A historical review of the practices of predominant combination therapy versus predominant monotherapy in the medical treatment of epilepsy reveals three sequential currents. After the introduction of phenytoin in 1938, as more antiepileptic drugs (AEDs) became available, it became common practice to prescribe multiple drugs for patients who were not controlled by one. If there was a rationale for this approach, it was mainly based on the assumption that AEDs interact synergistically and can provide more seizure protection together than alone. Even if this was true, the main limitation of this reasoning was that it did not factor in the consequences of combined side effects. Indeed, because of the increasing recognition of the frequent negative impact of polytherapy on the number and intensity of side effects, the concept of monotherapy and sequential monotherapy gained wide acceptance in the late 1970s and early 1980s. The proponents of monotherapy based their recommendations on repeated observations that the severity or number of side effects often diminished following a reduction in the number of AEDs, in most cases without appreciable loss in seizure control.^{1,3,10,22,27,28,33} In addition, the beneficial effect of adding a second drug after the failure of a first drug was found to be modest.²⁷ When patients who had undergone a temporal lobe resection were randomized to ongoing polytherapy or to reduction to carbamazepine monotherapy, both groups experienced the same seizure recurrence rate.¹⁴ However, drug-related side effects were less common in the monotherapy group (10%) than in the polytherapy group (30%). The concept of monotherapy was extended to the practice of “high-dose monotherapy.”¹⁵ Two main factors prompted the transition to the third era: (a) The realization that about one third of patients remained refractory even to high-dose monotherapy and (b) the release of many new AEDs after 1993. These newer AEDs have fewer or no pharmacokinetic interactions. Beginning in the 1990s, the concept of “rational polytherapy” was debated and became the object of intense discussion and speculation but of few rigorous clinical studies. The temptation to combine AEDs when single-drug therapy fails to render patients seizure free will endure. Therefore, the advantages and disadvantages of AED combinations must be assessed carefully, and it will always be important to evaluate and identify potentially beneficial specific drug combinations.

Table 1 lists some of the potential disadvantages and advantages of combination therapy. It seems that the disadvantages are more obvious and easier to document, and they will be discussed first.