Valproic acid is used in psychiatry as a mood stabilizer and can be very effective in reducing symptoms of agitation. Valproic acid may cause hyperammonemia through carnitine deficiency created by its inhibition of mitochondrial enzymes in the urea cycle. Clinical presentation of hyperammonemia usually involves lethargy and somnolence, which may also be noted with therapeutic serum concentration during valproic acid therapy. The diagnosis of hyperammonemia is often overlooked due to a clinical presentation that may include normal liver enzyme tests and serum valproate levels that are within the therapeutic range. Treatment modalities may include discontinuation of valproic acid therapy, lactulose, naloxone, and hemodialysis. Carnitine supplementation, for both prevention and acute treatment of hyperammonemia, has been anecdotally reported and may be considered. This article illustrates a case of an adult male with schizoaffective disorder who was treated with valproic acid and subsequently developed hyperammonemia, despite therapeutic valproic acid serum levels and normal liver enzyme tests. Possible causes of hyperammonemia and current treatment options will be described, as well as suggestions for monitoring for this adverse event in the clinical setting.
Coulter DL, Allen R.Hyperammonemia with valproic acid therapy. J Pediatr.1981;99:317-319.
2.
Rawat S., Borkowski W., Swick H.Valproic acid and secondary hyperammonemia. Neurology. 1981;31:1173-1174.
3.
Zaret BS, Beckner RR, Marini AM, Wagle W., Passerelli C.Sodium valproate-induced hyperammonemia without clinical hepatic dysfunction . Neurology. 1982;32(2):206-208.
4.
Weng TI, Shin FF, Chen WJUnusual causes of hyperammonemia in the ED. Am J Emer Med.2004;22(2):105-107.
5.
Kimmel R., Irwin S., Meyer JMValproic acid-associated hyperammonemic encephalopathy: a case report from the psychiatric setting. Int Clin Psychopharmacol.2005;20(1): 57-58.
6.
Elgudin L., Hall Y., Schubert G.Ammonia induced encephalopathy from valproic acid in a bipolar patient: a case report. Int J Psychiatr Med.2003;33(1):91-96.
7.
McCall M., Bourgeois JAValproic acid induced hyperammonemia: a case report. J Clin Psychopharmacol. 2004;24(5): 521-526.
8.
Feil D., Chuang K., Sultzer DLValproate-induced hyperammonemia as a cause of altered mental status. Am J Geriatr Psychiatry. 2002;10(4):476-478.
9.
Eze E., Workman M., Donley B.Hyperammonemia and coma developed by a woman treated with valproic acid for affective disorder. Psychiatr Serv.1998;49(10):1358-1359.
10.
Barrueto F. , Hack J.Hyperammonemia and coma without hepatic dysfunction induced by valproate therapy. Acad Emerg Med.2001;8(10):999-1001.
Fraser CM, Sills GJ, Forrest G., Thompson GG, Brodie MJEffects of antiepileptic drugs on glutamine synthetase activity in mouse brain . Br J Pharmacol.1999;126:1634-1638.
29.
Monfort P., Kosenko E., Erceg S., et al. Molecular mechanism of acute ammonia toxicity: role of NMDA receptors. Neurochem Int.2002;41:95-102.
30.
Cooper AJRole of glutamine in cerebral nitrogen metabolism and ammonia neurotoxicity . Ment Retard Dev Disabil Res Rev. 2001;7:280-286.
31.
Hertz L., Yu Ach, Kala G., Schousboe A.Neuronal-astrocytic and cytosolic-mitochondrial metabolite trafficking during brain activation, hyperammonemia, and energy deprivation. Neurochem Int.2000;37:83-102.
32.
Marcaida G. , Felipo V., Hermenegildo C., Minana MD, Grisola S.Acute ammonia toxicity is mediated by the NMDA type of glutamate receptors. FEBS Lett.1992;13(296):67-68.
33.
Prietsch V. , Lindner M., Zschocke J., et al. Emergency management of inherited metabolic diseases. J Inherit Metab Dis. 2002 ;25:531-546.
34.
Gidal BE, Garnett WREpilepsy. In: DiPiro JT, ed. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005:1023-1048.
Hoover JEGastrointestinal and liver drugs. In: Troy DB, ed. Remington: The Science and Practice of Pharmacy . 21st ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005: 1294-1317.
37.
Houghton BL , Bowers JBValproic acid overdose: a case report and review of therapy. Med Gen Med.2003;5(1):5.
38.
Roberge RJ, Francis EH3rd. Use of naloxone in valproic acid overdose: case report and review. J Emerg Med.2002;22(1): 67-70.
39.
Montero FJNaloxone in the reversal of coma induced by sodium valproate. Ann Emerg Med.1999;33(3):357-358.
40.
Alberto G., Erickson T., Popiel R., Narayanan M., Hryhorczuk D.Central nervous system manifestations of a valproic acid overdose responsive to naloxone. Ann Emerg Med.1989; 18(8):889-891.
Clark WR, Hamburger RJ, Lysaght M.Effect of membrane composition and structure on solute removal and biocompatibility in hemodialysis. Kidney Int.1999;56:2005-2015.
