Open-Label Dose Optimization of Methylphenidate Modified Release Long Acting (MPH-LA): A Post Hoc Analysis of Real-Life Titration from a 40-Week Randomized Trial

Abstract

Background and ObjectivesIn 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).MethodsPatients 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.ResultsAt 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.ConclusionsDose optimization with MPH-LA (40, 60, or 80 mg/day) improved treatment outcomes and was well-tolerated in adult ADHD patients.

Changes in behavior as side effects in methylphenidate treatment: review of the literature

“…In ten of the studies, participants were adults aged between 18 and 65 years. 15 , 31 – 33 , 45 , 51 – 55 , 65 Of the 2,783 participants included in these studies, 1,498 were males. In 33 of the studies, participants were aged between 3 and 17 years.…”

“…Of the studies, 27 did not provide information on the methods or definitions employed in the reporting of side effects. In one of the studies, side effects were reported if experienced by at least 1% of participants, 28 in four studies the cutoff was at least 2% of participants, 26 , 29 , 32 , 49 in one study at least 3% of participants, 24 in seven studies at least 5%, 25 , 30 , 33 , 44 , 54 , 55 , 61 , 65 and in two studies at least 10%. 31 , 66 Two of the studies recorded the most commonly observed side effects only.…”

Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity

“…In a randomized, placebo-controlled trial (Figure 1), Huss et al53 reported that several doses of MPH-LA (40, 60, and 80 mg) were determined to be optimal for a similar number of ADHD patients (n=152, n=177, and n=160, respectively). Further analysis of the MPH-LA study data showed that this was irrespective of the initial dose administered during Period 1 (Figure 2; previously unpublished data).…”

“…Huss et al designed the only clinical trial (NCT01259492) including both fixed- and flexible-dose phases that directly investigated the benefits of flexible-dose regimens 34,53. This MPH-LA trial encompassed both fixed- and flexible dosing in a single patient cohort (Figure 1).…”

“…The primary objectives of the trial were to 1) confirm the clinically effective dose range; 2) confirm the maintenance effect of MPH-LA; and 3) evaluate safety profile of MPH-LA vs placebo. The three-phase study design also allowed for post hoc analysis of the benefits of dose optimization 53. Symptomatic and functional responses to MPH-LA were evaluated using validated instruments, including the Diagnostic and Statistical Manual of Mental Disorders , 4th edition Attention-Deficit/Hyperactivity Disorder Rating Scale (DSM-IV ADHD RS), and Sheehan Disability Scale (SDS) 66,67.…”