Identification of Distinct Psychosis Biotypes Using Brain-Based Biomarkers

Abstract

Objective: 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.

Method: 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.

Results: 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.

Conclusions: 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.

FIGURE 1. Group Separations on Biomarker Composite Variables for Probands With Psychosis and Their First-Degree Relatives, by Proband Biotypea

^a Statistical comparisons of biotype proband groups were not computed because they were statistically constructed to be maximally separate on the variables included in the discriminant function analysis. Comparisons shown here were made by means of t tests. *p<0.01. **p<0.001. ***p<0.0001.

FIGURE 2. Distribution of Schizo-Bipolar Scale Scores of Probands With Psychosis, by Biotype and DSM Diagnosisa,b

^a Probands with schizophrenia have higher scores, probands with bipolar disorder with psychosis have lower scores, and probands with schizoaffective disorder have intermediate scores on the Schizo-Bipolar Scale (19), and all three clinical diagnoses are prominently represented within each biotype. These two features indicate that neurobiological distinctiveness of the biotypes is not captured by DSM diagnoses. ^b Because there are so many data points, some scores were pseudorandomly jittered around their mean.

FIGURE 3. Gray Matter Differences From Healthy Subjects in Voxel-Based Morphometry Results for Probands With Psychosis and Their First-Degree Relatives, by Proband Biotypea

^a Images are displayed in neurological convention. Outcomes are reported at p=0.05, with cluster-wise family-wise-error correction. ^b Biotype1had the most extensive volume reductions, with the largest effects in the frontal, cingulate, temporal, and parietal cortex, as well as basal ganglia and thalamus. Biotype 2 had volume reductions regionally overlapping with those in biotype 1, with the largest effects in the frontotemporal cortex, parietal cortex, and cerebellum, albeit of a lesser magnitude overall than for biotype 1. Biotype 3 had smaller clusters of reductions that were primarily distributed over frontal, cingulate, and temporal regions. ^c The biological relatives of biotype 1 probands showed predominantly anterior, mostly frontotemporal, gray matter volume differences. The relatives of biotype 2 probands showed posterior, mostly cerebellar, reductions. The relatives of biotype 3 probands showed small clusters of reductions limited to bilateral temporal regions and right inferior frontal regions.