Hyperammonemia Due to Valproic Acid in the Psychiatric Setting

Encephalopathy Induced by Combination Therapy with Valproic Acid and Topiramate: Challenging the Utility of Serum Ammonia Measurement

“…Increased ammonia concentrations in the CNS cause increased production and accumulation of glutamine within the astrocytes, which ultimately causes cerebral edema and astrocyte dysfunction. 2,6 Ammonia concentrations were not measured in the CNS of the patient described here, but ammonia is thought to rapidly cross the blood-brain barrier. 7 The mechanism for topiramate-induced encephalopathy has been suggested to involve accumulation of glutamate in the CNS due to direct inhibition of glutamine synthetase, a consequence of long-term topiramate therapy.…”

“…[1][2][3][4][5] Certain authors have proposed that this combination evokes a synergistic mechanism that produces hyperammonemia, which in turn results in encephalopathy. 2,6 Described here is a case of encephalopathy potentially induced by the combination of valproic acid and topiramate, in which serial serum ammonia measurements suggested that encephalopathy may occur before hyperammonemia. This case challenges the proposed mechanism in this clinical situation and the utility of measuring serum ammonia concentration…”

“…According to previous observations, as many as 50% of patients who are receiving valproic acid therapy are asymptomatic despite hyperammonemia, 6,7,12 whereas other patients experience encephalopathy in the presence of normal serum ammonia concentrations. 7,13,14 One hypothesis proposed to reconcile the presentation of encephalopathy with various concentrations of serum ammonia is that the threshold of CNS ammonia concentration that causes encephalopathy varies from one patient to another.…”

Encephalopathy Associated with Psychotropic Drug Therapy

“…In a prospective study, the significantly higher prevalence of asymptomatic hyperammonemia was found in the psychiatric patients treated with valproate than in the control, and there was a positive correlation between serum valproic acid concentrations and ammonia levels (Raja & Azzoni, 2002). Nevertheless, it should be noted that many cases with symptomatic encephalopathic symptoms reported up to date have serum valproic acid concentrations within therapeutic range (Carr & Shrewsbury, 2007;Marie-José, 2007).…”

“…It has been known that valproic acid occasionally induces hyperammonemic encephalopathy in patients with otherwise normal hepatic function (Carr & Shrewsbury, 2007;Marie-José, 2007). In most cases, encephalopathic symptoms appear in a few days after initiation of valproate therapy, with exceptional case reports with onset after longer therapeutic periods for several months or years.…”