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Background: To date, there are no empirically validated treatments of good quality for adolescents showing suicidality and non-suicidal self-injurious behavior. Risk factors for suicide are impulsive and non-suicidal selfinjurious behavior, depression, conduct disorders and child abuse. Behind this background, we tested the main hypothesis of our study; that Dialectical Behavioral Therapy for Adolescents is an effective treatment for these patients. Methods: Dialectical Behavioral Therapy (DBT) has been developed by Marsha Linehan - especially for the outpatient treatment of chronically non-suicidal patients diagnosed with borderline personality disorder. The modified version of DBT for Adolescents (DBT-A) from Rathus & Miller has been adapted for a 16-24 week outpatient treatment in the German-speaking area by our group. The efficacy of treatment was measured by a pre-/post- comparison and a one-year follow-up with the aid of standardized instruments (SCL-90-R, CBCL, YSR, ILC, CGI). Results: In the pilot study, 12 adolescents were treated. At the beginning of therapy, 83% of patients fulfilled five or more DSM-IV criteria for borderline personality disorder. From the beginning of therapy to one year after its end, the mean value of these diagnostic criteria decreased significantly from 5.8 to 2.75. 75% of patients were kept in therapy. For the behavioral domains according to the SCL-90-R and YSR, we have found effect sizes between 0.54 and 2.14. During treatment, non-suicidal self-injurious behavior reduced significantly. Before the start of therapy, 8 of 12 patients had attempted suicide at least once. There were neither suicidal attempts during treatment with DBT-A nor at the one-year follow-up. Conclusions: The promising results suggest that the interventions were well accepted by the patients and their families, and were associated with improvement in multiple domains including suicidality, non-suicidal self-injurious behavior, emotion dysregulation and depression from the beginning of therapy to the one-year follow-up. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate long-term weight gain associated with clozapine, olanzapine, and risperidone treatment and its clinical risk factors in children and adolescents. At four child and adolescent psychiatric departments, the weight and body mass index of initially hospitalized patients (aged 9.0–21.3 years) treated with clozapine ( n = 15), olanzapine ( n = 8), and risperidone ( n = 10) were prospectively monitored for 45 weeks. Clinical risk factors (age, gender, baseline weight, dosage, drug-naivety) were tested for their association with weight gain in the three groups. All three groups experienced significant weight gain between baseline and endpoint. The absolute and percentage average weight gains were significantly higher for the olanzapine group (16.2 ± 8.8 kg; 30.1 ± 18.9%) than for the clozapine (9.5 ± 10.4 kg; 14.8 ± 15.8%) and the risperidone (7.2 ± 5.3 kg; 11.5 ± 6.0%) groups. Olanzapine is associated with extreme long-term weight gain in children and adolescents that, in addition, is much higher than that expected in adults. Clozapine and risperidone are associated with a less marked weight gain in children and adolescents but also much higher than that expected in adults. These differences may affect compliance with medication and health risk. [ABSTRACT FROM AUTHOR]

Clozapine is a dibenzodiazepine derivative with established antipsychotic efficacyin adult patients with schizophrenic psychoses. There are more than 15 studies that have also demonstrated the antipsychotic efficacy of clozapine in childhood and adolescent schizophrenia. The main advantages of clozapine treatment in this age group in comparison with typical antipsychotics are: (i) high antipsychotic efficacy during an acute schizophrenic episode; (ii) better improvement in chronic cases with a high load of negative symptoms; and (iii) markedly fewer extrapyramidal adverse effects and, therefore, fairly good tolerability. However, because of its possible adverse effects on the haemopoetic system (granulocytopenia, agranulocytosis), clozapine should not be used as first-line antipsychotic medication. Other adverse effects are related to the cardiovascular system (hypotonia, tachycardia or arrhythmia), the central nervous system (epileptic seizures, fever) and liver function (transient increases in levels of hepatic transaminases). Two other frequent adverse effects are hypersalivation and body-weight gain, which may present a particular problem in adolescents and young adults. Careful monitoring of haematological parameters and other adverse effects are preconditions for a successful treatment programme. [ABSTRACT FROM AUTHOR]

Objective: Medication is commonly used in anorexia nervosa (AN) despite largely missing high grade evidence. Olanzapine (OLZ) is the best‐evidenced substance used off‐label in this group, with conflicting outcome regarding BMI, clinical and safety parameters. Therefore, it is important to strictly assure quality of treatment with OLZ in AN by using 'Therapeutic Drug Monitoring' according to AGNP‐guidelines, including serum levels and adverse drug reactions (ADRs) to support safety for adolescents with AN and attempt to generate an initial age‐ and disorder‐specific therapeutic reference range. Method: Sixty‐five adolescents with AN (aged 10–18) treated with OLZ (98% female; 97.5% AN‐restricting‐type) were prospectively observed, ADRs reported, and correlations between dosage and serum levels measured at trough level were calculated, a preliminary therapeutic range defined. Results: Mean dosage of OLZ was 8.15 (SD: 2.91) mg and 0.19 (SD: 0.07) mg/kg respectively, average concentration was 26.57 (SD: 13.46) ng/mL. Correlation between daily dosage/dosage per kg and serum level was 0.72 (**p < 0.001)/0.65 (**p < 0.001), respectively. ADRs with impairment were rare (6.3%). 75% improved clinically (CGI). BMI increased significantly by 1.5 kg/m2 (t = 10.6, p < 0.001). A preliminary therapeutic reference range is 11.9 and 39.9 ng/mL. Conclusions: OLZ in the hands of specialists is a well‐tolerated and safe treatment adjunct for adolescents with AN. Highlights: Olanzapine in adolescents with anorexia nervosa is a safe and well‐tolerated adjunct to a multidisciplinary inpatient treatment approach using therapeutic drug monitoring.Correlations of dosage and serum levels are high.A preliminary disorder‐ and age‐specific reference range was successfully defined for the first time. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Fluoxetine is the recommended first-line antidepressant in many therapeutic guidelines for children and adolescents. However, little is known about the relationships between drug dose and serum level as well as the therapeutic serum reference range in this age group. Within a large naturalistic observational prospective multicenter clinical trial ("TDM-VIGIL"), a transdiagnostic sample of children and adolescents (n = 138; mean age, 15; range, 7–18 years; 24.6% males) was treated with fluoxetine (10–40 mg/day). Analyses of both the last timepoint and all timepoints (n = 292 observations), utilizing (multiple) linear regressions, linear mixed-effect models, and cumulative link (mixed) models, were used to test the associations between dose, serum concentration, outcome, and potential predictors. The receiver operating curve and first to third interquartile methods, respectively, were used to examine concentration cutoff and reference values for responders. A strong positive relationship was found between dose and serum concentration of fluoxetine and its metabolite. Higher body weight was associated with lower serum concentrations, and female sex was associated with lower therapeutic response. The preliminary reference ranges for the active moiety (fluoxetine+norfluoxetine) were 208–328 ng/mL (transdiagnostically) and 201.5–306 ng/mL (depression). Most patients showed marked (45.6%) or minimal (43.5%) improvements and reported no adverse effects (64.9%). This study demonstrated a clear linear dose–serum level relationship for fluoxetine in youth, with the identified reference range being within that established for adults. [ABSTRACT FROM AUTHOR]

Findings of genetic overlap between Schizophrenia, Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) contributed to a renewed conceptualization of these disorders as laying on a continuum based on aetiological, pathophysiological and neurodevelopmental features. Given that cognitive impairments are core to their pathophysiology, we compared patients with schizophrenia, ADHD, ASD, and controls on ocular-motor and manual-motor tasks, challenging crucial cognitive processes. Group comparisons revealed inhibition deficits common to all disorders, increased intra-subject variability in schizophrenia and, to a lesser extent, ADHD as well as slowed processing in schizophrenia. Patterns of deviancies from controls exhibited strong correlations, along with differences that posited schizophrenia as the most impaired group, followed by ASD and ADHD. While vector correlations point towards a common neurodevelopmental continuum of impairment, vector levels suggest differences in the severity of such impairment. These findings argue towards a dimensional approach to Neurodevelopmental Disorders' pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Introduction Despite the growing evidence base for psychotropic drug treatment in pediatric patients, knowledge about the benefit-risk ratio in clinical practice remains limited. The 'Therapeutic Drug Monitoring (TDM)-VIGIL' study aimed to evaluate serious adverse drug reactions (ADRs) in children and adolescents treated with antidepressants and/or antipsychotics in approved ('on-label'), and off-label use in clinical practice. Methods Psychiatric pediatric patients aged 6-18 years treated with antidepressants and/or antipsychotics either on-label or off-label were prospectively followed between October 2014 and December 2018 within a multicenter trial. Follow-up included standardized assessments of response, serious ADRs and therapeutic drug monitoring. Results 710 youth (age=14.6±2.2 years, female=66.6%) were observed for 5.5 months on average; 76.3% received antidepressants, 47.5% antipsychotics, and 25.2% both. Altogether, 55.2% of the treatment episodes with antidepressants and 80.7% with antipsychotics were off-label. Serious ADRs occurred in 8.3% (95%CI=6.4–10.6%) of patients, mainly being psychiatric adverse reactions (77.4%), predominantly suicidal ideation and behavior. The risk of serious ADRs was not significantly different between patients using psychotropics off-label and on-label (antidepressants: 8.1% vs. 11.3%, p=0.16; antipsychotics: 8.7% vs 7.5%, p=0.67). Serious ADRs occurred in 16.6% of patients who were suicidal at enrollment versus 5.6% of patients who were not suicidal (relative risk 3.0, 95%CI=1.9-4.9). Conclusion Off-label use of antidepressants and antipsychotics in youth was not a risk factor for the occurrence of serious ADRs in a closely monitored clinical setting. Results from large naturalistic trials like ours can contribute to bridging the gap between knowledge from randomized controlled trials and real-world clinical settings. [ABSTRACT FROM AUTHOR]

Disorders with neurodevelopmental aetiology such as Attention-Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD) and Schizophrenia share commonalities at many levels of investigation despite phenotypic differences. Evidence of genetic overlap has led to the concept of a continuum of neurodevelopmental impairment along which these disorders can be positioned in aetiological, pathophysiological and developmental features. This concept requires their simultaneous comparison at different levels, which has not been accomplished so far. Given that cognitive impairments are core to the pathophysiology of these disorders, we provide for the first time differentiated head-to-head comparisons in a complex cognitive function, visual search, decomposing the task with eye movement-based process analyses. N = 103 late-adolescents with schizophrenia, ADHD, ASD and healthy controls took a serial visual search task, while their eye movements were recorded. Patients with schizophrenia presented the greatest level of impairment across different phases of search, followed by patients with ADHD, who shared with patients with schizophrenia elevated intra-subject variability in the pre-search stage. ASD was the least impaired group, but similar to schizophrenia in post-search processes and to schizophrenia and ADHD in pre-search processes and fixation duration while scanning the items. Importantly, the profiles of deviancy from controls were highly correlated between all three clinical groups, in line with the continuum idea. Findings suggest the existence of one common neurodevelopmental continuum of performance for the three disorders, while quantitative differences appear in the level of impairment. Given the relevance of cognitive impairments in these three disorders, we argue in favour of overlapping pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

The selective norepinephrine reuptake inhibitor atomoxetine is potentially among the first-line pharmacotherapy options for ADHD. Therapeutic drug monitoring (TDM) with the quantification and interpretation of atomoxetine serum concentrations is used to determine an individual dose followed by an optimal effectiveness and minimal side effects. The aim of this retrospective pharmacokinetic–pharmacodynamic analysis was to derive age-appropriate recommendations for the implementation of TDM to improve the efficacy and tolerability of atomoxetine in children and adolescents. Using the analytical method of high-performance liquid chromatography with UV detection, 94 serum concentrations of 74 patients between 6 and 21 years of age were determined. Therapeutic effectiveness and side effects were evaluated according to the categories "low", "moderate", and "significant". As part of TDM, a time interval with maximum concentrations of 1–3 h after the administration of atomoxetine was determined for blood sampling. In this time interval, a significant correlation between the weight-normalized dose and the serum concentrations was found. The efficacy as well as the tolerability proved to be mainly moderate or significant. A preliminary therapeutic reference range was between 100 and 400 ng/ml. Naturalistic studies have limitations. Therefore, and due to a limited study population, the results have to be regarded as preliminary observations that must be confirmed in further studies. The preliminary therapeutic reference range for children and adolescents proved to be narrower than the reference range for adult patients. However, due to good efficacy and tolerability an exact reference range remained difficult to determine. [ABSTRACT FROM AUTHOR]

Background: Body mass index (BMI) at hospital admission in patients with anorexia nervosa (AN) represents a prognostic marker for mortality, chronicity and future body weight. The current study focused on the associations between BMI standard deviation score (BMI-SDS) at admission and reasons for seeking inpatient treatment. Further interest was given to the relationship between premorbid weight and weight at admission, as well as the effect of both weight at referral and reasons for admission on treatment outcome. Methods: Data ascertained in the German Register of Children and Adolescents with AN were analysed to assess the parental and patient overlap for 23 predefined reasons for admission, using factor analyses and regressions models. Results: Complete parent-patient data sets were available for 360 patients out of 769. The highest consensus rates between parents and patients were obtained for weight and eating behavior related reasons and hyperactivity. Based on factor analysis, four factors emerged. Premorbid BMI-SDS, age and 'low body weight' as stated by patients or parents explained almost 40% of the variance of the BMI-SDS at admission. Conclusions: Results underscore the relevance of age and premorbid BMI for BMI at admission. Only single reasons for admission explained further variance, with 'low body weight' having the largest effect. Approximately 40% of the variance of BMI-SDS was explained. For the first time, the effect of premorbid BMI for BMI at admission was robustly demonstrated in a multicenter study. Of the variance in BMI-SDS at discharge, our model could explain 37%, with reasons for admission having a small effect. Further investigation of the reasons for admission would be worthwhile to improve treatment and prognosis. [ABSTRACT FROM AUTHOR]

Background: Brain-derived neurotrophic factor (BDNF) influences brain plasticity and feeding behaviour, and it has been linked to anorexia nervosa in numerous studies. Findings in mostly adult patients point to reduced serum BDNF levels in the acute stage of anorexia nervosa and rising levels with weight recovery. However, it is unclear whether this increase leads to normalization or supranormal levels, a difference that is potentially important for the etiology of anorexia nervosa and relapse. Methods: We measured serum BDNF at admission (n = 149), discharge (n = 130), 1-year follow-up (n = 116) and 2.5-year follow-up (n = 76) in adolescent female patients with anorexia nervosa hospitalized for the first time, and in healthy controls (n = 79). We analyzed associations with body mass index, eating disorder psychopathology and comorbidities. Results: Serum BDNF was only nominally lower at admission in patients with anorexia nervosa compared to healthy controls, but it increased continuously and reached supranormal levels at 2.5-year follow-up. BDNF was inversely associated with eating disorder psychopathology at discharge and positively associated with previous weight gain at 1-year follow-up. Limitations: We compensated for attrition and batch effects using statistical measures. Conclusion: In this largest longitudinal study to date, we found only nonsignificant reductions in BDNF in the acute stage of anorexia nervosa, possibly because of a shorter illness duration in adolescent patients. Supranormal levels of BDNF at 2.5-year follow-up could represent a pre-existing trait or a consequence of the illness. Because of the anorexigenic effect of BDNF, it might play an important predisposing role for relapse and should be explored further in studies that test causality. [ABSTRACT FROM AUTHOR]

Both DSM-5 and ICD-11 have provided weight cut-offs and severity specifiers for the diagnosis of anorexia nervosa (AN) in childhood, adolescence and adulthood. The aims of the current study focusing on inpatients aged < 19 years were to assess (1) the relationship between age and body mass index (BMI; kg/m2), BMI-centiles, BMI-standard deviation scores (BMI-SDS) and body height-SDS at referral, (2) the percentages of patients fulfilling the DSM-5 and ICD-11 weight criteria and severity categories for AN, and (3) the validity of the AN severity specifiers via analysis of both weight related data at discharge and inpatient treatment duration. The German Registry for Anorexia Nervosa encompassed complete data sets for 469 female patients (mean age = 15.2 years; range 8.9–18.9 years) with a diagnosis of AN (n = 404) or atypical AN (n = 65), who were ascertained at 16 German child and adolescent psychiatric hospitals. BMI at referral increased up to age 15 to subsequently plateau. Approximately one tenth of all patients with AN had a BMI above the fifth centile. The ICD-11 specifier based on a BMI-centile of 0.3 for childhood and adolescent AN entailed two equally sized groups of patients. Discharge data revealed limited validity of the specifiers. Height-SDS was not correlated with age thus stunting had no impact on our data. We corroborate the evidence to use the tenth instead of the fifth BMI-centile as the weight criterion in children and adolescents. Weight criteria should not entail major diagnostic shifts during the transition from adolescence to adulthood. The severity specifiers based on BMI or BMI-centiles do not seem to have substantial clinical validity. [ABSTRACT FROM AUTHOR]

Objective: Nocturnal enuresis (NE), daytime urinary incontinence (DUI), and fecal incontinence (FI) are common disorders in childhood and are frequently accompanied by comorbid psychiatric disorders. Despite a high association between urinary and fecal incontinence with psychiatric and neurodevelopmental disorders, research on comorbidity between incontinence and anorexia nervosa (AN) remains scarce. Yet, it is well known that somatic consequences of AN include metabolic and gastrointestinal disorders. The study sought to assess the prevalence of incontinence and constipation in children and adolescents with AN and to examine associations of these two symptoms with body weight at admission and with BMI changes during inpatient treatment. Methods: Data collected between 2015 and 2017 by a multicenter German web‐based registry for AN were analyzed. Three hundred and forty‐eight patients with AN (96.3% female, mean age = 15.1 ± 1.8 years) were assessed regarding AN subtype, psychiatric comorbidity, body weight, incontinence, and constipation. Results: Overall, 27.6% of patients had constipation, 1.8% had NE and 1.8% DUI. Prevalence of constipation did not significantly differ between AN subtypes. Constipation did not lead to any significant differences in weight/BMI changes during inpatient treatment. Discussion: This is the largest study of incontinence and constipation in patients with AN, so far. Our results indicate that constipation is highly prevalent in adolescent patients with AN and reflects a clinically relevant condition. Despite, patients with AN do not have an increased prevalence of incontinence compared with the general population. Future studies should include medical examinations like ultrasound and physical examination of the lower abdomen to evaluate the severity of constipation. [ABSTRACT FROM AUTHOR]

Objective: Recent preliminary studies indicated a seasonal association of BMI at admission to inpatient treatment for anorexia nervosa (AN), indicating lower BMI in the cold season for restrictive AN. An impaired thermoregulation was proposed as the causal factor, based on findings in animal models of AN. However, findings regarding seasonality of BMI and physical activity levels in the general population indicate lower BMI and higher physical activity in summer than in winter. Therefore, we aimed to thoroughly replicate the findings regarding seasonality of BMI at admission in patients with AN in this study. Method: AN subtype, age- and gender-standardized BMI scores (BMI-SDS) at admission, mean daily sunshine duration and ambient temperature at the residency of 304 adolescent inpatients with AN of the multi-center German AN registry were analyzed. Results: A main effect of DSM-5 AN subtype was found (F(2,298) = 6.630, p = .002), indicating differences in BMI-SDS at admission between restrictive, binge/purge and subclinical AN. No main effect of season on BMI-SDS at admission was found (F(1,298) = 4.723, p = .025), but an interaction effect of DSM-5 subtype and season was obtained (F(2,298) = 6.625, p = .001). Post-hoc group analyses revealed a lower BMI-SDS in the warm season for restrictive AN with a non-significant small effect size (t(203.16) = 2.140, p = .033; Hedges′g = 0.28). Small correlations of mean ambient temperature (r = −.16) and daily sunshine duration (r = −.22) with BMI-SDS in restrictive AN were found. However, the data were widely scattered. Conclusions: Our findings are contrary to previous studies and question the thermoregulatory hypothesis, indicating that seasonality in AN is more complex and might be subject to other biological or psychological factors, for example physical activity or body dissatisfaction. Our results indicate only a small clinical relevance of seasonal associations of BMI-SDS merely at admission. Longitudinal studies investigating within-subject seasonal changes might be more promising to assess seasonality in AN and of higher clinical relevance. [ABSTRACT FROM AUTHOR]

Merely looking at food images can already elicit psychophysiological fear and avoidance responses [[1]], which are reflected in an activation of the so-called fear network (FN) [[2]]. The dorsal ACC (dACC) and its transition into the dorsomedial PFC (dmPFC) are involved in conscious emotional appraisal [[6]] and may play a pivotal role in the reported negative appraisal of food stimuli in AN [[7]]. A hyperreactive dACC/dmPFC and other areas of the FN are observable in generalized anxiety disorder and specific phobias [[6]]. We hypothesize that pathological fear/threat appraisal in AN results in a hyperresponsive FN [[9]]. [Extracted from the article]

Objective High levels of expressed emotions (EE) and depressive symptoms (DS) are often found in caregivers of patients with anorexia nervosa (AN). Both parameters are considered to influence AN symptoms of the patient. Methods One hundred seventy adolescent women with AN and their caregivers were assessed at admission, discharge, at 1-year and 2.5-year follow up to evaluate AN symptoms of the patient and EE and DS of caregivers. Results The EE and DS were elevated at admission and decreased during treatment, criticism (as part of EE) exhibited again at the 2.5-year follow up. Caregivers of more severely ill patients reported significantly greater levels of EE and DS. Mothers were more affected than fathers. EE and DS were interrelated. Conclusion Caregivers of adolescent AN patients suffer from elevated levels of EE and DS. Further studies are needed to examine whether therapeutic interventions to reduce caregivers' EE and DS might have a positive influence on treatment outcome. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association. [ABSTRACT FROM AUTHOR]

Elevated serum leptin levels following rapid therapeutically induced weight gain in anorexia nervosa (AN) patients are discussed as a potential biomarker for renewed weight loss as a result of leptin-related suppression of appetite and increased energy expenditure. This study aims to analyze the predictive value of leptin levels at discharge as well as the average rate of weight gain during inpatient or day patient treatment for body weight at 1-year follow-up. 121 patients were recruited from the longitudinal Anorexia Nervosa Day patient versus Inpatient (ANDI) trial. Serum leptin levels were analyzed at referral and discharge. A multiple linear regression analysis to predict age-adjusted body mass index (BMI-SDS) at 1-year follow-up was performed. Leptin levels, the average rate of weight gain, premorbid BMI-SDS, BMI-SDS at referral, age and illness duration were included as independent variables. Neither leptin levels at discharge nor rate of weight gain significantly predicted BMI-SDS at 1-year follow-up explaining only 1.8 and 0.4 % of the variance, respectively. According to our results, leptin levels at discharge and average rate of weight gain did not exhibit any value in predicting weight at 1-year follow-up in our longitudinal observation study of adolescent patients with AN. Thus, research should focus on other potential factors to predict weight at follow-up. As elevated leptin levels and average rate of weight gain did not pose a risk for reduced weight, we found no evidence for the beneficial effect of slow refeeding in patients with acute AN. [ABSTRACT FROM AUTHOR]

Objective: Previous research has yielded evidence of increased attentional processing of negatively valenced body parts in women with anorexia nervosa (AN), especially for those with high depressive symptomatology. The present study extended previous research by implementing an experimental mood manipulation. Method: In a within-subjects design, female adolescents with AN (n = 12) and an age matched female control group (CG; n = 12) were given a negative and a positive mood induction at a one-week interval. After each mood induction, participants underwent a 3-min mirror exposure, while their eye movements were recorded. Results: After the positive mood induction, both AN and CG participants displayed longer and more frequent gazes towards their self-defined most ugly relative to their self-defined most beautiful body part. However, after the negative mood induction, only females with AN were characterized by increased attention to their most ugly compared to their most beautiful body part, while CG participants’ attention distribution was balanced. Furthermore, in the negative (but not in the positive) mood induction condition gaze frequency and duration towards the most ugly body part was significantly stronger in the AN group relative to the CG. Discussion: The results emphasize the role of negative mood in the maintenance of pathological information processing of the self-body. This increased body-related negativity-bias during negative mood may lead to the persistence and aggravation of AN patients’ body image disturbance. [ABSTRACT FROM AUTHOR]

Background Increased intra-subject variability ( ISV) in reaction times (RTs) is a promising endophenotype for attention-deficit hyperactivity disorder ( ADHD) and among the most robust hallmarks of the disorder. ISV has been assumed to represent an attentional deficit, either reflecting lapses in attention or increased neural noise. Here, we use an innovative single-trial event-related potential approach to assess whether the increased ISV associated with ADHD is indeed attributable to attention, or whether it is related to response-related processing. Methods We measured electroencephalographic responses to working memory oddball tasks in patients with ADHD ( N = 20, aged 11.3 ± 1.1) and healthy controls ( N = 25, aged 11.7 ± 1.1), and analysed these data with a recently developed method of single-trial event-related potential analysis. Estimates of component latency variability were computed for the stimulus-locked and response-locked forms of the P3b and the lateralised readiness potential (LRP). Results ADHD patients showed significantly increased ISV in behavioural ISV. This increased ISV was paralleled by an increase in variability in response-locked event-related potential latencies, while variability in stimulus-locked latencies was equivalent between groups. This result held across the P3b and LRP. Latency of all components predicted RTs on a single-trial basis, confirming that all were relevant for speed of processing. Conclusions These data suggest that the increased ISV found in ADHD could be associated with response-end, rather than stimulus-end processes, in contrast to prevailing conceptions about the endophenotype. This mental chronometric approach may also be useful for exploring whether the existing lack of specificity of ISV to particular psychiatric conditions can be improved upon. [ABSTRACT FROM AUTHOR]

Body mass index (BMI) is one of the most important outcome predictors in patients with anorexia nervosa (AN). A low premorbid BMI percentile calculated by the patients recalled premorbid weight and the height at first admission has been found to predict the BMI at first inpatient admission. In this study, we sought to confirm this relationship. We additionally analyze the relationship between premorbid BMI percentile and BMI percentile at discharge from the first inpatient treatment and at 1-year follow-up or alternatively if applicable upon readmission within this time period. We included 161 female patients aged 11-18 years of the multisite ANDI-trial with a DSM-IV diagnosis of AN. We used a multivariate statistical model including the independent variables age, duration of illness, duration of treatment, BMI at admission and BMI percentile at discharge. The relationship between premorbid BMI percentile and BMI at admission was solidly confirmed. In addition to premorbid BMI percentile, BMI at admission and age were significant predictors of BMI percentile at discharge. BMI percentile at discharge significantly predicted BMI percentile at 1-year follow-up. An additional analysis that merely included variables available upon referral revealed that premorbid BMI percentile predicts the 1-year follow-up BMI percentile. Further studies are required to identify the underlying biological mechanisms and to address the respective treatment strategies for AN patients with a low or high premorbid BMI percentile. [ABSTRACT FROM AUTHOR]

Summary Visfatin is a recently described protein that is thought to regulate the process of adipocyte differentiation. Findings suggest that visfatin may be actively involved in the control of weight regulatory networks. However, to what extent and which role it plays in eating disorders is still poorly understood, as mixed results have been reported. The aim of the current study was to investigate serum visfatin concentrations on a cross sectional sample between acute anorexia nervosa patients ( n = 44), weight recovered patients ( n = 13) and healthy controls ( n = 46) and a longitudinal sample of acute patients ( n = 57) during weight recovery at three different time-points. Results did not show significant differences in visfatin between the three groups; however, acute patients showed a higher visfatin/BMI-SDS ratio than controls and recovered patients. Longitudinal results revealed an increase of visfatin levels during therapy. Our results suggest that high ratios of visfatin/BMI-SDS could be a state marker in acute anorexia nervosa, displaying a compensatory mechanism of the individual to maintain normal visfatin levels under malnourished conditions. [ABSTRACT FROM AUTHOR]

The co-occurrence of motor and imitation disabilities often characterises the spectrum of deficits seen in patients with autism spectrum disorders (ASD). Whether these seemingly separate deficits are inter-related and whether, in particular, motor deficits contribute to the expression of imitation deficits is the topic of the present study and was investigated by comparing these deficits' cross-sectional developmental trajectories. To that end, different components of motor performance assessed in the Zurich Neuromotor Assessment and imitation abilities for facial movements and non-meaningful gestures were tested in 70 subjects (aged 6-29 years), including 36 patients with high-functioning ASD and 34 age-matched typically developed (TD) participants. The results show robust deficits in probands with ASD in timed motor performance and in the quality of movement, which are all independent of age, with one exception. Only diadochokinesis improves moderately with increasing age in ASD probands. Imitation of facial movements and of non-meaningful hand, finger, hand finger gestures not related to social context or tool use is also impaired in ASD subjects, but in contrast to motor performance this deficit overall improves with age. A general imitation factor, extracted from the highly inter-correlated imitation tests, is differentially correlated with components of neuromotor performance in ASD and TD participants. By developmentally fractionating developmentally stable motor deficits from developmentally dynamic imitation deficits, we infer that imitation deficits are primarily cognitive in nature. [ABSTRACT FROM AUTHOR]

Background In-patient treatment (IP) is the treatment setting of choice for moderately-to-severely ill adolescents with anorexia nervosa, but it is costly, and the risks of relapse and readmissions are high. Day patient treatment (DP) is less expensive and might avoid problems of relapse and readmission by easing the transition from hospital to home. We investigated the safety and efficacy of DP after short inpatient care compared with continued IP. Methods For this multicentre, randomised, open-label, non-inferiority trial, we enrolled female patients (aged 11-18 years) with anorexia nervosa from six centres in Germany. Patients were eligible if they had a body-mass index (BMI) below the tenth percentile and it was their first admission to hospital for anorexia nervosa. We used a computer- generated randomisation sequence to randomly assign patients to continued IP or DP after 3 weeks of inpatient care (1:1; stratified for age and BMI at admission). The treatment programme and treatment intensity in both study groups were identical. The primary outcome was the increase in BMI between the time of admission and a 12-month follow- up adjusted for age and duration of illness (non-inferiority margin of 0-75 kg/m2). Analysis was done by modified intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number Register, number ISRCTN67783402, and the Deutsches Register Klinischer Studien, number DRKS00000101. Findings Between Feb 2, 2007, to April 27, 2010, we screened 660 patients for eligibility, 172 of whom we randomly allocated to treatment: 85 to IP and 87 to DP. DP was non-inferior to IP with respect to the primary outcome, BMI at the 12-month follow-up (mean difference 0-46 kg/m2 in favour of DP (95% CI, -0 11 to 102; pnon-inferiority<0• 0001). The number of treatment-related serious adverse events was similar in both study groups (eight in the IP group, seven in the DP group). Three serious adverse events in the IP group and two in the DP group were related to suicidal ideation; one patient in the DP attempted suicide 3 months after she was discharged. Interpretation DP after short inpatient care in adolescent patients with non-chronic anorexia nervosa seems no less effective than IP for weight restoration and maintenance during the first year after admission. Thus, DP might be a safe and less costly alternative to IP. Our results justify the broad implementation of this approach. [ABSTRACT FROM AUTHOR]

Background: The resumption of menses is an important indicator of recovery in anorexia nervosa (AN). Patients with early-onset AN are at particularly great risk of suffering from the long-term physical and psychological consequences of persistent gonadal dysfunction. However, the clinical variables that predict the recovery of menstrual function during weight gain in AN remain poorly understood. The aim of this study was to investigate the impact of several clinical parameters on the resumption of menses in first-onset adolescent AN in a large, wellcharacterized, homogenous sample that was followed-up for 12 months. Methods: A total of 172 female adolescent patients with first-onset AN according to DSM-IV criteria were recruited for inclusion in a randomized, multi-center, German clinical trial. Menstrual status and clinical variables (i.e., premorbid body mass index (BMI), age at onset, duration of illness, duration of hospital treatment, achievement of target weight at discharge, and BMI) were assessed at the time of admission to or discharge from hospital treatment and at a 12- month follow-up. Based on German reference data, we calculated the percentage of expected body weight (%EBW), BMI percentile, and BMI standard deviation score (BMI-SDS) for all time points to investigate the relationship between different weight measurements and resumption of menses. Results: Forty-seven percent of the patients spontaneously began menstruating during the follow-up period. %EBW at the 12-month follow-up was strongly correlated with the resumption of menses. The absence of menarche before admission, a higher premorbid BMI, discharge below target weight, and a longer duration of hospital treatment were the most relevant prognostic factors for continued amenorrhea. Conclusions: The recovery of menstrual function in adolescent patients with AN should be a major treatment goal to prevent severe long-term physical and psychological sequelae. Patients with premenarchal onset of AN are at particular risk for protracted amenorrhea despite weight rehabilitation. Reaching and maintaining a target weight between the 15th and 20th BMI percentile is favorable for the resumption of menses within 12 months. Whether patients with a higher premorbid BMI may benefit from a higher target weight needs to be investigated in further studies. [ABSTRACT FROM AUTHOR]

Body mass index (BMI) at admission is an important predictor of outcome in adolescent eating disorders. However, few studies have investigated BMI at admission, its changes in recent years, or modifying factors, such as duration of illness and age at onset in different geographical regions. Thus, this study aimed to investigate changes in BMI at admission over the past decade in one clinic, the differences in BMI between various treatment sites and the influence of duration of illness before admission and age at admission. Our sample consisted of 158 adolescent female patients with anorexia nervosa (AN) admitted between 2001 and 2009 to a major university hospital and 169 adolescent female patients recruited in a multicenter study between 2007 and 2010. We assessed the differences between departments in different regions of Germany in the multi-site sample. Changes over time in age-adjusted BMI and age at admission as well as modifying factors for age-adjusted BMI at admission, such as age at admission and duration of illness, were assessed in a representative local sample. There were no significant differences between departments in different regions of Germany. Over the course of the local study, there was a small but significant increase in the age-adjusted BMI score and absolute BMI at admission. In addition, there was a positive association between year of admission and age at admission. Older adolescents with AN had a lower age-adjusted BMI score and a longer duration of illness at the time of admission. The BMI at admission, which is one of the most important predictors of outcome in AN, has increased slightly during the past 10 years. Education strategies for parents and professionals should continue to be improved to further shorten the duration of illness before admission, especially for older adolescents. [ABSTRACT FROM AUTHOR]

Background: Metabolic control and dietary management of patients with phenylketonuria (PKU) are based on single blood samples obtained at variable intervals. Sampling conditions are often not well-specified and intermittent variation of phenylalanine concentrations between two measurements remains unknown. We determined phenylalanine and tyrosine concentrations in blood over 24 hours. Additionally, the impact of food intake and physical exercise on phenylalanine and tyrosine concentrations was examined. Subcutaneous microdialysis was evaluated as a tool for monitoring phenylalanine and tyrosine concentrations in PKU patients. Methods: Phenylalanine and tyrosine concentrations of eight adult patients with PKU were determined at 60 minute intervals in serum, dried blood and subcutaneous microdialysate and additionally every 30 minutes postprandially in subcutaneous microdialysate. During the study period of 24 hours individually tailored meals with defined phenylalanine and tyrosine contents were served at fixed times and 20 min bicycle-ergometry was performed. Results: Serum phenylalanine concentrations showed only minor variations while tyrosine concentrations varied significantly more over the 24-hour period. Food intake within the patients' individual diet had no consistent effect on the mean phenylalanine concentration but the tyrosine concentration increased up to 300% individually. Mean phenylalanine concentration remained stable after short-term bicycle-exercise whereas mean tyrosine concentration declined significantly. Phenylalanine and tyrosine concentrations in dried blood were significantly lower than serum concentrations. No close correlation has been found between serum and microdialysis fluid for phenylalanine and tyrosine concentrations. Conclusions: Slight diurnal variation of phenylalanine concentrations in serum implicates that a single blood sample does reliably reflect the metabolic control in this group of adult patients. Phenylalanine concentrations determined by subcutaneous microdialysis do not correlate with the patients' phenylalanine concentrations in serum/blood. [ABSTRACT FROM AUTHOR]

A previous study showed that a single nucleotide polymorphism (SNP), −1438G/A (rs6311), found in the transcriptional control region of the gene that encodes the serotonin-receptor 2A (HTR2A) was associated with obsessive-compulsive disorder (OCD) in a sample of children and adolescents. In this study, we reanalyzed the association of this SNP with OCD in an enlarged population of 136 cases (55 previous + 81 new cases) and compared them to 106 newly recruited, healthy, age-matched controls. We also investigated whether this SNP or its copy number variations (CNV) was associated with OCD severity and age of onset. The CNV was analyzed in a DNA region located near rs6311. The results confirmed the association between the A-allele and early onset OCD in children and adolescents, with an odds ratio (OR) of 1.69 [95% CI (1.17, 2.46); p = 0.005]. Strikingly, we found that carriers of one copy (deletion) of the CNV were associated with a very early onset OCD (2.5 years earlier than the typical onset), and they had increased CY-BOCS scores (8.7 points higher compared to 'normal' CNV and duplications); which is related to increased severity of OCD symptoms ( p = 0.031; p = 0.004, respectively). Compared to the normal CNV and duplications, the association between the deletion and OCD showed an OR of 7.56 [95% CI (1.32, 142.84); p = 0.020]. These results pointed to the functional importance of this promoter region of HTR2A; it influenced the occurrence, the onset, and the severity of OCD. [ABSTRACT FROM AUTHOR]

Abstract: The gastrointestinal peptide hormone ghrelin promotes food intake and increases body weight and adiposity through activation of the growth hormone secretagogue receptor (GHSR1a). To promote its biological action ghrelin is acylated at its serine 3 residue by the recently discovered ghrelin O-acyltransferase (GOAT, a.k.a. membrane-bound O-acyltransferase 4, MBOAT4). Plasma levels of total and acyl-ghrelin are negatively correlated with body-mass-index (BMI); as lower the BMI as higher plasma levels of total and acylated ghrelin and vice versa. Accordingly, plasma levels of total and acyl-ghrelin are elevated in patients with anorexia nervosa (AN) and decline upon weight regain. The importance of the endogenous Goat/ghrelin system in the neuroendocrine adaptation to fasting was recently highlighted by the observation that acyl-ghrelin mediated elevation of growth hormone (GH) release prevents starvation induced hypoglycemia in Goat −/− mice. The aim of this study was to test if genetic variation of GOAT is implicated in the etiology of AN. We therefore assessed association of 6 tagging single nucleotide polymorphisms (tagSNPs), which were predicted to cover 96% the common genetic variability of GOAT plus 50 kb of the 5′ and 3′ flanking region, in 543 German patients with AN and 612 German normal and underweight healthy controls. Based on a recessive mode of inheritance we observed some evidence for association of the G/G genotype at SNP rs10096097 with AN (nominal two-sided p = 0.031). Based on our results we conclude that genetic variation in GOAT might be implicated in the etiology of AN. [Copyright &y& Elsevier]

To examine relations between movement disorders (MD) and psychopathological symptoms in an adolescent population with schizophrenia under treatment with predominantly atypical antipsychotics. MD symptoms and psychopathology were cross-sectionally assessed in 93 patients (aged 19.6 ± 2.2 years) using Tardive Dyskinesia Rating Scale (TDRS), Abnormal Involuntary Movement Scale (AIMS), Extrapyramidal Symptom Scale (EPS), Barnes Akathisia Scale (BAS), Brief Psychiatric Rating Scale (BPRS) and the Schedule for Assessment of Negative/Positive Symptoms (SANS/SAPS). All patients with MD symptoms (n = 37; 39.8 %) showed pronounced global psychpathological signs (SANS/SAPS, BPRS: p = 0.026, p = 0.033, p = 0.001) with predominant anergia symptoms (p = 0.005) and inclinations toward higher anxiety- and depression-related symptoms (p = 0.051) as well as increased thought disturbance (p = 0.066). Both negative symptoms and anergia showed trends for positive correlations with tardive dyskinesia (p = 0.068; p = 0.065) as well as significant correlations with parkinsonism symptoms (p = 0.036; p = 0.023). Akathisia symptoms correlated significantly with hostile and suspicious symptoms (p = 0.013). A superfactor-analysis revealed four factors supporting the aforementioned results. MD symptoms and psychopathology are in some respects related to each other. Motor symptoms representing on the one hand trait characteristics of schizophrenia might additionally be triggered by antipsychotics and finally co-occur with more residual symptoms within a long-term treatment. [ABSTRACT FROM AUTHOR]

To examine prevalence of movement disorders (MDs) such as tardive dyskinesia (TD), parkinsonism or akathisia in an adolescent population with schizophrenia and in relationship to predominantly atypical antipsychotic treatment. Ninety-three patients (aged 19.6±2.2 years) were ascertained in this cross-sectional/retrospective study. 76 patients (81.7%) received atypical, 10 (10.8%) typical antipsychotics and 7 (7.5%) combinations of atypical/typical antipsychotics. MD symptoms were assessed using Tardive Dyskinesia Rating Scale (TDRS), Abnormal Involuntary Movement Scale (AIMS), Extrapyramidal Symptom Scale (EPS), Barnes Akathisia Scale (BAS). Movement disorder symptoms were found in 37 patients (39.8%) fulfilling strict/subthreshold criteria for TD (5.4/11.8%), parkinsonism (2.2/25.8%) or akathisia (1.1/11.8%), respectively. Patients treated with typical antipsychotics displayed a significantly higher EPS-score ( P=0.036) and a tendency towards a higher BAS-score ( P=0.061) compared to patients with atypical antipsychotics. Treatment durations with typical/atypical antipsychotics showed trends towards advantages of atypical antipsychotics with regard to parkinsonism/akathisia symptoms ( P=0.061; P=0.054), but not with regard to TD symptoms ( P=0.003), possibly due to confounding effects. Under treatment with atypical antipsychotics MD symptoms are less prevalent and less pronounced than under typical antipsychotics. We speculate that the finding of relatively high prevalence rates of subthreshold MD symptoms may be, at least partially, explained by previous or combined therapy with typical antipsychotics. [ABSTRACT FROM AUTHOR]

Increased intra-subject variability of reaction times (ISV-RT) is one of the most consistent findings in attention-deficit/hyperactivity disorder (ADHD). Although the nature of this phenomenon is still unclear, it has been hypothesised to reflect interference from the Default Mode Network (DMN). So far, ISV-RT has been operationally defined either as a frequency spectrum of the underlying RT time series, or as a measure of dispersion of the RT scores distribution. Here, we use a novel RT analysis framework to link these hitherto unconnected facets of ISV-RT by determining the sensitivity of different measures of RT dispersion to the frequency content of the underlying RT time series. N=27 patients with ADHD and N=26 healthy controls performed several visual N-back tasks. Different measures of RT dispersion were repeatedly modelled after individual frequency bands of the underlying RT time series had been either extracted or suppressed using frequency-domain filtering. We found that the intra-subject standard deviation of RT preserves the “1/f noise” characteristic typical of human RT data. Furthermore and most importantly, we found that the ex-Gaussian parameter τ is rather exclusively sensitive to frequencies below 0.025 Hz in the underlying RT time series and that the particularly slow RTs, which nourish τ, occur regularly as part of an quasi-periodic, ultra-slow RT fluctuation. Overall, our results are compatible with the idea that ISV-RT is modulated by an endogenous, slowly fluctuating process that may reflect DMN interference. [ABSTRACT FROM AUTHOR]

Background: Metabolic control and dietary management of patients with phenylketonuria (PKU) are based on single blood samples obtained at variable intervals. Sampling conditions are often not well-specified and intermittent variation of phenylalanine concentrations between two measurements remains unknown. We determined phenylalanine and tyrosine concentrations in blood over 24 hours. Additionally, the impact of food intake and physical exercise on phenylalanine and tyrosine concentrations was examined. Subcutaneous microdialysis was evaluated as a tool for monitoring phenylalanine and tyrosine concentrations in PKU patients.Methods: Phenylalanine and tyrosine concentrations of eight adult patients with PKU were determined at 60 minute intervals in serum, dried blood and subcutaneous microdialysate and additionally every 30 minutes postprandially in subcutaneous microdialysate. During the study period of 24 hours individually tailored meals with defined phenylalanine and tyrosine contents were served at fixed times and 20 min bicycle-ergometry was performed.Results: Serum phenylalanine concentrations showed only minor variations while tyrosine concentrations varied significantly more over the 24-hour period. Food intake within the patients' individual diet had no consistent effect on the mean phenylalanine concentration but the tyrosine concentration increased up to 300% individually. Mean phenylalanine concentration remained stable after short-term bicycle-exercise whereas mean tyrosine concentration declined significantly. Phenylalanine and tyrosine concentrations in dried blood were significantly lower than serum concentrations. No close correlation has been found between serum and microdialysis fluid for phenylalanine and tyrosine concentrations.Conclusions: Slight diurnal variation of phenylalanine concentrations in serum implicates that a single blood sample does reliably reflect the metabolic control in this group of adult patients. Phenylalanine concentrations determined by subcutaneous microdialysis do not correlate with the patients' phenylalanine concentrations in serum/blood. [ABSTRACT FROM AUTHOR]