Treatment-resistant schizophrenia (TRS) impacts nearly one-third of patients who do not respond to dopamine-blocking antipsychotic medications. While clozapine can be effective for some, it is often introduced too late, and approximately half of patients with TRS do not respond to it. The lack of a standardized definition of TRS has led to inconsistent study results, hindering early detection and timely treatment. The International Treatment Response and Resistance in Psychosis group has proposed criteria for more accurate identification, but further refinement is needed. The clinical course of TRS is heterogeneous, with some patients showing early resistance, while others develop it after initial responses, potentially due to factors like relapses and neurobiological changes.

Recent studies suggest that TRS is a distinct subtype of schizophrenia with specific neurobiological factors, including dopamine and glutamate dysregulation. Clozapine remains the gold standard for treatment, but it is often underused due to delays in its initiation. For patients with ultra-treatment resistance, who do not respond to clozapine, adjunct treatments such as electroconvulsive therapy and repetitive transcranial magnetic stimulation have shown limited success. New therapeutic targets, including glutamatergic agents and GABA receptor stimulation, are being explored. To improve treatment outcomes, there is an urgent need for biomarkers and early detection strategies to predict responses to treatment, enabling quicker initiation of the most effective therapies.

Reference: Leung CC, Gadelrab R, Ntephe CU, McGuire PK, Demjaha A. Clinical Course, Neurobiology and Therapeutic Approaches to Treatment Resistant Schizophrenia. Toward an Integrated View. Front Psychiatry. 2019;10:601. doi: 10.3389/fpsyt.2019.00601.