Disease progression patterns of brain morphology in schizophrenia: More progressed stages in treatment-resistance

Abstract

Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to the development of clinically useful biomarkers. In this cross-sectional study, we adopted data-driven machine-learning techniques to classify and stage the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance. We included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging from 3 institutions. Cortical thickness and subcortical volumes calculated by FreeSurfer were converted into Z-scores using 73 healthy controls data. The Subtype and Stage Inference (SuStaIn) algorithm was used for unsupervised machine-learning classification and staging. As a result, SuStaIn identified three different subtypes: 1) subcortical volume reduction (SC) type (73 patients, 47.4%), in which volume reduction of subcortical structures occurs first and moderate cortical thinning follows, 2) globus pallidus hypertrophy and cortical thinning (GP-CX) type (42 patients, 27.3%), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, 3) cortical thinning (pure CX) type (39 patients, 25.3%), in which thinning of the insular and lateral temporal lobe cortices primarily happens. The remaining 23 patients were assigned to baseline stage of progression (no change). SuStaIn also found 84 stages of progression, and treatment-resistant schizophrenia showed significantly more progressed stages of progression than treatment-responsive cases (p=0.001). The GP-CX type presented in earlier stages than the pure CX type (p=0.009). In conclusion, the brain morphological progressions in schizophrenia can be classified into three subtypes by SuStaIn algorithm. Treatment resistance was associated with more progressed stages of the disease, which may suggest a novel biomarker for schizophrenia.