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Uriel Heresco-Levy, MD; Daniel C. Javitt, MD, PhD; Marina Ermilov, MD; Clara Mordel, MD; Gail Silipo, MA; Michael Lichtenstein, MA

Arch Gen Psychiatry. 1999;56:29-36.

Background  Disturbances of N-methyl-D-aspartate (NMDA) receptor–mediated glutamatergic neurotransmission may play an important role in the pathophysiology of negative symptoms of schizophrenia. Glycine, a small nonessential amino acid, functions as an obligatory coagonist at NMDA receptors through its action at a strychnine-insensitive binding site on the NMDA receptor complex. Glycine-induced augmentation of NMDA receptor–mediated neurotransmission may thus offer a potentially safe and feasible approach for ameliorating persistent negative symptoms of schizophrenia.

Methods  Twenty-two treatment-resistant schizophrenic patients participated in a double-blind, placebo-controlled, 6-week, crossover treatment trial with 0.8 g/kg per day of glycine added to their ongoing antipsychotic medication. Clinical assessments, including the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), the Simpson-Angus Scale for Extrapyramidal Symptoms, and the Abnormal Involuntary Movement Scale, were performed biweekly throughout the study. Clinical laboratory values and amino acid serum levels were monitored.

Results  Glycine treatment was well tolerated and induced increased glycine (P=.001) and serine (P=.001) serum levels. Glycine administration resulted in (l) a significant (P<.001) 30%±16% reduction in negative symptoms, as measured by the PANSS; and (2) a significant (P<.001) 30%±18% improvement in the BPRS total scores. The improvement in negative symptoms was unrelated to alterations in extrapyramidal effects or symptoms of depression. Low pretreatment glycine serum levels significantly predicted (r=0.80) clinical response.

Conclusion  These findings support hypoglutamatergic hypotheses of schizophrenia and suggest a novel approach for the pharmacotherapy of negative symptoms associated with this illness.

From the Ezrath Nashim-Herzog Memorial Hospital (Drs Heresco-Levy, Ermilov, and Mordel and Mr Lichtenstein), and Department of Psychiatry, Hadassah Medical School–Hebrew University (Dr Heresco-Levy), Jerusalem, Israel; and the Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, and the Department of Psychiatry, New York University, New York City (Dr Javitt and Ms Silipo).

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