Efficacy and Safety of Dexmethylphenidate Extended-Release Capsules in Adults with Attention-Deficit/Hyperactivity Disorder
ABSTRACT This multicenter, randomized, fixed-dose, double-blind, placebo-controlled study evaluated efficacy of extended-release dexmethylphenidate (d-MPH-ER) in adults with attention-deficit/hyperactivity disorder (ADHD).
Randomized adults with ADHD (n=221) received once-daily d-MPH-ER 20 mg, 30 mg, or 40 mg or placebo for 5 weeks. The primary efficacy variable was change from baseline to final visit in DSM-IV ADHD Rating Scale (ADHD-RS) total score. Secondary efficacy parameters included the proportion of patients with improvement>or=30% in ADHD-RS total score and final scores on Clinical Global Impressions-Improvement (CGI-I) scale.
Of 218 evaluable patients, 184 completed the study. All d-MPH-ER doses were significantly superior to placebo in improving ADHD-RS total scores. Placebo scores improved by 7.9; d-MPH-ER, 20 mg, improved by 13.7 (p=.006); d-MPH-ER, 30 mg, improved by 13.4 (p=.012); and d-MPH-ER, 40 mg, improved by 16.9 (p<.001). Overall distribution of CGI-I ratings at final visit was significantly better with each d-MPH-ER dosage than with placebo. There were no unexpected safety or tolerability concerns, based on experience with racemic methylphenidate (MPH) in adults and dexmethylphenidate (d-MPH) in children.
Once-daily d-MPH-ER at 20 mg, 30 mg, or 40 mg is a safe and effective treatment for adults with ADHD.
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- "Finally, are the observed drug effects on receptor availability quantitatively different in patients with ADHD and healthy volunteers? The latter question is especially topical (Sahakian and Morein- Zamir, 2007) because methylphenidate has been reported to augment several aspects of cognition in healthy subjects (Rapoport et al., 1978, 1980; Strauss et al., 1984; Koelega, 1993; Elliott et al., 1997; Mehta et al., 2000) similar to those improved in ADHD (Mehta et al., 2004; Turner et al., 2005; Clark et al., 2007; Spencer et al., 2007). The effects of methylphenidate and related stimulant drugs in healthy individuals have been shown to be baseline-dependent; i.e. those subjects with relatively low performance levels exhibit greater benefit after the drug (Naylor et al., 1985; Rogers et al., 1999; Mehta et al., 2000; Turner et al., 2003; Clatworthy et al., 2009). "
ABSTRACT: Through the combined use of (18)F-fallypride positron emission tomography and magnetic resonance imaging this study examined the neural mechanisms underlying the attentional deficits associated with attention deficit/hyperactivity disorder and their potential reversal with a single therapeutic dose of methylphenidate. Sixteen adult patients with attention deficit/hyperactivity disorder and 16 matched healthy control subjects were positron emission tomography and magnetic resonance imaging scanned and tested on a computerized sustained attention task after oral methylphenidate (0.5 mg/kg) and placebo administration in a within-subject, double-blind, cross-over design. Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits and reduced grey matter volume in fronto-striato-cerebellar and limbic networks, they had equivalent D2/D3 receptor availability and equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects. However, poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity. Methylphenidate significantly increased dopamine levels in all nigro-striatal regions, thereby normalizing dopamine levels in the left caudate in low performers. Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis. This finding was accompanied by an equally performance-dependent effect of the drug on dopamine release in the midbrain, whereby low performers showed reduced dopamine release in this region. Collectively, these findings support a dimensional model of attentional deficits and underlying nigro-striatal dopaminergic mechanisms of attention deficit/hyperactivity disorder that extends into the healthy population. Moreover, they confer midbrain dopamine autoreceptors a hitherto neglected role in the therapeutic effects of oral methylphenidate in attention deficit/hyperactivity disorder. The absence of significant case-control differences in D2/D3 receptor availability (despite the observed relationships between dopamine activity and attention) suggests that dopamine dysregulation per se is unlikely to be the primary cause underlying attention deficit/hyperactivity disorder pathology in adults. This conclusion is reinforced by evidence of neuroanatomical changes in the same set of patients with attention deficit/hyperactivity disorder.Brain 11/2013; 136(Pt 11):3252-70. DOI:10.1093/brain/awt263 · 9.20 Impact Factor
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- "The DRD4 gene, which produces a blunted response to dopamine (Van Tol, Wu, Guan, & Ohara, 1992), has demonstrated the most consistent association with ADHD across numerous meta-analytic studies (Faraone, Doyle, Mick, & Biederman, 2001; Loo et al., 2010; Wu, Xiao, Sun, Zou, & Zhu, 2012), and, thus, was examined in our sample of adolescents with and without ID. The dopamine transporter gene (DAT1) may be the candidate that is the most biologically plausible given that stimulant medications inhibit the dopamine transporter thereby increasing extracellular dopamine (Li & Lee, 2012; Spencer et al., 2007). Some previous studies have found an association between the DAT1 gene and ADHD (Brookes et al., 2006; Chen et al., 2003; Cook, Stein, Ellison, & Unis, 1995; Faraone et al., 2005; Loo et al., 2008, 2010; Todd et al., 2005), while others have not (Li, Sham, Owen, & He, 2006). "
ABSTRACT: Children and adolescents with intellectual disabilities (ID) are at heightened risk for developing ADHD. However, the validity of ADHD as a diagnosis for youth with ID remains controversial. To advance research on validity, the present study examined the hypothesized precursors to ADHD in typically developing adolescents (TD) and adolescents with ID, specifically with regard to family history of ADHD, molecular genetics, and neuropsychological functioning. Results indicated that youth ADHD symptoms were related to parental ADHD symptoms regardless of the adolescent's cognitive functioning. Additionally, findings suggested that the DRD4 genetic variant and adolescent set-shifting abilities were related to adolescent ADHD symptoms independent of cognitive functioning. This study provides an initial investigation of the biological correlates of ADHD among youth with ID.Research in developmental disabilities 05/2013; 34(7):2268-2279. DOI:10.1016/j.ridd.2013.02.025 · 4.41 Impact Factor
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- "ADHD is more prevalent in first degree relatives with persistent ADHD than those with childhood-limited ADHD (Faraone, Biederman, & Friedman, 2000) and the heritability of hyperactivity and inattention was estimated at 73% and 71%, respectively, in a recent meta-analysis (Nikolas & Burt, 2010). The dopamine transporter gene (DAT1; SLC6A3) is a compelling candidate gene for ADHD because stimulant medications for ADHD inhibit the dopamine (DA) transporter and increase extracellular DA (Spencer et al., 2007). The variable number of tandem repeats (VNTR) sequence in the 3¢ untranslated region (UTR) affected neural activation during working memory and response inhibition tasks using functional magnetic resonance imaging (Bertolino et al., 2008; Congdon, Constable, Lesch, & Canli, 2009). "
ABSTRACT: Although the association of the dopamine transporter (DAT1) gene and attention-deficit/hyperactivity disorder (ADHD) has been widely studied, far less is known about its potential interaction with environmental risk factors. Given that maltreatment is a replicated risk factor for ADHD, we explored the interaction between DAT1 and maltreatment with ADHD symptoms defined dimensionally and using latent class analysis (LCA). We tested the association of the 40 base-pair variable number of tandem repeats polymorphism in DAT1, maltreatment, and their interaction in 2,488 boys and girls from the National Longitudinal Study of Adolescent Health. In boys, ADHD symptoms were optimally defined by four classes (Combined, Hyperactive/Impulsive, Inattentive, and Normal), whereas in girls, ADHD symptoms were defined by three classes (Combined, Combined-Mild, Normal). A significant DAT1 × maltreatment interaction revealed that maltreated girls homozygous for the 10-repeat allele had more symptoms of ADHD, and were also 2.5 times more likely to be classified in the Combined ADHD group than in the Normal Group. The underlying structure of ADHD symptoms differed between boys and girls and DAT1 interacted with maltreatment to predict ADHD symptoms and ADHD status derived from LCA. Interactive exchanges between maltreatment and DAT1 for ADHD symptoms, and their implications for intervention, are discussed.Journal of Child Psychology and Psychiatry 05/2012; 53(9):997-1005. DOI:10.1111/j.1469-7610.2012.02563.x · 6.46 Impact Factor