Functional Coupling and Longitudinal Outcome Prediction in First-Episode Psychosis

Background Clinical outcomesfollowing a first episode of psychosis (FEP) are highly heterogeneous between patients. The identification of prognostic biomarkers would greatly facilitate personalized treatments. Psychosis patients often display brain-wide disruptions of inter-regional functional coupling (FC), with some being linked to symptom severity and remission. FC may thus hold prognostic potential for people experiencing psychosis.

Ninety antipsychotic-naïve FEP patients (51% female, 15-25 years) were randomized to receive either antipsychotic or placebo tablets for 6 months alongside psychosocial interventions. A subset of these patients also completed functional magnetic resonance imaging (55 with usable data at baseline and 37 at 3 months), which was used to evaluate whether baseline FC, or 3-month change in FC, could predict 6- and 12-month changes in symptoms and functioning, quantified using the Brief Psychiatric Rating Scale and the Social and Occupational Functioning Assessment Scale, respectively. We considered three different cross-validated prediction algorithms: (i) connectome-based predictive modelling; (ii) kernel ridge regression; and (iii) multilayer meta-matching.

All algorithms showed poor performance in predicting patients’ 6- and 12-month changes in symptoms and functioning (all rmean 0.05).

Our findings suggest that brain-wide measures of FC may not be suitable for predicting extended clinical outcomes over a 6- to 12-month period in FEP patients. Competing Interest Statement SC is supported by a Graduate Education Fund Scholarship from the American Australian Association. SF, MA-J, and AF reported receiving grants from the NHMRC and Australian Research Council during the conduct of the study. CP reported receiving grants from the Australian NHMRC and from the Lundbeck Foundation and personal fees from Lundbeck Australia Pty Ltd. Advisory Board for talks presented at educational meetings organized by Lundbeck. PM reported receiving grants from the Australian NHMRC, the Colonial Foundation, the National Alliance for Research on Schizophrenia and Depression, the Stanley Foundation, the National Institutes of Health, Wellcome Trust, the Australian and Victorian governments, and Janssen-Cilag (unrestricted investigator-initiated grant) during the conduct of the study; past unrestricted grant funding from Janssen-Cilag, AstraZeneca, Eli Lilly, Novartis, and Pfizer; and honoraria for consultancy and teaching from Janssen-Cilag, Eli Lilly, Pfizer, AstraZeneca, Roche, Bristol Myers Squibb, and Lundbeck. BN was supported by an NHMRC Senior Research Fellowship (Fellowship No. 1137687) and VLC was supported by an NHMRC EL2 Fellowship (Fellowship No. 1177370). BN, KA, and VLC were supported by a University of Melbourne Dame Kate Campbell Fellowship. AF reported receiving a grant from the Sylvia and Charles Viertel Foundation during this project. Clinical Trial ACTRN12607000608460 Funding Statement Janssen-Cilag partially supported the early years of this study with an unrestricted investigator-initiated grant and provided risperidone, paliperidone, and matched placebo for the first 30 participants. The study was then funded by an Australian National Health and Medical Research Project (NHMRC) grant (Grant No. 1064704 [to SMF, BO, BN, HPY, KA, MA-J, SH, SJW, PM, AF]). The funders had no role in study design, data collection, data analysis, data interpretation, writing, approval, or submission of this manuscript. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The current study uses data from a larger trial registered with the Australian New Zealand Clinical Trials Registry in November 2007 (ACTRN12607000608460) and received ethics approval from the Melbourne Health Human Research and Ethics committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Improved figure resolutions and PDF formatting. Data Availability All data produced in the present study are available upon reasonable request to the authors. Code to reproduce all main results figures is available at https://github.com/izachp/psychosis-FC-prediction.