Cognitive and behavioral effects of lamotrigine and topiramate in healthy volunteers
Meador KJ, Loring DW, Vahle VJ, Ray PG,Werz MA, Fessler AJ, Ogrocki P, et al.;
Commented by , 22 Aug 2005
Background
Adverse effects on cognition and behaviour are an important concern with antiepileptic drug (AED) therapy (ref. 1). There have been few comparisons of the effects of new generation AEDs on these measures.
Aim
To compare the cognitive and subjective behavioural effects of lamotrigine and topiramate in healthy volunteers.
Methods
- The study used a randomized double-blind cross-over design with a wash-out period between treatments
- Duration of each treatment was 12 weeks (7 titration, 4 maintenance, 1 down-titration). Dosages were escalated slowly to the target dosage of 300 mg/day for both drugs.
- Neuropsychological testing (17 measures, yielding 41 variables of cognitive function and subjective behavioural effects) were tested at pre-treatment, end of the maintenance period, and post-treatment.
Results
In 33 out of 41 (80%) variables (47 subjects), performance was significantly better on lamotrigine than on topiramate. No comparison was in favour of topiramate.
Compared with off-drug periods, performance on topiramate was significantly worse in 36 of 80 variables (88%), and no variable favoured topiramate. Lamotrigine was significantly worse than off-drug in 7 (17%) variables and better than off-drug on 4 (10%) variables.
Professor Perucca's comments
Studying cognitive and behavioural effects of AEDs in healthy volunteers has advantages and limitations. Advantages include avoiding the confounding effects of suppression of ictal activity and underlying pathology.
Limitations relate to the non-feasibility of studying long-term effects, and the possibility of findings not being representative of drug influences in a diseased brain.
This is one of the best studies ever performed in this area. Merits include:
- A large sample size (75 subjects randomized)
- Relatively slow titration rates, reducing the impact of titration-dependent adverse effects
- Long treatment duration, at least for healthy volunteers (12 weeks on each AED!)
- A comprehensive neuropsychological assessment
Although one might question the lack of correction for multiple comparisons in the statistical analysis, the weight of the evidence leaves no doubt that lamotrigine had much fewer cognitive and behavioural side effects than topiramate.
Improved performance on lamotrigine vs topiramate spanned a broad range of measures, including attention/vigilance, memory, language, cognitive/motor speed, graphomotor coding, reading/naming speed, and subjective behavioural measures.
Overall, results are in keeping with other evidence that topiramate can have problematic cognitive/behavioral effects (ref. 2; ref. 3; ref. 4; ref. 4a; ref. 5; ref. 6; ref. 7), whereas lamotrigine has a low propensity to cause such effects (ref. 8; ref. 9; ref. 10; ref. 11).
Of 75 randomized subjects, only 48 completed the study. Withdrawal for adverse events occurred in 7 subjects on lamotrigine, and 9 subjects on topiramate. These withdrawals are unlikely to bias the results because discontinuation due to CNS adverse events was also more common with topiramate (6 subjects, including one requiring hospitalization for psychosis, vs 1 on lamotrigine).
Although the data provide solid evidence that lamotrigine 300 mg/day is far less likely to interfere adversely with cognition and behaviour than topiramate 300 mg/day, the clinical value of the study, which was sponsored by the manufacturer of lamotrigine, is limited by the questionable selection of dosages.
In fact, both lamotrigine and topiramate have been found to be efficacious as monotherapy for epilepsy and other indications at much lower dosages. For example, in different studies, median effective dosages of lamotrigine in newly diagnosed epilepsy have been in the order of 150 mg/day (ref. 12; ref. 13) or 200 mg/day (ref. 14). For topiramate monotherapy, 100 mg/day has been proposed as the optimal target dosage, both in migraine and in epilepsy (ref. 15). In a randomized controlled trial in newly diagnosed epilepsy, topiramate 100 mg/day did not differ in efficacy from topiramate 200 mg/day, and was associated with fewer discontinuation due to adverse events (ref. 16), Finally, the median maintenance dosage of topiramate monotherapy in a naturalistic setting was found to be 150 mg/day (ref. 17).
Does the difference in propensity to cause cognitive/behavioural effects between lamotrigine and topiramate equally hold at dosages, which are more likely to be used on the majority of patients given initial monotherapy? This is an important question that unfortunately this study cannot answer.
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