Glutamate hypothesis in schizophrenia

Abstract

Schizophrenia is a chronic and severe psychiatric disorder that has profound impact on an individual’s life and on society. Thus, developing more effective therapeutic interventions is essential. Over the past quarter‐century, an abundance of evidence from pharmacologic challenges, post‐mortem studies, brain imaging, and genetic studies supports the role of glutamatergic dysregulation in the pathophysiology of schizophrenia, and the results of recent randomized clinical trials based on this evidence have yielded promising results. In this article, we review the evidence that alterations in glutamatergic neurotransmission, especially focusing on the N‐methyl‐d‐aspartate receptor (NMDAR) function, may be a critical causative feature of schizophrenia, how this contributes to pathologic circuit function in the brain, and how these insights are revealing whole new avenues for treatment development that could reduce treatment‐resistant symptoms, which account for persistent disability.

Toward the establishment of neurophysiological indicators for neuropsychiatric disorders using transcranial magnetic stimulation‐evoked potentials: A systematic review

“…Specifically, combined TMS-EEG has permitted the development of novel neuromodulation targeted at non-motor areas, 144 suggesting that it can be used for expansion of the range of stimulation protocols. Further elucidation of the effects of neuromodulation on TEP-related biomarkers could be helpful to the application of TMS-EEG as a useful biometric to assess clinical effectiveness in a wide range of neuropsychiatric disorders, including major depression, bipolar disorder, 145 schizophrenia, 146 addiction, autism spectrum disorders, attention deficit hyperactivity disorder, and mild cognitive impairment.…”

Sound frequency dependence of duration mismatch negativity recorded from awake rats

“…In recent decades, MMN amplitude reduction has been considered to represent NMDA‐type glutamate receptor (NMDAR) hypofunction . Impaired glutamatergic neurotransmission is thought to be a significant cause of schizophrenia because noncompetitive antagonists of the NMDAR induce schizophrenia‐like symptoms including cognitive impairment .…”

“…In recent decades, MMN amplitude reduction has been considered to represent NMDA-type glutamate receptor (NMDAR) hypofunction. 29 Impaired glutamatergic neurotransmission is thought to be a significant cause of schizophrenia because noncompetitive antagonists of the NMDAR induce schizophrenia-like symptoms including cognitive impairment. 29 Our findings in nonhuman animals contribute to the establishment of MMN as a translational biomarker that reflects trait and state in psychiatric disorders, leading to the development of new drugs (eg, NMDAR-targeted) and therapies.…”

Looking beyond the usual suspects: sulfide stress in schizophrenia pathophysiology

“…Synapse dysfunction, in particular dopaminergic neurotransmission dysregulation (Snyder, ), impairment of glutamatergic neurons (Uno & Coyle, ), and abnormalities of neuronal connectivity involving interneurons in the hippocampus and prefrontal cortex (Mukherjee et al , ) have been suggested to underline the pathophysiology of schizophrenia. As a matter of fact, the first antipsychotic drug, chlorpromazine, was shown to block dopamine receptors (Carlsson, ).…”

“…In spite of current treatment that largely consists in antipsychotic drugs combined with psychological therapies, social support, and rehabilitation, developing more effective therapeutic interventions is an essential issue. EMBO Mol Med (2019) 11: e10983 See also: M Ide et al (December 2019) S ynapse dysfunction, in particular dopaminergic neurotransmission dysregulation (Snyder, 1976), impairment of glutamatergic neurons (Uno & Coyle, 2019), and abnormalities of neuronal connectivity involving interneurons in the hippocampus and prefrontal cortex (Mukherjee et al, 2019) have been suggested to underline the pathophysiology of schizophrenia. As a matter of fact, the first antipsychotic drug, chlorpromazine, was shown to block dopamine receptors (Carlsson, 2001).…”