Valproate originally saw the light of day in the German laboratory of Beverly Burton, in 1882. She was engaged in research on fatty acids, and synthesized a new one, called 2-propylvaleric acid. But she was not able to make this acid into a salt, which is necessary in order to turn it into a solid form, and so she stopped working on it. The compound resurfaced in the 1940s when German scientists were working on creating food substitutes as part of the war effort. They succeeded in turning coal into a mixture of triglycerides that tasted a bit like butter, and they called it ersatzbutter. In analyzing this promising substance, they isolated the same acid that Beverly Burton had discovered in 1882. They gave it a new name, valproic acid. It turned out that it was not very useful as a nutritional supplement, however, because most of it was excreted unchanged. However, it was useful as a solvent, and it found use as a way of dissolving other drugs for research in laboratories. Fast forward to 1960, in a pharmacology laboratory at the University of Grenoble. Pierre Eymard was trying to develop a plant derivative called khelline as an antispasmodic. But he kept facing a stumbling block – khelline was very hard to dissolve. He learned about the wonderful solvent effects of valproic acid, and used it to dissolve khelline. When he injected this mixture into patients, it produced profound relaxation, leading Eymard’s supervisor, Carraz, to screen valproic acid for behavioral effects. Carraz added sodium to it, creating sodium valproate, eventually doing studies of epileptics, leading to its first wide clinical use as an anticonvulsant.
In 1983, Abbott obtained a license for its use in the U.S., and came up with a new way of making the salt – by adding another sodium ion, turning it into sodium divalproate. They received a patent for this, because they successfully argued that it was easier on the stomach than valproic acid. Eventually, “Depakote” received FDA approval for the treatment of both epilepsy and bipolar disorder.
Source: David Healy, Mania: A Short History of Bipolar Disorder. Baltimore: The Johns Hopkins University Press, 2008.