Symptom Remission and Brain Cortical Networks at First Clinical Presentation of Psychosis: The OPTiMiSE Study

Abstract

Individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, that may be particularly prominent, already at illness onset, in those more likely to have poorer symptom remission following treatment with the first antipsychotic. The identification of strong neuroanatomical markers of symptom remission could thus facilitate stratification and individualized treatment of patients with schizophrenia. We used magnetic resonance imaging at baseline to examine brain regional and network correlates of subsequent symptomatic remission in 167 medication-naïve or minimally treated patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder entering a three-phase trial, at seven sites. Patients in remission at the end of each phase were randomized to treatment as usual, with or without an adjunctive psycho-social intervention for medication adherence. The final follow-up visit was at 74 weeks. A total of 108 patients (70%) were in remission at Week 4, 85 (55%) at Week 22, and 97 (63%) at Week 74. We found no baseline regional differences in volumes, cortical thickness, surface area, or local gyrification between patients who did or did not achieved remission at any time point. However, patients not in remission at Week 74, at baseline showed reduced structural connectivity across frontal, anterior cingulate, and insular cortices. A similar pattern was evident in patients not in remission at Week 4 and Week 22, although not significantly. Lack of symptom remission in first-episode psychosis is not associated with regional brain alterations at illness onset. Instead, when the illness becomes a stable entity, its association with the altered organization of cortical gyrification becomes more defined.

Keywords: MRI; OPTiMiSE; cortical thickness; first episode; gyrification; schizophrenia; trial.

Fig. 1.

Sankey diagram of remission status. Remission status flow diagram for three study remission observations. Box and flow widths are proportionate to the number of patients given in brackets as [n]. Flows are colored by the remission status at the target (blue = Nonremitted, yellow = Remitted). Remission status is determined from PANSS scores using modified Andreasen criteria. Week 22 and Week 74 flows include last available PANSS observation data (at Week 22, this was used for 42 patients, with 29 remitted at last observation; at Week 74, this was used for 62 patients, with 33 remitted at last observation).

Fig. 2.

LGI network correlations and Week 74 remission. To illustrate the origin of network edge differences, bivariate scatterplots of local gyrification indices underlying 2 of the significantly affected edges in the LGI structural covariance network are displayed. Values on the x and y axes are residualized for covariates and then for display standardized to the mean and standard deviation of the control group. Ellipses show the 95% confidence ellipse centered on the mean. Lines are OLS regression fits.

Fig. 3.

Disturbed LGI network edges and Week 74 remission. A shows an axial view of the LGI covariance network. Nodes are arranged according to the region’s center of gravity with minor adjustments to reduce overlap. A key to region labels is provided in Supplementary Table S5. Edges most affected by participants Week 74 remission status are shown in red. Solid red lines (n = 29) indicate significant edges (NBS P < .05, network forming threshold P < .005). For reference, gray edges display the control group network thresholded at 15% density (the lowest connected density threshold). The background image is a rendering of the pial surfaces. B shows an alternate view of the network presented in A: a rotated sagittal view of the left frontal regions where most significant differences were seen. C shows the evolution of the remission-related differences in the edges of the affected network at Week 74. Although a statistically significant effect did not emerge at Week 4 or Week 22, LGI covariance was reduced. D, a spaghetti plot showing a consistent evolution of the Fisher z-test effect size (Remission > Nonremission), for each of the network edges which were observed to differ between remission and nonremission at Week 74. Of note, some edges are as impacted as Z = 3 (P < .005 uncorrected) at Week 4. For color, please see the figure online.