[ARTICLE] Eslicarbazepine acetate as a replacement for levetiracetam in people with epilepsy developing behavioral adverse events – Full Text

Abstract

Background

Psychiatric and behavioral side effects (PBSEs) are a major cause of antiepileptic drug (AED) withdrawal. Levetiracetam (LEV) is a recognized first-line AED with good seizure outcomes but recognized with PBSEs. Eslicarbazepine (ESL) is considered to function similarly to an active metabolite of the commonly used carbamazepine (CBZ). Carbamazepine is used as psychotropic medication to assist in various psychiatric illnesses such as mood disorders, aggression, and anxiety.

Aim

The aim was to evaluate the psychiatric profile of ESL in people who had LEV withdrawn due to PBSEs in routine clinical practice to see if ESL can be used as a possible alternative to LEV.

Methods

A retrospective observational review was conducted in two UK epilepsy centers looking at all cases exposed to ESL since its licensing in 2010. The ESL group was all patients with treatment-resistant epilepsy who developed intolerable PBSEs to LEV, subsequently trialed on ESL. The ESL group was matched to a group who tolerated LEV without intolerable PBSEs. Psychiatric disorders were identified from case notes. The Hamilton Depression Scale (HAM-D) was used to outcome change in mood. Clinical diagnoses of a mental disorder were compared between groups using the Fisher’s exact test. Group differences in HAM-D scores were assessed using the independent samples t-test (alpha = 0.05).

Results

The total number of people with active epilepsy in the two centers was 2142 of whom 46 had been exposed to ESL. Twenty-six had previous exposure to LEV and had intolerable PBSEs who were matched to a person tolerating LEV. There was no statistical differences in the two groups for mental disorders including mood as measured by HAM-D (Chi-square test: p = 0.28).

Conclusion

The ESL was well tolerated and did not produce significant PBSEs in those who had PBSEs with LEV leading to withdrawal of the drug. Though numbers were small, the findings suggest that ESL could be a treatment option in those who develop PBSEs with LEV and possibly other AEDs.


1. Background

Epilepsy is a neurological condition with an enduring predisposition to generate seizures and is associated with cognitive, psychological, and social issues [1]. Neuropsychiatric disorders are also more prevalent in people with epilepsy than in the general population [2] ;  [3]. There is, however, still ambiguity as to whether these comorbidities are the result of a direct link such as a genetic predisposition or structural cause leading to seizures and psychiatric problems or if seizures over time lead to psychiatric symptoms [4].

Treatment strategies in epilepsy need to be tailored to the individual and in particular, clinicians when choosing the appropriate antiepileptic drug (AED) medication need to pay attention not only to seizure patterns but also to a number of different parameters such as age, gender, comorbidities, and cognitive state.

Up to 75% of people with epilepsy may at some point have mental health issues. Antiepileptic drugs also have the potential to impact on mental health and cognition [5] ;  [6], and treatment with some AEDs is associated with the occurrence of psychiatric and behavioral side effects (PBSEs) while other may have beneficial psychotropic effects [7][8][9] ;  [10]. The PBSEs are often overlooked in epilepsy management and, withdrawal of an AED occurs only if the impact of these symptoms is significant and usually a risk to self or others.

Understanding psychotropic effects of (AEDs) is crucial but knowledge is limited. Carbamazepine (CBZ)-purported mode of action is via the modulation of voltage-sensitive sodium channels. Apart from antiepileptic action, CBZ is also used as a mood stabilizer and has proven efficacy in affective disorders. Oxcarbazepine (OXB) is structurally related to CBZ and is a prodrug that is converted into licarbazepine. The active form licarbazepine is the S enantiomer, known as eslicarbazepine (ESL). The presumed mechanism of action is as for CBZ. Conversely, OXB has never been proven to work as a mood stabilizer. In view of similarities of the postulated mechanism of action but a better tolerability profile, OXB has been used “off label” in mood management.

Levetiracetam (LEV), a commonly prescribed AED in the UK, is associated with PBSEs including irritability, depression, and anxiety [9] ;  [11]. A study suggested that PBSEs occurred in around 17% of people exposed to commonly used AEDs. Nearly 1 in 5 study participants on LEV reported PBSEs to LEV. However for CBZ the reported PBSEs were significantly lower [11]. The ESL did not figure in this study. Another study suggested that PBSEs with ESL were < 2.5%. While side effects such as irritability, anxiety, and aggressive behavior have been associated with other AEDs, rates of aggression and agitation were comparable between ESL and placebo [12]. […]

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