Serum concentrations, therapeutic response and side effects in children and adolescents with impulsive-aggressive symptoms during risperidone therapy.

INTRODUCTION: The aim of this prospective naturalistic study was to examine for the first time the relationship between dosage, serum concentration and clinical outcome in children and adolescents with impulsive-aggressive symptoms during risperidone therapy. METHODS: Steady state trough serum concentrations of risperidone and 9-hydroxyrisperidone (the active moiety) were measured in 103 subjects. 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: We found a linear relationship between the risperidone dose and the serum concentration of the active moiety (Spearman rho=0.53) and no correlation between the serum concentration and either the therapeutic effect or side effects. There was no effect of gender and co-medication. DISCUSSION: This study has the typical limitations of naturalistic studies, therefore our results should be interpreted with caution. Based on the serum concentrations at the therapeutically effective dose range (0.25-1.5 mg/day) we obtained first information on a possibly appropriate therapeutic serum range for the risperidone treatment of children and adolescents with impulsive-aggressive symptoms. Further studies with greater sample sizes are needed to validate our results and to examine the influence of genetic polymorphisms on the serum concentration of risperidone.

Therapeutic drug monitoring of quetiapine in adolescents with psychotic disorders.

INTRODUCTION: There are developmental and age-dependent differences in the pharmacokinetics and the pharmacodynamics of drugs in children and adolescents. Therefore, there is a need to carry out standardised studies to find out therapeutic ranges of plasma/serum concentrations in psychopharmacotherapy of children and adolescents. The aim of this prospective study was to examine the relationship between quetiapine serum concentration, treatment response, and side effects in a clinical setting to elucidate the age-specific therapeutic range of quetiapine in adolescents. METHODS: Over a period of two years, therapeutic drug monitoring (TDM) was routinely performed in 21 adolescents (mean age was 15.9+/-1.5 years, 57% male) with psychotic disorders according to the guidelines of the AGNP TDM expert group. The psychopathology was assessed by using the Clinical Global Impression Scale (CGI) and the Brief Psychiatric Rating Scale (BPRS). Side effects were assessed by using the Dose Record and Treatment Emergent Symptom Scale (DOTES). Trough quetiapine concentrations were determined under steady state conditions after multiple-dose regimes (median 600 mg/day; range 100-800 mg/day). RESULTS: There was a marked variability of the serum concentrations, ranging from 19-877 ng/ml. 40.8% of the determined values were below and 24.5% above the therapeutic range (70-170 ng/ml) recommended for adults. None of the patients had severe side effects. We found a weak correlation between dose and serum concentration of quetiapine and no relationship between serum concentration and treatment response. DISCUSSION: There are several limitations of this study, and our results should therefore be interpreted with caution. Notwithstanding, differences in the ontogenesis of pharmacokinetics and pharmacodynamics may be the reason for the difference in the relationship between blood concentrations and therapeutic response to psychopharmaca in children, adolescents and adults. Further studies using larger samples, baseline assessment of psychopathology, definition of the treatment interval and investigation of clinically relevant interactions with various co-medications are warranted to improve the limitations of this pilot study.

Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood with substantial heritability. Pharmacological and molecular genetic studies as well as characterization of animal models have implicated serotonergic dysfunction in the pathophysiology of ADHD. Here, we investigated the effect of polymorphic variants in the gene of the tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in children and adolescents with ADHD. We analyzed three single nucleotide polymorphisms (SNPs) in and downstream of the transcriptional control region of the TPH2 gene in 103 families with 225 affected children. Allelic association in families with more than one affected child was assessed using the pedigree disequilibrium test. Preferential transmissions were detected for the two SNPs in TPH2's regulatory region (rs4570625, P=0.049; rs11178997, P=0.034), but not for the third SNP in intron 2 (rs4565946, P=0.3517). Haplotype analysis revealed a strong trend of association between the regulatory region SNPs (rs4570625, rs11178997) and ADHD (P=0.064). Our results link potentially functional TPH2 variations to the pathophysiology of ADHD, and further support the relevance of 5-HT in disorders related to altered motor activity and cognitive processes.

[Obsessive-compulsive disorders in children and adolescents--a review]. / Der Verlauf von Zwangsstörungen mit Beginn im Kindes- und Jugendalter--eine Literaturübersicht.

OBJECTIVE: Presented is a review of the literature on the medium- and long-term course of obsessive-compulsive disorder (OCD) with onset in childhood or adolescence. METHODS: Using the data bank MEDLINE, relevant studies published since 1983 were investigated. Older studies were included if their results complemented those of recent studies. RESULTS: Follow-up studies point to a rather unfavorable course of childhood OCD. At the time of follow-up investigations, 30% to 70% of the patients still suffered from obsessive-compulsive symptoms or had a diagnosis of OCD. Other clinical disorders were diagnosed in 20% to 95% of them. One to two thirds of former patients had received at least one diagnosis of a personality disorder. Multicomorbidity was common. Impairment of the patients' psychosocial adjustment especially affected relationships and sexuality. Most of the variables examined in childhood or adolescence had no significant predictive power as to the course of obsessive-compulsive disorders. CONCLUSIONS: Differences between the results of the follow-up studies can partly be explained by the different study designs employed. Results on the course of childhood OCD point to the high stability of the disorder and the accompanying rate of comorbidity. This has to be taken into account in the diagnosis (supplementary diagnosis of comorbid disorders and family diagnostics) and therapy of childhood OCD (offering long-term therapeutic advice and booster sessions, treatment of comorbid disorder, inclusion of the family).

[Pharmacotherapy of compulsive disorders in childhood and adolescence]. / Pharmakotherapie von Zwangsstörungen im Kindes- und Jugendalter.

OBJECTIVES: The review addresses the issue of the extent to which pharmacological treatment of obsessive-compulsive disorders (OCD) in childhood and adolescence is based on empirical studies. METHODS: Current literature is evaluated, including studies of adult cohorts if these contain approaches relevant for the pharmacological treatment of children and adolescents. RESULTS: The number of qualified empirical studies is few. These studies have shown clomipramine and serotonin-reuptake inhibitors to be very effective in the therapy of obsessive-compulsive disorders in childhood and adolescence. On the basis of the studies available, no specific recommendation can be made with regard to pharmacological dosage. For clomipramine the effective daily dose probably ranges somewhere between 75-150 mg, for fluoxetin between 20-60 mg, and for fluvoxamine between 100-250 mg. However, it must be kept in mind that in individual cases, improvement sometimes will not be noticeable until after 8 to 10 weeks of treatment have elapsed. CONCLUSION: Clomipramine and serotonin-reuptake inhibitors are effective in the treatment of obsessive-compulsive disorders in children and adolescents. There is an urgent need for therapy studies of obsessive-compulsive disorders in childhood and adolescence. Placebo-controlled studies of pharmacological treatment, controlled studies of psychotherapeutic treatment, and comparative studies of pharmacological and psychotherapeutic approaches are necessary.