Cellular and Molecular Neurobiology

, Volume 26, Issue 4–6, pp 363–382 | Cite as

Glutamate and Schizophrenia: Beyond the Dopamine Hypothesis

  • Joseph T. CoyleEmail author


1. After 50 years of antipsychotic drug development focused on the dopamine D2 receptor, schizophrenia remains a chronic, disabling disorder for most affected individuals.

2. Studies over the last decade demonstrate that administration of low doses of NMDA receptor antagonists can cause in normal subjects the negative symptoms, cognitive impairments and physiologic disturbances observed in schizophrenia.

3. Furthermore, a number of recently identified risk genes for schizophrenia affect NMDA receptor function or glutamatergic neurotransmission.

4. Placebo-controlled trials with agents that directly or indirectly activate the glycine modulatory site on the NMDA receptor have shown reduction in negative symptoms, improvement in cognition and in some cases reduction in positive symptoms in schizophrenic patients receiving concurrent antipsychotic medications.

5. Thus, hypofunction of the NMDA receptor, possibly on critical GABAergic inter-neurons, may contribute to the pathophysiology of schizophrenia.


schizophrenia dopamine glutamate d-serine glycine negative symptoms d-amino acid oxidase 



Some of the research described in this review was supported by a National Institute of Mental Health Conte Center on the Neurobiology of Schizophrenia (MH P50-60450) and MH RO1-572901 and a Lieber Senior Investigator Award from the National Alliance for Research on Schizophrenia and Affective Disorder (NARSAD) to JTC.


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© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Harvard Medical SchoolMcLean HospitalBelmontUSA
  2. 2.Harvard Medical SchoolMcLean HospitalBelmontUSA

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