (AN) is a serious mental disorder with a high mortality rate and often a chronic course. In contrast to many other common mental disorders, there is no drug therapy approved for AN. METHODS: We performed a narrative literature review to consider whether a choline-containing molecule, such as phosphatidylcholine (PC), with an omega (ω)-3 long chain polyunsaturated fatty acid (LCPUFA) could be a potential future medicinal treatment for AN. RESULTS: Choline and LCPUFAs have individually shown benefit for mental health. Case series and pilot studies suggest ω-3 LCPUFAs may be effective in eating disorders. However, pharmacodynamic and pharmacokinetic considerations suggest a greater benefit from the combination of both components. CONCLUSION: The combination of a choline-containing molecule with an ω-3 LCPUFA may be clinically effective and well tolerated. This idea is supported by the current literature on the role of inflammation, the microbiome, the gut-brain-axis, hormonal, neurotransmitter and intracellular signalling, and on the structure and fluidity of nerve cells membranes in patients with AN.

Psychiatric comorbidity as a risk factor for mortality in people with anorexia nervosa.

Anorexia nervosa (AN) is found associated with increased mortality. Frequent comorbidities of AN include substance use disorders (SUD), affective disorders (AD) and personality disorders (PD). We investigated the influence of these psychiatric comorbidities on all-cause mortality with demographic and socioeconomic factors considered as confounders in the observation window between January 2007 and March 2016 for 1970 people with AN, using data from the case register of the South London and Maudsley (SLaM) NHS Foundation Trust, an almost monopoly-secondary mental healthcare service provider in southeast London. We retrieved data from its Clinical Records Interactive Search (CRIS) system as data source. Mortality was ascertained through nationwide tracing by the UK Office for National Statistics (ONS) linked to CRIS database on a monthly basis. A total of 43 people with AN died during the observation period. Standardized Mortality Ratio (SMR) with England and Wales population in 2012 as standard population for our study cohort was 5.21 (95% CI 3.77, 7.02). In univariate analyses, the comorbidity of SUD or PD was found to significantly increase the relative risks of mortality (HRs = 3.10, 95% CI 1.21, 7.92; and 2.58, 95% CI 1.23, 5.40, respectively). After adjustment for demographic and socioeconomic covariates as confounders, moderately but not significantly elevated risks were identified for SUD (adjusted HR = 1.39, 95% CI 0.53, 3.65) and PD (adjusted HR = 1.58, 95% CI 0.70, 3.56). These results suggest an elevated mortality in people with AN, which might be, at least partially, explained by the existence of the comorbidities SUD or PD.