One of the primary objectives of psychiatry as a clinical medicine is the early detection and intervention of mental illness. In this discipline, familial or genetic high-risk (FHR/GHR) studies through offspring or relatives of those with schizophrenia have a long tradition as a preventative intervention strategy (Cannon, 2005; Erlenmeyer-Kimling and Cornblatt, 1987; Rasic et al., 2014). However, due to the challenges associated with long-term follow-up and low yield in GHR studies, a clinical approach specifically targeting individuals with impending psychosis onset has emerged as promising research alternative (Miller and McGlashan, 2000; Yung et al., 1996). The ultra/clinical high-risk for psychosis (UHR/CHR; CHR-P in this paper) concept has been proposed and developed to detect and prevent the transition to psychosis early (Cannon et al., 2008; Fusar-Poli et al., 2013; McGorry et al., 2009; Ruhrmann et al., 2010). CHR-P is used to diagnose individuals who experience very short periods of psychotic symptoms or have subthreshold psychotic symptoms that intensify over time. A similar trend has also been in bipolar disorder. Traditionally, FHR/GHR studies have been conducted as early intervention studies for bipolar disorder (Birmaher et al., 2009; DelBello and Geller, 2001; McIntosh et al., 2006), but clinical high-risk for bipolar (CHR-B) studies, which have recently integrated the clinical high-risk concept, have also garnered considerable attention (Correll et al., 2007; Hafeman et al., 2016). These studies are based on clinical symptom patterns, such as subthreshold mania, depression with cyclothymic features, subthreshold mixed episodes, etc., and they reflect the natural courses of bipolar disorder, encompassing a wider range of clinical features (Bechdolf et al., 2010; Correll et al., 2014; Fusar-Poli et al., 2018). In addition to genetic risk factors, clinical risk factors play a substantial role in predicting the onset of bipolar disorder; consequently, this model will play a more significant part in the early intervention of bipolar disorder. While recent studies indicated that CHR-P is highly specific for psychosis other than pluripotential to various severe mental illnesses (Webb et al., 2015; Woods et al., 2018), not all CHR-P develop psychosis only, in addition to psychosis, but nonconverters exhibit a range of clinical trajectories (Addington et al., 2011; Lee et al., 2014; Lin et al., 2015). Moreover, psychosis can occur in non-psychotic disorders as well as subthreshold psychotic symptoms are also present during prodrome of bipolar disorder (Duffy et al., 2007; Hartmann et al., 2020; Lee et al., 2018). The comorbidity and heterogeneity of CHR-P have raised concerns about the concept's validity. Selective and non-epidemiological sampling, confounding factors, and the natural fluctuation of the dimensional expression of psychosis, further obscure the demarcation of CHR-P (van Os and Guloksuz, 2017). This demonstrates the limitations of a unitary disease model for predicting the transition as well as the conceptual confusion caused by the frequent overlap of symptoms between the clinical high-risk states.

A method for expanding to a wide variety of disorders has been proposed to circumvent the limitations of a unitary outcome model. The transdiagnostic approach, dubbed the clinical staging model, has various symptom clusters with diffuse boundaries as the disease develops, the demarcations between the diseases become more distinct, and individual diseases emerge (McGorry et al., 2018; Shah et al., 2022). The concept enables more flexible predictions of various outcomes for CHR prior to the onset of a specific disorder. The CHARM cohort, which introduces a transdiagnostic and clinical staging approach, is actually preemptively exploring this assumption (Hartmann et al., 2019). Preliminary result of the cohort reveals high-risk subjects have extensive symptom overlap in clinical staging 1 B, and the undifferentiated subthreshold individuals manifest more distinct illness in stage 2 (Hartmann et al., 2020). Research in this pluripotential framework is anticipated to provide a more holistic understanding of the pathophysiology of mental illnesses (Fusar-Poli et al., 2018; Hafeman et al., 2016; Van Meter et al., 2019).

Nonetheless, several uncertainties persist. CHR-P is more specific for the onset of psychosis than non-psychotic disorders, yet individuals at clinical high-risk for non-psychotic disorders may also develop psychosis, albeit at a low incidence rate. However, there is a dearth of prospective non-psychosis studies that adopt the clinical high-risk concept instead of the genetic high-risk concept, necessitating further investigation into the incidence of psychosis in the clinical high-risk group for non-psychotic disorders. Moreover, anxiety or mood symptoms could precede the onset of psychotic symptoms in the illness trajectory or present as accompanying symptoms, necessitating a more extended follow-up period to discern the precise disorder that the high-risk group may develop.

This prospective cohort study aimed to investigate the characteristics and clinical outcomes of clinical high-risk individuals with the potential to develop a diverse range of psychiatric disorders as a pluripotent high-risk group from a transdiagnostic perspective. To construct a pluripotent high-risk cohort, we classified at-risk individuals into four categories, namely, psychosis risk, bipolar risk, depression risk, and undifferentiated risk. We hypothesized that the pluripotent high-risk group would exhibit a higher incidence of psychosis compared to the existing cohort that is restricted to specific diseases, and there would be a mutual transition between different risk conditions.