Understanding and Breaking the Intergenerational Cycle of Abuse in Families Enrolled in Routine Mental Health and Welfare Services by Investigating the Feasibility and Effectiveness of a Mentalization-Based Early Intervention Program (UBICA-II Study): Study Protocol for a Non-Randomized, Open-Label, Single-Arm Feasibility Study.

Although home visiting programs have generally shown small overall effects on the prevention of child maltreatment, at-risk families with severe strain do not seem to benefit sufficiently from this support. A crucial factor for success seems to be the quality of the service system. The aim of the current study is to evaluate the effects of mentalization-based team supervision on the already existing welfare service of a German early prevention program (EPP). This will be a non-randomized, open-label, single-arm feasibility study. The EPP staff will be trained according to the mentalization-based team approach (MB-TA) and regularly receive MFT supervision by a trained and experienced child and adolescent psychiatrist. A minimum of eighty-four families with defined risk factors with children below 24 months of age and pregnant women in the third trimester will be included. Assessments will take place at T0 (after inclusion in the study), at T1 (after family care ends, as an intermediate assessment,) and at T2 (as a follow-up). We hypothesize that the risk of maltreatment can be reduced by strengthening the skills and capacities of the primary care system. This will be evaluated at the end of the follow-up period by comparing the Parental Stress Index (PSI) scores of all participants pre- and postintervention. Stress levels and mentalization abilities will be assessed as feasibility endpoints for the participating EPP teams.

Unexpected identification of obesity-associated mutations in LEP and MC4R genes in patients with anorexia nervosa.

Mutations leading to a reduced or loss of function in genes of the leptin-melanocortin system confer a risk for monogenic forms of obesity. Yet, gain of function variants in the melanocortin-4-receptor (MC4R) gene predispose to a lower BMI. In individuals with reduced body weight, we thus expected mutations leading to an enhanced function in the respective genes, like leptin (LEP) and MC4R. Therefore, we have Sanger sequenced the coding regions of LEP and MC4R in 462 female patients with anorexia nervosa (AN), and 445 healthy-lean controls. In total, we have observed four and eight variants in LEP and MC4R, respectively. Previous studies showed different functional in vitro effects for the detected frameshift and non-synonymous variants: (1) LEP: reduced/loss of function (p.Val94Met), (2) MC4R: gain of function (p.Val103Ile, p.Ile251Leu), reduced or loss of function (p.Thr112Met, p.Ser127Leu, p.Leu211fsX) and without functional in vitro data (p.Val50Leut). In LEP, the variant p.Val94Met was detected in one patient with AN. For MC4R variants, one patient with AN carried the frameshift variant p.Leu211fsX. One patient with AN was heterozygous for two variants at the MC4R (p.Val103Ile and p.Ser127Leu). All other functionally relevant variants were detected in similar frequencies in patients with AN and lean individuals.

[New aspects in etiology and treatment of adolescent anorexia nervosa-a postulated bio-psycho-social model and the impact of the COVID-19 pandemic]. / Neue Aspekte in der Ätiologie und Therapie der jugendlichen Anorexia nervosa ­ ein postuliertes biopsychosoziales Modell und die Auswirkungen der COVID-19-Pandemie.

Anorexia nervosa is one of the most frequent chronic disorders of adolescence associated with a high mortality. During the COVID-19-pandemic, the number of hospitalized children and adolescents with anorexia nervosa significantly increased. This article outlines new research findings to decode the etiology of this serious disorder, especially a genetic disposition and changes of metabolism. Against the background of increasing rates during the COVID-19 pandemic, the importance of the gene-environment interaction is discussed, and new treatment forms are described. Besides the development of new biological treatment strategies, there is also some important progress in psychotherapeutic interventions. Carers should always be integrated when treating children and adolescents with anorexia nervosa, which is especially emphasized in the new "home treatment" setting. The new concept of anorexia nervosa as a metabo-psychiatric disorder gives us hope for new research ideas and treatment strategies in this often-debilitating disorder of childhood and adolescence.

Premorbid body weight predicts weight loss in both anorexia nervosa and atypical anorexia nervosa: Further support for a single underlying disorder.

OBJECTIVE: For adolescents, DSM-5 differentiates anorexia nervosa (AN) and atypical AN with the 5th BMI-centile-for-age. We hypothesized that the diagnostic weight cut-off yields (i) lower weight loss in atypical AN and (ii) discrepant premorbid BMI distributions between the two disorders. Prior studies demonstrate that premorbid BMI predicts admission BMI and weight loss in patients with AN. We explore these relationships in atypical AN. METHOD: Based on admission BMI-centile < or ≥5th, participants included 411 female adolescent inpatients with AN and 49 with atypical AN from our registry study. Regression analysis and t-tests statistically addressed our hypotheses and exploratory correlation analyses compared interrelationships between weight loss, admission BMI, and premorbid BMI in both disorders. RESULTS: Weight loss in atypical AN was 5.6 kg lower than in AN upon adjustment for admission age, admission height, premorbid weight and duration of illness. Premorbid BMI-standard deviation scores differed by almost one between both disorders. Premorbid BMI and weight loss were strongly correlated in both AN and atypical AN. DISCUSSION: Whereas the weight cut-off induces discrepancies in premorbid weight and adjusted weight loss, AN and atypical AN overall share strong weight-specific interrelationships that merit etiological consideration. Epidemiological and genetic associations between AN and low body weight may reflect a skewed premorbid BMI distribution. In combination with prior findings for similar psychological and medical characteristics in AN and atypical AN, our findings support a homogenous illness conceptualization. We propose that diagnostic subcategorization based on premorbid BMI, rather than admission BMI, may improve clinical validity. PUBLIC SIGNIFICANCE: Because body weights of patients with AN must drop below the 5th BMI-centile per DSM-5, they will inherently require greater weight loss than their counterparts with atypical AN of the same sex, age, height and premorbid weight. Indeed, patients with atypical AN had a 5.6 kg lower weight loss after controlling for these variables. In comparison to the reference population, we found a lower and higher mean premorbid weight in patients with AN and atypical AN, respectively. Considering previous psychological and medical comparisons showing little differences between AN and atypical AN, we view a single disorder as the most parsimonious explanation. Etiological models need to particularly account for the strong relationship between weight loss and premorbid body weight.

Lost in between-the transition process from a child and adolescent eating disorder service to adult mental health services in the German health care system.

INTRODUCTION: In young adults with anorexia nervosa (AN), the process of transition from a child and adolescent mental health service (CAMHS) to an adult mental health service (AMHS) has been recognized as critical, and many patients fear falling through the gap between the two types of service. As reports about the transition process in emerging adults with AN are scarce, the present study aimed to explore the problems and experiences of this age group. METHOD: We screened our registry for patients with AN who had been treated as inpatients during childhood and/or adolescence and come of age during the last 3 years. Thirty-two female patients [mean age 20.3 (1.2) y.] agreed to participate in a semistructured personal or telephone interview assessing their demographic and clinical data, whether they had finalised the transition, and their wishes and experiences regarding the transition process. RESULTS: Only approximately one-third of the participants had already undergone the transition. Nearly 60% of the former patients were still cared for by a CAMHS, and only 12.5% had stopped treatment for AN. Approximately 60% were exclusively or additionally cared for by their general practitioner. More than 50% of the participants still lived with their parents. Approximately 90% of the participants who remained in a CAMHS expressed concerns about transitioning, mostly about losing their trusted therapist and the assumption of personal responsibility. CONCLUSION: Patients with AN often delay the transition from a CAMHS to an AMHS, which they experience as intimidating and overwhelming. Thus, patients should be better prepared for the transition, which should be linked to "developmental readiness" and not to chronological age. Because many patients still live with their family of origin, parents and their family physician should be closely involved in the transition process.

Longitudinal analysis of the gut microbiome in adolescent patients with anorexia nervosa: microbiome-related factors associated with clinical outcome.

There is mounting evidence regarding the role of gut microbiota in anorexia nervosa (AN). Previous studies have reported that patients with AN show dysbiosis compared to healthy controls (HCs); however, the underlying mechanisms are unclear, and data on influencing factors and longitudinal course of microbiome changes are scarce. Here, we present longitudinal data of 57 adolescent inpatients diagnosed with AN at up to nine time points (including a 1-year follow-up examination) and compare these to up to six time points in 34 HCs. 16S rRNA gene sequencing was used to investigate the microbiome composition of fecal samples, and data on food intake, weight change, hormonal recovery (leptin levels), and clinical outcomes were recorded. Differences in microbiome composition compared to HCs were greatest during acute starvation and in the low-weight group, while diminishing with weight gain and especially weight recovery at the 1-year follow-up. Illness duration and prior weight loss were strongly associated with microbiome composition at hospital admission, whereas microbial changes during treatment were associated with kilocalories consumed, weight gain, and hormonal recovery. The microbiome at admission was prognostic for hospital readmission, and a higher abundance of Sutterella was associated with a higher body weight at the 1-year follow-up. Identifying these clinically important factors further underlines the potential relevance of gut microbial changes and may help elucidate the underlying pathophysiology of gut-brain interactions in AN. The characterization of prognostically relevant taxa could be useful to stratify patients at admission and to potentially identify candidate taxa for future supplementation studies aimed at improving AN treatment.

Intra-individual cortical networks in Anorexia Nervosa: Evidence from a longitudinal dataset.

OBJECTIVE: This work investigates cortical thickness (CT) and gyrification patterns in Anorexia Nervosa (AN) before and after short-term weight restoration using graph theory tools. METHODS: 38 female adolescents with AN underwent structural magnetic resonance imaging scans at baseline and after - on average - 3.5 months following short-term weight restoration while 53 age-matched healthy controls (HCs) were scanned once. Graph measures were compared between groups and longitudinally within the AN group. Associations with clinical measures such as age of onset, duration of illness, BMI standard deviation score (BMI-SDS), and longitudinal weight changes were tested via stepwise regression. RESULTS: Cortical thickness graphs of patients with acute AN displayed lower modularity and small-world index (SWI) than HCs. Modularity recovered after weight gain. Reduced global efficiency and SWI were observed in patients at baseline compared to HCs based on gyrification networks. Significant associations between local clustering of CT at admission and BMI-SDS, and clustering/global efficiency of gyrification and duration of illness emerged. CONCLUSIONS: Our results indicate a shift towards less organised CT networks in patients with acute AN. After weight recovery, the disarrangement seems to be partially reduced. However, longer-term follow-ups are needed to determine whether cortical organizational patterns fully return to normal.

Involuntary Treatment for Child and Adolescent Anorexia Nervosa-A Narrative Review and Possible Advances to Move Away from Coercion.

BACKGROUND: Children and adolescents with psychiatric disorders frequently experience hospital treatment as coercive. In particular, for patients with severe anorexia nervosa (AN), clinical and ethical challenges often arise if they do not voluntarily agree to hospital admission, often due to the ego-syntonic nature of the disorder. In these cases, involuntary treatment (IVT) might be life-saving. However, coercion can cause patients to experience excruciating feelings of pressure and guilt and might have long-term consequences. METHODS: This narrative review aimed to summarize the current empirical findings regarding IVT for child and adolescent AN. Furthermore, it aimed to present alternative treatment programs to find a collaborative method of treatment for young AN patients and their families. RESULTS: Empirical data on IVT show that even though no inferiority of IVT has been reported regarding treatment outcomes, involuntary hospital treatment takes longer, and IVT patients seem to struggle significantly more with weight restoration. We argue that more patient- and family-oriented treatment options, such as home treatment, might offer a promising approach to shorten or even avoid involuntary hospital admissions and further IVT. Different home treatment approaches, either aiming at preventing hospitalization or at shortening hospital stays, and the results of pilot studies are summarized in this article.

International consensus on patient-centred outcomes in eating disorders.

The effectiveness of mental health care can be improved through coordinated and wide-scale outcome measurement. The International Consortium for Health Outcomes Measurement has produced collaborative sets of outcome measures for various mental health conditions, but no universal guideline exists for eating disorders. This Position Paper presents a set of outcomes and measures for eating disorders as determined by 24 international experts from professional and lived experience backgrounds. An adapted Delphi technique was used, and results were assessed through an open review survey. Final recommendations suggest outcomes should be tracked across four domains: eating disorder behaviours and cognitions, physical health, co-occurring mental health conditions, and quality of life and social functioning. Outcomes are collected using three to five patient-reported measures. For children aged between 6 years and 12 years, the measures include the Children's Eating Attitude Test (or, for those with avoidant restrictive food intake disorder, the Eating Disorder in Youth Questionnaire), the KIDSCREEN-10, and the Revised Children's Anxiety and Depression Screener-25. For adolescents aged between 13 years and 17 years, the measures include the Eating Disorder Examination Questionnaire (EDE-Q; or, for avoidant restrictive food intake disorder, the Nine-Item Avoidant Restrictive Food Intake Disorder Screener [NIAS]), the two-item Patient Health Questionnaire (PHQ-2), the nine-item Patient Health Questionnaire (PHQ-9), the two-item Generalised Anxiety Disorder (GAD-2), the seven-item Generalised Anxiety Disorder (GAD-7), and the KIDSCREEN-10. For adults older than 18 years, measures include the EDE-Q (or, for avoidant restrictive food intake disorder, the NIAS), the PHQ-2, the PHQ-9, the GAD-2, the GAD-7, the Clinical Impairment Assessment, and the 12-item WHO Disability Assessment Schedule 2.0. These questionnaires should be supplemented by information on patient characteristics and circumstances (ie, demographic, historical, and clinical factors). International adoption of these guidelines will allow comparison of research and clinical interventions to determine which settings and interventions work best, and for whom.

Action initiation and punishment learning differ from childhood to adolescence while reward learning remains stable.

Theoretical and empirical accounts suggest that adolescence is associated with heightened reward learning and impulsivity. Experimental tasks and computational models that can dissociate reward learning from the tendency to initiate actions impulsively (action initiation bias) are thus critical to characterise the mechanisms that drive developmental differences. However, existing work has rarely quantified both learning ability and action initiation, or it has relied on small samples. Here, using computational modelling of a learning task collected from a large sample (N = 742, 9-18 years, 11 countries), we test differences in reward and punishment learning and action initiation from childhood to adolescence. Computational modelling reveals that whilst punishment learning rates increase with age, reward learning remains stable. In parallel, action initiation biases decrease with age. Results are similar when considering pubertal stage instead of chronological age. We conclude that heightened reward responsivity in adolescence can reflect differences in action initiation rather than enhanced reward learning.

Gut Microbiota and Brain Alterations after Refeeding in a Translational Anorexia Nervosa Rat Model.

The gut microbiota composition is causally involved in the regulation of body weight. Through the gut-brain axis, microbiota play a role in psychiatric disorders including anorexia nervosa (AN). Previously, we showed microbiome changes to be associated with brain volume and astrocyte reductions after chronic starvation in an AN animal model. Here, we analyzed whether these alterations are reversible after refeeding. The activity-based anorexia (ABA) model is a well-established animal model that mimics several symptoms of AN. Fecal samples and the brain were analyzed. Like previous results, significant alterations in the microbiome were observed after starvation. After refeeding, including the normalization of food intake and body weight, α- and ß-diversity, as well as the relative abundance of specific genera, were largely normalized in starved rats. Brain parameters appeared to normalize alongside microbial restitution with some aberrations in the white matter. We confirmed our previous findings of microbial dysbiosis during starvation and showed a high degree of reversibility. Thus, microbiome alterations in the ABA model appear to be mostly starvation-related. These findings support the usefulness of the ABA model in investigating starvation-induced effects on the microbiota-gut-brain axis to help comprehend the pathomechanisms of AN and potentially develop microbiome-targeted treatments for patients.

Sex-dependent clinical presentation, body image, and endocrine status in long-term remitted anorexia nervosa.

OBJECTIVE: Although anorexia nervosa (AN) in males has recently gained attention, knowledge of its psychological and physiological outcomes is still scarce. We explore sex-specific characteristics of long-term remitted AN with respect to residual eating disorder (ED) psychopathology, body image, and endocrinology. METHOD: We recruited 33 patients with AN in remission for at least 18 months (24 women, 9 men) and 36 matched healthy controls (HCs). Eating disorder psychopathology and body image ideals were assessed via clinical interviews, questionnaires, and an interactive 3D body morphing tool. Plasma levels of leptin, free triiodothyronine, cortisol, and sex hormones were quantified. Univariate models controlled for age and weight were used to test for the effects of diagnosis and sex. RESULTS: Both patient groups showed residual ED psychopathology but normal weight and hormone levels relative to HCs. Male remitted patients demonstrated significantly stronger muscularity-focused body image ideals, evident in interviews, self-reports, and behavioural data, than both female patients and HCs. CONCLUSIONS: Sex-specific body image characteristics in patients with remitted AN point towards the need to adjust test instruments and diagnostic criteria to male-specific psychopathology. In the future, sufficiently powered studies should evaluate the risk of men with AN developing muscle dysmorphia in the long term.

Genetic variants in genes involved in creatine biosynthesis in patients with severe obesity or anorexia nervosa.

Increased thermogenesis in brown adipose tissue might have an obesity-reducing effect in humans. In transgenic mice, depletion of genes involved in creatine metabolism results in disrupted thermogenic capacity and altered effects of high-fat feeding on body weight. Data analyses of a sex-stratified genome-wide association study (GWAS) for body mass index (BMI) within the genomic regions of genes of this pathway (CKB, CKMT1B, and GATM) revealed one sex-dimorphic BMI-associated SNP in CKB (rs1136165). The effect size was larger in females than in males. A mutation screen of the coding regions of these three candidate genes in a screening group (192 children and adolescents with severe obesity, 192 female patients with anorexia nervosa, and 192 healthy-lean controls) identified five variants in each, CKB and GATM, and nine variants in the coding sequence of CKMT1B. Non-synonymous variants identified in CKB and CKMT1B were genotyped in an independent confirmation study group (781 families with severe obesity (trios), 320 children and adolescents with severe obesity, and 253 healthy-lean controls). In silico tools predicted mainly benign yet protein-destabilizing potentials. A transmission disequilibrium test in trios with severe obesity indicated an obesity-protective effect of the infrequent allele at rs149544188 located in CKMT1B. Subsequent correlation analyses in 1,479 individuals of the Leipzig Obesity BioBank revealed distinct correlations of CKB with the other two genes in omental visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT). Furthermore, between-subject comparisons of gene expression levels showed generally higher expressions of all three genes of interest in VAT than in SAT. Future in vitro analyses are needed to assess the functional implications of these findings.

Lipocalin 2 - mutation screen and serum levels in patients with anorexia nervosa or obesity and in lean individuals.

Context: The bone-derived adipokine lipocalin-2 is relevant for body weight regulation by stimulating the leptin-melanocortin pathway. Objective: We aimed to (i) detect variants in the lipocalin-2 gene (LCN2) which are relevant for body weight regulation and/or anorexia nervosa (AN); (ii) describe and characterize the impact of LCN2 and MC4R variants on circulating lipocalin-2 level. Methods: Sanger sequencing of the coding region of LCN2 in 284 children and adolescents with severe obesity or 287 patients with anorexia nervosa. In-silico analyses to evaluate functional implications of detected LCN2 variants. TaqMan assays for rare non-synonymous variants (NSVs) in additional independent study groups. Serum levels of lipocalin-2 were measured by ELISA in 35 females with NSVs in either LCN2 or MC4R, and 33 matched controls without NSVs in the two genes. Results: Fourteen LCN2-variants (five NSVs) were detected. LCN2-p.Leu6Pro and p.Gly9Val located in the highly conserved signal peptide region may induce functional consequences. The secondary structure change of lipocalin-2 due to LCN2-p.Val89Ile may decrease solubility and results in a low lipocalin-2 level in a heterozygotes carrier (female recovered from AN). Lean individuals had lower lipocalin-2 levels compared to patients with obesity (p = 0.033). Conclusion: Lipocalin-2 levels are positively associated with body mass index (BMI). Single LCN2-variants might have a profound effect on lipocalin-2 levels.

The role of the brain-derived neurotrophic factor (BDNF) in anorexia nervosa.

The brain-derived neurotrophic factor (BDNF) is a growth factor belonging to the neurotrophin family which plays a pivotal role in the differentiation, survival, and plasticity of neurons in the central nervous system. Evidence suggests that BDNF is an important signal molecule in the regulation of energy balance and thus implicated in body weight control. The discovery of BDNF-expressing neurons in the paraventricular hypothalamus which is important in the regulation of energy intake, physical activity, and thermogenesis gives more evidence to the suggested participation of BDNF in eating behavior. Until now it remains questionable whether BDNF can be used as a reliable biomarker for eating disorders such as anorexia nervosa (AN) as available findings on BDNF levels in patients with AN are ambiguous. AN is an eating disorder characterized by a pathological low body weight in combination with a body image disturbance typically developing during adolescence. A severe drive for thinness leads to restrictive eating behavior often accompanied by physical hyperactivity. During therapeutic weight restoration an increase of BDNF expression levels seems desirable as it might improve neuronal plasticity and survival which is essential for learning processes and thereby essential for the success of the psychotherapeutic treatment of patients. On the contrary, the well-known anorexigenic effect of BDNF might favor relapse in patients as soon as the BDNF levels significantly increase during weight rehabilitation. The present review summarizes the association between BDNF and general eating behavior and especially focuses on the eating disorder AN. In this regard findings from preclinical AN studies (activity-based anorexia model) are outlined as well.

"What Made My Eating Disorder Worse?" The Impact of the COVID-19 Pandemic from the Perspective of Adolescents with Anorexia Nervosa.

(1) Background: the COVID-19 pandemic and subsequent confinements have led to a dramatic increase in anorexia nervosa (AN) in adolescent patients, whereas the effect on symptom severity and the influencing factors are not yet clear, especially not from the adolescents' perspective. (2) Methods: from February to October 2021, 38 adolescent patients with AN completed an adjusted version of the COVID Isolation Eating Scale (CIES), a self-report questionnaire asking for ED symptomatology before and during the COVID-19 pandemic and for their experiences with remote treatment. (3) Results: patients reported a significant negative impact of confinement on ED symptoms, depression, anxiety, and emotional regulation. During the pandemic, engagement with weight and body image was related to social media, and mirror checking increased. The patients were more preoccupied with cooking recipes and had more eating-related conflicts with their parents. However, the differences in the amount of engagement with social media actively glorifying AN before and during the pandemic did not remain significant after correction for multiple comparisons. The minority of patients who received remote treatment found it to be only limitedly helpful. (4) Conclusions: from the patients' perspective, the COVID-19 pandemic-associated confinement had a detrimental effect on the symptoms of adolescent patients with AN.

[Fecal Microbiota Transplants in the Context of (Child and Adolescent) Psychiatric Disorders]. / Fäkale Mikrobiotatransplantationen im Zusammenhang mit (kinder- und jugend-)psychiatrischen Erkrankungen.

Fecal Microbiota Transplants in the Context of (Child and Adolescent) Psychiatric Disorders Abstract: There has recently been a significant increase in interest in gut microbiota and its interaction with the brain (gut-brain axis). Not only are the findings of microbiome research interesting for basic scientists, they also offer relevant insights for clinical practice. A causal relationship between gut microbiome and various somatic diseases such as diabetes mellitus, inflammatory bowel diseases, and obesity as well as psychiatric diseases such as major depression, anxiety disorders, and eating disorders seems plausible. To study the causal relationship of intestinal bacteria with individual phenotypes, researchers apply so-called stool transplantations (fecal microbiota transplantations) in the preclinical context. For this purpose, they transfer microbiota samples from patients into laboratory animals to observe possible changes in phenotype. In the clinical context, fecal microbiota transplantation is already being used with therapeutic intentions for selected diseases, for example, recurrent infections with Clostridioides difficile or inflammatory bowel diseases; they have already become part of the official clinical guidelines for C. difficile. For many other diseases, however, including mental illnesses, the potential of using fecal transplantations for therapeutic purposes is still being explored. Previous findings suggest that the intestinal microbiome, particularly fecal microbiota transplantations, represent a promising starting point for new therapeutic approaches.