Ando Masazumi, Amayasu Hideaki, Itai Takahiro, Yoshida Hisahiro
Department of Drug Metabolism and Disposition, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588 Japan.
Department of Pharmacy, Heartful Kawasaki Hospital, 2-1-3 Shimonoge, Takatsu-ku, Kawasaki, Kanagawa 213-0006 Japan.
Biopsychosoc Med. 2017 Jul 5;11:19. doi: 10.1186/s13030-017-0101-0. eCollection 2017.
Administration of valproic acid (VPA) is complicated with approximately 0.9% of patients developing hyperammonemia, but the pathogenesis of this adverse effect remains to be clarified. The aim of the present study was to search for mechanisms associated with VPA-induced hyperammonemia in the light of changes in serum amino acids concentrations associated with the urea cycle of schizophrenic patients.
Blood samples (10 mL) were obtained from 37 schizophrenic patients receiving VPA for the prevention of violent behaviors in the morning after overnight fast. Blood concentrations of ammonia, VPA, free carnitine, acyl-carnitine, and 40 amino acids including glutamate and citrulline were measured for each patient. Univariate and multivariate regression analyses were performed to identify amino acids or concomitantly administered drugs that were associated with variability in the blood concentrations of ammonia.
The blood ammonia level was positively correlated with the serum glutamate concentration ( = 0.44, < 0.01) but negatively correlated with glutamine ( = -0.41, = 0.01), citrulline ( = -0.42, = 0.01), and glycine concentrations ( = -0.54, < 0.01). It was also revealed that the concomitant administration of the mood stabilizers ( = 0.04) risperidone ( = 0.03) and blonanserin ( < 0.01) was positively associated with the elevation of the blood ammonia level.
We hypothisized that VPA would elevate the blood ammonia level of schizophrenic patients. The observed changes in serum amino acids are compatible with urea cycle dysfunction, possibly due to reduced carbamoyl-phosphate synthase 1 (CPS1) activity. We conclude that VPA should be prudently prescribed to schizophrenic patients, particularly those receiving mood stabilizers or certain antipsychotics.
丙戊酸（VPA）的使用存在并发症，约0.9%的患者会发生高氨血症，但其不良反应的发病机制仍有待阐明。本研究旨在根据与精神分裂症患者尿素循环相关的血清氨基酸浓度变化，探寻与VPA诱导的高氨血症相关的机制。
从37名接受VPA预防暴力行为的精神分裂症患者中，在禁食过夜后的早晨采集10毫升血液样本。测量每位患者血液中的氨、VPA、游离肉碱、酰基肉碱以及包括谷氨酸和瓜氨酸在内的40种氨基酸的浓度。进行单变量和多变量回归分析，以确定与氨血浓度变化相关的氨基酸或同时服用的药物。
血氨水平与血清谷氨酸浓度呈正相关（=0.44，<0.01），但与谷氨酰胺（=-0.41，=0.01）、瓜氨酸（=-0.42，=0.01）和甘氨酸浓度呈负相关（=-0.54，<0.01）。还发现，同时服用心境稳定剂（=0.04）、利培酮（=0.03）和布南色林（<0.01）与血氨水平升高呈正相关。
我们推测VPA会升高精神分裂症患者的血氨水平。观察到的血清氨基酸变化与尿素循环功能障碍相符，可能是由于氨甲酰磷酸合成酶1（CPS1）活性降低所致。我们得出结论，VPA应谨慎用于精神分裂症患者，尤其是那些正在服用心境稳定剂或某些抗精神病药物的患者。
