Systems biology, complexity, and the impact on antiepileptic drug discovery

The number of available anticonvulsant drugs increased in the period spanning over more than a century, amounting to the current panoply of nearly two dozen so-called antiepileptic drugs (AEDs). However, none of them actually prevents/reduces the post-brain insult development of epilepsy in man, and in no less than a third of patients with epilepsy, the seizures are not drug-controlled. Plausibly, the enduring limitation of AEDs' efficacy derives from the insufficient understanding of epileptic pathology. This review pinpoints the unbalanced reductionism of the analytic approaches that overlook the intrinsic complexity of epilepsy and of the drug resistance in epilepsy as the core conceptual flaw hampering the discovery of truly antiepileptogenic drugs. A rising awareness of the complexity of epileptic pathology is, however, brought about by the emergence of nonreductionist systems biology (SB) that considers the networks of interactions underlying the normal organismic functions and of SB-based systems (network) pharmacology that aims to restore pathological networks. By now, the systems pharmacology approaches of AED discovery are fairly meager, but their forthcoming development is both a necessity and a realistic prospect, explored in this review.