The Cognitive Effect of the New Generation of Antiepileptic Drugs
abstract & commentary
Source: Martin R, et al. Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology 1999;52:321-327.
Once the decision to initiate treatment with antiepileptic medications has been made, then one must ask which drug to add or substitute. The clinician must often balance the desired efficacy of a particular drug against its possible adverse cognitive effects. Many epileptic patients are cognitively impaired as a result of their illness and the cognitive effects of an antiepileptic medication may be obscured by a patient’s pretreatment cognitive ability or confounded by an improvement in cognition due to improved seizure control. Martin and colleagues attempt to quantify the cognitive effects of the new antiepileptic medications, topiramate, gabapentin, and lamotrigine, by studying the effect of each medication in a population of normal, healthy young adults.
Martin et al evaluated a group of 17 healthy young adults and randomized each subject to receive one of the three drugs studied. To study the effects of acute dosing, each subject received a single dose of one of the three medications (topiramate 2.8 mg/kg in 6 subjects; lamo-trigine 3.5 mg/kg in 5 subjects; gabapentin 17 mg/kg in 6 subjects). Cognitive effects of each medication were evaluated three hours after the acute dose by using a panel of cognitive tests that assessed sustained attention, psychomotor speed, memory, language, mood, and adverse effects. Lamotrigine and gabapentin induced no change in the subject’s cognitive performance compared to baseline. Topiramate, however, induced a marked deterioration in language, with a 50% decline in verbal fluency and with a three-fold increase in error rate in a visual attention task. Similar effects were also seen following chronic dosing of each medication.
The cognitive effects of topiramate, gabapentin, and lamotrigine after chronic dosing were assessed over the course of a 30-day dose escalation period. Over this period, each subject received a progressive increase in dose to a predetermined target dose (topiramate 5.7mg/kg/d, lamotrigine 7.1mg/kg/d, and gabapentin 35mg/kg/d). Serum levels of each antiepileptic drug were measured at the end of 30 days; all were in the therapeutic range. Cognitive performance, omitting the early naming and fluency test, was assessed after two and four weeks of treatment using the tests used in the acute dosing phase. The subjects receiving lamotrigine and gabapentin again showed no impairment on cognitive testing compared to their pretreatment baseline. In fact, the subjects in the lamotrigine and gabapentin groups improved in visual attention tasks, which Martin et al attributed to practice effect. In contrast, subjects in the topiramate-treatment group showed worsened visual performance compared to baseline. The topiramate-treatment group also had a decline in verbal memory compared to baseline. Statistically significant differences in the verbal memory performance between each treatment group were not consistent at the two- and four-week assessments, but did favor lamotrigine and gabapentin over topiramate. Finally, the subjects receiving lamotrigine and gabapentin did not evidence any change in mood. The mood scores in the topiramate subjects, however, worsened; their subscale scores rating depression, confusion, and anger-hostility all worsened over the treatment period when compared to the pretreatment baseline scores.
COMMENTARY
Martin et al recognize the limits of their study, which include the small size of the group studied and the relatively rapid dose titration schedule used. Not discussed, however, is the method used to select the target doses for the three drugs studied. Differences in the relative doses taken may account in part for the observed cognitive effects. To be able to determine accurately the cognitive effects of the medications studied, dose response curves should be used. Martin et al concede that a slower escalation dose may also have reduced the incidence of side effects, but they note that lamotrigine, which is also best increased slowly, did not produce cognitive side effects when used in a similar titration schedule.
In choosing to test the cognitive effects of each drug in normal healthy adults, Martin et al have identified, and partially quantified, the differential cognitive effects of each of the medications studied. They have not excluded subtle effects on cognition by each of the drugs tested, since a large study population may be necessary to resolve more subtle cognitive effects of each drug. Moreover, the effect in a population of epileptic patients may be less predictable than the effect in normal adults, since the effects of uncontrolled seizures, and the efficacy of each drug in controlling seizures, is purposefully not included in the present study. Though the study by Martin et al provides additional information to the clinician choosing an antiepileptic treatment, this decision ultimately rests on the clinical assessment of the patient’s medical condition, expected response to treatment, and tolerability of anticipated side effects. —fred a. lado & solomon l. moshé (Dr. Lado is EEG Fellow, Department of Neurology, Montefiore Medical Center-Albert Einstein College of Medicine, Bronx, NY. Dr. Moshé is Professor and Director, Pediatric Neurology and Clinical Neurophysiology, Department of Neurology, Montefiore Medical Center-Albert Einstein College of Medicine, Bronx, NY.)
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