A Randomized, Placebo-Controlled Trial of OROS Methylphenidate in Adults with Attention-Deficit/Hyperactivity Disorder

Harvard University, Cambridge, Massachusetts, United States
Biological Psychiatry (Impact Factor: 10.26). 06/2006; 59(9):829-35. DOI: 10.1016/j.biopsych.2005.09.011
Source: PubMed


The objective of this study was to evaluate the safety and efficacy of once-daily OROS methylphenidate (MPH) in the treatment of adults with DSM-IV attention-deficit/hyperactivity disorder (ADHD).
We conducted a randomized, 6-week, placebo-controlled, parallel-design study of OROS MPH in 141 adult subjects with DSM-IV ADHD, using standardized instruments for diagnosis. OROS MPH or placebo was initiated at 36 mg/day and titrated to optimal response, depending on efficacy and tolerability, up to 1.3 mg/kg/day.
Treatment with OROS MPH was associated with clinically and statistically significant reductions in DSM-IV symptoms of inattention and hyperactivity/impulsivity relative to subjects treated with placebo. At endpoint, 66% of subjects (n = 44) receiving OROS MPH and 39% of subjects (n = 29) [corrected] receiving placebo attained our a priori definition of response of much or very much improved on the Clinical Global Impression-Improvement scale plus a >30% reduction in Adult ADHD Investigator System Report Scale score. OROS MPH was associated with small but statistically significant increases in systolic blood pressure (3.5 +/- 11.8 mm Hg), diastolic blood pressure (4.0 +/- 8.5 mm Hg), and heart rate (4.5 +/- 10.5 bpm).
These results show that treatment with OROS MPH in daily doses of up to 1.3 mg/kg/day was effective in the treatment of adults with ADHD. Because of the potential for increases in blood pressure and heart rate, subjects receiving treatment with MPH should be monitored for changes in blood pressure parameters during treatment.

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    • "We also incorporated a variety of clinic-relevant study design elements: combination of neuroimaging and neuropsychological assessments, enabling exploration of behavioral improvement accompanied by the neural changes; a comparative trial between two active treatment arms, instead of placebo arm, providing valuable guidance towards therapeutic decisions; and a longer treatment duration (up to 12 weeks) rather than a single dose study design. Despite the acute effects of methylphenidate, clinical efficacy of both medications does not maximally differentiate from placebo until weeks of treatment (Biederman et al., 2006; Montoya et al., 2009) implying the importance of investigations on the long term treatment effect. In order to achieve maximal effect of atomoxetine (Montoya et al., 2009), treatment duration of 12 weeks was utilized in our study, which is in fact one of the longest intervention among the randomized clinical trial utilizing imaging techniques. "
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    ABSTRACT: Methylphenidate and atomoxetine are effective in treating attention-deficit/hyperactivity disorder (ADHD) with underlying distinct pharmacological mechanisms. To relate neural mechanisms to clinical response, we conducted a comparative trial to differentiate the changes in brain activation of drug-naïve children with ADHD when performing neuropsychological tasks after 12 weeks of pharmacotherapy. We randomized 50 drug-naïve children with ADHD, aged 7-17, to treatment with methylphenidate (n=25) or atomoxetine (n=25). These children were scanned twice with functional magnetic resonance imaging (fMRI) during the counting Stroop task before and after treatment. Focused attention and impulsivity were assessed twice by using the Conner's Continuous Performance Test (CCPT). The final sample for fMRI analysis comprised 20 in the methylphenidate group and 22 in the atomoxetine group. Atomoxetine decreased activations in the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex, which correlated with improvement in focused attention assessed by the CCPT. In contrast, methylphenidate increased activations in the inferior frontal gyrus, which correlated with the decreasing severity of impulsivity assessed by the CCPT. The current findings suggest that differential therapeutic effects on neuronal changes induced by 12-week treatment atomoxetine and methylphenidate may contribute to behavioral improvement.
    Full-text · Article · Sep 2015 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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    • "Attention Deficit/Hyperactivity Disorder (ADHD) is a common chronic psychiatric disorder, characterized by a pattern of developmentally inappropriate inattention, motor restlessness and impulsivity, which affects between 3 and 7% of school age children, according to DSM-IV criteria (American Psychiatric Association, 1994; Polanczyk et al., 2007). Prospective follow-up studies found that approximately 50% of children with ADHD show symptoms that continue into adulthood, and when left untreated, are associated with substance abuse, depression, unemployment and criminal offenses (Biederman et al., 2006; Molina et al., 2009). However, the precise neurobiological mechanisms underlying the pathophysiology of ADHD are currently unknown. "
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    ABSTRACT: Attention Deficit/Hyperactivity Disorder (ADHD) and autism spectrum disorder (ASD) are highly comorbid, and both disorders share executive function deficits. Accumulating evidence suggests that ASD patients have significantly lower peripheral oxytocin (OXT) levels compared with their normal counterparts, and that the repetitive behavior seen in ASD is related to abnormalities in the OXT system. In this study, we investigated whether serum levels of OXT are altered in pediatric patients with ADHD. We measured serum OXT levels: drug naive ADHD (n=23), medicated ADHD (n=13), and age- and sex- matched, neurotypical controls (n=22). Patients were evaluated using the ADHD-RS. Serum levels of OXT in total subjects with ADHD were significantly decreased compared with those of neurotypical controls, and serum levels of OXT in drug naive ADHD patients were significantly lower than those in medicated ADHD patients. Interestingly, there was a significant negative correlation between serum OXT levels and ADHD-RS total scores, as well as ADHD-RS inattentive scores in all ADHD patients. In conclusion, this study suggests that decreased levels of OXT may play a role in the pathophysiology of patients with ADHD and its inherent inattentiveness. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
    Full-text · Article · Jun 2015
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    • "Furthermore, in both the clinician-rated scales, CGI-I and CGI-S, a higher proportion of patients showed improvement than in observations during the dose confirmation phase. These results are consistent with other short-term dose optimization studies evaluating efficacy of methylphenidate in adults with ADHD [2, 9, 14, 15]. The present study is of particular interest as improved symptomatic effects were observed upon dose optimization, and clinical optimization of dosing did not depend on the prior fixed MPH-LA dose in the initial phase. "
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    ABSTRACT: Background and Objectives In the management of attention-deficit hyperactivity disorder (ADHD) in adults it is important to recognize that individual patients respond to a wide range of methylphenidate doses. Studies with methylphenidate modified release long acting (MPH-LA) in children have reported the need for treatment optimization for improved outcomes. We report the results from a post hoc analysis of a 5-week dose optimization phase from a large randomized, placebo-controlled, multicenter 40-week study (9-week double-blind dose confirmation phase, 5-week open-label dose optimization phase, and 26-week double-blind maintenance of effect phase). Methods Patients entering the open-label dose optimization phase initiated treatment with MPH-LA 20 mg/day; up/down titrated to their optimal dose (at which there was balance between control of symptoms and side effects) of 40, 60, or 80 mg/day in increments of 20 mg/week by week 12 or 13. Safety was assessed by monitoring the adverse events (AEs) and serious AEs. Efficacy was assessed by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Attention-Deficit Hyperactivity Disorder Rating Scale (DSM-IV ADHD RS) and Sheehan Disability Scale (SDS) total scores. Results At the end of the dose confirmation phase, similar numbers of patients were treated optimally with each of the 40, 60, and 80 mg/day doses (152, 177, and 160, respectively) for MPH-LA. Mean improvement from baseline in the dose confirmation phase in total scores of DSM-IV ADHD RS and SDS were 23.5 ± 9.90 and 9.7 ± 7.36, respectively. Conclusions Dose optimization with MPH-LA (40, 60, or 80 mg/day) improved treatment outcomes and was well-tolerated in adult ADHD patients.
    Full-text · Article · Jul 2014 · Clinical Drug Investigation
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