The neurobiology unique to treatment resistance may involve more glutamatergic related abnormalities than disruptions involving dopamine. Clozapine has a unique and complex pharmacological profile (having a higher affinity to D4 receptors than to D2 receptors) and a higher binding affinity to many other non-dopaminergic receptors. Clozapine is able to normalize glutamate neurotransmission by increasing NMDA receptor activity in the cortex by a number of different mechanisms. It has been demonstrated that antagonism of D4 receptors can regulate glutamatergic transmission by upregulating AMPA receptors and providing homeostatic stabilization of the excitation of PFC pyramidal neurons by indirect enhancement of NMDA activity (134). Clozapine has also been shown to reduce the reuptake of glutamate in the cortex by decreasing the expression of glutamate transporters located on both glial and neuronal cells in cortical and subcortical areas (135). Clozapine has the ability to antagonize glycine transporter-1 (GlyT1) sites for reuptake of glycine by glial cells (136), and can increase glial D-serine release and enhance the release of glutamate via activation of NMDA receptors (137) which may help to regulate some of the downstream glutamate abnormalities that have been found in TRS (73, 74).