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

Michael Huss, Praveen Duhan, Preetam Gandhi, Chien-Wei Chen, Carsten Spannhuth, Vinod Kumar, Michael Huss, Praveen Duhan, Preetam Gandhi, Chien-Wei Chen, Carsten Spannhuth, Vinod Kumar

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disorder characterized by hyperactivity and/or inattention and is often associated with a substantial impact on psychosocial functioning. Methylphenidate (MPH), a central nervous system stimulant, is commonly used for pharmacological treatment of adults and children with ADHD. Current practice guidelines recommend optimizing MPH dosage to individual patient needs; however, the clinical benefits of individual dose optimization compared with fixed-dose regimens remain unclear. Here we review the available literature on MPH dose optimization from clinical trials and real-world experience on ADHD management. In addition, we report safety and efficacy data from the largest MPH modified-release long-acting Phase III clinical trial conducted to examine benefits of dose optimization in adults with ADHD. Overall, MPH is an effective ADHD treatment with a good safety profile; data suggest that dose optimization may enhance the safety and efficacy of treatment. Further research is required to establish the extent to which short-term clinical benefits of MPH dose optimization translate into improved long-term outcomes for patients with ADHD.

Keywords: ADHD; attention-deficit/hyperactivity disorder; dose optimization; methylphenidate.

Conflict of interest statement

Disclosure MH has received unrestricted grants to conduct Investigator Initiated Trials (IIT) with products of Engelhard Arzeimittel and Medice. He has received speaker honoraria and travel support and served as an advisor for Lilly, Shire, Medice, Novartis, Engelhard Arzneimittel, Acelion, and Lundbeck. He also holds an international patent on Doppler radar to assess ADHD. PD is an employee of Novartis Healthcare Pvt Ltd and has been working as Medical Affairs Director for the Established Medicines Franchise of Novartis Healthcare Pvt Ltd. PG is an employee of Novartis Pharma AG and has been working as Medical Director for the Established Medicines Franchise of Novartis Pharma AG. CWC is an employee of Novartis Pharmaceuticals Corporation. CS is a full-time employee of Novartis Pharma AG. VK is an employee of Novartis Pharmaceuticals Corporation and owns stocks in the company.

Figures

Figure 1
Figure 1
The MPH-LA trial design includes a combination of fixed-dose (Period 1) and flexible-dose (Period 2 and Period 3) periods in a single study to assess the efficacy of MPH-LA in adult ADHD and to identify the individualized optimal dose for patients. Reproduced from Huss M, Ginsberg Y, Tvedten T, et al. Methylphenidate hydrochloride modified-release in adults with attention deficit hyperactivity disorder: a randomized double-blind placebo-controlled trial. Adv Ther. 2014;31(1):44–65. Abbreviations: ADHD, attention-deficit/hyperactivity disorder; MPH-LA, methylphenidate modified release long-acting formulation.
Figure 2
Figure 2
Individualized optimal dose achieved at the end of the open-label, flexible-dose (Period 2) shown by randomized dose received in Period 1. Abbreviation: MPH-LA, methylphenidate modified-release long-acting formulation.
Figure 3
Figure 3
LS mean change in (A) DSM-IV ADHD RS (n=119, n=116, n=119, and n=118, respectively) and (B) SDS total (n=113, n=115, n=117, and n=113, respectively) score from baseline 1 to end of Period 1 by optimal dose achieved in Period 2. Data were analyzed using an analysis of covariance model with treatment and center as factors, and baseline score as a covariate. P-values correspond to each group versus placebo. Abbreviations: DSM-IV ADHD RS, Diagnostic and Statistical Manual of Mental Disorders, 4th edition Attention-Deficit/Hyperactivity Disorder Rating Scale; LS mean, least square mean; MPH-LA, methylphenidate modified-release long-acting formulation; SDS, Sheehan Disability Scale.

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