Valproate-induced hyperammonemia manifested with delirium

A 50-year-old female patient was diagnosed with bipolar I disorder. Her first depressive episode was in her teens, and first manic episode at 45 years of age. She was admitted to acute psychiatric ward for a manic episode presenting herself with mood liability, talkativeness, violence, and grandiose delusions. The results of initial laboratory examinations were all within normal limits. On admission day one, the patient received daily valproic acid (VPA) 1,000 mg, lorazepam 2 mg, and flurazepam 30 mg. VPA was uptitrated to 1,300 mg/day on day four in addition to her daily clotiapine 40 mg and chlorpromazine 50 mg while her behaviors became more disturbing. With increased VPA dosage to 1,500 mg/day, her elated mood and grandiosity were gradually improved, but she started to develop confusion, disorganized behaviors, and aggravated daytime somnolence. Chlorpromazine was discontinued on day 14 and changed to olanzapine 5 mg/day. The laboratory data on day 19 demonstrated to have normal serum liver enzymes but elevated serum VPA level (124.1 mcg/mL) and hyperammonemia (111.3 mcmol/L). VPA dosage was reduced from 1,500 to 1,300 mg/ day. But her consciousness fluctuation and disorientation were worsened with increasing serum VPA level (126.7 mcg/mL) and hyperammonemia (434.9 mcmol/L). VPA was totally discontinued on day 22, and she received emergency fluid resuscitation. She received lactulose to eliminate the hyperammonemia. After VPA discontinuation, the patient’s disorientation was gradually recovered with olanzapine 10 mg/day alone. Serum ammonia returned to normal range on day 25, and she became oriented and regained clear consciousness one week later. Four weeks after VPA discontinuation, she was eventually discharged home under olanzapine 20 mg/day. Figure 1 shows the temporal relationship of her clinical symptoms, laboratory findings, and VPA dosage.