Is There an Association Between Antiepileptic Drug Use and Dementia Risk? A Case-Control Study

Abstract

Background:

Previous research has found a positive association between the use of antiepileptic drugs (AEDs) and dementia. However, there have been some concerns about the generalizability of its findings.

Objective:

The goal of this case-control study was to analyze the association between AED use and dementia risk in Germany.

Methods:

This study included patients who had received a first dementia diagnosis from one of 1,203 general practitioners or 202 neuropsychiatrists between 2013 and 2017 (index date). Controls without dementia were matched (1:1) to dementia cases by age, gender, physician, diagnosis of mild cognitive impairment, and observation time prior to the index date. Two regression models were used to analyze the association between AED use and dementia risk after adjusting for comorbidities and co-prescribed drugs. AEDs were included as a dichotomous variable in Model 1 (ever versus never use) and as a continuous variable in Model 2 (duration of treatment in years).

Results:

A total of 50,575 cases with dementia and 50,575 controls without dementia were included in this study. Model 1 (odds-ratio [OR] = 0.99) and Model 2 (OR = 1.00) showed no significant association between AED use and dementia risk. However, prescriptions for levetiracetam generic brands (Model 1: OR = 1.70; Model 2: OR = 1.36) were associated with an increased dementia risk.

Conclusions:

Overall, AED use was not significantly associated with dementia risk in patients followed by general practitioners and neuropsychiatrists in Germany between 2013 and 2017. Nonetheless, the potential deleterious effects of levetiracetam generic brands on cognition deserve further investigation.

Keywords

Antiepileptic drug case-control study dementia Germany risk factor

INTRODUCTION

Dementia is a neurodegenerative condition affecting between 5% and 7% of all adults 60 years or older [1]. The number of people living with dementia worldwide is expected to reach 66 million in 2030 and 115 million in 2050. At the individual level, dementia has a significant impact on disability [2], depression [3], and mortality [4]. Dementia is also associated with a substantial economic burden on a societal level [5, 6]. Therefore, the identification of novel risk factors for dementia is a public health priority.

In recent years, it has been suggested that there is a bidirectional relationship between epilepsy and dementia [7]. For example, in a register-based follow-up study including adults between 50 and 75, epilepsy was associated with a 1.5-fold increase in the risk of developing dementia [8]. A more recent study revealed that Alzheimer’s disease was a significant predictor of seizures, even after adjustment for several confounders [9]. The bidirectional association between epilepsy and dementia might be explained by the fact that these two conditions share common vascular risk factors (e.g., coronary artery disease, stroke, hypertension) [7]. Given this context, the prescription of antiepileptic drugs (AEDs) might be an effective strategy to prevent cognitive decline and dementia in patients affected by epilepsy. However, previous research has found a positive association between the use of AEDs and dementia [10, 11]. Of particular importance is the study by Taipale and colleagues which found the regular use of AEDs to be associated with an increase in the risk of incident dementia and Alzheimer’s disease [11]. The claim made by the authors is that AEDs can affect cognition by inhibiting neurotransmission and suppressing neuronal excitability [12]. Although the Taipale study has advanced the field, there have been some concerns about the validity of its methodology and the generalizability of its findings. For example, the authors did not use a strict definition for the diagnosis of dementia [13].

Therefore, the goal of this case-control study was to analyze the hypothetical association between AED use and dementia risk in 101,150 individuals from Germany.

METHODS

Database

The present study is based on data from the Disease Analyzer database (IQVIA), which compiles drug prescriptions, diagnoses, as well as basic medical and demographic data obtained directly and in anonymous format from computer systems used in the practices of general practitioners and specialists [14]. Diagnoses (International Classification of Diseases, 10th revision [ICD-10]), prescriptions (Anatomical Therapeutic Chemical [ATC] Classification system), and the quality of reported data are being monitored by IQVIA based on a number of criteria (e.g., completeness of documentation, linkage between diagnoses and prescriptions).

The sampling methods used for the selection of physicians’ practices were appropriate for obtaining a representative database of general and specialized practices in Germany [14]. Prescription statistics for several drugs were very similar to data available from pharmaceutical prescription reports. The age groups for given diagnoses in the Disease Analyzer database also corresponded well with those in corresponding disease registries. Finally, this database has already been used in studies focusing on AEDs [15, 16] and dementia [17].

Study population

This study included patients with a first dementia diagnosis documentation (ICD-10: F01, F03, G30) from one of 1,203 general practitioners or 202 neuropsychiatrists between January 2013 and December 2017 (index date). The inclusion criteria were as follows: 1) age ≥60 years at index date; and 2) observation time of at least 12 months prior to the index date. After applying similar inclusion criteria, controls without dementia were matched (1:1) to dementia cases by age, gender, physician (general practitioner or neuropsychiatrist), diagnosis of mild cognitive impairment (F06.7), and observation time prior to the index date (in years). The index date for the controls was a randomly selected visit between January 2013 and December 2017 (Fig. 1).

Fig.1

Selection of study patients.

Study outcome and variables

The main outcome of the study was the risk of dementia as a function of AED use (ATC: N03A). AEDs included levetiracetam (N03AX14), valproate (N03AG01), clonazepam (N03AE01), topiramate (N03AX11), carbamazepine (N03AF01), lamotrigine (N03AX09), gabapentin (N03AX12), pregabalin (N03AX16), primidone (N03AA03), and others (N03A excluding substances listed). Covariables included age, gender, physician, observation time prior to the index date, comorbidities (i.e., epilepsy [ICD-10: G40, G41], hypertension [I10], diabetes [E10-E14], hyperlipidemia [E78], coronary heart disease [I24, I25], stroke including transient ischemic attack [I63, I64, G45], intracranial injury [S06], depression [F32, F33], bipolar disorder [F31], mental and behavioral disorders due to use of alcohol [F10], migraine [G43], osteoporosis [M80, M81]), and co-prescribed drugs (i.e., benzodiazepines [ATC: N06C0], antidepressants [N06A], antipsychotics [N05A]).

Statistical analyses

Descriptive analyses were obtained for all demographic and clinical variables, and differences between cases and controls were evaluated using chi-squared tests for categorical variables and the Wilcoxon signed-rank test for age. Two regression models were used to analyze the association between AED use and dementia risk after adjusting for comorbidities and co-prescribed drugs. AEDs were included as a dichotomous variable in Model 1 (ever versus never use) and as a continuous variable in Model 2 (duration of treatment in years). A p-value of <0.05 was considered statistically significant. All analyses were carried out using SAS 9.4 (SAS Institute, Cary, USA).

RESULTS

Patient characteristics

The study included 50,575 cases with dementia and 50,575 controls without dementia. (Table 1) displays the basic characteristics of study patients after (1:1) matching by age, gender, physician, diagnosis of mild cognitive impairment, and observation time prior to the index date. The mean age was 81.0 years (SD = 7.4 years), and 61.5% of patients were women. The majority of study patients were treated by general practitioners (89.6%), and 28.8% had been observed for 1–3 years prior to the index date. The most frequent comorbidity was hypertension (73.3% in dementia patients and 68.3% in controls), while the most commonly co-prescribed drugs were antidepressants (32.1% and 24.1%, respectively).

Table 1

Basic characteristics of study patients after (1:1) matching by age, gender, physician, diagnosis of mild cognitive impairment, and observation time prior to the index date (in years)

Variable	Dementia (%)	No dementia (%)	p ^a
N	50,575	50,575
Age (mean, SD)	81.0 (7.4)	81.0 (7.4)	1.000
Age 60–69 years	6.8	6.8	1.000
Age 70–79 years	33.8	33.8	1.000
Age 80–89 years	45.6	45.6	1.000
Age≥90 years	12.8	12.8	1.000
Male	38.5	38.5	1.000
Female	61.5	61.5	1.000
Treated by a general practitioner	89.6	89.6	1.000
Treated by a neuropsychiatrist	10.4	10.4	1.000
Observation time prior to the index date in years (mean, SD)	8.2 (6.3)	8.2 (6.3)	1.000
1–3 years	28.8	28.8	1.000
4–5 years	16.2	16.2	1.000
6–10 years	24.8	24.8	1.000
11–15 years	15.7	15.7	1.000
>15 years	14.5	14.5	1.000
Epilepsy	3.2	1.9	<0.001
Hypertension	73.3	68.3	<0.001
Diabetes	36.6	27.9	<0.001
Hyperlipidemia	43.9	39.7	<0.001
Coronary heart disease	32.4	26.3	<0.001
Stroke including transient ischemic attack	15.7	10.6	<0.001
Intracranial injury	2.0	1.1	<0.001
Depression	33.3	22.9	<0.001
Bipolar disorder	0.6	0.5	0.003
Mental and behavioral disorders due to use of alcohol	2.6	1.3	<0.001
Migraine	2.8	2.6	0.009
Osteoporosis	17.9	15.5	<0.001
Prescription of benzodiazepines	6.9	5.0	<0.001
Prescription of antidepressants	32.1	24.1	<0.001
Prescription of antipsychotics	20.7	10.5	<0.001

Data are expressed as percentages unless otherwise specified. ^a p-values were based on chi-squared tests except for age (Wilcoxon test).

Association between AED use and dementia risk

The results of the first multivariate logistic regression model are shown in (Table 2). Overall, there was no significant association between ever use of AEDs and dementia risk (odds ratio [OR] = 0.99, 95% confidence interval [CI]: 0.95–1.04). However, in the first model, levetiracetam (OR = 1.49, 95% CI: 1.30–1.70) and valproate use (OR = 1.28, 95% CI: 1.10–1.49) were associated with an increased dementia risk, while the use of pregabalin (OR = 0.94, 95% CI: 0.89–1.00) was associated with a decreased dementia risk. Table 3 displays the results of the second multivariate logistic regression model. Overall, the prescription of AEDs was not associated with a dementia risk (OR = 1.00, 95% CI: 0.99–1.01). Sensitivity analyses were used to assess whether the use of original or generic brands of levetiracetam and valproate had an impact on dementia risk (Table 4). With regard to levetiracetam, generic brands (i.e., Model 1: OR = 1.70, 95% CI: 1.46–1.98; Model 2: OR = 1.36, 95% CI: 1.24–1.50) but not the original brand (Model 1: OR = 0.84, 95% CI: 0.70–1.01; Model 2: OR = 0.90, 95% CI: 0.83–0.97) were positively associated with dementia risk. There was no significant association between the use of original and generic brands of valproate and the risk of dementia. Finally, the epilepsy-dementia relationship was found to be significant in both models (i.e., Model 1: OR = 1.51, 95% CI: 1.38–1.65; Model 2: OR = 1.51, 95% CI: 1.38–1.65).

Table 2

Association between antiepileptic drug use and dementia risk in patients followed by general practitioners and neuropsychiatrists in Germany [Model 1]

Variable	Adjusted OR (95% CI)	p
Epilepsy	1.51 (1.38–1.65)	<0.001
Any antiepileptic drug	0.99 (0.95–1.04)	0.774
Levetiracetam	1.49 (1.30–1.70)	<0.001
Valproate	1.28 (1.10–1.49)	0.002
Clonazepam	1.15 (0.92–1.43)	0.213
Topiramate	1.08 (0.78–1.50)	0.633
Carbamazepine	1.04 (0.94–1.14)	0.477
Lamotrigine	1.01 (0.83–1.22)	0.951
Gabapentin	0.94 (0.88–1.00)	0.062
Pregabalin	0.94 (0.89–1.00)	0.043
Primidone	0.82 (0.66–1.02)	0.076
Other antiepileptic drugs	1.18 (0.98–1.44)	0.076

OR, odds-ratio; CI, confidence interval. Model 1: ever use versus never use. The model was adjusted for epilepsy, hypertension, diabetes, hyperlipidemia, coronary heart disease, stroke including transient ischemic attack, intracranial injury, depression, bipolar disorder, mental and behavioral disorders due to use of alcohol, migraine, osteoporosis, prescription of benzodiazepines, prescription of antidepressants, and prescription of antipsychotics.

Table 3

Association between antiepileptic drug use and dementia risk in patients followed by general practitioners and neuropsychiatrists in Germany [Model 2]

Variable	Adjusted OR per year of treatment (95% CI)	p
Epilepsy	1.51 (1.38–1.65)	<0.001
Any antiepileptic drug	1.00 (0.99–1.01)	0.743
Levetiracetam	1.07 (1.03–1.13)	0.003
Valproate	1.04 (1.00–1.08)	0.045
Clonazepam	1.01 (0.96–1.07)	0.695
Topiramate	1.01 (0.91–1.11)	0.877
Carbamazepine	1.01 (0.99–1.03)	0.505
Lamotrigine	0.99 (0.94–1.04)	0.567
Gabapentin	1.00 (0.97–1.02)	0.688
Pregabalin	0.99 (0.96–1.01)	0.202
Primidone	0.94 (0.86–1.02)	0.117

OR, odds-ratio; CI, confidence interval. Model 2: duration of treatment in years (increase per year of treatment). The model was adjusted for epilepsy, hypertension, diabetes, hyperlipidemia, coronary heart disease, stroke including transient ischemic attack, intracranial injury, depression, bipolar disorder, mental and behavioral disorders due to use of alcohol, migraine, osteoporosis, prescription of benzodiazepines, prescription of antidepressants, and prescription of antipsychotics.

Table 4

Association between the use of original or generic brands of levetiracetam and valproate and dementia risk in patients followed by general practitioners and neuropsychiatrists in Germany [Model 1 and Model 2]

Model	Variable	Adjusted OR (95% CI)	p
1	Levetiracetam (original brand)	0.84 (0.70–1.01)	0.063
2	Levetiracetam (original brand)	0.90 (0.83–0.97)	0.004
1	Levetiracetam (generic brands)	1.70 (1.46–1.98)	<0.001
2	Levetiracetam (generic brands)	1.36 (1.24–1.50)	<0.001
1	Valproate (original brand)	1.11 (0.86–1.45)	0.421
2	Valproate (original brand)	1.06 (0.98–1.14)	0.098
1	Valproate (generic brands)	1.19 (1.00–1.41)	0.052
2	Valproate (generic brands)	1.04 (0.99–1.09)	0.075

OR, odds-ratio; CI, confidence interval. Model 1: ever use versus never use; Model 2: duration of treatment in years (increase per year of treatment). The models were adjusted for epilepsy, hypertension, diabetes, hyperlipidemia, coronary heart disease, stroke including transient ischemic attack, intracranial injury, depression, bipolar disorder, mental and behavioral disorders due to use of alcohol, migraine, osteoporosis, prescription of benzodiazepines, prescription of antidepressants, and prescription of antipsychotics.

DISCUSSION

Main findings

The present case-control study, which included 101,150 patients followed by 1,203 general practitioners and 202 neuropsychiatrists in Germany between 2013 and 2017, found that there was no significant association between AED use and dementia risk. However, when the most frequently prescribed AEDs were analyzed separately, it was observed that levetiracetam generic brands were positively associated with a dementia risk. Finally, epilepsy was associated with a substantial increase in the risk of developing dementia.

Interpretation of the findings

The major finding of this study is that there was no significant relationship between AED use and dementia risk. To the best of our knowledge, only two studies have previously investigated the potential association between the prescription of AEDs and the risk of being diagnosed with dementia [10, 11]. In 2007, Carter and colleagues showed in 5,376 individuals 65 and older that, after adjusting for age, gender, and baseline Modified Mini-Mental State (3MS), AED users were at a higher risk for dementia but not for Alzheimer’s disease than AED non-users [10]. When several AEDs were analyzed separately (i.e., phenytoin, carbamazepine, primidone, valproate, barbiturates, gabapentin), the association was only significant in people who were prescribed phenytoin. Interestingly, the association between AED use and dementia risk was no longer present after patients with head trauma or stroke were excluded, suggesting that these two conditions, which are frequently associated with dementia [18, 19], might have been potential confounding factors. Later, in 2018, Taipale et al. observed when using data from Finland (N = 353,576) and Germany (N = 101,625) that the prevalence of AED use was higher in dementia cases than in controls without dementia (i.e., 7.6% versus 6.6% in Finland, 7.3% versus 5.2% in Germany) [11]. Moreover, there was a positive association between AED use and both incident dementia (OR = 1.28) and Alzheimer’s disease (OR = 1.15), and the risk of developing dementia tended to increase with increasing exposure to AEDs. Finally, the odds of developing dementia were particularly high in patients using AEDs with known adverse cognitive effects (e.g., valproate, phenytoin, phenobarbital). Although the findings of this study are of great interest, they should be interpreted in light of several limitations. First, the authors did not use a strict definition for the diagnosis of dementia in participants from Germany, and they included delirium superimposed on dementia (ICD-10: F05.1), senile degeneration of brain (G31.1), Leigh’s disease (G31.82), and degenerative disease of nervous system (G31.9). Second, the regression analyses failed to adjust for several risk factors for dementia, such as mild cognitive impairment [20], head trauma [19], and migraine [21]. Therefore, the positive association between AED use and dementia risk that was reported in this study might be explained by at least one of these confounding factors. Third, as previously stated by Helmstaedter and colleagues [13], the prevalence of regular AED users was higher than the prevalence of epilepsy in people from Finland (i.e., 4.4% versus 1.6% in dementia cases, 4.1% versus 1.2% in controls without dementia), suggesting that the majority of regular AED prescriptions were given for other conditions than epilepsy. Unfortunately, there was no information on the variety of diagnoses that justified the regular use of AEDs.

Although there was no significant AED use-dementia risk relationship in our case-control study, levetiracetam generic drugs were found to be associated with an increased dementia risk. These findings must be interpreted with great caution, and more research should be conducted to corroborate these results before drawing any conclusions. Several studies have found that levetiracetam has no harmful effect on cognitive function in patients with epilepsy [22, 23], and particularly in the elderly [24]. In addition, real-life data on brand-to-generic AED switching in levetiracetam users are reassuring, and this pattern of prescription is not associated with an increase in the risk of side effects [25, 26]. That being said, it is possible that some of the newest generic brands of levetiracetam have negative effects on cognitive function in older individuals with epilepsy and that these effects have not been investigated yet. Interestingly, Lang and colleagues observed, in 3,530 individuals with epilepsy followed in neurological practices in Germany between 2011 and 2016, that those with seizures had switched more frequently from branded to generic molecules than those without seizures [16]. These findings might be explained by differences in active pharmaceutical compounds but also by differences in excipients between branded and generic antiepileptic molecules. Finally, in this case-control study conducted in Germany, pregabalin was found to be negatively associated with dementia risk, but there was some discrepancy between the two multivariate regression models.

We further showed that epilepsy was a significant risk factor for the subsequent development of dementia. In 2016, Miller and colleagues observed that cognitive deficits were more severe in elderly patients with epilepsy than in matched controls and that polymedication and anxiety increased the risk of poor cognitive function [27]. Moreover, it was estimated, in a cross-sectional population-based study conducted in the UK, that the overall rate ratio of dementia was around 25 in epilepsy adults between 16–64 and around 6 in those over 64 [28]. The association between epilepsy and dementia is likely mediated by numerous conditions (i.e., stroke, hypertension, repeated head injury). Interestingly, there is also a growing body of evidence, showing that epilepsy and dementia share underlying pathological mechanisms, such as dysregulation of kinases, tau aggregation, and amyloid-β deposition [7].

Strengths and limitations

The main strengths of this study are the use of real-world data, the high number of cases and controls available for analysis, and the number of comorbidities and co-prescribed drugs included in the multivariate regression analyses. However, our study was also subject to several limitations that should be mentioned at this point. Firstly, although epilepsy centers play an important role in the treatment and management of epilepsy in Germany, we were unable to include patients from these centers. Secondly, since the diagnosis of dementia relied on ICD–10 codes only, and since there was no data on biomarkers that are indicative of dementia, we cannot rule out the possibility of misdiagnosis. Thirdly, there was no information on the factors motivating the prescription of AEDs. For example, it is possible that the prescription of levetiracetam and valproate was particularly frequent in people with a severe form of epilepsy, which may have biased the present findings.

Conclusion

Overall, antiepileptic drug use was not significantly associated with an increased dementia risk in patients followed by general practitioners and neuropsychiatrists in Germany between 2013 and 2017. Nonetheless, the potential deleterious effects of generic levetiracetam brands on cognition deserve further investigation.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/18-1194r1).

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