Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study.

CONTEXT Agents that enhance N-methyl-D-aspartate (NMDA) function through the glycine modulatory site (D-serine, glycine, or D-cycloserine) or through glycine transporter 1 (sarcosine) improve the symptoms of patients with stable chronic schizophrenia. OBJECTIVE To determine whether NMDA-glycine site agonists or glycine transporter-1 inhibitors have better efficacy and whether NMDA receptor-enhancing agents have beneficial effects for acute exacerbation of schizophrenia. DESIGN Randomized, double-blind, placebo-controlled trial. SETTING Inpatient units of 2 major medical centers in Taiwan. Patients Sixty-five schizophrenic inpatients with acute exacerbation. INTERVENTIONS Six weeks of treatment with sarcosine (2 g/d), D-serine (2 g/d), or placebo and concomitant optimal risperidone therapy. MAIN OUTCOME MEASURES Positive and Negative Syndrome Scale (PANSS) and Scale for the Assessment of Negative Symptoms (SANS) (20 and 17 items) total scores. RESULTS The sarcosine group revealed more reductions in PANSS total scores than the placebo (P = .04) and D-serine (P<.001) groups. Sarcosine adjunctive treatment was also superior to placebo in reducing SANS-20 (P = .007) and SANS-17 (P = .003) scores and to D-serine in decreasing SANS-20 (P = .006) and SANS-17 (P = .002) scores. The PANSS-general, PANSS-cognitive, and PANSS-depressive symptoms scores and SANS-alogia and SANS-blunted affect scores improved significantly more in sarcosine-cotreated patients than in risperidone monotherapy patients (P< or =.02 for all). Sarcosine adjunctive therapy also surpassed D-serine in terms of PANSS-general, PANSS-positive, PANSS-negative, and PANSS-depressive symptoms scores (P< or =.04 for all). D-serine and risperidone cotreatment did not differ significantly from risperidone monotherapy in all efficacy domains. CONCLUSIONS This first short-term treatment study on NMDA receptor-enhancing agents suggests that sarcosine, superior to D-serine, can benefit not only patients with long-term stable disease but also acutely ill persons with schizophrenia. This finding indicates that a glycine transporter 1 inhibitor may be more efficacious than NMDA-glycine site agonists for adjuvant treatment of schizophrenia, at least during the acute phase. Further studies are needed.

[1]  F. Bymaster,et al.  In Vivo Characterization of Changes in Glycine Levels Induced by GlyT1 Inhibitors , 2003, Annals of the New York Academy of Sciences.

[2]  U. Ahlfors,et al.  The UKU side effect rating scale: A new comprehensive rating scale for psychotropic drugs and a cross‐sectional study of side effects in neuroleptic‐treated patients , 1987, Acta psychiatrica Scandinavica. Supplementum.

[3]  E. Lock,et al.  D-serine-induced nephrotoxicity: possible interaction with tyrosine metabolism. , 2004, Toxicology.

[4]  D. Javitt,et al.  High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia , 2004, Biological Psychiatry.

[5]  D. Javitt,et al.  Placebo-controlled trial of D-cycloserine added to conventional neuroleptics, olanzapine, or risperidone in schizophrenia. , 2002, The American journal of psychiatry.

[6]  P. Albert,et al.  Models for longitudinal data: a generalized estimating equation approach. , 1988, Biometrics.

[7]  C. Harding,et al.  sar: a genetic mouse model for human sarcosinemia generated by ethylnitrosourea mutagenesis. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[8]  T. Barnes.  A Rating Scale for Drug-Induced Akathisia , 1989, British Journal of Psychiatry.

[9]  S. Deutsch,et al.  A "glutamatergic hypothesis" of schizophrenia. Rationale for pharmacotherapy with glycine. , 1989, Clinical neuropharmacology.

[10]  J. Lindenmayer,et al.  Five‐Factor Model of Schizophrenia Initial Validation , 1994, The Journal of nervous and mental disease.

[11]  J. Coyle,et al.  Modulation of N-methyl-D-aspartate receptor function by glycine transport. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Are Tryptophan and 5-Hydroxytryptophan Effective Treatments for Depression? A Meta-Analysis∗ , 2002, The Australian and New Zealand journal of psychiatry.

[13]  J. Coyle,et al.  A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia. , 1999, Archives of general psychiatry.

[14]  L. Ryan,et al.  ASSESSING NORMALITY IN RANDOM EFFECTS MODELS , 1989 .

[15]  O. Blin,et al.  Antipsychotic and anxiolytic properties of risperidone, haloperidol, and methotrimeprazine in schizophrenic patients. , 1996, Journal of clinical psychopharmacology.

[16]  A. Lajtha,et al.  Reversal of phencyclidine-induced effects by glycine and glycine transport inhibitors , 1999, Biological Psychiatry.

[17]  D. Javitt,et al.  Glycinergic augmentation of NMDA receptor-mediated neurotransmission in the treatment of schizophrenia. , 1996, Psychopharmacology bulletin.

[18]  Shan Xie,et al.  Reversal of Phencyclidine-Induced Dopaminergic Dysregulation by N-Methyl-D-Aspartate Receptor/Glycine-site Agonists , 2004, Neuropsychopharmacology.

[19]  D. Javitt,et al.  Comparative effects of glycine and d-cycloserine on persistent negative symptoms in schizophrenia: a retrospective analysis , 2004, Schizophrenia Research.

[20]  D. Javitt,et al.  Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. , 1999, Archives of general psychiatry.

[21]  Yue-Cune Chang,et al.  Fine-tuning risperidone dosage for acutely exacerbated schizophrenia: clinical determinants , 2004, Psychopharmacology.

[22]  H. Möller,et al.  Amisulpride vs. risperidone in the treatment of acute exacerbations of schizophrenia , 1999, Psychiatry Research.

[23]  L. Cao,et al.  Risperidone versus haloperidol in the treatment of acute exacerbations of chronic inpatients with schizophrenia: a randomized double-blind study , 2001, International clinical psychopharmacology.

[24]  T. Branchek,et al.  Cloning and expression of a glycine transporter reveal colocalization with NMDA receptors , 1992, Neuron.

[25]  J. Coyle,et al.  Glutamatergic neurotransmission involves structural and clinical deficits of schizophrenia , 1998, Biological Psychiatry.

[26]  S. Kay,et al.  The positive and negative syndrome scale (PANSS) for schizophrenia. , 1987, Schizophrenia bulletin.

[27]  W. Chiu,et al.  Risperidone in acutely exacerbated schizophrenia: dosing strategies and plasma levels. , 2000, The Journal of clinical psychiatry.

[28]  R. Dingledine,et al.  Structural requirements for activation of the glycine coagonist site of N-methyl-D-aspartate receptors expressed in Xenopus oocytes. , 1989, Molecular pharmacology.

[29]  A. Brown,et al.  Pharmacological assessment of the role of the glycine transporter GlyT-1 in mediating high-affinity glycine uptake by rat cerebral cortex and cerebellum synaptosomes , 2001, Neuropharmacology.

[30]  Charles R. Yang,et al.  Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo. , 2003, Journal of neurophysiology.

[31]  Yue-Cune Chang,et al.  D-Alanine Added to Antipsychotics for the Treatment of Schizophrenia , 2006, Biological Psychiatry.

[32]  G. Simpson,et al.  A RATING SCALE FOR EXTRAPYRAMIDAL SIDE EFFECTS , 1970, Acta psychiatrica Scandinavica. Supplementum.

[33]  H. Levy,et al.  Massachusetts Metabolic Disorders Screening Program: III. Sarcosinemia. , 1984, Pediatrics.

[34]  Nicholas Lange,et al.  D-serine added to antipsychotics for the treatment of schizophrenia , 1998, Biological Psychiatry.

[35]  D. Richter,et al.  Inactivation of the Glycine Transporter 1 Gene Discloses Vital Role of Glial Glycine Uptake in Glycinergic Inhibition , 2003, Neuron.

[36]  T. Piepponen,et al.  Risperidone versus zuclopenthixol in the treatment of acute schizophrenic episodes: a double‐blind parallel‐group trial , 1995, Acta psychiatrica Scandinavica.

[37]  M. Eschenbrenner,et al.  Cloning and mapping of the cDNA for human sarcosine dehydrogenase, a flavoenzyme defective in patients with sarcosinemia. , 1999, Genomics.

[38]  Joseph T. Coyle,et al.  The Glutamatergic Dysfunction Hypothesis for Schizophrenia , 1996, Harvard review of psychiatry.

[39]  D. Javitt,et al.  Double-Blind, Placebo-Controlled, Crossover Trial of Glycine Adjuvant Therapy for Treatment-Resistant Schizophrenia , 1996, British Journal of Psychiatry.

[40]  Akira Sawa,et al.  Schizophrenia: Diverse Approaches to a Complex Disease , 2002, Science.

[41]  O. Lingjaerde,et al.  Risperidone versus perphenazine in the treatment of chronic schizophrenic patients with acute exacerbations , 1993, Acta psychiatrica Scandinavica.

[42]  H. Lane,et al.  Risperidone-carbamazepine interactions: is cytochrome P450 3A involved? , 1998, Journal of Clinical Psychiatry.

[43]  Nicholas Lange,et al.  Glycine transporter I inhibitor, N-Methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia , 2004, Biological Psychiatry.

[44]  E. Lindström,et al.  Symptoms at index admission as predictor for 1‐5 year outcome in schizophrenia , 1996, Acta psychiatrica Scandinavica.