Contrasting Case-Control and Normative Reference Approaches to Capture Clinically Relevant Structural Brain Abnormalities in Patients With First-Episode Psychosis Who Are Antipsychotic Naive

Abstract

ImportanceTo make progress toward precision psychiatry, it is crucial to move beyond case-control studies and instead capture individual variations and interpret them in the context of a normal range of biological systems.ObjectiveTo evaluate whether baseline deviations from a normative reference range in subcortical volumes are better predictors of antipsychotic treatment response than raw volumes in patients with first-episode psychosis (FEP) who were naive to antipsychotic medication.Design, Setting, and ParticipantsIn this prospective longitudinal study, patients with first-episode psychosis who were referred from different clinical settings (emergency department, inpatient units, and outpatient clinics) at the University of Alabama at Birmingham were included. A total of 286 patients were screened, 114 consented, 104 enrolled in the treatment trial, and 85 completed the trial. Patients were observed for 16 weeks. Controls were matched by age and sex. Data were collected between June 2016 and July 2021, and data were analyzed from August 2021 to June 2022.InterventionsRisperidone on a flexible dosing scheme for 16 weeks. There was an option to switch to aripiprazole for excessive adverse effects.Main Outcomes and MeasuresThe main outcome of this study was to evaluate, in patients with FEP who were naive to antipsychotic medication, the association of baseline raw volumes and volume deviations in subcortical brain regions with response to antipsychotic medication. Raw brain volumes or volume deviation changes after treatment were not examined.ResultsOf 190 included participants, 111 (58.4%) were male, and the mean (SD) age was 23.7 (5.5) years. Volumes and deviations were quantified in 98 patients with FEP, and data from 92 controls were used as comparison for case-control contrasts and reference curve calibration. In case-control contrasts, patients with FEP had lower raw thalamus (P = .002; F = 9.63; df = 1), hippocampus (P = .009; F = 17.23; df = 1), amygdala (P = .01; F = 6.55; df = 1), ventral diencephalon (P = .03; F = 4.84; df = 1), and brainstem volumes (P = .004; F = 8.39; df = 1). Of 98 patients, 36 patients with FEP (36%) displayed extreme deviations. Associations with treatment response significantly differed between raw volume and deviation measures in the caudate (z = −2.17; P = .03) and putamen (z = −2.15; P = .03).Conclusions and RelevanceThese data suggest that normative modeling allows capture of interindividual heterogeneity of regional brain volumes in patients with FEP and characterize structural pathology in a clinically relevant fashion. This holds promise for progress in precision medicine in psychiatry, where group-level studies have failed to derive reliable maps of structural pathology.

Phenome-wide Investigation of Behavioral, Environmental, and Neural Associations with Cross-Disorder Genetic Liability in Youth of European Ancestry

“…22 OCD has been previously linked to increased intra-frontoparietal network connectivity 23,24 , as in the present study, and may reflect over control and excessive monitoring tendencies typical of compulsive disorders. Psychotic PRS was associated with lower par orbitalis thickness, lower ventral diencephalon volume, and lower fractional anisotropy of the corpus callosum, consistent with previous research on clinical high risk for psychosis (though pars orbitalis thickness may be associated especially with more chronic diseases stages) 25–27 . Neurodevelopmental PRS was negatively associated with global gray matter volume, as well as right cortical thickness, whereas Internalizing PRS showed no significant associations with neural metrics.…”

Estimating cortical thickness trajectories in children across different scanners using transfer learning from normative models

“…Pronounced cortical thinning has been found persistently in areas surrounding the central sulcus and temporal lobes (Martinussen et al, 2005; Nagy et al, 2011; Zubiaurre-Elorza et al, 2012) as well as thicker cortices in frontal regions surrounding the anterior cingulate cortex (Bjuland et al, 2013). The current approach has been shown to capture structural deviations better than case-control studies as they are more sensitive to individual heterogeneity (Remiszewski et al, 2022). It also offers improved insights in longitudinal cohorts, as these deviation scores are not cofounded by site-effects.…”

“…Instead, symptoms in individual patients can be related to extreme deviation from the normative range (Fraza et al, 2021;Marquand, Wolfers, et al, 2016;Zabihi et al, 2019). This has shown the potential to detect morphological differences in patient populations which were not evident using standard techniques (Remiszewski et al, 2022).…”

“…Instead, symptoms in individual patients can be related to extreme deviation from the normative range (Fraza et al, 2021; Marquand, Wolfers, et al, 2016; Zabihi et al, 2019). This has shown the potential to detect morphological differences in patient populations which were not evident using standard techniques (Remiszewski et al, 2022). Additionally, a Hierarchical Bayesian Regression (HBR) approach to normative modeling has been shown to efficiently accommodate inter-site variation and to provide good computational scaling, which is useful when using large studies, longitudinal studies, or combining smaller studies together, that are acquired across multiple sites (Bayer et al, 2021; Kia et al, 2022; Rutherford, Fraza, et al, 2022).…”

Change to Open Access Status

“…The Brief Report titled “Contrasting Case-Control and Normative Reference Approaches to Capture Clinically Relevant Structural Brain Abnormalities in Patients With First-Episode Psychosis Who Are Antipsychotic Naive,” published online September 28, 2022, was changed to open access status under the CC-BY license. This article was corrected online.…”