VANCOUVER—Methylphenidate, a therapy approved for the treatment of attention deficit hyperactivity disorder (ADHD), lessens cognitive deficits associated with epilepsy, according to the results of a double-blind, placebo-controlled trial. Although the trial was small, the benefit was observed in multiple cognitive domains and persisted among patients who participated in an open-label extension after the double-blind portion of the study was completed.
“To the best of our knowledge, this is the first epilepsy study in adults using this type of established objective and standardized measures to evaluate multiple cognitive domains,” reported Jesse Adams, MD, who is completing a neuropsychiatry fellowship at Stanford University School of Medicine in California. The results of the trial, which was conducted with immediate-release methylphenidate, were presented by Dr. Adams at the 68th Annual Meeting of the American Academy of Neurology.
Thirty-five patients were enrolled and 31 completed the double-blind portion. Of those completing, 24 had focal seizure types, six had generalized seizure activity, and one had unclassified seizure activity. A broad array of seizure subtypes was represented. The age range of participants was 20 to 60 (median age, 35.3). The median duration of epilepsy was 12.5 years.
The study was conducted with a crossover design in three periods. Each patient received single dose placebo, 10 mg of methylphenidate, and 20 mg of methylphenidate in a random order one week apart. The primary cognitive measures were the Connors Continuous Performance Task (CPT), the Symbol-Digit Modalities Test (SDMT), and Medical College of Georgia Paragraph Memory Test (MCGPMT). These, along with additional cognitive tests employed as secondary measures, were administered at baseline and at the end of each period of treatment. Although not all differences reached statistical significance, cognitive performance on either dose of methylphenidate was consistently better than on placebo. The greatest difference was observed for the SDMT. Dr. Adams characterized the effect size in this measure as “moderate to large.” While other differences were more modest, the direction of benefit was consistently in favor of methylphenidate.
For example, an advantage was observed for CPT variables of hits, omissions, and detectability. No significant difference in cognitive performance could be detected when the two doses of methylphenidate were compared with each other.
Of the four patients who did not complete the double-blind portion of the study, one taking the 20-mg dose withdrew for cognitive problems, another taking the 20-mg was lost to follow-up, and one taking the 10-mg dose withdrew for agitation and tachycardia. A fourth participant who received 40 mg withdrew for tachycardia. However, the same patient participated in the open-label study on a lower dose without further complaints. Methylphenidate was otherwise well tolerated, although several patients, including those taking placebo, reported agitation.
At the end of the double-blind portion of the study, 30 participants elected to enter a four-week open-label extension. Patients were started on 5 mg or 10 mg with upward titration permitted as tolerated. Two patients left the extension before completion due to anxiety. However, testing at the end of this period continued to show improvements in cognitive function for those who remained on methylphenidate. In addition, improvement in a validated epilepsy quality-of-life instrument on methylphenidate was characterized as having “a large effect size.” Of the 28 patients who completed the open-label extension, 22 elected to continue taking methylphenidate.
Concern has been expressed about the potential for methylphenidate to trigger seizures, but this effect was not observed in this study. The seizure rate was not statistically different during the double-blind trial, compared with baseline.
—Theodore Bosworth
