Glutamate hypothesis in schizophrenia

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• Schizophrenia is a chronic and severe psychiatric disorder that has a profound impact on both an individual’s life and on society. It is characterized clinically by positive symptoms (i.e., hallucinations, delusions, disorganized thinking, and grossly disorganized or abnormal motor behavior), negative symptoms (i.e., diminished emotional expression, avolition, alogia, anhedonia, and asociality), and cognitive deficits (i.e., deficits in attention, working memory, and executive function). The cognitive deficits are known to appear before clinical diagnosis1 and are strongly linked to functional outcomes, such as academic and occupational function and independent living.

• The prevalence of schizophrenia has been estimated to be approximately 1% in the general population, and it exhibits high heritability

• Existence of people with psychiatric symptoms, such as hallucinations and delusions (phrenitis), was already known in the era of Hippocrates

• The dopamine hypothesis can account for certain aspects of the psychopathology of schizophrenia, especially positive symptoms

• antipsychotics have negligible effects on negative and cognitive symptoms, the most robust predictors of disability in schizophrenia

• Glutamate is recognized as the most abundant excitatory amino acid neurotransmitter in the brain. It activates G protein-coupled metabotropic (mGlu) receptors and ionotropic receptors. The ionotropic receptors are divided into three subtypes based on their sensitivity to high-affinity selective ligands: NMDAR, α-amino-3-hydroxy-5-methylisoxaole-4-propionate receptors, and kainite receptors.

• Glycine is an α-amino acid, which also has a role as an inhibitory neurotransmitter via binding to strychnine-sensitive glycine receptors. Furthermore, glycine enhances NMDA channel opening via the GMS of the NMDAR