Concluding remarks Treatment resistance in schizophrenia continues to be a therapeutic challenge in psychiatry. Within the spectrum of the disease, neural circuits within specific brain regions and their structural and functional links to corresponding regions seem to be further disrupted in TRS. In this review, we have examined TRS from a circuit-based perspective. We highlighted attempts by leading schizophrenia clinicians and researchers to standardize the definition of treatment resistance in schizophrenia and have identified and incorporated recommended terminology with regards to the clinical sub-specifiers or symptom phenotypes that are common to TRS. We discussed the developments of network-based science from the early pioneers who recognized psychiatric illness and schizophrenia as a disease of neuronal and functional disconnectivity. With the development of neuroimaging methods, modern-day connectionists have built upon these theories and have continued to develop and advance network connectomic science today. Our review of schizophrenia and TRS within a connectome context suggests that the structural and functional alterations may be greater in those patients with persistent treatment-resistant symptoms, indicating that there may be fundamental differences within brain network properties that contribute to the inability to integrate the activity and function of distributed neuronal networks that are specific to TRS. Cortical network oscillations and GBO in particular have been reviewed to understand their role in the integration of neuronal information across large neuronal ensembles in the illness. The complex relationship involved in the synchronized firing between excitatory pyramidal cells and inhibitory GABAergic interneurons were also reviewed, including findings specific to dysfunctional inhibitory networks in schizophrenia and parvalbumin interneuron dysfunction and what role these cells may play in dysfunctional pyramidal cell inhibition in schizophrenia. We conclude the review with an overview of several augmenting pharmacological treatments, such as glutamate NMDA receptor and GABA interneuron modulators as well as NO-based treatments and how they may be viewed within a circuit context. Neurosurgical and neuromodulatory approaches were also discussed to highlight a number of beneficial circuit-based targets that may improve circuit integration and treatment response in TRS and improve treatment refractory symptoms in patients who have demonstrated poor response to alternative treatment approaches. The precise mapping of cellular and system-level networks to both on (excitatory) and off (inhibitory) circuit phenotypes specific to treatment-resistant disease remains challenging. Understanding the complexity of the cellular properties that are involved in dysfunctional brain networks in TRS will be critical toward future research in neural circuit-specific pharmacotherapeutics and directed neuromodulation treatments in schizophrenia. The ongoing interest and innovation that has been dedicated toward the understanding of the neural circuitry of schizophrenia and targeted treatment of TRS will hopefully improve personalized outcomes of those suffering from this debilitating disease.