Serum Concentration-Dose Relationship and Modulation Factors in Children and Adolescents Treated with Fluvoxamine.

INTRODUCTION: Fluvoxamine is used in children and adolescents ('youths') for treating obsessive compulsive disorder (OCD) but also off-label for depressive and anxiety disorders. This study aimed to investigate the relationship between fluvoxamine dose and serum concentrations, independent correlates of fluvoxamine concentrations, and a preliminary therapeutic reference range (TRR) for youths with OCD and treatment response. METHODS: Multicenter naturalistic data of a therapeutic drug monitoring service, as well as prospective data of the 'TDM Vigil study' (EudraCT 2013-004881-33), were analyzed. Patient and treatment characteristics were assessed by standardized measures, including Clinical Global Impressions-Severity (CGI-S) and -Change (CGI-I), with CGI-I of much or very much improved defining treatment response and adverse drug reactions using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Multivariable regression analysis was used to evaluate the influence of sex, age, body weight, body mass index (BMI), and fluvoxamine dose on fluvoxamine serum concentrations. RESULTS: The study included 70 youths (age = 6.7-19.6 years, OCD = 78%, mean fluvoxamine dose = 140.4 (range = 25-300) mg/d). A weak positive correlation between daily dose and steady-state trough serum concentrations was found (rs = 0.34, p = 0.004), with dose variation explaining 16.2% of serum concentration variability. Multivariable correlates explaining 25.3% of the variance of fluvoxamine concentrations included higher fluvoxamine dose and lower BMI. Considering responders with OCD, the estimated TRR for youths was 55-371 ng/mL, exceeding the TRR for adults with depression of 60-230 ng/mL. DISCUSSION: These preliminary data contribute to the definition of a TRR in youth with OCD treated with fluvoxamine and identify higher BMI as a moderator of lower fluvoxamine concentrations.

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.

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.

Clinical pharmacokinetics of antipsychotics in pediatric populations: a scoping review focusing on dosing regimen.

INTRODUCTION: Achieving optimal clinical responses and minimizing side effects through precision dosing of antipsychotics in children and adolescents with psychiatric disorders remains a challenge. Identifying patient characteristics (covariates) that affect pharmacokinetics can inform more effective dosing strategies and ultimately improve patient outcomes. This review aims to provide greater insight into the impact of covariates on the clinical pharmacokinetics of antipsychotics in pediatric populations. AREAS COVERED: A comprehensive literature search was conducted, and the main findings regarding the effects of the covariates on the pharmacokinetics of antipsychotics in children and adolescents are presented. EXPERT OPINION: Our study highlights significant covariates, including age, sex, weight, CYP2D6 phenotype, co-medication, and smoking habits, which affect the pharmacokinetics of antipsychotics. However, the findings were generally limited by the small sample sizes of naturalistic, open-label, observational studies, and the homogeneous subgroups. Dosing based on weight and preemptive genotyping could prove beneficial for optimizing the dosing regimen in pediatric populations. Future research is needed to refine dosing recommendations and establish therapeutic reference ranges critical for precision dosing and Therapeutic Drug Monitoring (TDM). The integration of individual patient characteristics with TDM can further optimize the efficacy and safety of antipsychotics for each patient.

Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial.

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.

Therapeutic drug monitoring in adolescents with anorexia nervosa for safe treatment with adjunct olanzapine.

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.

Therapeutic Reference Range for Olanzapine in Schizophrenia: Systematic Review on Blood Concentrations, Clinical Effects, and Dopamine Receptor Occupancy.

Objective: Aiming at revising the therapeutic reference range for olanzapine, the present study highlights the association between blood olanzapine levels, clinical effects, and dopamine D2-receptor occupancy for oral and long-acting injectable (LAI) formulations.Data Sources: Databases were systematically searched for randomized controlled trials (RCTs) and uncontrolled trials concerning blood olanzapine levels in relation to clinical outcomes or D2-receptor occupancy using MEDLINE (PubMed), Web of Science, PsycINFO, and Cochrane Library (March 2021, updated in December 2021). We excluded articles not written in English or German and non-human data. Search terms included olanzapine, blood level, drug monitoring, PET, and SPECT.Study Selection: The process of study selection followed a previously published protocol and PRISMA guidelines. A total of 2,824 articles were identified through database search and 1 article via reference list check. Thirty-four studies were suitable for qualitative synthesis, and 13 studies were included in the quantitative analysis.Data Extraction: Reviewers performed data extraction and quality assessment of the included studies independently following the review protocol.Results: Evidence for a relationship between blood olanzapine level and efficacy/side effects (constipation) is considered low (Level C). In total, 3 studies of moderate quality consistently showed therapeutic thresholds of around 20 ng/mL for olanzapine 12 hours post-dose. This threshold is in line with findings from positron emission tomography (PET) studies that suggest optimal drug efficacy (65%-80% D2-receptor occupancy) between 17 and 44 ng/mL.Conclusions: We suggest a therapeutic reference range of 20-40 ng/mL for olanzapine oral and LAI formulations. In this range, optimal treatment response is expected in patients with schizophrenia and schizophrenia spectrum disorders. Side effects, especially weight gain, may already occur at therapeutic levels. However, higher plasma concentrations are in general well tolerated and should not necessarily require a dose reduction in case of good response and tolerance.

A Complex Intervention to Prevent Medication-Related Hospital Admissions.

BACKGROUND: Children are often treated off-label and are at a disadvantage in pharmacotherapy. The aim of this study was to implement and evaluate a quality assurance measure (PaedPharm) for pediatric pharmacotherapy whose purpose is to reduce medication-related hospitalizations among children and adolescents. METHODS: PaedPharm consisted of the digital pediatric drug information system PaedAMIS, pediatric pharmaceutical quality circles (PaedZirk), and an adverse drug event (ADE) reporting system (PaedReport). The intervention was implemented in a cluster-randomized trial (DRKS 00013924) in 12 regions, with a pediatric and adolescent medicine clinic in each and a total of 152 surrounding private practitioners, in 6 sequences over 8 quarters. In addition to the proportion of ADE-related hospital admissions (primary endpoint), comprehensive process evaluation included other endpoints such as coverage, user acceptance, and relevance to practice. RESULTS: 41 829 inpatient admissions were recorded, of which 5101 were patients of physicians who participated in our study. 4.1% of admissions were ADE-related under control conditions, and 3.1% under intervention conditions (95% CI: [2.3; 5.9] and [1.8; 4.5], respectively). A model-based comparison yielded an intervention effect of 0.73 (population-based odds ratio; [0.39; 1.37]; p = 0.33). PaedAMIS achieved moderate user acceptance and PaedZirk achieved high user acceptance. CONCLUSION: The introduction of PaedPharm was associated with a decrease in medication-related hospitalizations that did not reach statistical significance. The process evaluation revealed broad acceptance of the intervention in outpatient pediatrics and adolescent medicine.

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.

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.

Value of a web-based pediatric drug information system to prevent serious adverse drug reactions in child and adolescent psychiatry.

Psychotropic drugs are frequently prescribed 'off-label' to children and adolescents and carry the risk of serious adverse drug reactions (sADR). We examined the frequency of sADRs of psychotropic drugs in pediatric inpatients and explored their potential preventability through following the recommendations of a web-based pediatric drug information system (PDIS). The potential socio-economic impacts of using this online system is also addressed. Routine clinical data from all inpatients treated in a child and adolescent psychiatry department between January 2017 and December 2018 were retrospectively examined for the occurrence of sADRs as defined by the European Medicines Agency. The preventability of the sADRs was assessed based on the information of the PDIS. Furthermore, the expected prolongation of the hospital stay due to sADRs was calculated as well as the associated treatment costs. The study was supported by the Innovation Fund of the Joint Federal Committee, grant number 01NVF16021. In total, 1036 patients were screened of whom 658 (63.5%) received psychopharmacological treatment. In 53 (8.1%) of these patients 54 sADRs were documented, of which 37 sADRs were identified as potentially preventable through PDIS. Mitigating sADR through PDIS would likely have prevented prolonged hospital stays and conferred considerable savings for health insurance companies. PDIS provides systematic and evidence-based information about pediatric psychopharmacotherapy and helps to prevent prescribing errors. Therefore, PDIS is a useful tool to increase drug therapy safety in child and adolescent psychiatry. Further prospective studies are needed to confirm the results.

Serious Adverse Drug Reactions to Antipsychotics in Minors with Multiple Disabilities: Preventability and Potential Cost Savings by Therapeutic Drug Monitoring.

INTRODUCTION: Children and adolescents with multiple disabilities and mental disorders (CAMD) are frequently treated with antipsychotic drugs. However, CAMD are particularly susceptible to serious adverse drug reactions (sADRs). This retrospective study examined the frequency of sADRs to antipsychotics in CAMD. Further, the potential preventability of these sADRs through therapeutic drug monitoring (TDM) and the potential socio-economic benefits of TDM were explored. METHODS: Routine clinical data of all patients treated at a specialized psychiatric clinic for CAMD between January 2017 and December 2018 were retrospectively examined. Data on the occurrence of sADRs (definition according to the European Medicines Agency), their causality with antipsychotics, as well as their preventability (Schumock criteria) were extracted from patient files. The prolongation of the hospital stay due to sADRs was calculated, and the cost savings were estimated if TDM had been applied. The data were based on a subsample of the KiDSafe project, supported by the Innovation Fund of the Joint Federal Committee, grant number 01NVF16021. RESULTS: One hundred two CAMD who were administered at least one antipsychotic drug during inpatient treatment were identified. Of these patients, 22 (21.6%) sADRs with a possible causal relationship with the antipsychotic treatment were documented. Eleven sADRs (50%) could potentially have been prevented through TDM. Mitigating sADRs through TDM likely would have prevented prolonged hospital stays and thus conferred considerable savings for health insurance companies. DISCUSSION: The routine implementation of TDM is urgently recommended for antipsychotic treatment in CAMD to increase drug therapy safety.

Common Genetic Variation and Age of Onset of Anorexia Nervosa.

Background: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche. Methods: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (<13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Results: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h 2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.

PTBP2 - a gene with relevance for both Anorexia nervosa and body weight regulation.

Genetic factors are relevant for both eating disorders and body weight regulation. A recent genome-wide association study (GWAS) for anorexia nervosa (AN) detected eight genome-wide significant chromosomal loci. One of these loci, rs10747478, was also genome-wide and significantly associated with body mass index (BMI). The nearest coding gene is the Polypyrimidine Tract Binding Protein 2 gene (PTBP2). To detect mutations in PTBP2, Sanger sequencing of the coding region was performed in 192 female patients with AN (acute or recovered) and 191 children or adolescents with (extreme) obesity. Twenty-five variants were identified. Twenty-three of these were predicted to be pathogenic or functionally relevant in at least one in silico tool. Two novel synonymous variants (p.Ala77Ala and p.Asp195Asp), one intronic SNP (rs188987764), and the intronic deletion (rs561340981) located in the highly conserved region of PTBP2 may have functional consequences. Ten of 20 genes interacting with PTBP2 were studied for their impact on body weight regulation based on either previous functional studies or GWAS hits for body weight or BMI. In a GWAS for BMI (Pulit et al. 2018), the number of genome-wide significant associations at the PTBP2 locus was different between males (60 variants) and females (two variants, one of these also significant in males). More than 65% of these 61 variants showed differences in the effect size pertaining to BMI between sexes (absolute value of Z-score >2, two-sided p < 0.05). One LD block overlapping 5'UTR and all coding regions of PTBP2 comprises 56 significant variants in males. The analysis based on sex-stratified BMI GWAS summary statistics implies that PTBP2 may have a more pronounced effect on body weight regulation in males than in females.

Therapeutic drug monitoring of sertraline in children and adolescents: A naturalistic study with insights into the clinical response and treatment of obsessive-compulsive disorder.

BACKGROUND: Sertraline is a selective serotonin reuptake inhibitor with specific indications in child and adolescent psychiatry. Notwithstanding its frequent use and clinical benefits, the relationship between pharmacokinetics, pharmacodynamics, efficacy, and tolerability of sertraline across indications, particularly in non-adult patients, is not fully understood. METHOD: This naturalistic therapeutic drug monitoring (TDM) study was conducted in a transdiagnostic sample of children and adolescents treated with sertraline (n = 78; mean age, 14.22 ± 2.39; range, 7-18 years) within the prospective multicenter "TDM-VIGIL" project. Associations between dose, serum concentration, and medication-specific therapeutic and side effects based on the Clinical Global Impression scale were examined. Tolerability was measured qualitatively with the 56-item Pediatric Adverse Event Rating Scale. RESULTS: A strong linear positive dose-serum concentration relationship (with dose explaining 45% of the variance in concentration) and significant effects of weight and co-medication were found. Neither dose nor serum concentration were associated with side effects. An overall mild-to-moderate tolerability profile of sertraline was observed. In contrast with the transdiagnostic analysis that did not indicate an effect of concentration, when split into depression (MDD) and obsessive-compulsive disorder (OCD) diagnoses, the probability of clinical improvement significantly increased as both dose and concentration increased for OCD, but not for MDD. CONCLUSIONS: This TDM-flexible-dose study revealed a significant diagnosis-specific effect between sertraline serum concentration and clinical efficacy for pediatric OCD. While TDM already guides clinical decision-making regarding compliance, dose calibration, and drug-drug interactions, combining TDM with other methods, such as pharmacogenetics, may facilitate a personalized medicine approach in psychiatry.

Serious Adverse Drug Reactions in Children and Adolescents Treated On- and Off-Label with Antidepressants and Antipsychotics in Clinical Practice.

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.

Reasons for admission and variance of body weight at referral in female inpatients with anorexia nervosa in Germany.

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.

BDNF levels in adolescent patients with anorexia nervosa increase continuously to supranormal levels 2.5 years after first hospitalization.

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.

Vitamin D Level Trajectories of Adolescent Patients with Anorexia Nervosa at Inpatient Admission, during Treatment, and at One Year Follow Up: Association with Depressive Symptoms.

(1) Background: Evidence has accumulated that patients with anorexia nervosa (AN) are at higher risk for vitamin D deficiency than healthy controls. In epidemiologic studies, low 25(OH) vitamin D (25(OH)D) levels were associated with depression. This study analyzed the relationship between 25(OH)D serum levels in adolescent patients and AN and depressive symptoms over the course of treatment. (2) Methods: 25(OH)D levels and depressive symptoms were analyzed in 93 adolescent (in-)patients with AN from the Anorexia Nervosa Day patient versus Inpatient (ANDI) multicenter trial at clinic admission, discharge, and 1 year follow up. Mixed regression models were used to analyze the relationship between 25(OH)D levels and depressive symptoms assessed by the Beck Depression Inventory (BDI-II). (3) Results: Although mean 25(OH)D levels constantly remained in recommended ranges (≥50 nmol/L) during AN treatment, levels decreased from (in)patient admission to 1 year follow up. Levels of 25(OH)D were neither cross-sectionally, prospectively, nor longitudinally associated with the BDI-II score. (4) Conclusions: This study did not confirm that 25(OH)D levels are associated with depressive symptoms in patients with AN. However, increasing risks of vitamin D deficiency over the course of AN treatment indicate that clinicians should monitor 25(OH)D levels.

[Therapeutic drug monitoring to optimize psychopharmacotherapy in children and adolescents - Update and guidelines for practice]. / Therapeutisches Drug Monitoring zur Optimierung der Psychopharmakotherapie von Kindern und Jugendlichen.

Therapeutic drug monitoring to optimize psychopharmacotherapy in children and adolescents - Update and guidelines for practice Abstract. Despite the improved evidence base, many uncertainties remain in child and adolescent psychiatric pharmacotherapy about the efficacy and tolerability of drugs, which are often prescribed off-label or in combination therapy in this age group. Because medium- to long-term use is unavoidable in many cases, clinicians should minimize adverse drug reactions as far as possible and tailor an effective dosage to the individual characteristics of the patient. Not only are children and adolescents particularly vulnerable to certain adverse drug effects, they are also exposed to iatrogenic risks from dosing or application errors, which can lead to under- or overdosing with correspondingly negative effects on the success of the therapy. In addition to determining a strict indication, it is therefore essential to establish precise dosage and systematic monitoring of the safety of the psychopharmacotherapy. This article introduces therapeutic drug monitoring as a useful clinical tool and describes how its correct application in practice can improve the efficacy as well as the safety and tolerability of psychotropic therapy in children and adolescents for the immediate benefit of patients. Keywords: Psychopharmacotherapy, adverse drug reactions, pharmacovigilance, therapeutic drug monitoring, quality assurance.