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

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

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

No Relation between Therapeutic Response to Methylphenidate and its Cardiovascular Side Effects in Children with Attention-Deficit/Hyperactivity Disorder

Objective The aim of this study was to examine the relation between therapeutic response to methylphenidate (MPH) and its associated short term cardiovascular side effects (Systolic Blood Pressure-SBP, Diastolic Blood Pressure-DBP and Heart Rate-HR changes) in children with ADHD, based on the hypothesis that these parameters share common underlying mechanisms. Method A double-blind placebo-controlled crossover clinical trial of children 6 to 12 years old diagnosed with ADHD was done. The children were given one week of 0.5 mg/kg MPH and one week of placebo (divided into two equal doses, given twice every day). On the morning of the third day of each week, Blood Pressure (BP) and HR were recorded immediately before (at time 0) and after (at time 10 and 45 minutes) administration of MPH. Children were grouped into 4 categories according to their therapeutic response (large, moderate, mild or no response) to MPH. A mixed model analysis of variance was performed to determine whether response groups were different with regard to cardiovascular side effects. Results All variables were comparable among the four groups 10 min after treatment with MPH and with placebo. Small but significant (p < 0.001) increases were seen in SBP (3.65 mm of Hg) and DBP (3.99 mm of Hg) 45 minutes after administration of MPH. A small but significant decrease in HR (3.3 beats per minute) was observed 45 min after administration of placebo. No significant differences in SBP, DBP and HR were found between response groups. Conclusions MPH causes a small but significant change in BP at 45 minutes after administration. No changes in HR were observed with MPH at 45 minutes. Responders to MPH treatment do not differ from non-responders in occurrence of BP and HR changes, at least within 45 minutes after administration and with the MPH dosage used in the study

Efficacy of methylphenidate in children with attention-deficit hyperactivity disorder and learning disabilities: a randomized crossover trial

Objective: To determine whether children with attention-deficit hyperactivity disorder (ADHD) and learning disabilities respond differently to methylphenidate (MPH) compared with children with ADHD only. Methods: We conducted a prospective, double-blind, placebo-controlled, randomized, 2-week crossover trial of MPH, during which response to MPH was assessed. Learning ability was appraised using the Wide Range Achievement Test, Revised (WRAT-R), for English-speaking students and the Test de rendement pour francophones for French-speaking students. The study was conducted at the Douglas Hospital, a McGill University–affiliated teaching hospital in Montréal. Ninety-five children, aged 6–12 years, who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), criteria for ADHD participated in the study, which ran from 2001 to 2004. The outcome measure used was the Consensus Clinical Response, an indicator of the degree of clinical improvement shown when taking MPH. Results: The proportion of children with learning disabilities who responded to MPH (55%) was significantly smaller (χ(2)1 = 4.5, p = 0.034) than the proportion of children without learning disabilities who responded adequately to MPH (75%). This difference was mainly because of children with mathematics disability being particularly unresponsive to MPH (χ(2)1 = 4.5, p = 0.034). Children with reading disability did not show this pattern of poor response (χ(2)1 = 1.0, p = 0.33). Conclusion: Children with ADHD and comorbid learning disability tended to respond more poorly to MPH. In particular, children with disability in mathematics responded less to MPH than those without disability in mathematics. Additional therapy may be indicated for this group of patients

Comprehensive phenotype/genotype analyses of the norepinephrine transporter gene (SLC6A2) in ADHD: relation to maternal smoking during pregnancy.

Despite strong pharmacological evidence implicating the norepinephrine transporter in ADHD, genetic studies have yielded largely insignificant results. We tested the association between 30 tag SNPs within the SLC6A2 gene and ADHD, with stratification based on maternal smoking during pregnancy, an environmental factor strongly associated with ADHD.Children (6-12 years old) diagnosed with ADHD according to DSM-IV criteria were comprehensively evaluated with regard to several behavioral and cognitive dimensions of ADHD as well as response to a fixed dose of methylphenidate (MPH) using a double-blind placebo controlled crossover trial. Family-based association tests (FBAT), including categorical and quantitative trait analyses, were conducted in 377 nuclear families.A highly significant association was observed with rs36021 (and linked SNPs) in the group where mothers smoked during pregnancy. Association was noted with categorical DSM-IV ADHD diagnosis (Z=3.74, P=0.0002), behavioral assessments by parents (CBCL, P=0.00008), as well as restless-impulsive subscale scores on Conners'-teachers (P=0.006) and parents (P=0.006). In this subgroup, significant association was also observed with cognitive deficits, more specifically sustained attention, spatial working memory, planning, and response inhibition. The risk allele was associated with significant improvement of behavior as measured by research staff (Z=3.28, P=0.001), parents (Z=2.62, P=0.009), as well as evaluation in the simulated academic environment (Z=3.58, P=0.0003).By using maternal smoking during pregnancy to index a putatively more homogeneous group of ADHD, highly significant associations were observed between tag SNPs within SLC6A2 and ADHD diagnosis, behavioral and cognitive measures relevant to ADHD and response to MPH. This comprehensive phenotype/genotype analysis may help to further understand this complex disorder and improve its treatment. Clinical trial registration information - Clinical and Pharmacogenetic Study of Attention Deficit with Hyperactivity Disorder (ADHD); www.clinicaltrials.gov; NCT00483106