Manfred Gerlach

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 (r_s = 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.

Studies have strongly suggested a disturbed regulation of dopaminergic neurotransmission in attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease (PD). A genetic and phenotypic overlap between both disorders is discussed. A well-studied risk gene for PD is the gene coding for α-synuclein (SNCA). α-Synuclein, a protein located primarily in the presynaptic vesicles, has been suggested to play a role in the modulation of dopamine transporter (DAT) function. DAT is the target of psychostimulants for the treatment of ADHD and plays a key role in regulating the dopamine concentrations in the synaptic cleft. In our sample consisting of German families with children affected by ADHD, we tested for association of allelic variants of two functionally relevant polymorphisms of the α-synuclein gene (NACP-Rep1: 156 families, 232 children; rs356219: 195 families, 284 children) with ADHD. Transmission disequilibrium test analysis revealed no over-transmission for NACP-Rep1 (OR 1, p_nom = 1 p_adj = 1) and rs356219 (OR 1.28; p_nom = 0288) in affected siblings. However, a subanalysis on trios with index children showed a nominal association of rs356219 with ADHD (OR 1.43, p_nom = 0.020), which survived Bonferroni correction (p_adj = 0.039); again, no association for NACP-Rep1 (OR 0.8, p = 0.317, p_adj = 0.634) was found. In conclusion, we found in our pilot study a trend for an association of the rs356219 genotype in SNCA that may affect α-synuclein function and contribute to the aetiology of ADHD. In light of the small sample size of our study, the link between PD and ADHD through dopamine-related neurobiology warrants further investigations. Future studies on SNCA in large ADHD samples should focus on specified symptoms and traits, e.g. attentional capacities or emotional dysregulation.

The use of second-generation antipsychotics in children and adolescents has greatly increased during the last decennia and contrasts with uncertainties about safety and efficacy due to a relative lack of clinical (authorization) trials in this age group. In order to optimize the benefit-harm balance for the individual patient, careful patient monitoring has been advised and should include Therapeutic Drug Monitoring (TDM). However, systematic research about the value of TDM in pediatric neuropsychiatry is scant. Data of children and adolescents treated with aripiprazole, clozapine, olanzapine, and quetiapine in daily clinical practice were collected from a German TDM registry in order to compare the distributions of serum concentrations with the recommended therapeutic ranges for adults. For example, only 23 (33.8%) of 68 patients (mean age 16.7 years) treated with clozapine (mean daily dose 319 mg) had values within the recommended range for adults. On the contrary, in the children and adolescents (mean age 15.9 years) treated with olanzapine (mean daily dose 12 mg) 81 (70.4%) of 115 patients had a serum concentration within the recommended range. If confirmed in larger patient samples and complemented with data on clinical outcomes in a standardized manner, these data could lead to the definition of therapeutic ranges of serum concentrations for second generation antipsychotics in the pediatric population. The concepts of these preliminary studies funded by the Federal Ministry of Education and Research (BMBF 001EZ0937) are currently implemented in a multicenter project on pharmacovigilance (TDM-VIGIL) funded by the Federal Institute for Drugs and Medical Devices (BfArM 73.05/3832 – 397285/12).

Introduction: Quetiapine is used frequently in the treatment of children and adolescents with different psychiatric disorders despite not being licensed for this age group. The aim of this observational study was to examine the relationship between dosage, serum concentration and therapeutic response in children and adolescents treated with quetiapine in daily clinical practice. Methods: Steady state trough serum concentrations of quetiapine were measured in 122 children and adolescents as part of a routine TDM-program. The therapeutic effect was assessed by the Clinical Global Impression Improvement subscale (CGI-I) and side effects by the Udvalg for Kliniske Undersogelser-side effect rating scale (UKU). Results: A weak linear relationship between the bodyweight adjusted daily dose (mean (SD); 6.1 (4.1)mg/kg) and serum concentration (mean (SD); 78.5 (93.1) ng/ml) of quetiapine was found (Pearson r²=0.13). The majority (77.9%) of the measured serum concentrations were below, 20.5% within and 1.6% above the therapeutic window (100–500ng/ml) suggested for adults. Serum concentrations were not significantly influenced by gender, smoking-habits or co-medication. 43% of the patients showed very good or good improvement, 48% little improvement, 7% no change and only 2% deteriorated. 45.1% of the patients had side effects; most of them mild. However, no correlation between serum concentration and neither the therapeutic nor side effects was found. Discussion: Our results suggest a lower therapeutic window of quetiapine for children and adolescents and higher dosing than in adult psychiatric patients. Further studies with greater sample sizes and diagnosis-specific as well as age-specific psychometric instruments are needed to confirm our findings.

Introduction and Aims: Aripiprazole is an atypical antipsychotic used in the treatment of children and adolescents with various psychiatric disorders despite limited data on dosing, efficacy and safety in this patient group. In this observational study, the relationship between dosage, serum concentration and clinical outcomes in children and adolescents treated with aripiprazole for different diagnoses such as schizophrenia and Tourette-syndrome was examined. Methods: Steady state trough serum concentrations of aripiprazole were measured in 76 children and adolescents within a routine TDM-service. The therapeutic effect was evaluated with the Clinical Global Impression Improvement Scale (CGI-I) and side effects with the Udvalg for Kliniske Undersogelser-side effect rating scale (UKU). Results: A linear relationship between the body weight-normalized aripiprazole daily dose (mean (SD); 0.19 (0.11)mg/kg) and the serum concentration (mean (SD); 212 (155) ng/ml) was found (Pearson r=0.60). The explained variability was higher in children 2=0.53) than in adolescents (r²=0.33). Serum concentrations were significantly influenced by age (p=0.02) and sex (p=0.02), with children and males showing lower mean serum concentrations, however, there was no significant influence by comedication (p=0.23) or smoking habits (p=0.18). A good or very good therapeutic effect (equivalent to CGI-I 1 or 2) was seen in 46.7% of the patients. Side effects were documented in 55.3%. There was no correlation between serum concentrations and side effects (Spearman ρ=0.07) nor therapeutic effects (Spearman ρ=0.17). Conclusion: Further studies are needed to evaluate our results on larger sample sizes and with more precise information about the patients' characteristics and the course of treatment.

Introduction: The aim of this prospective naturalistic study was to examine the relationship between dosage, serum concentration and clinical outcome in children and adolescents using sertraline for depressive, obsessive-compulsive or anxiety symptoms with the overarching goal to obtain an age-specific therapeutic serum concentration range for sertraline. Methods: Steady state trough serum concentrations of sertraline were measured in 66 patients aged 10 to 18 (mean 15.1) years. The therapeutic effect was assessed by the clinical global impression improvement subscale and side effects by the Udvalg for Kliniske Undersogelser-Side Effect Rating Scale. Results: A linear relationship between the dose and the serum concentration of sertraline (Pearson r = 0.68) was found. Mean serum concentrations were not significantly influenced by age, gender and comedication. 73% of the measured drug levels in children and adolescents were assessed within the therapeutic window (10–50 microg/l) suggested for adults. No reationship between the serum concentration of sertraline and the therapeutic effect could be found. Patients with documented side effects had higher mean serum levels of sertraline (p = 0.08). Discussion: Further studies with greater sample sizes and diagnose-specific as well as age-specific psychometric instruments are needed to validate our results.

Psychopharmacotherapy in children and adolescents is characterized by an increased susceptibility for adverse events and an increased risk of ineffective treatment due to specific age-dependent and developmental characteristics in comparison to adults. Dosing in paediatric psychiatric patients requires careful handling, since the dose recommendations for adults can not simply be extrapolated to minors because of pharmacokinetic and pharmacodynamic differences. In addition, psychopharmacotherapy in children and adolescents is hampered by lack of high quality evidence on efficacy and safety in many indications and subsequently a high degree of off-label use. Therapeutic Drug Monitoring (TDM) is an established and useful tool in psychiatry to individualize and optimize the outcomes (efficacy/safety balance) of psychopharmacological drug treatment in the individual patient by dose adjustments based upon measured serum concentrations. In children and adolescents the administration of psychotropic drugs is a general indication for performing TDM. However, TDM studies specific in these age groups are necessary to identify age and indication specific therapeutic ranges of serum concentrations. Systematic collection of data on drug exposure, serum concentrations and clinical characteristics as well as outcomes can generate such practice-based evidence. A German-Swiss-Austrian competence network for TDM in child and adolescent psychiatry using a multi-centre internet-based data infrastructure was founded to document and collect demographic, safety and efficacy data as well as blood concentrations of psychotropic drugs in children and adolescents (further information: www.tdm-kjp.com). ^* Parts of this paper are based on the article „Therapeutisches Drug Monitoring in der Kinder- und Jugendpsychiarie” [18] as well as on “Drug monitoring in child and adolescent psychiatry for improved efficacy and safety of psychopharmacotherapy” [22].

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from “strongly recommended” to “potentially useful”. Evidence-based “therapeutic reference ranges” and “dose related reference ranges” were elaborated after an extensive literature search and a structured internal review process. A “laboratory alert level” was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint eff ort.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous disorder influenced by complex gene-gene as well as gene-environment interactions. It is therefore not surprising that animals with distinctly different neural defects more or less model the behavioral characteristics of this disorder. Dopamine transporter knock-out (DAT-KO) mice display a phenotype typical for ADHD such as hyperactivity, cognitive impairment and paradoxical calming responses to methylphenidate (MPH) treatment. The aims of our study were to explore the effect of MPH treatment on gene expression in this mouse model and whether the co-factor stress provoked by intra-peritoneal drug application influences the results. Our study revealed distinct influences of the DAT genotype, different types of MPH treatment as well as stress resulting from drug application on the expression levels of investigated immediate early genes (IEGs), also shown to be markers for neuronal activity. In general, the co-factor stress induced an increase in IEGs expression comparing to naïve animals that possibly caused masking effects to the MPH treatment. Additionally, chronic MPH treatment compared to acute MPH treatment attenuates IEGs expression. As stress also interacts with MPH influencing different neural networks and transmitter systems in the brain it can be looked upon as an important co-factor not only in the context of treatment response but also in the context of pathophysiological mechanisms.