Glycinergic augmentation of NMDA receptor-mediated neurotransmission in the treatment of schizophrenia.

Phencyclidine (PCP) induces a psychotic state closely resembling schizophrenia in normal individuals. PCP and related agents induce their unique behavioral effects by blocking neurotransmission mediated at N-methyl-D-aspartate (NMDA)-type glutamate receptors, indicating that dysfunction of NMDA receptor-mediated neurotransmission may play a crucial role in the pathophysiology of schizophrenia. NMDA receptors are activated by the amino acids glutamate and glycine, working at independent binding sites. Glutamate cannot be administered exogenously because of excitotoxicity. In contrast, glycine administered exogenously may potentiate NMDA receptor-mediated neurotransmission in vivo following peripheral administration. In rodents, glycine is effective in elevating brain glycine levels and reversing PCP-induced hyperactivity at doses of 0.8 g/kg and above. Three studies have now been completed utilizing moderate to high (0.4-0.8 g/kg/day) doses of glycine, added to neuroleptics, for the treatment of schizophrenia. Across studies, 15 to 30 percent improvement in negative symptoms was observed with no corresponding worsening of positive symptoms. Although preliminary, these studies indicate that dietary supplementation with glycine or treatment with other glycinergic agents may be effective in the treatment of schizophrenia.