Symptom domain circuits
Patients who have a phenotype of psychosis that is responsive to dopamine-blocking medication may have dysregulated striatal hyperdopaminergia related to circuit abnormalities within the fronto-striatal complex of the mesolimbic dopaminergic pathway. Glutamatergic projections from the PFC to the ventral tegmental area (VTA) normally regulate dopamine release in the nucleus accumbens. Within this circuit phenotype, hypofunctioning NMDA glutamate receptors on cortical parvalbumin+ GABAergic interneurons will cause an excessive release of glutamate within the VTA. Hyperglutamatergia then leads to overstimulation (on circuit phenotype) of dopaminergic neurons within the mesolimbic dopamine pathway and excessive release of dopamine within limbic structures, such as the nucleus accumbens, amygdala and hippocampus (130, 131). Hyperdopaminergia within the fronto-striatal circuit underlies the beneficial positive symptom domain response that treatment-responsive patients achieve with D2-blocking medications.
Negative and cognitive symptom domain circuitry involves cortical brainstem glutamate projections that communicate within the mesocortical dopamine circuit. Glutamatergic projections from the cortex onto hypofunctioning NMDA glutamate receptors located on cortical parvalbumin+ interneurons leads to the excessive release of glutamate in the VTA. The excessive stimulation of pyramidal VTA neurons then leads to the inhibition (off circuit phenotype) of mesocortical dopamine neurons and insufficient dopamine release in the PFC and subsequent negative and cognitive symptoms in schizophrenia (130, 131).
In those patients who fail to respond to antipsychotic medication, it has been demonstrated that although D2 receptor occupancy is identical to treatment-responsive patients, the lack of efficacy from D2-blocking medication may indicate that hyperdopaminergia may not be related to the symptoms associated with non-response to medications (132). Higher levels of striatal dopamine synthesis capacity have been found in patients with schizophrenia who responded to treatment vs. those patients with TRS who have much lower striatal dopamine levels comparable to healthy controls (72). Also, fronto-striatal dysconnectivity is more pervasive and widely distributed anatomically in TRS as compared to treatment-responsive individuals which may also explain the limited efficacy of dopamine-blocking medication targeting D2 receptors within the fronto-striatal circuit in TRS (133).
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).
It is difficult to map the underlying circuit pathology in ultra-resistant schizophrenia due to the heterogeneity of the illness and limited studies that have explicitly examined this population. Due to multidimensional symptom domains resistant to clozapine, ultra-resistant schizophrenia can be described as the most severe phenotype of the illness that is mediated by multiple mechanisms far beyond dysregulated striatal hyperdopaminergia and glutamate NMDA receptor hypofunction.