The history of valproate in clinical neuroscience.

The scientific and medical history of valproic acid is relatively long, compared with other frequently used psychopharmacologic agents. Valproic acid was used as an organic solvent in research laboratories for eight decades, until the fortuitous observation of action against pentylenetetrazol-induced convulsions in rodents. Early clinical experience emphasized therapy of absence seizures in primary generalized epilepsies. During two decades of controlled trials in partial-onset and generalized-onset seizures and myoclonus, valproate was established as the prototypical broad-spectrum antiepileptic drug. Anecdotal observations in patients with both epilepsy and migraine headaches who were started on valproate led to prospective, randomized trials that established antimigraine efficacy. Early observations suggested antimanic actions; more than a decade later, controlled clinical trials established significant efficacy of valproate in mania. Antiproliferative effects of valproate were unexpectedly noted during mechanistic studies; two decades later a maintenance adjunctive or chemopreventive role in oncology is being defined. While pharmacokinetic studies appear definitive, completion of comprehensive pharmacodynamic investigations of valproate's biochemical actions and clinical utility is yet to be achieved.