AbstractThough gray matter deficits have been consistently revealed in chronic treated schizophrenia, it is still not clear whether there are different brain alterations between chronic never treated and treated patients. To explore the different patterns of gray matter alterations among chronic never treated patients and those treated with monotherapy, we recruited 35 never-treated chronic schizophrenia patients with illness durations ranging from 5 to 48 years, 20 illness duration-matched risperidone monotherapy and 20 clozapine monotherapy patients, and 55 healthy controls. GM (surface area, cortical thickness, and cortical volume) measures were extracted and compared using ANCOVA across the four groups followed by post hoc tests. Relative to controls, both treated and never-treated chronic schizophrenia patients showed reduced GM mainly involving the bilateral medial and rostral middle frontal, left banks superior temporal sulcus, left fusiform, and left pericalcarine cortex and increased in the left cuneus. Compared with the untreated patient group, the two treated groups showed reductions mainly in the bilateral prefrontal, temporal, and left inferior parietal lobules. The clozapine monotherapy patients demonstrated more severe decreases in the bilateral prefrontal cortex and left cuneus and less severe decreases in the left ventral temporal lobe than risperidone monotherapy patients. These findings provide new insights into the long-term effects of antipsychotic treatment on gray matter alterations in schizophrenia patients. Furthermore, the characteristic findings of reductions in the inferior parietal lobule might be specific for long-term antipsychotic treatment, which could be a possible target for medication development in the future.