Elsevier

Epilepsy & Behavior

Volume 9, Issue 3, November 2006, Pages 424-431
Epilepsy & Behavior

Neuropsychological and psychiatric impact of add-on titration of pregabalin versus levetiracetam: A comparative short-term study

https://doi.org/10.1016/j.yebeh.2006.07.011Get rights and content

Abstract

Cognitive and behavioral impairments are common in patients with epilepsy. Multiple factors may contribute to these difficulties; among them is antiepileptic drug (AED) treatment. We examined the short-term impact of two new add-on AEDs, pregabalin (PGB) and levetiracetam (LEV), on cognition and psychiatric states in 20 adult patients with medically refractory partial epilepsy, before and shortly after add-on titration. According to an open, prospective comparative trial, add-on PGB was titrated to 300 mg and add-on LEV to 1000 mg in 10 patients each. Patients were assessed before (T1) and 2 weeks after (T2) addition of the AED. During the trial, seizure frequency did not change significantly in either group. With PGB, patients manifested partly significant impairments in episodic memory of verbal and visual information. Psychiatric states were unchanged. With LEV treatment, we saw improvements in visual short-term memory performance and psychiatric states (i.e., interpersonal sensibility, depression, and anxiety). The comparison between PGB and LEV revealed a trend toward higher anxiety scores and higher variability in hostility scores with PGB that was significantly different from the trend with LEV. No significant differences were apparent in all other neuropsychological and psychiatric parameters investigated. This short-term study suggests that add-on LEV has a favorable neuropsychological and psychiatric impact. The negative neuropsychological effects of PGB may reflect temporary effects under titration. Still, the results did not confirm the promising effects on psychiatric comorbidity that have been emphasized by other reports.

Introduction

Epilepsy is one of the most common chronic neurological disorders, with a prevalence of about 0.5–1% in the general population [1]. Epileptic seizures result from synchronized paroxysmal bursts of electrical activity in cortical regions and have the potential to spread over the entire brain. It is possible that in patients with active partial epilepsies, an ongoing underlying continuous electrical network disturbance interferes with basic cognitive, emotional, and behavioral output. This may lead to the development of structural changes in the architecture of these networks, contributing to a persisting alteration of cognitive function [2]. A study on the impact of epilepsy from the patient’s perspective listed poor memory as one of the greatest concerns [3]. Memory performance may be influenced by attention or executive dysfunction, subtle language deficits, and mood disorders [4]. Impairments in attention and executive function tests characterizing frontal lobe disturbances have been recognized in patients with memory dysfunction [5]. In addition to these pathophysiological mechanisms, the manifestation of a seizure often disrupts the typical behavioral routines that make up the interface between one’s environment and one’s peers. These psychosocial difficulties are often partly responsible for problems such as unemployment, school failure, and social isolation. They can also facilitate psychiatric symptoms, such as reactive depression, panic attacks, and other anxiety disorders.

The major aim of antiepileptic drug (AED) therapy is to treat epilepsy by controlling seizures. Although AEDs have the potential to reduce seizure activity, they can also cause problems by dampening neuronal excitability throughout the brain and altering neurochemical systems that have impact on cognition, mood, and behavior. Optimal treatment of epilepsy should address adequate seizure control with minimal side effects.

The efficiency and side effects of the older AEDs such as phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) in monotherapy and as adjuncts to other drugs are relatively well established [6], [7]. Cognitive side effects associated with these drugs can be clinically significant [8]. However, even some of these older AEDs (VPA, CBZ) are considered to have mood-modulating effects in affective disorders [7].

Since the 1990s, a variety of new AEDs have been introduced [9]. They have been promoted as equally effective as and better tolerated than the first-generation AEDs. It has been claimed that one of these new AEDs, pregabalin (PGB), may have a beneficial psychiatric impact. We therefore investigated PGB under clinical conditions and compared it with add-on levetiracetam (LEV), another promising new AED.

Preclinical and clinical data suggest that PGB has analgesic, anxiolytic, and anticonvulsant properties [10], [11], [12], [13]. The most frequent adverse effects of PGB were dizziness, somnolence, peripheral edema, headache, and dry mouth [12]. These effects appeared to be dose-related. Most often they were mild or moderate at the effective dose of 300 mg/day. In this study, we tested the psychiatric impact of PGB beyond its anticonvulsant efficacy, under clinical conditions, in patients with poorly controlled partial epilepsies.

LEV is a new AED with a generally favorable tolerability profile [14]. It is effective as adjunctive therapy in patients with refractory partial onset seizures with or without secondary generalization. The side effect profile of LEV is generally limited to irritability, somnolence, and, in some cases, dizziness and sedation. Depression, agitation, and personality disorders have occasionally been noted as possible side effects [14]. Dinkelacker et al. reported aggressive episodes with LEV treatment in 3.5% of their patients. Nine of the affected patients developed severe aggressive symptoms [15]. Smith and Humason [16] noted that behavioral changes were among the most common adverse events in patients with LEV.

Therefore, we thought that LEV might be an appropriate comparator among new AEDs to address effects on cognitive and psychiatric function.

Section snippets

Patients

We included 24 adult patients (aged 22–52) who had a medically refractory partial epilepsy with simple partial (SPS) or complex partial (CPS) seizures with or without generalized tonic–clonic seizures (GTCS).

Four patients dropped out from the study: In one case, the dosage was elevated above the target dose of PGB (300 mg) before the second examination could be performed. In the other three cases, the PGB dosage remained below 300 mg: One patient was immediately transferred to presurgical

Qualitative self-perception and impact on seizures with PGB and LEV

One week after 300 mg of PGB, the main self-perceived physical effects were tiredness and dizziness. Although patients did not notice many changes in cognitive abilities, some claimed to have more difficulty concentrating on one task for a longer time. With 1000 mg of LEV, the most consistent observation was that these patients felt more alert and therefore demonstrated fewer problems during a sustained task. There were no relevant changes in seizure frequency between T1 and T2 in both groups.

PGB

The

Discussion

The major result of our study was that it did not reflect the promising profile of PGB among the full range of generalized anxiety disorders described in the literature [12]. LEV, which has sometimes been noted as an AED with potential negative psychiatric effects, had a favorable profile with respect to distinct variables, at least under the conditions of treatment initiation and titration. It is important to note that the questionnaires used in this study were not sensitive enough to address

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