[Brief history of the development of valproate in bipolar disorders]

The anticonvulsant properties of N-dipropylacetic acid (valproic acid) were discovered in 1967 by Meunier and Carraz. It very soon became widely used in epilepsy, generally in the form of sodium valproate. Divalproate, an equimolar combination of valproic acid and sodium valproate has been available in the United States for this indication since 1983. The development of this drug for use in bipolar disorders occurred in two stages. Antimanic and prophylactic activity was demonstrated for valpromide, a primary amide of valproic acid (Lambert et al., 1968-71). The preliminary studies conducted by Lambert were not repeated outside France and it was only much later that the efficacy of derivatives of valproic acid in bipolar disorders was demonstrated in studies undertaken in Germany with sodium valproate (Enrich and Von Zerssen, 1980-85), and then in the USA with divalproate in the last decade. The majority of controlled studies were performed with divalproate and demonstrated the efficacy of this drug in monotherapy during manic episodes (Pope et al., 1991) (Bowden et al, 1994), and divalproate was approved by the FDA in 1995 in this indication. The results of the study by Bowden and the findings of other open studies suggest a wider spectrum of activity for divalproate than for lithium with a good efficacy profile in subtypes of mania in which the effects of lithium are mediocre: dysphoric mania, rapid cycling mania and forms of mania secondary to organic brain disease. The prospective studies by Puzynski and Klosiewicz (1984) and by Lambert and Venaud (1992) demonstrated the prophylactic activity of valpromide, with slightly greater efficacy being noted against manic episodes than against depressive episodes. The study by Bowden et al. (2000) shows that good efficacy of divalproate in acute manic episodes in a given patient may be predictive of efficacy of the drug in maintenance therapy. The field of bipolar disorders currently appears much wider and more heterogeneous than has long been held. Current therapeutic strategy is dominated by thymoregulators. In such long-term therapy where poor compliance constitutes a risk factor for treatment failure, use of valproate (valpromide, divalproate) has the twin advantage of being easy to manage and well tolerated in the long-term. During coadministration of thymoregulators, which is often necessary due to their limited individual efficacy, general consensus exists regarding the therapeutic value of combined divalproate and lithium.