Heterogeneity of brain structure alterations in patients with never-treated first episode schizophrenia
Yuan Xiao1, Bo Tao1, Jiaxin Zeng1, Gui Fu1, Biqu Tang1, Wenjing Zhang1, Siyi Li1, Su Lui1, and Qiyong Gong1

1West China Hospital of Sichuan University, Chengdu, China


Although schizophrenia is a heterogeneous clinical syndrome, one important question that remains largely unanswered is whether the complex and subtle deficits revealed by MRI could be used as objective biomarkers to resolve neurobiological heterogeneity within this disorder. Using clustering analysis and structural MRI, first-episode schizophrenia patients were classified into three subtypes. The three subtypes of patients showed different morphological alterations.


The schizophrenia syndrome is a highly complex mental illness, with a large number of independent risk genes1, heterogeneity of clinical presentation2. But one important question that remains largely unanswered is whether the complex and subtle deficits revealed by MRI could be used as objective biomarkers to resolve neurobiological heterogeneity within this disorder.


To address this question, 163 drug-naïve first-episode schizophrenia (FES) patients and a confirmation dataset of chronically treated patients (n=133) were recruited in this study. High-resolution anatomic data were acquired and processed via Freesurfer software to obtain cerebral gray matter (cortical thickness, surface area, and cortical volume) measurements. Subsequently, a density peak-based clustering algorithm was employed to intuitively classify schizophrenia into subtypes with distinct neuroanatomical patterns in both FES dataset and confirmation dataset. Then, clinical symptoms were measured for each subtypes using the Positive and Negative Syndrome Scale (PANSS).


By using structural MRI in a large sample of never-treated FES, we showed patients with schizophrenia can be subdivided into three subtypes defined by different neuroanatomic alterations in FES, and those subtypes were also observed in the confirmation sample. Subtype One of FES showed subtle cortical area alteration than healthy controls. Subtype Two of FES showed mainly increased surface area and cortical volume in left inferior parietal, superior frontal, superior temporal and right fusiform cortex than healthy controls. Subtype Three of FES showed mainly decreased surface area and cortical volume in left precentral, inferior temporal, right superior parietal and rostral middle frontal cortex relative to healthy controls. There was no significant difference for severity of clinical symptoms among the three subtypes of FES patients measured by PANSS scores.


Current findings, in a sample of never-treated FES patients, demonstrated three subtypes of patients with distinct patterns of gray matter alteration. Further, the three subtypes’ pattern were confirmed by another dataset of chronically treated patients, suggesting the subtyping defined by FES structural MRI are relatively stable after illness onset. It is also interesting to see that clinical symptoms are quite similar across the three subtypes supporting the notion that schizophrenia syndrome could have different biological base but share similar symptoms nearly the onset of illness.


Our findings revealed potential different neurobiologically subtypes of schizophrenia syndrome without the confounding effect of medication, which could help to compressively explain the complex and heterogeneous findings of schizophrenia.


This study was supported by the National Natural Science Foundation of China (GrantsNos. 81371527, 81671664, and 81621003). Dr. Lui would also like to acknowledge the support from Chang Jiang Scholars (Award No. Q2015154) of China, and the National Program for Support of Top-notch Young Professionals (National Program for Special Support of Eminent Professionals, Organization Department of the Communist Party of China Central Committee, Award No. W02070140). Dr. Xiao would like to acknowledge the support from China Postdoctoral Science Foundation, as well as Postdoctoral Science Foundation from West China Hospital and Sichuan University.


1. Fabbri C, Serretti A. Role of 108 schizophrenia-associated loci in modulating psychopathological dimensions in schizophrenia and bipolar disorder. Oct 2017;174(7):757-764.

2. Meda SA, Clementz BA, Sweeney JA, et al. Examining Functional Resting-State Connectivity in Psychosis and Its Subgroups in the Bipolar-Schizophrenia Network on Intermediate Phenotypes Cohort. Biological psychiatry. Cognitive neuroscience and neuroimaging. Nov 2016;1(6):488-497.


Clustering results of three subtypes in FES patients.

Cortical structural alteration analysis in FES subtypes.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)