Valproic Acid and Hypersensitivity Syndrome

Mr. A, a 48-year-old man, had been diagnosed with schizoaffective disorder 30 years previously and had been treated with haloperidol, fluphenazine, promethazine, and biperiden. He was admitted to a psychiatric hospital with schizomanic syndrome and was treated initially with oral haloperidol, fluphenazine, diazepam, clomethiazole, promethazine, biperiden, and vitamins B₁ and B₆. On day 3, his therapy was switched to prolonged-release oral valproic acid, amisulpride, and lithium; administration of vitamins B₁ and B₆ was continued.

Three weeks after initiation of therapy, Mr. A developed a generalized maculopapular rash with lymphadenopathy and fever (39.1°C); his total WBC count was 14.2 cells/nl, and his levels of transaminases and creatinine were slightly elevated.

We discontinued valproic acid and vitamins B₁ and B₆ after diagnosing a severe adverse drug reaction presenting as hypersensitivity syndrome. We introduced olanzapine with prednisolone (initially 80 mg/day). The skin rash as well as other clinical symptoms (including an intermittently elevated WBC count of 37.9 cells/nl with maximal eosinophilia of 24%) remitted completely in the next week. Therapy with corticosteroids was tapered over 3 weeks. After release from the hospital, Mr. A remained stable over the following 3 months while taking olanzapine, amisulpride, and lithium.

A skin patch test performed at 3 months to test for valproate and vitamins B₁ and B₆ (pure and 30% in distilled water, respectively) gave a positive reading for the valproic acid preparations at 72 hours, while three healthy volunteers were negative for these compounds.