Schizophrenia, a common mental illness affecting 1% of the worldwide population, remains a leading cause of chronic disability among young adults.¹ Antipsychotic medications are the mainstay of treatment because there is strong empirical evidence that these drugs reduce psychotic symptomsand relapse rates in schizophrenia patients.² Even though the majority of patients receive antipsychotics and benefit from reduction in psychotic symptoms, many patients continue to have negative symptoms, cognitive impairments, and progressive brain tissue loss.^3-13 The causes underlying these brain abnormalities are unclear and have been a focus of much debate^14,15 and many literature reviews.^16,17

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

IN VIVO neuroimaging has provided compelling evidence for structural^1-3 and functional^4,5 brain abnormalities in schizophrenia. Findings of enlarged lateral ventricles, third ventricles, and cortical sulcal cerebrospinal fluid (CSF) spaces; reductions in medial temporal lobe structures and frontal lobes; and abnormalities in subcortical structures have been replicated fairly consistently in many magnetic resonance imaging (MRI) studies.³ However, except for the association between poor outcome and enlarged lateral ventricles, the significance of the other commonly replicated brain abnormalities on functional outcome in schizophrenia remains uncertain.⁶ Furthermore, the onset and longitudinal evolution of these anomalies during the course of schizophrenia have not been well characterized.