The experimental and clinical evidence in support of “rational polytherapy” is sparse, and to date, no clear evidence-based indications can be made to help physicians in their choice of a specific drug combination against specific forms of epilepsy. This article briefly reviews the data available in the literature and obtained from studies conducted in humans to evaluate which main AED combinations might possess supraadditive, synergistic effects in terms of efficacy, with infraadditive toxicity. By far, the most documented association resulting in supraadditive anticonvulsant effects against focal seizures is that of VPA and LTG. There are some indications that combinations of drugs with different primary mechanisms of action may be more effective than combining drugs with the same mechanisms of action. However, further animal and human research studies that focus both on toxicity and anticonvulsant effects of various combinations of AEDs are required.
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