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Summary: Purpose: This study compared the cognitive effects of carbamazepine (CBZ) and gabapentin (GBP) in healthy senior adults by using a randomized, double-blind crossover design.
Methods: Thirty-four senior adults were randomized to receive one of the two drugs followed by a 5-week treatment period. A 4-week washout phase preceded initiation of the second drug. Antiepileptic drugs (AEDs) were titrated to target doses of either CBZ (800 mg/day) or GBP (2,400 mg/day). Primary outcome measures were standardized neuropsychological tests of attention/vigilance, psychomotor speed, motor speed, verbal and visual memory, and the Profile of Mood State (POMS), yielding a total of 17 variables. Each subject received cognitive testing at predrug baseline, end of first drug phase, end of second drug phase, and 4 weeks after completion of the second drug phase.
Results: Fifteen senior adults (mean age, 66.5 years; range, 59–76 years) completed the study. Seniors completing the study did not differ significantly from noncompleting seniors in terms of demographic features or baseline cognitive performances. Fifteen of the 19 seniors not completing the study dropped out while receiving CBZ. Adverse events were frequently reported for both AEDs, although they were more common for CBZ. Mean serum levels for the completers were within midrange clinical doses (CBZ, 6.8 μg/ml; GBP, 7.1 μg/ml). Significant differences between CBZ and GBP were found for only one of 11 cognitive variables, with better attention/vigilance for GBP, although the effect was modest. Performances on the nondrug average were significantly better on 45% of cognitive variables compared with CBZ and 36% compared with GBP. The overall pattern of means favored GBP over CBZ on 15 of 17 (p < 0.001), nondrug over CBZ on 17 of 17 (p < 0.0000), and nondrug over GBP on eight of 17 (NS).
Conclusions: Mild cognitive effects were found for both AEDs compared with the nondrug average condition. The magnitude of difference between the two AEDs across the cognitive variables was modest. Self-reported mood was not significantly affected by either AED. However, overall tolerability and side-effect profile of CBZ were poorer than those of GBP in senior adults at doses and titration rates reported in this study.
Epidemiologic estimates indicate that the incidence of epilepsy in senior adults has increased over the past several decades, with annual estimates of new epilepsy cases in those older than 60 years approaching 45–50,000 in the United States (1). The prevalence rate of active epilepsy in persons older than 60 years now approaches 1% (2). Treatment for senior adults with epilepsy has relied on the incorporation of studies on younger patients that do not fully account for the complex physiologic and pharmacokinetic changes that occur with aging (3). This complexity makes an already difficult treatment selection even more so, when considering the range of medication side effects and interactions that are more problematic in the elderly.
The potential for adverse cognitive effects of antiepileptic drugs (AEDs) within the older population is considerable, given age-related increases in drug sensitivity, which could exacerbate already existing declining cognitive abilities. In addition, elderly patients are likely receiving multiple medications for non–epilepsy-related medical/neurologic conditions that could complicate already drug-sensitive biologic systems. Developing and using AEDs that minimize the risk to cognitive function in senior adults with epilepsy is an important issue that has not been sufficiently examined, especially in light of trends suggesting that the number of new cases of epilepsy in older adults is increasing because of declining mortality and general aging of the American population.
To date, the potential cognitive effect of AEDs in senior epilepsy populations has received limited attention. However, one study specifically examined the comparative cognitive effects of phenytoin (PHT) and valproate (VPA) monotherapy in groups of elderly-onset seizure patients (4). Patients with new-onset partial seizures or generalized tonic–clonic seizures were recruited from their community physicians into the study. They found only minor changes in cognitive test performance over the course of 1 year taking either AED compared with predrug baseline (4). Additionally, minimal differences were found between the two AEDs with regard to impact on cognitive function. However, they used a parallel-group design that tends to reduce the statistical power compared with a randomized crossover design. The two groups of seniors were, however, randomized to AED and were matched across several demographic variables.
To gain greater understanding of the potential anticonvulsant effects on cognition, healthy adult populations should be used because seizure effects, underlying cerebral injury, and concurrent medical factors can confound evaluating the cognitive effects of AEDs with epilepsy. Meador et al. (5) recently presented data demonstrating mild untoward effects of three common first-line AEDs in a group of young healthy adults with a randomized, double-blinded, incomplete-block crossover design. More than half of the neurocognitive variables exhibited negative AED effects when compared with nondrug baselines.
For the older patient with epilepsy, gabapentin (GBP) may offer an alternative to the more traditional AEDs that are known to have significant side-effect profiles in the elderly (6). GBP has demonstrated few sedative and cognitive effects in the young epilepsy population (7). One recent study found that senior adults patients with epilepsy taking an average GBP dose of 2,700 mg/day reported few adverse events (AEs), with three patients reporting fatigue, and two reporting unsteadiness (8). Unfortunately, no study to date has explored the potential cognitive effects of GBP in either senior adults with epilepsy or in healthy senior adults.
At present, carbamazepine (CBZ) is considered a standard drug of choice for seniors with epilepsy and ranks next to PHT in prescribed popularity (9). However, AEs do occur with CBZ, including cognitive effects. Recently, data from healthy young adults demonstrated mild negative effects of CBZ on cognitive function compared with baseline conditions when administered at common clinical dosage (10). Sparse effort has been directed to the study of the potential cognitive effects of CBZ in senior adults despite its widespread clinical use for chronic seizures and other conditions. Read et al. (11) recently found no significant changes in various cognitive task performances in senior adults who took an extra dose of their AED medication (either CBZ, VPA, or PHT). They concluded that cognitive impairment does not develop when modest dose increases are given in patients taking therapeutic monotherapy AED.
Our study compared the potential cognitive and behavioral effects of CBZ and GBP in a double-blind, randomized crossover design. The use of independent community-dwelling healthy senior adults negates the impact of the epileptic state and allows generalization to populations who may use these AEDs for non–seizure-related treatment.
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Despite the prevalence of epilepsy in the elderly, little is known about the potential cognitive and behavioral effects of commonly used AEDs in this population. This study enlisted a group of healthy senior adults exposed to GBP and CBZ. This study used a healthy senior population to eliminate the confound of seizures on cognitive performance and to allow extrapolation of results to other conditions treated with these AEDs. The central aim of this study was to examine differential cognitive effects of GBP and CBZ. Previous attention to potential neuropsychological effects of AEDs in seniors has been limited and has compared only more traditional AEDs (4,11). This study demonstrated that for the 11 cognitive variables, only a single measure of attention was statistically different between the two AEDs. Although mean variable comparison (sign test) found that performance with GBP was better than that with CBZ on nine of 11 variables, the magnitude of difference between the AEDs was modest (typically <0.5 SD).
A secondary aim of this study was to examine AED effects compared with a nondrug condition. Untoward cognitive effects were found for both GBP and CBZ compared with the average nondrug condition. Both AEDs produced statistically worse performance on tests of verbal memory and motor speed compared with the nondrug average condition. Seniors experienced more difficulty recalling prose passages while receiving either AED compared with nondrug baseline, even with the practice of a second learning trial. This effect persisted over the delayed-recall condition. These drug effects ranged in magnitude from 0.5 to 1 SD unit difference from nondrug average baseline performances. Overall, AEDs negatively affected performances ranging from 9 to 30% worse compared with the nondrug average condition. No statistical differences were noted favoring either AED over the nondrug average condition across any of the cognitive tasks. These effect sizes appeared similar in magnitude to test–retest effects reported in a study of cognitive effects of either VPA or PHT monotherapy in seniors with epilepsy (4). Additionally, when the overall pattern of AED versus average nondrug condition was examined, all 17 variables (cognitive tests and mood ratings) favored the average nondrug condition over CBZ, whereas eight of the 17 variable means favored the nondrug average condition over GBP. However, it should be noted that this study did not have a placebo condition, so subjects were always aware when they were receiving an AED.
These results have some consistency with recent comparative AED studies using healthy young adults (5,10). Healthy senior adults, like young adults, do experience drug effects that affect some areas of cognitive functioning. AEDs such as phenobarbital (PB) and, to a lesser degree, PHT, VPA, and CBZ, produce modest cognitive effects in younger adults. Likewise, standardized cognitive tasks measuring attention/vigilance, memory, and cognitive/motor speed appear sensitive to the effects of therapeutic range dosage of these older AEDs in senior adults.
Previous research has identified positive mood effects and subjective ratings of improved well-being in seizure patients after unblinded treatment with GBP (25,26). Other studies using low-dose GBP for augmentative treatment for bipolar and schizoaffective disorders have found significant mood-stabilizing effects (27,28). However, the present study found no statistically significant differences between the two AEDs across any of the six POMS subscales. However, when examined for overall distribution of the mean drug differences, the POMS subscales consistently favored GBP over both CBZ and the nondrug average condition across all subscales. The statistical probability of finding such consistency is quite low, although like that of the cognitive variable comparisons, the magnitude of effect was modest. However, the results suggest that GBP may have a mild mood-enhancing effect consistent with findings from previous research. The mild positive mood finding for GBP was somewhat surprising, in that our senior adults were experiencing normal mood to begin with, whereas more dramatic mood effects from GBP may be more likely in patient groups who are more likely to be depressed. The robustness of these findings awaits larger sample sizes and use in elderly seizure patients.
In this study, subjects receiving either AED frequently experienced AEs. Seniors reported a high incidence of sedative effects across both drugs that tended to occur early in the titration phase. Senior adults are known to have increased susceptibility to the effects of AEDs for both pharmacokinetic and pharmacodynamic reasons (29). Side effects were the critical factor to the study dropout rate. Potentially dangerous symptoms of unsteadiness and dizziness were commonly reported, especially when receiving CBZ. Interestingly, although AEs were reported with GBP, these did not lead to study discontinuation as compared with CBZ. Arguably, slower titration schedules and lower end-state dose levels for this study may have reduced the incidence of side effects. In this study, titration times and end-dose points were both designed to reflect recent experimental findings (22,23). The titration rate used in our study may not be typical of the clinical situation for management of seizures in the elderly and therefore may have contributed to the high study dropout. However, it should be pointed out that AED tolerability, in a recent multicenter study of CBZ and lamotrigine (LTG) efficacy in elderly epilepsy patients with slower titration rates, was similar to that in our study (30). In that study, the titration rate for CBZ was very slow, occurring over a 6-week period. The final median dose was 400 mg/day (range, 200–800 mg/day) with median ABL of 6.9 mg/l. However, even with the slower titration in that study, the dropout rate for CBZ at 70 days was 40% and ∼55% at the end of 168 days. In comparison, the 70-day dropout rate for the present study was 56%.
A major limitation of this study was the small sample size of completers, only 15 subjects. Despite the double-blinded crossover design that has subjects serving as their own controls, the sample size may have limited the power necessary to minimize a type II error. However, with a double-blinded crossover design, subjects served as their own controls, attenuating potential sample-selection bias that may be found in parallel-group designs. The impact of practice effect is acknowledged, but scores for the non-AED conditions were averaged to lessen any impact from repeated testing exposures. Such repeated measurement of nondrug average performance has been used successfully in previous AED cognitive studies (5). Despite the small sample, statistical differences did emerge when comparing the nondrug average condition with the AED conditions. However, with the exception of one cognitive variable, no drug–drug comparison was statistically different. When we applied nonparametric pattern comparisons to the data, CBZ resulted in a consistently less favorable pattern of cognitive performance and self-report mood compared with the non-AED condition (95% of the comparisons) and with GBP (88% of the comparisons). However, again emphasis must be placed on the relatively small magnitude of between-AED differences. Although these differences could be clinically significant in some patients, it should be emphasized that potential cognitive effects are only one of many factors in determining AED selection for epilepsy in the individual patient.
In terms of potential clinical relevance of the present findings, much is known about the impact of aging on drug metabolism and increased risk of drug AEs (31,32). The increased susceptibility to mental impairments related to age-associated diseases (i.e., stroke and dementia) makes the potential for adverse events related to AEDs even more important (29). For example, rehabilitative efforts in the dementia or stroke patient may be further complicated by exacerbation of cognitive difficulties from AED treatment. In addition, AEDs are achieving a wider use for non–epilepsy-related conditions such as neuropathic pain (33). The present study found that the magnitude of cognitive and behavioral effects for the two AEDs was modest for most tasks (i.e., mean performance change, ∼0.25 to 0.5 SD from baseline), but more significant for the verbal memory and motor speed tasks (0.5–1 SD from baseline). Such findings have potential clinical relevance because CBZ is one of the most prescribed AEDs in the United States and is the first- or second-choice prescribed AED for seizures in the elderly (9). CBZ is also commonly prescribed for the treatment of non–epilepsy-related psychiatric conditions, particularly bipolar affective disorder (34). Both 800 mg/day of CBZ and 2,400 mg/day of GBP are typical end-dose points in several controlled trial studies on AED seizure efficacy (35,36). However, future studies will be needed to clarify issues related to the appropriate titration rate of AEDs in senior adults to minimize AEs, as well as whether long-term cognitive habituation is affected by longer-term use of AEDs.