Objectives: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalized treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues and drug–drug interactions. Methods: Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimization without specific indications, conversion factors, factors for calculation of dose-related drug concentrations and metabolite-to-parent ratios were calculated. Results: This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuropsychiatric agents into clinical routine. Conclusions: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment.

We aimed to compare the clinical data at first presentation to inpatient treatment of children (<14 years) vs. adolescents (≥14 years) with anorexia nervosa (AN), focusing on duration of illness before hospital admission and body mass index (BMI) at admission and discharge, proven predictors of the outcomes of adolescent AN. Clinical data at first admission and at discharge in 289 inpatients with AN (children: n = 72; adolescents: n = 217) from a German multicenter, web-based registry for consecutively enrolled patients with childhood and adolescent AN were analyzed. Inclusion criteria were a maximum age of 18 years, first inpatient treatment due to AN, and a BMI <10th BMI percentile at admission. Compared to adolescents, children with AN had a shorter duration of illness before admission (median: 6.0 months vs. 8.0 months, p = 0.004) and higher BMI percentiles at admission (median: 0.7 vs. 0.2, p = 0.004) as well as at discharge (median: 19.3 vs. 15.1, p = 0.011). Thus, in our study, children with AN exhibited clinical characteristics that have been associated with better outcomes, including higher admission and discharge BMI percentile. Future studies should examine whether these factors are actually associated with positive long-term outcomes in children.

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.

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.

Risperidone is commonly used to treat different psychiatric disorders worldwide. Knowledge on dose–concentration relationships of risperidone treatment in children and adolescents with schizophrenia or other psychotic disorders is, however, scarce and no age-specific therapeutic ranges have been established yet. Multicenter data of a therapeutic drug monitoring service were analyzed to evaluate the relationship between risperidone dose and serum concentration of the active moiety (risperidone (RIS) plus its main metabolite 9-hydroxyrisperidone (9-OH-RIS)) in children and adolescents with psychotic disorders. Patient characteristics, doses, serum concentrations and therapeutic outcomes were assessed by standardized measures. The study also aimed to evaluate whether the therapeutic reference range for adults (20–60 ng/ml) is applicable for minors. In the 64 patients (aged 11–18 years) included, a positive correlation between daily dose and the active moiety (RIS_am) concentration was found (r_s = 0.49, p = 0.001) with variation in dose explaining 24% (r_s² = 0.240) of the variability in serum concentrations. While the RIS_am concentration showed no difference, RIS as well 9-OH-RIS concentrations and the parent to metabolite ratio varied significantly in patients with co-medication of a CYP2D6 inhibitor. Patients with extrapyramidal symptoms (EPS) had on average higher RISam concentrations than patients without (p = 0.05). Considering EPS, the upper threshold of the therapeutic range of RIS_am was determined to be 33 ng/ml. A rough estimation method also indicated a possibly decreased lower limit of the preliminary therapeutic range in minors compared to adults. These preliminary data may contribute to the definition of a therapeutic window in children and adolescents with schizophrenic disorders treated with risperidone. TDM is recommended in this vulnerable population to prevent concentration-related adverse drug reactions.

Introduction: The use of psychotropic drugs in children and adolescents is widespread but associated with suboptimal treatment effects. Therapeutic drug monitoring (TDM) can improve safety of psychotropic drugs in children and adolescents, but is not routinely performed. A major reason is that the relationship between drug concentrations and effects is not well known. Areas covered: This systematic review evaluated studies assessing the relationship between psychotropic drug concentrations and clinical outcomes in children and adolescents, including antipsychotics, psychostimulants, alpha-agonists, antidepressants and mood-stabilizers. PRISMA guidelines were used and a quality assessment of the retrieved studies was performed. 67 eligible studies involving 24 psychotropic drugs were identified from 9,298 records. The findings were generally heterogeneous and the majority of all retrieved studies was not of sufficient quality. For 11 psychotropic drugs a relationship between drug concentrations and side-effects and/or effectiveness was evidenced in reasonably reported and executed studies, but these findings were barely replicated. Expert opinion: In order to better support routine TDM in child- and adolescent psychiatry, future work must improve in aspects of study design, execution and reporting to demonstrate drug concentration-effect relationships. The quality criteria proposed in this work can guide future TDM research. Systematic review protocol and registration PROSPERO CRD42018084159