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Decreased Serum Levels of D-Serine in Patients With Schizophrenia
Evidence in Support of the N-Methyl-D-Aspartate Receptor Hypofunction Hypothesis of Schizophrenia
Kenji Hashimoto, PhD;
Takeshi Fukushima, PhD;
Eiji Shimizu, MD, PhD;
Naoya Komatsu, MD, PhD;
Hiroyuki Watanabe, MD, PhD;
Naoyuki Shinoda, MD, PhD;
Michiko Nakazato, MD, PhD;
Chikara Kumakiri, MD, PhD;
Shin-ichi Okada, MD, PhD;
Hisanori Hasegawa, BS;
Kazuhiro Imai, PhD;
Masaomi Iyo, MD, PhD
Arch Gen Psychiatry. 2003;60:572-576.
Background The hypofunction of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors has been implicated in the pathophysiology of schizophrenia. Several lines of evidence suggest that D-serine may function as an endogenous agonist of the glycine site of the NMDA receptor. The aim of this study was to examine whether serum levels of D- and L-serine in patients with schizophrenia are different from those of healthy controls.
Methods Forty-two patients with schizophrenia and 42 age- and sex-matched healthy controls were enrolled in this study. Symptoms were assessed using the Brief Psychiatric Rating Scale. Serum levels of total serine and D- and L-serine were measured by high-performance liquid chromatography.
Results Serum levels of D-serine in the patients with schizophrenia were significantly (z = -3.30, P = .001) lower than those of healthy controls. In contrast, serum levels of total (D and L) serine (z = -2.40, P = .02) and L-serine (z = -2.49, P = .01) in the schizophrenic patients were significantly higher than those of controls. In addition, the percentage of D-serine in the total serine in the schizophrenic patients was significantly (z = -4.78, P<.001) lower than that of controls, suggesting that the activity of serine racemase, an enzyme catalyzing the formation of D-serine from L-serine, may have been reduced in the schizophrenic patients.
Conclusions Reduced levels of D-serine may play a role in the pathophysiology of schizophrenia, and serum D- and L-serine levels might provide a measurable biological marker for schizophrenia.
From the Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba (Drs Hashimoto, Shimizu, Komatsu, Watanabe, Shinoda, Nakazato, Kumakiri, Okada, and Iyo), and Department of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo (Drs Fukushima and Imai and Mr Hasegawa), Japan.
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