Despite an improved understanding of the underlying pathophysiology of schizophrenia, particularly with regard to cellular mechanisms contributing to the GBO, a multitude of questions remain. Of utmost importance to the current review is the validity of these findings, many of which have been garnered from animal models of schizophrenia, to TRS. Current cellular and animal models have significant limitations in modeling the illness and few, if any, attempts have been made to replicate the treatment-resistant presentation of the disorder. Secondly, further investigation is required to understand the complex interplay between excitatory glutamatergic cells and inhibitory interneurons in the dysfunctional circuitry of schizophrenia. Specifically, a better understanding of the cellular properties that give rise to the GBO are necessary to better understand approaches for treatment. And lastly, novel treatments and therapeutics need to be designed to target the pathophysiological functioning of GBO circuitry. These approaches may include pharmacological stimulation of the neural circuitry or might be targeted through novel non-pharmacological approaches, such as rTMS which can directly stimulate the GBO.