The emerging role of glutamate in the pathophysiology and treatment of schizophrenia

被引:684
作者
Goff, DC
Coyle, JT
机构
[1] Harvard Univ, Sch Med, Consolidated Dept Psychiat, Belmont, MA 02478 USA
[2] Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA
关键词
D O I
10.1176/appi.ajp.158.9.1367
中图分类号
R749 [精神病学];
学科分类号
100205 ;
摘要
Objective: Research has implicated dysfunction of glutamatergic neurotransmission in the pathophysiology of schizophrenia. This review evaluates evidence from preclinical and clinical studies that brain glutamatergic neurotransmission is altered in schizophrenia, may affect symptom expression, and is modulated by antipsychotic drugs. Method: A comprehensive review of scientific articles published over the last decade that address the role of glutamate in the pathophysiology of schizophrenia was carried out. Results: Glutamatergic neurons are the major excitatory pathways linking the cortex, limbic system, and thalamus, regions that have been implicated in schizophrenia. Postmortem studies have revealed alterations in pre- and postsynaptic markers for glutamatergic neurons in several brain regions in schizophrenia. The N-methyl-D-aspartic acid (NMDA) subtype of glutamate receptor may be particularly important as blockade of this receptor by the dissociative anesthetics reproduces in normal subjects the symptomatic manifestations of schizophrenia, including negative symptoms and cognitive impairments, and increases dopamine release in the mesolimbic system. Agents that indirectly enhance NMDA receptor function via the glycine modulatory site reduce negative symptoms and variably improve cognitive functioning in schizophrenic subjects receiving typical antipsychotics. Conclusions. Dysfunction of glutamatergic neurotransmission may play an important role in the pathophysiology of schizophrenia, especially of the negative symptoms and cognitive impairments associated with the disorder, and is a promising target for drug development.
引用
收藏
页码:1367 / 1377
页数:11
相关论文
共 150 条
  • [41] Goff D, 1999, SCHIZOPHR RES, V36, P280
  • [42] A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia
    Goff, DC
    Tsai, G
    Levitt, J
    Amico, E
    Manoach, D
    Schoenfeld, DA
    Hayden, DL
    McCarley, R
    Coyle, JT
    [J]. ARCHIVES OF GENERAL PSYCHIATRY, 1999, 56 (01) : 21 - 27
  • [43] GOFF DC, 1995, AM J PSYCHIAT, V152, P1213
  • [44] A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia
    Goff, DC
    Henderson, DC
    Evins, AE
    Amico, E
    [J]. BIOLOGICAL PSYCHIATRY, 1999, 45 (04) : 512 - 514
  • [45] Goff DC, 1996, AM J PSYCHIAT, V153, P1628
  • [46] Goff DC, 2000, PHARM TOXIC, P121
  • [47] GOFF DC, 1995, AM J PSYCHIAT, V152, P1730
  • [48] Grunze HCR, 1996, J NEUROSCI, V16, P2034
  • [49] DECREASED HIPPOCAMPAL EXPRESSION OF A GLUTAMATE RECEPTOR GENE IN SCHIZOPHRENIA
    HARRISON, PJ
    MCLAUGHLIN, D
    KERWIN, RW
    [J]. LANCET, 1991, 337 (8739) : 450 - 452
  • [50] Dopamine receptor gene expression in hippocampus is differentially regulated by the NMDA receptor antagonist MK-801
    Healy, DJ
    MeadorWoodruff, JH
    [J]. EUROPEAN JOURNAL OF PHARMACOLOGY, 1996, 306 (1-3) : 257 - 264