The International Journal of Neuropsychopharmacology

Research Article

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

Hsien-Yuan Lanea1a2, Ching-Hua Lina3, Yu-Jhen Huanga1, Chun-Hui Liaoa1, Yue-Cune Changa4 and Guochuan E. Tsaia5 c1

a1 Departments of Psychiatry, China Medical University and Hospital, Taichung, Taiwan

a2 Institute of Clinical Medical Science, China Medical University Medical College, Taichung, Taiwan

a3 Department of Adult Psychiatry, Kai-Suan Psychiatric Hospital, Kaohsiung, Taiwan

a4 Department of Mathematics, Tamkang University, Taipei, Taiwan

a5 Department of Psychiatry, Harbor–UCLA Medical Center, and the Los Angeles Biomedical Research Institute, Torrance, CA, USA


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.

(Received July 24 2009)

(Reviewed September 02 2009)

(Revised September 22 2009)

(Accepted October 06 2009)

(Online publication November 04 2009)


c1 Address for correspondence: G. E. Tsai, M.D., Ph.D., Department of Psychiatry, Harbor–UCLA Medical Center, HH212, 1000 W. Carson Street, Torrance, CA 90509, USA. Tel.: (1)310-781-1401 Fax: (1) 310-328-5546 Email: