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 ¼ 0.049; rs11178997, P ¼ 0.034), but not for the third SNP in intron 2 (rs4565946, P ¼ 0.3517). Haplotype analysis revealed a strong trend of association between the regulatory region SNPs (rs4570625, rs11178997) and ADHD (P ¼ 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. Keywords: ADHD; serotonin; TPH2; sib pairs Attention-deficit/hyperactivity disorder (ADHD) is a common syndrome first diagnosed in childhood and frequently persistent throughout adult life. Prevalence ranges between 3 and 9% dependent on the nature of the population sampled and the method of ascertainment.1,2 Although heritability estimates are consistently high, averaging around 0.8, ADHD is a genetically complex disorder characterized by multifactorial inheritance involving numerous genes of moderate effect. 2-5While an imbalance in dopaminergic neurotransmission appears to be an important factor predisposing to ADHD, interaction between the dopamine (DA) and serotonin (5-HT) systems has been implicated in both the pathophysiology of ADHD and the mechanism of action of widely used stimulant compounds. By inhibition of the dopamine transporter (DAT), which was reported to be increased in the striatum in ADHD patients, 6 methylphenidate (MPH) is highly effective in reducing the symptoms of ADHD. DAT knockout (KO) mice display a phenotype with increased locomotor activity, 7 which is reversed by MPH-induced increases in 5-HT neurotransmission. 8On the other hand, the hyperlocomotion in DAT KO mice is attenuated by the selective 5-HT reuptake inhibitor (SSRI) fluoxetine or the 5-HT precursor 5-hydroxytryptophan. 9 Early studies reported low platelet 5-HT levels in ADHD patients 10,11 and there is an extensive data base that ADHD-specific syndromal dimensions including impulsive behavior, aggressiveness and substance abuse are linked to alterations

Keywords: obsessive-compulsive disorder; 5HT 2A polymorphism; association study; child and adolescent psychiatry Positive association between obsessive compulsive disorder (OCD) and the A-allele of the 5-HT 2A -receptor promoter polymorphism −1438G/A has recently been reported in adults. We performed an association analysis of this polymorphism in 55 children and adolescents with OCD and in 223 controls consisting of unrelated students. We detected statistically significant differences in genotype (P < 0.05) and allele frequencies (P < 0.05) between individuals with OCD and controls. In this, to our knowledge, first association study based on children and adolescents with OCD, we confirm an association of the A-allele of the 5-HT2A receptor gene with OCD.

Psychopathology in severely anorexic patients often seems to be of compulsive and delusional quality rendering therapeutic approaches extremely difficult. With conventional therapeutic regimes failing, administration of the novel antipsychotic olanzapine induced remarkable improvement in five cases reported here. Paranoid ideation concerning body image or weight gain decreased and sedative effects helped to reduce inner tensions and phobia with respect to food intake. Olanzapine, therefore, might represent an important therapeutic tool in anorexic patients who present the following characteristics: long-term history of anorexia nervosa mostly with several hospitalisations, missing perception of their severe state of illness, refusal of therapy, delusional quality of anorexic thinking, risk of discontinuation of therapy with life-threatening consequences.

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.

Pharmacological and challenge study data showed an involvement of the serotonergic system in the development of obsessive-compulsive disorder (OCD). We studied transmission disequilibrium of polymorphisms in three candidate genes of the serotonergic pathway in 64 trios comprising patients with early onset OCD and both of their parents. Polymorphisms of the following genes were studied: tryptophan hydroxylase 1 (rs1800532), serotonin transporter (polymorphism in the promoter region; 5-HTTLPR) and the serotonin 1 B receptor (rs6296). This is, to our knowledge, one of the first family based association studies pertaining to children and adolescents with OCD. We did not detect transmission disequilibrium of the investigated polymorphisms in OCD. Hence, these polymorphisms do not play a major role in the genetic predisposition to early onset OCD.