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Am J Psychiatry. 2016 Apr 1;173(4):373-84. doi: 10.1176/appi.ajp.2015.14091200. Epub 2015 Dec 7.

Identification of Distinct Psychosis Biotypes Using Brain-Based Biomarkers.

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From the Departments of Psychology and Neuroscience, Bio-Imaging Research Center, University of Georgia, Athens; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn., and the Institute of Living, Hartford Hospital, Hartford, Conn.; and the Department of Psychiatry, Harvard Medical School, Boston.

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Clinical phenomenology remains the primary means for classifying psychoses despite considerable evidence that this method incompletely captures biologically meaningful differentiations. Rather than relying on clinical diagnoses as the gold standard, this project drew on neurobiological heterogeneity among psychosis cases to delineate subgroups independent of their phenomenological manifestations.


A large biomarker panel (neuropsychological, stop signal, saccadic control, and auditory stimulation paradigms) characterizing diverse aspects of brain function was collected on individuals with schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis (N=711), their first-degree relatives (N=883), and demographically comparable healthy subjects (N=278). Biomarker variance across paradigms was exploited to create nine integrated variables that were used to capture neurobiological variance among the psychosis cases. Data on external validating measures (social functioning, structural magnetic resonance imaging, family biomarkers, and clinical information) were collected.


Multivariate taxometric analyses identified three neurobiologically distinct psychosis biotypes that did not respect clinical diagnosis boundaries. The same analysis procedure using clinical DSM diagnoses as the criteria was best described by a single severity continuum (schizophrenia worse than schizoaffective disorder worse than bipolar psychosis); this was not the case for biotypes. The external validating measures supported the distinctiveness of these subgroups compared with clinical diagnosis, highlighting a possible advantage of neurobiological versus clinical categorization schemes for differentiating psychotic disorders.


These data illustrate how multiple pathways may lead to clinically similar psychosis manifestations, and they provide explanations for the marked heterogeneity observed across laboratories on the same biomarker variables when DSM diagnoses are used as the gold standard.

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