Treatment-resistant schizophrenia: pathophysiology and the role of neuroimaging and therapeutics

SUMMARY Treatment-resistant schizophrenia (TRS) is a clinically challenging subtype of schizophrenia affecting up to 30% of patients, defined by persistent symptoms despite adequate trials of at least two antipsychotics. This review explores the complex neurobiology of TRS, highlighting the limitations of the dopamine hypothesis and emphasising the roles of glutamatergic, cholinergic and neurodevelopmental mechanisms. It outlines neuroimaging techniques (e.g. positron emission tomography, functional and structural magnetic resonance imaging, and proton magnetic resonance spectroscopy) used to explore neurotransmitter activity and structural brain changes in psychosis, and in TRS in particular, and gives an overview of their findings and utility. It also discusses frameworks like TRRIP and the INTEGRATE algorithm, which aim to facilitate earlier diagnosis and treatment. Integrating neuroimaging into practice may improve diagnosis and clinical outcomes and advance precision medicine approaches; emerging non-dopaminergic treatment options, such as xanomeline–trospium, may offer promising alternatives to standard clozapine treatment for TRS. Future research should prioritise biomarker discovery and the development of novel therapies beyond dopaminergic targets.