Does memantine improve memory in subjects with focal-onset epilepsy and memory dysfunction? A randomized, double-blind, placebo-controlled trial

Abstract

Objective: Excitotoxic injury involving N-methyl-d-aspartate (NMDA) receptor hyperactivity contributes to epilepsy-related memory dysfunction (ERMD). Current treatment strategies for ERMD have limited efficacy and fail to target the underlying pathophysiology. The present pilot study evaluated the efficacy of memantine, an NMDA receptor antagonist, for the treatment of ERMD in adults with focal-onset seizures.

Methods: Subjects underwent cognitive testing at baseline, after a 13-week randomized, parallel-group, double-blinded phase (of memantine titrated to 10 mg bid or placebo), and following a 13-week open-label extension phase (of memantine titrated to 10 mg bid). The selective reminding test (SRT) continuous long-term retrieval (CLTR) score and 7/24 Spatial Recall Test learning score served as the primary outcome measures. Secondary measures included tests of attention span, fluency, visual construction, and response inhibition, as well as assessments of quality of life, depression, sleepiness, and side effects.

Results: Seventeen subjects contributed data to the blinded phase (n = 8 memantine, n = 9 placebo). No significant differences were seen between groups on the primary or secondary outcome measures. Pooled data at the end of the open-label phase from 10 subjects (initially randomized to memantine n = 3 or placebo n = 7) demonstrated statistically significant improvement from baseline in CLTR score, memory-related quality of life, spatial span, and response inhibition. No significant changes were evident in depression, sleepiness, side effects, or seizure frequency throughout the trial.

Significance: Results demonstrated no significant effect of memantine on cognition when assessed at the end of the blinded period. Pooled data at the end of the open-label phase showed significant improvement over baseline performance in measures of verbal memory, frontal-executive function, and memory-related quality of life. These improvements, however, may be due to practice effects and should be interpreted cautiously. Findings suggest a favorable safety profile of memantine in the setting of epilepsy.

Trial registration: ClinicalTrials.gov NCT01054599.

Keywords: Cognition; Memory disorders; N-methyl-d-aspartate; Receptors; Seizures.

Conflict of interest statement

Conflict of interest

None of the authors has any conflict of interest to disclose.

Published by Elsevier Inc.

Figures

Fig. 1.

Titration of medication. Identical memantine titration schedules were employed in both Phase 1 and Phase 2.

Fig. 2.

Study flow diagram. AED = antiepileptic drug, GTC = generalized tonic–clonic seizure, WTAR = Wechsler Test of Adult Reading.

Fig. 3.

Hair plots of individual subject performance. Hair plots of individual subject performance on the primary outcome measures, (A) 7/24 Spatial Recall Test learning score and (B) SRT-CLTR score, do not cluster into clear groups of “responders” or “nonresponders.”