The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD

<p>Abstract</p> <p>Background</p> <p>Animal models of ADHD suggest that the paradoxical calming effect of methylphenidate on motor activity could be mediated through its action on serotonin transmission. In this study, we have investigated the relationship between the 5-HTTLPR polymorphism in the serotonin transporter gene (<it>SLC6A4</it>) and the response of ADHD relevant behaviors with methylphenidate treatment.</p> <p>Methods</p> <p>Patients between ages 6-12 (n = 157) were assessed with regard to their behavioral response to methylphenidate (0.5 mg/kg/day) using a 2-week prospective within-subject, placebo-controlled (crossover) trial. The children were then genotyped with regard to the triallelic 5-HTTLPR polymorphism in the <it>SLC6A4 </it>gene. Main outcome measure: Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) at baseline and at the end of each week of treatment with placebo and methylphenidate. For both outcome measurements, we used a mixed model analysis of variance to determine gene, treatment and gene × treatment interaction effects.</p> <p>Results</p> <p>Mixed model analysis of variance revealed a gene × treatment interaction for CGI-Parents but not for CGI-Teachers. Children homozygous for the lower expressing alleles (<it>s+l_G= s'</it>) responded well to placebo and did not derive additional improvement with methylphenidate compared to children carrying a higher expressing allele (<it>l_A</it>). No genotype main effects on either CGI-Parents or CGI-teachers were observed.</p> <p>Conclusions</p> <p>A double blind placebo-controlled design was used to assess the behavioral effects of methylphenidate in relation to the triallelic 5-HTTLPR polymorphism of the <it>SLC6A4 </it>gene in children with ADHD. This polymorphism appears to modulate the behavioral response to methylphenidate in children with ADHD as assessed in the home environment by parents. Further investigation is needed to assess the clinical implications of this finding.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00483106</p

Relation between therapeutic response and side effects induced by methylphenidate as observed by parents and teachers of children with ADHD

<p>Abstract</p> <p>Background</p> <p>The desired (therapeutic) and undesired (side) effects of methylphenidate might have underlying correlations. The aim of this study was to explore the strength and the possible sources of these correlations.</p> <p>Methods</p> <p>One hundred and fifty-seven children with ADHD (6-12 years) were administered placebo and methylphenidate (0.5 mg/kg in a divided b.i.d. dose), each for a one-week period, in a double-blind, crossover trial. Therapeutic response was assessed using the Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers), while side effects were assessed using the Barkley Side Effects Rating Scale (SERS).</p> <p>Results</p> <p>The side effect profile as assessed by the SERS was similar to that of previous studies with insomnia, decreased appetite, and headaches showing significant treatment effects (p < 0.005). These "somatic/physical" side effects did not correlate with CGI-Parents or CGI-Teachers. However, the side effects of "irritability", "proneness to crying", and "anxiousness" showed significant relationships with CGI-Parents. These "mood/anxiety" side effects showed no significant correlations with the CGI-Teachers.</p> <p>Conclusion</p> <p>The greater "mood/anxiety" side effects on methylphenidate and placebo, the less the parents observe improvement of their children while treated with methylphenidate. This suggests that the correlations between "mood/anxiety" side effects and poor response to treatment may be driven by observer effects rather than biological commonalities between therapeutic and side effects of methylphenidate.</p

Catechol-O-Methyltransferase (COMT) Val(108/158 )Met polymorphism does not modulate executive function in children with ADHD

BACKGROUND: An association has been observed between the catechol-O-methyltransferase (COMT) gene, the predominant means of catecholamine catabolism within the prefrontal cortex (PFC), and neuropsychological task performance in healthy and schizophrenic adults. Since several of the cognitive functions typically deficient in children with Attention Deficit Hyperactivity Disorder (ADHD) are mediated by prefrontal dopamine (DA) mechanisms, we investigated the relationship between a functional polymorphism of the COMT gene and neuropsychological task performance in these children. METHODS: The Val(108/158 )Met polymorphism of the COMT gene was genotyped in 118 children with ADHD (DSM-IV). The Wisconsin Card Sorting Test (WCST), Tower of London (TOL), and Self-Ordered Pointing Task (SOPT) were employed to evaluate executive functions. Neuropsychological task performance was compared across genotype groups using analysis of variance. RESULTS: ADHD children with the Val/Val, Val/Met and Met/Met genotypes were similar with regard to demographic and clinical characteristics. No genotype effects were observed for WCST standardized perseverative error scores [F(2,97 )= 0.67; p > 0.05], TOL standardized scores [F(2,99 )= 0.97; p > 0.05], and SOPT error scores [F(2,108 )= 0.62; p > 0.05]. CONCLUSIONS: Contrary to the observed association between WCST performance and the Val(108/158 )Met polymorphism of the COMT gene in both healthy and schizophrenic adults, this polymorphism does not appear to modulate executive functions in children with ADHD

Cardiometabolic risk and the MTHFR C677T variant in children treated with second-generation antipsychotics

Second-generation antipsychotics (SGAs) are increasingly being used to treat children with a variety of psychiatric illnesses. Metabolic syndrome (MetS), a risk factor for cardiovascular disease, is a side-effect of SGA-treatment. We conducted a cross-sectional study and assessed the association of the methylenetetrahydrofolate reductase (MTHFR) C677T variant with features of MetS in SGA-treated (n=105) and SGA–naïve (n=112) children. We targeted the MTHFR C677T variant, because it is associated with risk for cardiovascular disease, and features of MetS in adults without psychiatric illness. MetS in children is based on the presence of any three of the following: waist circumference ⩾90th percentile for age and sex; plasma triglyceride ⩾1.24 mmol l−1; plasma high-density lipoprotein-cholesterol ⩽1.03 mmol l−1; systolic or diastolic blood pressure ⩾90th percentile for age, sex, and height; and fasting glucose ⩾5.6 mmol l−1. We found that 15% of SGA-treated children had MetS compared with 2% of SGA-naïve children (OR 8.113, P<0.05). No effect of the MTHFR C677T variant on psychiatric diagnosis was observed. The MTHFR 677T allele was associated (P<0.05) with MetS (OR 5.75, 95% CI= 1.18–28.12) in SGA-treated children. Models adjusted for duration of SGA treatment, ethnicity, sex, age and use of other medications revealed a positive relationship between the MTHFR 677T allele and diastolic blood pressure Z-scores (P=0.001) and fasting plasma glucose (P<0.05) in SGA-treated children. These findings illustrate the high prevalence of MetS in SGA-treated children and suggest metabolic alterations associated with the MTHFR C677T variant may have a role in the development of MetS features in SGA-treated children

In Silico Whole Genome Association Scan for Murine Prepulse Inhibition

Background The complex trait of prepulse inhibition (PPI) is a sensory gating measure related to schizophrenia and can be measured in mice. Large-scale public repositories of inbred mouse strain genotypes and phenotypes such as PPI can be used to detect Quantitative Trait Loci (QTLs) in silico. However, the method has been criticized for issues including insufficient number of strains, not controlling for false discoveries, the complex haplotype structure of inbred mice, and failing to account for genotypic and phenotypic subgroups. Methodology/Principal Findings We have implemented a method that addresses these issues by incorporating phylogenetic analyses, multilevel regression with mixed effects, and false discovery rate (FDR) control. A genome-wide scan for PPI was conducted using over 17,000 single nucleotide polymorphisms (SNPs) in 37 strains phenotyped. Eighty-nine SNPs were significant at a false discovery rate (FDR) of 5%. After accounting for long-range linkage disequilibrium, we found 3 independent QTLs located on murine chromosomes 1 and 13. One of the PPI positives corresponds to a region of human chromosome 6p which includes DTNBP1, a gene implicated in schizophrenia. Another region includes the gene Tsn which alters PPI when knocked out. These genes also appear to have correlated expression with PPI. Conclusions/Significance These results support the usefulness of using an improved in silico mapping method to identify QTLs for complex traits such as PPI which can be then be used for to help identify loci influencing schizophrenia in humans

Association between 5-HT2A, TPH1 and GNB3 genotypes and response to typical neuroleptics: a serotonergic approach

<p>Abstract</p> <p>Background</p> <p>Schizophrenia is a common psychiatric disease affecting about 1% of population. One major problem in the treatment is finding the right the drug for the right patients. However, pharmacogenetic results in psychiatry can seldom be replicated.</p> <p>Methods</p> <p>We selected three candidate genes associated with serotonergic neurotransmission for the study: serotonin 2A (<it>5-HT2A</it>) receptor gene, tryptophan hydroxylase 1 (<it>TPH1</it>) gene, and G-protein beta-3 subunit (<it>GNB3</it>) gene. We recruited 94 schizophrenia patients representing extremes in treatment response to typical neuroleptics: 43 were good responders and 51 were poor responders. The control group consisted of 392 healthy blood donors.</p> <p>Results</p> <p>We do, in part, replicate the association between <it>5-HT2A </it>T102C polymorphism and response to typical neuroleptics. In female patients, C/C genotype was significantly more common in non-responders than in responders [OR = 6.04 (95% Cl 1.67–21.93), p = 0.005] or in the control population [OR = 4.16 (95% CI 1.46–11.84), p = 0.005]. <it>TPH1 </it>A779C C/A genotype was inversely associated with good treatment response when compared with non-responders [OR = 0.59 (95% Cl 0.36–0.98), p = 0.030] or with the controls [OR = 0.44 (95% CI 0.23–0.86, p = 0.016], and <it>GNB3 </it>C825T C/T genotype showed a trend-like positive association among the male patients with a good response compared with non-responders [OR = 3.48 (95% Cl 0.92–13.25), p = 0.061], and a clearer association when compared with the controls [OR = 4.95 (95% CI 1.56–15.70), p = 0.004].</p> <p>Conclusion</p> <p>More findings on the consequences of functional polymorphisms for the role of serotonin in the development of brain and serotonergic neurotransmission are needed before more detailed hypotheses regarding susceptibility and outcome in schizophrenia can be formulated. The present results may highlight some of the biological mechanisms in different courses of schizophrenia between men and women.</p

The quantification of COMT mRNA in post mortem cerebellum tissue: diagnosis, genotype, methylation and expression

BACKGROUND: The COMT gene is located on chromosome 22q11, a region strongly implicated in the aetiology of several psychiatric disorders, in particular schizophrenia. Previous research has suggested that activity and expression of COMT is altered in schizophrenia, and is mediated by one or more polymorphisms within the gene, including the functional Val(158)Met polymorphism. METHOD: In this study we examined the expression levels of COMT mRNA using quantitative RT-PCR in 60 post mortem cerebellum samples derived from individuals with schizophrenia, bipolar disorder, depression, and no history of psychopathology. Furthermore, we have examined the methylation status of two CpG sites in the promoter region of the gene. RESULTS: We found no evidence of altered COMT expression or methylation in any of the psychiatric diagnoses examined. We did, however, find evidence to suggest that genotype is related to COMT gene expression, replicating the findings of two previous studies. Specifically, val(158)met (rs165688; Val allele) rs737865 (G allele) and rs165599 (G allele) all showed reduced expression (P < 0.05). Finally, we observe a strong sexual dimorphism in COMT expression, with females exhibiting significantly greater levels of COMT mRNA. CONCLUSION: The expression of COMT does not appear to be altered in the cerebellum of individuals suffering from schizophrenia, bipolar disorder or depression, but does appear to be influenced by single nucleotide polymorphisms within the gene

Atypical development of the executive attention network in children with chromosome 22q11.2 deletion syndrome

Impairment in the executive control of attention has been found in youth with chromosome 22q11.2 deletion syndrome (22q11.2DS). However, how this impairment is modified by other factors, particularly age, is unknown. Forty-six typically developing and 53 children with 22q11.2DS were tested with the attention networks task (ANT) in this cross-sectional study. We used logarithmic transform and linear modeling to assess age effects on the executive index of the ANT. Mixed modeling accounted for between subject variability, age, handedness, catecholamine-O-transferase (COMT; codon 158) genotype, and gender on performance for all experimental conditions (cue × flanker) and their two-level interactions. Children with 22q11.2DS showed a relative, age-dependent executive index impairment but not orienting or alerting network index impairments. In factorial analysis, age was a major predictor of overall performance. There was a significant effect of the 22q11.2DS on overall performance. Of note, children with 22q11.2DS are specifically vulnerable to incongruent flanker interference, especially at younger ages. We did not find an overall effect of COMT genotype or handedness. Children with 22q11.2DS demonstrated age-related impairment in the executive control of attention. Future investigation will likely reveal that there are different developmental trajectories of executive attentional function likely related to the development of schizophrenia in 22q11.2DS

Phenotypic Consequences of Copy Number Variation: Insights from Smith-Magenis and Potocki-Lupski Syndrome Mouse Models

The characterization of mice with different number of copies of the same genomic segment shows that structural changes influence the phenotypic outcome independently of gene dosage