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Original Investigation
November 2018

Mapping the Heterogeneous Phenotype of Schizophrenia and Bipolar Disorder Using Normative Models

Author Affiliations
  • 1Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
  • 2Donders Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands
  • 3Norwegian Centre for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  • 4Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
  • 5Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands
  • 6Karakter Child and Adolescent Psychiatry University Centre, Radboud University Medical Centre, Nijmegen, the Netherlands
  • 7Department of Psychology, University of Oslo, Oslo, Norway
  • 8Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
  • 9Centre for Functional MRI of the Brain, University of Oxford, Oxford, United Kingdom
  • 10Department of Neuroimaging, Institute of Psychiatry, King’s College London, London, United Kingdom
JAMA Psychiatry. 2018;75(11):1146-1155. doi:10.1001/jamapsychiatry.2018.2467
Key Points

Question  Is the focus on the average patient disguising interindividual differences among patients with mental disorders?

Findings  In this study of magnetic resonance imaging data from 218 patients with schizophrenia spectrum disorders and 256 healthy control individuals, mapping of interindividual differences in brain structure revealed that only a few brain loci had the same abnormalities in more than 2% of patients with the same disorder despite robust group-level differences in multiple brain regions between patients and control individuals.

Meaning  These findings suggest that the idea of the average patient is a noninformative construct that falls apart when mapping interindividual differences and provide a framework toward precision medicine in psychiatry.

Abstract

Importance  Schizophrenia and bipolar disorder are severe and complex brain disorders characterized by substantial clinical and biological heterogeneity. However, case-control studies often ignore such heterogeneity through their focus on the average patient, which may be the core reason for a lack of robust biomarkers indicative of an individual’s treatment response and outcome.

Objectives  To investigate the degree to which case-control analyses disguise interindividual differences in brain structure among patients with schizophrenia and bipolar disorder and to map the brain alterations linked to these disorders at the level of individual patients.

Design, Setting, and Participants  This study used cross-sectional, T1-weighted magnetic resonance imaging data from participants recruited for the Thematically Organized Psychosis study from October 27, 2004, to October 17, 2012. Data were reanalyzed in 2017 and 2018. Patients were recruited from inpatient and outpatient clinics in the Oslo area of Norway, and healthy individuals from the same catchment area were drawn from the national population registry.

Main Outcomes and Measures  Interindividual differences in brain structure among patients with schizophrenia and bipolar disorder. Voxel-based morphometry maps were computed, which were used for normative modeling to map the range of interindividual differences in brain structure.

Results  This study included 218 patients with schizophrenia spectrum disorders (mean [SD] age, 30 [9.3] years; 126 [57.8%] male), of whom 163 had schizophrenia (mean [SD] age, 31 [8.7] years; 105 [64.4%] male) and 190 had bipolar disorder (mean [SD] age, 34 [11.3] years; 79 [41.6%] male), and 256 healthy individuals (mean [SD] age, 34 [9.5] years; 140 [54.7%] male). At the level of the individual, deviations from the normative model were frequent in both disorders but highly heterogeneous. Overlap of more than 2% among patients was observed in only a few loci, primarily in frontal, temporal, and cerebellar regions. The proportion of alterations was associated with diagnosis and cognitive and clinical characteristics within clinical groups. Patients with schizophrenia, on average, had significantly reduced gray matter in frontal regions, cerebellum, and temporal cortex. In patients with bipolar disorder, mean deviations were primarily present in cerebellar regions.

Conclusions and Relevance  This study found that group-level differences disguised biological heterogeneity and interindividual differences among patients with the same diagnosis. This finding suggests that the idea of the average patient is a noninformative construct in psychiatry that falls apart when mapping abnormalities at the level of the individual patient. This study presents a workable route toward precision medicine in psychiatry.

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