Glutamatergic Dysfunction and Glutamatergic Compounds for Major Psychiatric Disorders: Evidence From Clinical Neuroimaging Studies

Abstract

Excessive glutamate release has been linked to stress and many neurodegenerative diseases. Evidence indicates abnormalities of glutamatergic neurotransmission or glutamatergic dysfunction as playing an important role in the development of many major psychiatric disorders (e.g., schizophrenia, bipolar disorder, and major depressive disorder). Recently, ketamine, an N-methyl-d-aspartate antagonist, has been demonstrated to have promisingly rapid antidepressant efficacy for treatment-resistant depression. Many compounds that target the glutamate system have also become available that possess potential in the treatment of major psychiatric disorders. In this review, we update evidence from recent human studies that directly or indirectly measured glutamatergic neurotransmission and function in major psychiatric disorders using modalities such as magnetic resonance spectroscopy, positron emission tomography/single-photon emission computed tomography, and paired-pulse transcranial magnetic stimulation. The newer generation of antidepressants that target the glutamatergic system developed in human clinical studies is also reviewed.

Keywords: NMDA antagonist; antidepressant; glutamate; major psychiatric disorders; neuroimaging.

Figure 1

After-vs.-before changes of glucose metabolism in response to low-dose ketamine in treatment-resistant depressives (FWE-corrected, p < 0.001). Patients showed decreased glucose metabolism in limbic structures, such as amygdala (AMG) and hippocampus (shown in blue color) and increased function in prefrontal cortex (PFC) (shown in red color) after ketamine treatment. The placebo group lacked the PFC activation (14). The findings of prefronto-amygdala changes in response to ketamine provided supports that low-dose ketamine could reverse glutamatergic dysfunction of the mood circuit.

Figure 2

Schematic diagrams and glutamatergic compounds for NMDA receptor, AMPA receptor, mGluR, and glutamatergic neurotransmission, respectively. GlyT1, glycine transporter type-1.