The findings suggest that the abuse potential of oral methylphenidate is strongly influenced by the rate of delivery and not solely by the magnitude of plasma concentration or brain transporter occupancy. These results advance understanding of the underlying central effects of methylphenidate in humans and identify a potentially less abusable methylphenidate formulation.

This community-based study was designed to evaluate treatment outcomes with OROS methylphenidate (MPH) and atomoxetine in children with attentiondeficit/hyperactivity disorder (ADHD), as assessed by physicians and parents in a setting that resembles clinical practice. In a multicenter, prospective, open-label study, children 6 to 12 years of age with ADHD were randomized (2:1, respectively) to 3 weeks of treatment with once-daily OROS MPH or atomoxetine. Investigatorrated measures of symptoms included the ADHD Rating Scale (ADHD-RS) and the Clinical Global Impression-Improvement of Illness scale (CGI-I). Assessments were made at baseline and during a telephone interview in week 1, a clinic visit in week 2, and a final clinic visit in week 3. In total, 1323 patients received OROS MPH (n = 850) or atomoxetine (n = 473). Significant reductions from baseline in investigator-evaluated ADHD-RS scores were observed among patients receiving OROS MPH and those receiving atomoxetine. At the end of the study, mean decreases from baseline ADHD-RS scores were 20.24 for OROS MPH and 16 for atomoxetine (P < .001). Between-treatment differences appeared to increase over time (2.77, 3.44, and 4.24 at weeks 1, 2, and 3, respectively; P < .001). Treatment response (ie, 25% reduction from baseline ADHD-RS scores) was significantly greater at each evaluation for patients taking OROS MPH than for those taking atomoxetine (P < .001). Similar percentages of patients taking OROS MPH (4.8%) and atomoxetine (5.5%) withdrew because of adverse events. Although community-based studies often lack the control of randomized, placebo-controlled trials, these results nevertheless suggest greater ADHD symptom improvement with OROS MPH compared with atomoxetine.

We examined the efficacy and tolerability of augmentation with an extended release formulation of methylphenidate (OROS MPH, Concerta) in patients with major depression who were nonresponders or partial responders to antidepressants. Sixty subjects with treatment-resistant depression (TRD) participated in a 4-week, randomized, double-blind, placebo-controlled study of augmentation with methylphenidate (18-54 mg/d). The preexisting antidepressant dose was unchanged. The primary efficacy measure was change in the 21-item Hamilton Depression Rating Scale from randomization to end of treatment. Data were analyzed with intent-to-treat with last observation carried forward approach. There were no statistically significant differences between the methylphenidate (n = 30) and placebo (n = 30) groups in reduction in 21-item Hamilton Depression Rating Scale scores (drug, -6.9; placebo, -4.7) from baseline to end of treatment (F1,47 = 1.24, P = 0.22), although responders were numerically higher in the extended-release methylphenidate group (40.0%) than in the placebo group (23.3%). On the secondary efficacy measures of changes in Clinical Global Impression-Improvement and Severity scores and Beck Depression Inventory-Second Edition, the drug failed to separate from placebo, although the proportion of responders in the drug group were numerically higher than placebo. There were no significant differences in weight, heart rate, and blood pressure changes between the 2 groups. The common adverse events were loss of appetite, nausea, headache, and anxiety. The mean dose of drug was 34.2 mg/d. The study did not demonstrate a statistically significant benefit for augmentation with methylphenidate in TRD. Combination of methylphenidate with antidepressants was well tolerated. Adequately powered, randomized, controlled trials are necessary to fully evaluate the efficacy of extended-release methylphenidate in TRD.

This was a double-blind, placebo-controlled, randomized, 5-period crossover study in 49 healthy subjects with a history of light (occasional) recreational stimulant use, to evaluate the abuse-related subjective effects of oral osmotic-controlled extended-release methylphenidate with comparable doses of immediate-release methylphenidate. Healthy subjects with a history of light recreational stimulant use were enrolled in the study if they demonstrated a positive response to a 20-mg dose of d-amphetamine and a negative placebo response. Enrolled subjects received single doses of placebo, 54 and 108 mg osmotic-controlled extended-release methylphenidate, and 50 and 90 mg immediate-release methylphenidate. For each treatment, pharmacokinetics, pharmacodynamics, and safety were assessed for 24 hours. Subjective data were collected through standard questionnaires and visual analog scales for positive, stimulant, negative, and other effects. Immediate-release and osmotic-controlled extended-release methylphenidate produced expected plasma concentration-time profiles of d-methylphenidate. Both doses of immediate-release methylphenidate (50 and 90 mg) produced statistically significantly higher subjective effects (eg, positive, stimulant) with respect to placebo for all measures. The higher osmotic-controlled extended-release methylphenidate dose of 108 mg also produced statistically significant differences from placebo for most measures. However, the most commonly prescribed therapeutic dose of osmotic-controlled extended-release methylphenidate (54 mg) did not produce significant differences from placebo for most measures. In addition, for comparable dose levels, osmotic-controlled extended-release methylphenidate produced lower positive and stimulant subjective effects than immediate-release methylphenidate, and low-dose immediate-release methylphenidate (50 mg) produced greater subjective effects than high-dose osmotic-controlled extended-release methylphenidate, with many effects demonstrating statistically significant differences. These data support the hypothesis that a formulation can modulate abuse potential by controlling the rate and extent of drug delivery.

The primary objective of this study was to determine if the abuse liability of methylphenidate is governed by formulation differences that affect rates of drug delivery. In this double-blind, placebo-controlled, randomized, crossover study, subjects with a history of recreational drug use received single oral doses of placebo, 60 mg of immediate-release methylphenidate (IR) and 108 mg of extended-release methylphenidate (osmotic release oral system [OROS]). Over 24 hours after dosing, blood was collected to determine plasma concentrations of methylphenidate, and subjects completed subjective assessments of abuse liability (Addiction Research Center Inventory, Drug Rating Questionnaire-Subject, and Subjective Drug Value). The abuse-related subjective effects of IR and OROS methylphenidate were statistically significantly different from placebo, confirming the overall validity of the study. Although a higher dose of OROS methylphenidate was used compared with IR methylphenidate (108 mg vs 60 mg), subjective effects were consistently lower for OROS compared with IR methylphenidate (statistically significant for 3 of 6 measures of positive effects), particularly at early time points. In general, pharmacokinetic-pharmacodynamic parameters were correlated from a poor to modest degree, with greater correlations observed for IR methylphenidate. In addition, a post hoc "qualification" method was developed, which demonstrated that pharmacological qualification might improve the assessment of subjective effects. Although requiring epidemiological confirmation, the results suggest that OROS methylphenidate, with its characteristic slow ascending plasma concentration profile, may have lower abuse potential. This conclusion is reflected by lower subjective responses during early hours as compared with the IR formulation with its rapid drug delivery and accompanying greater subjective effects.

There are limited data to indicate effective treatment strategies for antidepressant-related sexual dysfunction, in particular for patients with treatment-resistant major depression. We subanalyzed our published data whether augmentation with methylphenidate extended release (OROS MPH) improved sexual dysfunction associated with antidepressants in patients with treatment-resistant major depression. The primary efficacy measure was the change in Arizona Sexual Experiences Survey (ASEX) from baseline to end of treatment in an intent-to-treat analysis with last observation carried forward approach. There were no significant differences between the 2 groups in terms of changes in ASEX scores over time (F1,35 = 1.14; P = 0.32), although the numerical decrease in ASEX score was greater in OROS MPH (mean change, -4.5; 20.1% decrease) than in the placebo group (mean change, -0.6; 2.6% decrease). Augmentation with OROS MPH showed no statistically significant benefit in antidepressant-related sexual dysfunction, although addition of OROS MPH to antidepressants did not worsen preexisting sexual dysfunction. Adequately powered controlled trials are needed to fully evaluate the efficacy of OROS MPH in this area.

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