A Dose-Response Study of OROS Methylphenidate in Children With Attention-Deficit/Hyperactivity Disorder

Abstract

ABSTRACT. Objective. OROS methylphenidate HCL (MPH) is a recently developed long-acting stimulant medication used to treat attention-deficit/hyperactivity disorder (ADHD). This study was conducted to examine dosage effects on ADHD symptoms and stimulant side effects and to explore potential moderating effects of ADHD subtype.Methods. Children with ADHD combined type (ADHD-CT) or predominantly inattentive type (ADHD-PI; n ‫؍‬ 47), ages 5 to 16 years, underwent a placebocontrolled, crossover trial using forced titration with weekly switches at 3 dosage levels. Parent and teacher ratings of ADHD symptoms were used to evaluate efficacy. In addition, vital signs and standardized measures of stimulant side effects were obtained weekly.Results. Parent ratings were more sensitive to treatment effects than teacher ratings. ADHD symptoms and Clinical Global Impressions Severity Index ratings at each dose condition differed significantly from placebo and baseline ratings, which did not differ from one another. For those with ADHD-CT, there was a clear linear dose-response relationship, with clinically significant reductions in ADHD Rating Scale-IV scores occurring in two thirds to three fourths of the subjects during either 36-or 54-mg dose conditions. Children with ADHD-PI, conversely, were more likely to respond optimally to lower doses and derived less benefit from higher doses, with 60% displaying significant improvement on the ADHD Rating Scale-IV at 36 mg or lower. Mild stimulant side effects were reported during placebo and at all dosage levels. With the exception of insomnia and decreased appetite, which were more common at higher doses, parent report of side effects was not related to dose. In addition, younger and smaller children were more likely to display sleep difficulties and decreased appetite at the higher dose levels Although pulse rate increased slightly with increasing dose, there were no dose effects on blood pressure.Conclusions. In children with ADHD-CT, the most common subtype of ADHD, increasing doses of stimulant medication were associated with increased improvement of inattention and hyperactivity symptoms. In children with ADHD-PI, symptom improvement occurred at lower doses and less benefit was derived from higher doses. In both ADHD subtypes, higher doses were associated with parent ratings of increased insomnia and decreased appetite. Pediatrics 2003;112:e404 -e413. URL: http://www.pediatrics.org/cgi/content/full/112/5/e404; attention-deficit/hyperactivity disorder, methylphenidate, pharmacologic treatment.ABBREVIATIONS. ADHD, attention-deficit/hyperactivity disorder; MPH, methylphenidate; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; ADHD-PI, attentiondeficit/hyperactivity disorder predominantly inattentive type; ADD, attention-deficit disorder; ADHD-CT, attention-deficit/hyperactivity disorder combined type; ODD, oppositional defiant disorder; ADHD RS-IV, ADHD Rating Scale-IV: Home Edition; CGI, Clinical Global Impressions Severity Index; SERS, Side Effect R...

Dopamine Transporter Genotype and Methylphenidate Dose Response in Children with ADHD

“…All participants completed a semistructured diagnostic interview conducted with the parents and child by a child and adolescent psychiatrist or psychologist (HALP diagnostic interview available from senior author), and met DSM-IV criteria for ADHD based upon the interview and a 'best estimate' diagnosis based upon a standardized 4-6 h evaluation. Diagnostic procedures and subjects are described in more detail in a previous paper (Stein et al, 2003).…”

“…MPH-and amphetamine (AMP)-based stimulant medications are the most common medical treatments for ADHD (Elia et al, 1999;Conners, 2002), and at low to moderate dosage levels, there is generally an inverse linear doseresponse effect on ADHD symptoms (eg Douglas et al, 1986;Stein et al, 2003). In this paper, we report the results of a prospective, placebo-controlled study of DAT1 genotypes and dose-related MPH response.…”

A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents

“…The statistical results from the other studies were less clearly presented (see Appendix 12), although Stein and colleagues 92 reported that as the ER-MPH dose was increased from 0 to 54 mg, parentrated ADHD symptoms decreased in a linear manner ( p < 0.001).…”

“…The other study in this category measured other behavioural outcomes using scales such as the ADHD Rating Scale IV. 92 Details from these results are presented in Appendix 12. …”

“…Stein and colleagues 92 reported results for CGI severity scores. They observed that overall impairment decreased with increasing doses of MPH ( p < 0.001).…”