Hyperglutamatergia may be a distinct feature of TRS and be differentiated from treatment-responsive disease since greater abnormalities in glutamate function have been found in those patients with TRS while maintaining a relatively normal and intact dopamine function. Neuroimaging measures using fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) as a PET radiotracer found a higher level of striatal dopamine synthesis capacity in patients with schizophrenia who responded to treatment vs. those patients with TRS who had equivalent striatal dopamine levels found in healthy controls (72). The same group later utilized proton magnetic resonance spectroscopy (1H-MRS) imaging in TRS to examine glutamate changes that may be specific to antipsychotic treatment-resistance (73). This was the first group to report high glutamate and glutamine levels in the anterior cingulate cortex (ACC) in TRS as compared to those with schizophrenia in remission, and another group has since replicated this finding (74).
Increased concentrations of glutamate found in the ACC that are specific to TRS are consistent with both the glutamate hyperfunction and the NMDA receptor hypofunction hypotheses of schizophrenia. Normally, glutamate is responsible for regulating inhibitory tone in the brain by binding to NMDA receptors on GABAergic interneurons. The structural mechanism that may cause NMDA receptor hypofunction in TRS can lead to disinhibition of pyramidal neurons and excitatory pathways by the understimulation of inhibitory GABA interneurons (75). The downstream effect can then cause an increase in glutamate release from presynaptic pyramidal neurons and binding to α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors and may be a compensatory effect of the NMDA blockade (75–78). The hyperglutamatergic state can initiate calcium influx and cellular toxicity which, over time, can be detrimental to neuronal networks (79). In treatment-resistant disease, excitatory inputs from pyramidal neurons within the ACC circuit could also be disinhibited, leading to increased glutamate efflux and generating symptoms that fail to respond to D2-blocking medications. Glutamate-mediated excitotoxicity may be responsible for the widespread brain abnormalities and severity of symptoms that are found in TRS.