Is the mechanism of action of antiseizure drugs a key element in the choice of treatment?

Abstract

About 25 antiseizure drugs are available for the treatment of patients with epilepsy. The choice of the most suited drug for a specific patient is primarily based on the results of the pivotal randomized clinical trials and on the patient’s characteristics and comorbidities. Whether or not the mechanism of action of the antiseizure drugs should be also taken into account to better predict the patient’s response to the treatment remains a matter of debate. Despite the apparent complexity and diversity of antiseizure drug mechanisms of action, the reality unfortunately remains that they are very close, in particular with regard to their relationship with the pathophysiology of epilepsy. With the only exception of the association between lamotrigine and sodium valproate, there are no clinical data that formally support a synergistic association between certain antiseizure drugs in terms of efficacy. However, anticipating risk of adverse events by limiting as far as possible the combination of drugs, which share the same mechanisms of action, is undoubtedly an important driver of daily therapeutic decisions.

Clinical Management of Drug Resistant Epilepsy: A Review on Current Strategies

“…The primary mechanism of action of the drugs currently available in the treatment of epilepsy can be grouped into five broad categories: 51 (i) Modulation of voltage-gated ion channels, (ii) modulation of neurotransmitter release, (iii) potentiation of GABAergic transmission, (iv) blockade of glutamatergic transmission, and (v) ASD with a different mechanism of action. Apart from few exceptions discussed below, these mechanisms of action share a similar effect on the epileptic networks: through modification of the excitation/inhibition balance, they decrease the excitability of the neuronal network and consequently the risk of seizure initiation or propagation.…”

“…Synergistic association is the most interesting, but the majority of preclinical and clinical studies are not designed to distinguish synergic, additive or antagonist associations. 51 …”

“…Synergistic association is the most interesting, but the majority of preclinical and clinical studies are not designed to distinguish synergic, additive or antagonist associations. 51 A systematic review 93 evaluated published preclinical data with a possible synergistic effect of the association of ASD. A total of 107 studies were included, with a synergistic effect reported in 54%.…”

“…38 However, a key aspect of rational polytherapy is that it should not be only viewed as a way to improve efficacy but also as an important factor for ASD tolerability. 51 Associations of ASDs can favor the occurrence of adverse events. 92 This is particularly true for sodium channel blockers which associations can increase the risk of vertigo, ataxia, diplopia.…”

“…Accordingly, limiting the association of ASD with the same mechanism of action may be important. 51 More generally, in patients who have failed several ASDs, the decision to substitute ASD regimen to another should always be individualized in order to balance at the patient individual level the expected efficacy of the new ASD and its safety profile. Accordingly, a combination might be useful in a given patient but not pertinent in another because the risk of adverse events resulting from her/his comorbidities overcomes the potential benefit of that combination.…”