Neurostructural, Neurofunctional, and Clinical Features of Chronic, Untreated Schizophrenia: A Narrative Review

Studies of individuals with chronic, untreated schizophrenia (CUS) can provide important insights into the natural course of schizophrenia and how antipsychotic pharmacotherapy affects neurobiological aspects of illness course and progression. We systematically review 17 studies on the neuroimaging, cognitive, and epidemiological aspects of CUS individuals. These studies were conducted at the Shanghai Mental Health Center, Institute of Mental Health at Peking University, and Huaxi MR Research Center between 2013 and 2021. CUS is associated with cognitive impairment, severe symptoms, and specific demographic characteristics and is different significantly from those observed in antipsychotic-treated individuals. Furthermore, CUS individuals have neurostructural and neurofunctional alterations in frontal and temporal regions, corpus callosum, subcortical, and visual processing areas, as well as default-mode and somatomotor networks. As the disease progresses, significant structural deteriorations occur, such as accelerated cortical thinning in frontal and temporal lobes, greater reduction in fractional anisotropy in the genu of corpus callosum, and decline in nodal metrics of gray mater network in thalamus, correlating with worsening cognitive deficits and clinical outcomes. In addition, striatal hypertrophy also occurs, independent of antipsychotic treatment. Contrasting with the negative neurostructural and neurofunctional effects of short-term antipsychotic treatment, long-term therapy frequently results in significant improvements. It notably enhances white matter integrity and the functions of key subcortical regions such as the amygdala, hippocampus, and striatum, potentially improving cognitive functions. This narrative review highlights the progressive neurobiological sequelae of CUS, the importance of early detection, and long-term treatment of schizophrenia, particularly because treatment may attenuate neurobiological deterioration and improve clinical outcomes.