Adaptive phase I study of OROS methylphenidate treatment of attention deficit hyperactivity disorder with epilepsy

Abstract

OBJECTIVE-To pilot a randomized controlled trial of OROS-Methylphenidate (MPH) to treat ADHD plus epilepsy.METHOD-Thirty-three patients, 6-18 years, taking antiepileptic drugs and with a last seizure 1-60 months prior were assigned to a maximum daily dose of 18, 36, or 54mg of OROS-MPH in a double-blind placebo-controlled crossover trial. In the past year, Dr. Stephen Faraone has received consulting fees and has been on Advisory Boards for Eli Lilly, McNeil and Shire and has received research support from Eli Lilly, Pfizer, Shire and the National Institutes of Health. In previous years, Dr. Faraone has received consulting fees or has been on Advisory Boards or has been a speaker for the following sources: Shire, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. In previous years he has received research support from Eli Lilly, Shire, Pfizer and the National Institutes of Health. Dr. Joseph Biederman is currently receiving research support from the following sources: Alza, AstraZeneca, Bristol Myers Squibb, Eli Lilly and Co., Janssen Pharmaceuticals Inc., McNeil, Merck, Organon, Otsuka, Shire, NIMH, and NICHD. In 2009, Dr. Joseph Biederman received a speaker's fee from the following sources: Fundacion Areces, Medice Pharmaceuticals, and the Spanish Child Psychiatry Association. In previous years, he has received research support, consultation fees, or speaker's fees for/from the following additional sources: Abbott, AstraZeneca, Celltech, Cephalon, Eli Lilly and Co., Esai, Forest, Glaxo, Gliatech, Janssen, McNeil, NARSAD, NIDA, New River, Novartis, Noven, Neurosearch, Pfizer, Pharmacia, The Prechter Foundation, Shire, The Stanley Foundation, UCB Pharma, Inc. and Wyeth. Dr. Blaise Bourgeois has received grant/research support from Eisai, Ovation and UCB Pharma. In the past two years, he has also received consulting fees from Genzyme and Bayer Material Science.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. RESULTS-There were no serious adverse events and no carry over effects in the crossover trial. OROS-MPH reduced ADHD symptoms more than placebo treatment. There were too few seizures during the active (5) and placebo arms (3) to confidently assess seizure risk; however, considering exposure time, we observed an increased daily risk of seizures with increasing dose of OROS-MPH, suggesting that potential safety concerns need further study. NIH Public AccessCONCLUSION-A larger study to assess the effect of OROS-MPH on seizure risk is needed. A crossover design including subjects with frequent seizures could maximize power and address high patient heterogeneity and re...

Neurobehavioral Comorbidities in Children With Active Epilepsy: A Population-Based Study

“…Although there have been limited studies on interventions to treat/manage behavioral comorbidities in childhood epilepsy, studies that have been carried out suggest a good response. [28][29][30] Therefore, identification of such difficulties should be an integral part of management in childhood epilepsy. With respect to cognitive impairments in childhood epilepsy, there is an urgent need to develop an enhanced understanding of the neurobiological basis of the impairments, as such an understanding is likely to lead to the development of behavioral or pharmacological treatments that may improve cognitive outcome and also impact positively on behavioral comorbidities.…”

Comparing stimulant effects in youth with ADHD symptoms and epilepsy

“…Three out of these 36 patients had new onset seizures compared to one of the 169 with a normal EEG. A randomized controlled crossover study of 33 children with ADHD and epilepsy demonstrated good efficacy for an extended release-MPH preparation (OROS-MPH), but found some evidence of increased seizure risk with higher MPH doses [13]. Yoo and colleagues assessed tolerability and effectiveness of MPH with respect to quality of life improvements for patients with ADHD and epilepsy.…”

The pharmacological management of psychiatric comorbidities in patients with epilepsy

“…In general terms, there is more data on methylphenidate than amphetamine in patients with epilepsy and ADHD. Three randomised, double-blind, placebo-controlled, cross-over trials showed that methylphenidate 0.3-1 mg/kg/day is effective and well tolerated in children with epilepsy and ADHD with response rates ranging between 60% and 70% (73)(74)(75). For amphetamine, there is just a retrospective study of 36 patients with epilepsy and ADHD that compared response rates of amphetamine and methylphenidate and showed a significant improvement in 63% of patients taking methylphenidate versus 24% of those on amphetamine (76).…”

“…However, especially for methylphenidate, clinical data from both RCT and open trials clearly suggests that this is not the case as no seizure worsening has been demonstrated in any single trial (73)(74)(75)81). Data on amphetamines are very limited (82).…”