Plasma ammonia levels in patients treated with valproic acid

Author(s): Hirofumi Tesen, Asuka Katsuki, Hikaru Hori, Kiyokazu Atake, Reiji Yoshimura, Jun Nakamura


Valproic acid (VPA) is used as a treatment for individuals with epilepsy, migraine, and psychiatric disorders such as bipolar disorder. Hyperammonemia has been reported to be associated with patients treated with VPA. Here we investigated the relationships among plasma ammonia concentrations, VPA dosages and plasma VPA concentrations, and we attempted to identify the factors associated with VPA-induced hyperammonemia.


This was a retrospective chart-review investigating inpatients at The University of Occupational and Environmental Health, Japan (UOEH) Hospital from September 2003 to March 2014. We examined the cases of 430 inpatients. The patients’ diagnoses of schizophrenia, mood disorder and other psychiatric disorders were based on the DSM-IV-TR criteria. The upper normal limit of plasma ammonia is 54 μg/dl according to our hospital’s reference; we defined hyperammonemia as a plasma ammonia level above this value. We examined the correlations among the VPA dose, plasma VPA concentrations and plasma ammonia concentrations. We used Pearson’s correlation coefficient to examine the relationship between pairs of variables and performed a multiple regression analysis to identify variables that were associated with the plasma VPA concentrations and with the plasma ammonia concentrations.


Of the 430 hospitalized patients, 139 patients were eligible. We observed that 84 of these patients (60.4%) had hyperammonemia. Sex (female) and VPA dosage were associated with the plasma VPA concentrations. Concomitant antidepressant dosage and plasma VPA concentrations were associated with the plasma ammonia concentrations.


We identified a high frequency of hyperammonemia among asymptomatic patients receiving VPA. Because asymptomatic hyperammonemia can potentially induce ammonia neurotoxicity, patients being treated with VPA should be monitored closely, especially if they have clinical symptoms and risk factors.

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