Neurotoxicity Associated With Free Valproic Acid

Mr. A was a 49-year-old single Caucasian man who was admitted to a state hospital with a diagnosis of schizoaffective disorder, manic. His other disorders included type II diabetes mellitus and hyperlipidemia that were treated with metformin, 850 mg b.i.d., atorvastatin, 20 mg at bedtime, and regular insulin coverage. Vivid delusions and hallucinations were refractory to treatment with multiple antipsychotic agents. Agitation, irritability, and mood swings led to the addition of divalproex sodium. A regimen of 56 mg/day of perphenazine, 2000 mg/day of extended-release divalproex sodium, 6 mg/day of lorazepam, 50 mg/day of sertraline, and 2 mg/day of benztropine did not lead to symptom abatement or, initially, altered cognition or sensorium. After 2 months, the hospital staff noted an ataxic gait, confusion, and slurred speech. Reducing Mr. A’s perphenazine dose yielded no benefit. Tapering his lorazepam and benztropine led to modest sensorium clearing; however, after 5–6 days, the staff noted increasing confusion, disorientation, and ataxia. His serum valproic acid level was 86.1 μg/ml (normal range=50–125), his albumin level was 3.8 g/dl (normal range=3.2–5.2), and his liver function tests, ammonia levels, and platelet count were within normal limits. His free valproic acid was found to be 15 μg/ml (normal range=5–10), so his dose of extended-release divalproex sodium was reduced to 1000 mg/day, and his sensorium returned to normal in approximately 3 days.