Currently, there are no customized neural circuit-specific and targeted therapies that can address the neural-dysconnectivity in schizophrenia. Despite the lack of precision and ubiquitous targets of pharmacological methods, the use of adjunctive agents to antipsychotic medications may be conceptualized within a circuit context to help improve neuronal network integration and treatment response in TRS. In many cases, augmentation strategies are needed to improve the residual psychopathology symptom domains that have been non-responsive to antipsychotic drugs (including clozapine). Usually in those patients who have not responded to clozapine, a variety of other antipsychotic medications, antidepressants, anticonvulsants, benzodiazepines or a variety of glutamate augmenting agents have been attempted. Clinical studies have used a variety of agents that can enhance glutamate NMDA receptors (on connectomic) function in an attempt to improve downstream GABAergic (off connectomic) inhibitory effects. GABA interneuron modulators have also been recently investigated as an attempt to inhibit pyramidal cell firing, as well as NO-based therapies to improve intracellular NMDA receptor signaling and other direct circuit-targeted neurosurgical and neuromodulation strategies for their therapeutic benefit in treatment resistant disease.