Elsevier

Biological Psychiatry

Volume 55, Issue 5, 1 March 2004, Pages 452-456
Biological Psychiatry

Original article
Glycine transporter I inhibitor, N-Methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia

https://doi.org/10.1016/j.biopsych.2003.09.012Get rights and content

Abstract

Background

Hypofunction of N-methyl-D-aspartate glutamate receptor had been implicated in the pathophysiology of schizophrenia. Treatment with D-serine or glycine, endogenous full agonists of the glycine site of N-methyl-D-aspartate receptor, or D-cycloserine, a partial agonist, improve the symptoms of schizophrenia. N-methylglycine (sarcosine) is an endogenous antagonist of glycine transporter-1, which potentiates glycine's action on N-methyl-D-aspartate glycine site and can have beneficial effects on schizophrenia.

Methods

Thirty-eight schizophrenic patients were enrolled in a 6-week double-blind, placebo-controlled trial of sarcosine (2 g/d), which was added to their stable antipsychotic regimens. Twenty of them received risperidone. Measures of clinical efficacy and side effects were determined every other week.

Results

Patient who received sarcosine treatment revealed significant improvements in their positive, negative, cognitive, and general psychiatric symptoms. Similar therapeutic effects were observed when only risperidone-treated patients were analyzed. Sarcosine was well-tolerated, and no significant side effect was noted.

Conclusions

Sarcosine treatment can benefit schizophrenic patients treated by antipsychotics including risperidone. The significant improvement with the sarcosine further supports the hypothesis of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Glycine transporter-1 is a novel target for the pharmacotherapy to enhance N-methyl-D-aspartate function.

Section snippets

Subjects

Patients were recruited from the day program and inpatient units of Taipei City Psychiatry Center and Kaoshiung Medical University, which are major medical centers in Taiwan. The research protocol was approved by the above Institutional Review Boards (IRBs). Sarcosine is a natural amino acid. It is regulated as food supplement and investigational new drug application (IND) is not required in Taiwan. After a description of the study to the patients, written informed consent was obtained.

Results

Characteristics of the schizophrenic illness were similar in the two groups, except the onset of the illness (Table 1). Both groups had similar ratios of paranoid versus nonparanoid subtypes of schizophrenia. Though the sarcosine group has earlier onset of the illness than the placebo group, the sarcosine group improved in the outcome measures, but the placebo group did not improve.

Discussion

Our findings indicate that sarcosine, acting as an antagonist on the GlyT-1, can improve positive, negative, cognitive, and other psychiatric symptoms of schizophrenia. Since there is no other neurotransmission site at which sarcosine acts except the known GlyT-1 site, the effect of sarcosine is likely due to its action on the GlyT-1. Together with the positive findings of D-serine (Tsai et al 1998a), glycine (Heresco-Levy et al 1999), and D-cycloserine treatments van Berckel et al., 1996, Goff

Acknowledgements

We thank Dr. Joseph T. Coyle for his critical review of the manuscript. Sarcosine is protected by US patent 6228875, for which GT is an inventor. This work was supported by funding from the National Science Council (Taiwan) NSC 91-2314-B-039-033 and the National Health Research Institutes (Taiwan) NHRI-EX-91-9134PI and NHRI-EX-92-9134PI (HL). GT is supported partly by Grant Nos. P50 MH60450-01 and R01 MH51290-08, a Stanley Foundation Research Award, and a National Alliance for Research on

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