Glycine Transporter I Inhibitor, N-methylglycine (Sarcosine), Added to Clozapine for the Treatment of Schizophrenia Hsien-Yuan Lane, Chieh-Liang Huang, Po-Lun Wu, Yi-Ching Liu, Yue-Cune Chang, Pao-Yen Lin, Po-Wei Chen, and Guochuan Tsai Background: Agonists at the N-methyl-D-aspartate (NMDA)-glycine site (D-serine, glycine, D-alanine and D-cycloserine) and glycine transporter-1 (GlyT-1) inhibitor (N-methylglycine, or called sarcosine) both improve the symptoms of stable chronic schizophrenia patients receiving concurrent antipsychotics. Previous studies, however, found no advantage of D-serine, glycine, or D-cycloserine added to clozapine. The present study aims to determine the effects of sarcosine adjuvant therapy for schizophrenic patients receiving clozapine treatment. Methods: Twenty schizophrenic inpatients enrolled in a 6-week double-blind, placebo-controlled trial of sarcosine (2 g/day) which was added to their stable doses of clozapine. Measures of clinical efficacy and side-effects were determined every other week. Results: Sarcosine produced no greater improvement when co-administered with clozapine than placebo plus clozapine at weeks 2, 4, and 6. Sarcosine was well tolerated and no significant side-effect was noted. Conclusions: Unlike patients treated with other antipsychotics, patients who received clozapine treatment exhibit no improvement by adding sarcosine or agonists at the NMDA-glycine site. Clozapine possesses particular efficacy, possibly related to potentiation of NMDA-mediated neurotransmission. This may contribute to the clozapine’s unique clinical efficacy and refractoriness to the addition of NMDA-enhancing agents. Key Words: Glutamate, GlyT-1, N-methyl-D-aspartate, sarcosine, schizophrenia, treatment I n addition to dopaminergic neurotransmission, glutamatergic neurotransmission has been implicated in the pathophysiol- ogy of schizophrenia (Olney and Farber 1995; Tsai and Coyle 2001). N-methyl-D-aspartate (NMDA) receptor, a subtype of ionotropic glutamate receptor, plays an important role in neuro- development and cognition. Glutamate and glycine (or D-serine) serve as co-agonists at the NMDA receptor with activation of both the glutamate and glycine sites required for channel opening (Thomson et al 1989). The glycine transporter-1 (GlyT-1) plays a pivotal role in maintaining the concentration of glycine within synapses at a sub-saturating level. The anatomical distribution of GlyT-1 is parallel to that of the NMDA receptor (Smith et al 1992). Supporting the critical role GlyT-1 plays in NMDA neurotrans- mission, GlyT-1 inhibitor, a sarcosine analogue, N[3-(4=-fluoro- phenyl)-3-(4=-phenylphenoxy)propyl]sarcosine (NFPS) and the GlyT-1 mutant mice have been shown to enhance NMDA neurotransmission and antipsychotic properties (Bergeron et al 1998; Chen et al 2003; Kinney et al 2003; Tsai et al 2004). The potency of a series of GLYT-1 antagonists for inhibiting phen- cyclidine (PCP)-induced hyperactivity in vivo correlated signifi- cantly with their potency in antagonizing GlyT-1 in vitro (Javitt et al 1999). The most compelling link between the NMDA system and schizophrenia concerns the mechanism of action of the psychot- omimetic drug PCP, which is a NMDA antagonist (for reviews, see Tsai and Coyle 2001; Halberstadt 1995; Javitt and Zukin 1991). The psychosis induced by NMDA antagonists causes not only positive symptoms similar to the action of dopaminergic agonists but also negative symptoms and cognitive deficits associated with schizophrenia (Grotta 1994; Herrling 1994; Javitt and Zukin 1991; Kristensen et al 1992; Krystal et al 1994). Deutsch et al (1989) was the first to propose glycinergic inter- ventions at the strychnine-insensitive glycine binding site on the NMDA receptor complex (NMDA-glycine site) for the treatment of schizophrenia. Several studies had demonstrated the clinical benefits of treatment for schizophrenia targeting the NMDA-glycine site and no significant side effect was noted. These included D-serine (Heresco-Levy et al 2005; Tsai et al 1998a, 1998b), glycine (Heresco-Levy et al 1996, 1999, 2004), D-alanine (Tsai et al 2006) and D-cycloserine (Goff et al 1999a; Heresco-Levy et al 2002; van Berckel et al 1996) and the GlyT-1 inhibitor sarcosine (Lane et al 2005; Tsai et al 2004). These add-on treatments usually improve the symptoms of chronically stable schizophrenia. However, not all studies are positive; several recent reports did not demon- strate clinical efficacy include those by Carpenter et al (2004), Duncan et al (2004), and Goff et al (2005). Our recent study suggests that add-on treatment with sarcosine to stable antipsy- chotic regimens improves all the critical symptom clusters of chronically stable schizophrenia patients on atypical (risperi- done) or typical antipsychotics (Tsai et al 2004). D-serine, D-alanine and sarcosine can also improve positive symptoms in chronic schizophrenia patients on stable doses of typical or atypical antipsychotics, but excluding clozapine (Heresco-Levy et al 2005; Tsai et al 1998a, 2004, 2006). A very recent study suggests that sarcosine, superior to D-serine, can benefit acutely ill schizophrenia patients with concurrent risperidone therapy (Lane et al 2005). This finding indicates that a GlyT-1 inhibitor may be more efficacious than NMDA-glycine site agonists for adjuvant treatment of schizophrenia (Lane et al 2005). From the Departments of Psychiatry (H-YL, C-LH, P-LW, Y-CL), China Medical University and Hospital, Taichung; Institutes of Life Sciences and Math- ematics (Y-CC), Tamkang University, Taipei; Department of Psychiatry (P-YL), Chang Gung Memorial Hospital, Kaohsiung; Department of Psy- chiatry (P-WC), Taichung Chin-Ho Hospital, Taichung, Taiwan; Depart- ment of Psychiatry (GT), Harbor University of California at Los Angeles, Medical Center, Torrance, California. Address reprints requests to Guochuan E. Tsai, M.D., Ph.D., Department of Psychiatry, Harbor-UCLA Medical Center, F9, 1000 W. Carson Street, Torrance, CA 90509; E-mail: etsai@labiomed.org. Received November 21, 2005; revised March 13, 2006; accepted April 7, 2006. BIOL PSYCHIATRY 2006;60:645– 649 0006-3223/06/$32.00 doi:10.1016/j.biopsych.2006.04.005 © 2006 Society of Biological Psychiatry