Selection of antiepileptic drug polytherapy based on mechanisms of action:The evidence reviewed

Purpose: When monotherapy with antiepileptic drugs (AEDs) fails, combinatio n therapy is tried in an attempt to improve effectiveness by improving effi cacy, tolerability, or both. We reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected fo r combination therapy based on their mechanisms of action, and if so, which combinations are associated with increased effectiveness. Because various designs and methods of analysis were used in these studies, it was also nec essary to evaluate the appropriateness of these approaches. Methods: Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in thes e papers. Results: Thirty-nine papers were identified reporting on two-drug AED combi nations. Several combinations were reported to offer improved effectiveness , but no uniform approach was used in either animal or human studies for th e evaluation of pharmacodynamic drug interactions; efficacy was often the o nly end point. Conclusions: There is evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantage ous. Combining two GABA mimetic drugs or combining an AMPA antagonist with an NMDA antagonist may enhance efficacy, but tolerability is sometimes redu ced. Combining two sodium channel blockers seems less promising. However, g iven the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical bur rational appro ach for evaluating AED combinations is of fundamental importance. This woul d involve appropriate testing of all possible combinations in animal models and subsequent evaluation of advantageous combinations in clinical trials. Testing procedures in animals should include the isobologram method, and t he concept of drug load should be the basis of studies in patients with epi lepsy.