Past Issues

The Hypothesis of NMDA Receptor Hypofunction for Schizophrenia

Huey-Jen Chang, Hsien-Yuan Lane, Guochuan E. Tsai

Schizophrenia, a multifactorial mental disorder with polygenic inheritance as
well as environmental infl uences, encompasses a characteristic group of symptoms
and neurocognitive defi cits. Cognitive function, a major determinant of quality
of life and overall function in schizophrenia, contributes more to the prognosis
of the disease than positive symptoms, such as delusions or hallucinations. Although
its exact etiological mechanisms remain relatively unknown, extensive
studies are ongoing to explore. Among them, one of the primary causal factors is
dysfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptors. This
article reviews the clinical limitations of current antipsychotics in treating the core
symptoms of schizophrenia and the trend in the reconceptualization of the disease
nature and treatment modalities. The NMDA receptor model plays a critical role in
the revolution of pharmaceutical industry as a new set of drug targets in addition
to those based on the traditional monoaminergic models is proposed. The evidence
of NMDA receptor hypofunction in schizophrenia is accumulating from the investigations
on the modulation of glutamatergic system, particularly the intrinsic
NMDA/glycine site, through genetic research and various clinical trials. A group
of “NMDA-enhancing agents,” being used either as adjuncts to typical/atypical
antipsychotics or as monotherapy, in schizophrenic patients, particularly those
with refractory negative and cognitive symptoms, offer effi cacy in preclinical and
early clinical trials. Novel therapeutic agents acting as NMDA enhancers show
promise as the next wave of drug development for schizophrenia.
Key Word schizophrenia, NMDA receptor hypofunction, negative symptoms, cognitive function
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