Alexandros Smyrnis Christos Theleritis Panagiotis Ferentinos Nikolaos Smyrnis ^*

• National and Kapodistrian University of Athens, Athens, Greece

Background Associating temporal variation of biomarkers with the onset of psychotic relapse could help demystify the pathogenesis of psychosis as a pathological brain state, while allowing for timely intervention, thus ameliorating clinical outcome. In this systematic review, we evaluated the predictive accuracy of a broad spectrum of biomarkers for psychotic relapse. We also underline methodological concerns, focusing on the value of prospective studies for relapse onset estimation. Methods Following the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines, a list of search strings related to biomarkers and relapse was assimilated and run against the PubMed and Scopus databases, yielding a total of 808 unique records. After exclusion of studies related to the distinction of patients from controls or treatment effects, the 42 remaining studies were divided into 5 groups, based on the type of biomarker used as a predictor: the genetic biomarker subgroup (n = 4, or 9%), the blood-based biomarker subgroup (n = 15, or 36%), the neuroimaging biomarker subgroup (n = 10, or 24%), the cognitive-behavioral biomarker subgroup (n = 5, or 12%) and the wearables biomarker subgroup (n = 8, or 19%). Results In the first 4 groups, several factors were found to correlate with the state of relapse, such as the genetic risk profile, Interleukin-6, Vitamin D or panels consisting of multiple markers (blood-based), ventricular volume, grey matter volume in the right hippocampus, various functional connectivity metrics (neuroimaging), working memory and executive function (cognition). In the wearables group, machine learning models were trained based on features such as heart rate, acceleration, and geolocation, which were measured continuously. While the achieved predictive accuracy differed compared to chance, its power was moderate (max reported AUC = 0.77). Discussion The first 4 groups revealed risk factors, but cross-sectional designs or sparse sampling in prospective studies did not allow for relapse onset estimations. Studies involving wearables provide more concrete predictions of relapse but utilized markers such as geolocation do not advance pathophysiological understanding. A combination of the two approaches is warranted to fully understand and predict relapse.