Skip to main content
    • Aa
    • Aa
  • The International Journal of Neuropsychopharmacology, Volume 13, Issue 4
  • May 2010, pp. 451-460

A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and d-serine add-on treatment for schizophrenia

  • Hsien-Yuan Lane (a1) (a2), Ching-Hua Lin (a3), Yu-Jhen Huang (a1), Chun-Hui Liao (a1), Yue-Cune Chang (a4) and Guochuan E. Tsai (a5)
  • DOI:
  • Published online: 04 November 2009

Recent evidence indicates that enhancing N-methyl-d-aspartate (NMDA) neurotransmission with the treatment of NMDA/glycine site agonists, such as d-serine, or a glycine transporter-1 (GlyT-1) antagonist, N-methylglycine (sarcosine), can improve symptoms of schizophrenia. To compare these two novel approaches, 60 patients with chronic schizophrenia were enrolled into a 6-wk double-blind, placebo-controlled trial of add-on treatments at the reported effective dosages (2 g/d). Clinical assessments were conducted every other week. Treatment group×treatment duration interaction analysis by multiple linear regression showed that sarcosine was superior to placebo at all four outcome measures of Positive and Negative Syndrome Scale (PANSS) total (p=0.005), Scale for the Assessment of Negative Symptoms (SANS) (p=0.021), Quality of Life (QOL) (p=0.025), and Global Assessment of Functioning (GAF) (p=0.042). However, d-serine did not differ significantly from placebo in any measure. Sarcosine treatment was better than d-serine in effect sizes for all outcome measures. Sarcosine also surpassed placebo in most of the measures of five PANSS factors and five SANS subscales. All treatments were well tolerated. These findings suggest that the GlyT-1 inhibitor is more efficacious than the NMDA/glycine site agonist in treatment for schizophrenia, including life quality and global function, at the dosages tested.

Corresponding author
Address for correspondence: G. E. Tsai, M.D., Ph.D., Department of Psychiatry, Harbor–UCLA Medical Center, HH212, 1000 W. Carson Street, Torrance, CA90509, USA. Tel.: (1)310-781-1401Fax: (1) 310-328-5546Email:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

TRE Barnes (1989). A rating scale for the drug-induced akathesia. British Journal of Psychiatry 154, 672676.

R Bergeron , T Meyer , J Coyle , R Greene (1998). Modulation of N-methyl-d-aspartate receptor function by glycine transport. Proceedings of the National Academy of Sciences USA 95, 1573015734.

RW Buchanan , DC Javitt , SR Marder , NR Schooler , (2007). The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. American Journal of Psychiatry 164, 15931602.

L Chen , M Muhlhauser , CR Yang (2003). Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo. Journal of Neurophysiology 89, 691703.

JT Coyle (1996). The glutamatergic dysfunction hypothesis for schizophrenia. Harvard Review of Psychiatry 3, 241253.

SI Deutsch , J Mastropaolo , BL Schwartz , RB Rosse , (1989). A ‘glutamatergic hypothesis’ of schizophrenia: rationale for pharmacotherapy with glycine. Clinical Neuropharmacology 12, 113.

M Eschenbrenner , MS Jorns (1999). Cloning and mapping of the cDNA for human sarcosine dehydrogenase, a flavoenzyme defective in patients with sarcosinemia. Genomics 59, 300308.

FH Glorieux , CR Scriver , E Delvin , F Mohyuddin (1971). Transport and metabolism of sarcosine in hypersarcosinemic and normal phenotypes. Journal of Clinical Investigation 50, 23132322.

DC Goff , L Herz , T Posever , V Shih , (2005). A six month, placebo-controlled trial of d-cycloserine co-administered with conventional antipsychotics in schizophrenia patients. Psychopharmacology (Berlin) 179, 144150.

DC Goff , G Tsai , J Levitt , E Amico , (1999). A placebo-controlled trial of d-cycloserine added to conventional neuroleptics in patients with schizophrenia. Archives of General Psychiatry 56, 2127.

J Gomeza , S Hulsmann , K Ohno , V Eulenburg , (2003). Inactivation of the glycine transporter 1 gene discloses vital role of glial glycine uptake in glycinergic inhibition. Neuron 40, 785796.

MF Green , KH Nuechterlein , JM Gold , DM Barch , (2004). Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biological Psychiatry 56, 301307.

CO Harding , P Williams , DM Pflanzer , RE Colwell , (1992). Sar: a genetic mouse model for human sarcosinemia generated by ethylnitrosourea mutagenesis. Proceedings of the National Academy of Sciences USA 89, 26442648.

DW Heinrichs , TE Hanlon , WT Carpenter (1984). The quality of life scale: an instrument for rating the schizophrenic deficit syndrome. Schizophrenia Bulletin 10, 388398.

HJ Herdon , FM Godfrey , AM Brown , S Coulton , (2001). Pharmacological assessment of the role of the glycine transporter GlyT-1 in mediating high-affinity glycine uptake by rat cerebral cortex and cerebellum synaptosomes. Neuropharmacology 41, 8896.

U Heresco-Levy , M Ermilov , P Lichtenberg , G Bar , (2004). High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biological Psychiatry 55, 165171.

U Heresco-Levy , M Ermilov , J Shimoni , B Shapira , (2002). Placebo-controlled trial of d-cycloserine added to conventional neuroleptics, olanzapine, or risperidone in schizophrenia. American Journal of Psychiatry 159, 480482.

U Heresco-Levy , DC Javitt (2004). Comparative effects of glycine and d-cycloserine on persistent negative symptoms in schizophrenia: a retrospective analysis. Schizophrenia Research 66, 8996.

U Heresco-Levy , DC Javitt , R Ebstein , A Vass , (2005). d-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biological Psychiatry 57, 577585.

U Heresco-Levy , DC Javitt , M Ermilov , C Mordel , (1996). Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia. British Journal of Psychiatry 169, 610617.

U Heresco-Levy , DC Javitt , M Ermilov , C Mordel , (1999). Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Archives of General Psychiatry 56, 2936.

DC Javitt (2008). Glycine transport inhibitors and the treatment of schizophrenia. Biological Psychiatry 63, 68.

DC Javitt , A Balla , S Burch , R Suckow , (2004). Reversal of phencyclidine-induced dopaminergic dysregulation by N-methyl-d-aspartate receptor/glycine-site agonists. Neuropsychopharmacology 29, 300307.

DC Javitt , A Balla , H Sershen , A Lajtha (1999). A. E. Bennett Research Award. Reversal of phencyclidine-induced effects by glycine and glycine transport inhibitors. Biological Psychiatry 45, 668679.

KW Johnson , A Clemens-Smith , G Nomikos , R Davis , (2003). In vivo characterization of changes in glycine levels induced by GlyT1 inhibitors. Annals of the New York Academy of Sciences 1003, 412414.

J Karasawa , K Hashimoto , S Chaki (2008). d-serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats. Behavioural Brain Research 186, 7883.

SR Kay , LA Opler , A Fiszbein (1987). Positive and negative syndrome scale (PANSS) manual. Schizophrenia Bulletin 13, 261276.

HY Lane , YC Chang , CC Chiu , SH Lee , (2004). Fine-tuning risperidone dosage for acute schizophrenia: clinical determinants. Psychopharmacology 172, 393399.

HY Lane , YC Chang , YC Liu , CC Chiu , (2005). Sarcosine (N-methylglycine) or d-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. Archives of General Psychiatry 62, 1196–1024.

HY Lane , WC Chiu , JCY Chou , ST Wu , (2000). Risperidone in acutely exacerbated schizophrenia: dosing strategies and plasma levels. Journal of Clinical Psychiatry 61, 209214.

HY Lane , CL Huang , PL Wu , YC Liu , (2006). Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biological Psychiatry 60, 645649.

HY Lane , YC Liu , CL Huang , YC Chang , (2008). Sarcosine (N-methylglycine) treatment for acute schizophrenia: a randomized, double-blind study. Biological Psychiatry 63, 9–12.

N Lange , L Ryan (1989). Assessing normality in random effects models. Annals of Statistics 17, 624642.

JP Lindenmayer , R Bernstein-Hyman , S Grochowski (1994). Five factor model of schizophrenia. Initial validation. Journal of Nervous and Mental Disorder 182, 631638.

ML Martínez-Chantar , M Vázquez-Chantada , U Ariz , N Martínez , (2008). Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice. Hepatology 47, 11911199.

RL Rosnow , R Rosenthal (1996). Computing contrasts, effect sizes, and counternulls on other people's published data: general procedures for research consumers. Pyschological Methods 1, 331340.

K Shaw , J Turner , C Del Mar (2002). Are tryptophan and 5-hydroxytryptophan effective treatments for depression? A meta-analysis. Australian and New Zealand Journal of Psychiatry 36, 488491.

KE Smith , LA Borden , PR Hartig , T Branchek , (1992). Cloning and expression of a glycine transporter reveal colocalization with NMDA receptors. Neuron 8, 927935.

A Sreekumar , LM Poisson , TM Rajendiran , AP Khan , (2009). Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457, 910914.

G Tsai , JT Coyle (2001). Glutamatergic mechanisms in schizophrenia. Annual Review of Pharmacology & Toxicology 42, 165179.

G Tsai , HY Lane , P Yang , MY Chong , (2004 b). Glycine transporter I inhibitor, N-methylglycine (sarcosine) added to antipsychotics for the treatment of schizophrenia. Biological Psychiatry 55, 452456.

G Tsai , M Martina , R Bergeron , J Berger-Sweeney , (2004 a). Gene knockout study of glycine transporter type 1. Proceedings of the National Academy of Sciences USA 101, 84858490.

G Tsai , P Yang , Y Chang , M Chong (2006). d-alanine added to antipsychotics for the treatment of schizophrenia. Biological Psychiatry 59, 230234.

G Tsai , P Yang , L Chung , N Lange , (1998). d-serine added to antipsychotic for the treatment of schizophrenia. Biological Psychiatry 44, 10811089.

RE Williams , EA Lock (2004). d-serine-induced nephrotoxicity: possible interaction with tyrosine metabolism. Toxicology 201, 231238.

CH Yen , JH Hung , YF Ueng , SP Liu , (2009). Glycine N-methyltransferase affects the metabolism of aflatoxin B1 and blocks its carcinogenic effect. Toxicology and Applied Pharmacology 235, 296304.

SL Zeger , KY Liang , PS Albert (1988). Models for longitudinal data: a generalized estimating equation approach. Biometrics 44, 10491060.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The International Journal of Neuropsychopharmacology
  • ISSN: 1461-1457
  • EISSN: 1469-5111
  • URL: /core/journals/the-international-journal-of-neuropsychopharmacology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *