Ultra-high-risk paradigm: lessons learnt and new directions

Abstract

Within the embryonic early psychosis field in the early 1990s, the conceptualisation and definition of an at-risk or ultra-high-risk (UHR) mental state for psychosis was a breakthrough which transformed the clinical and research landscape in psychiatry. Twenty-five years later, we have a new evidence base that has illuminated the neurobiology of the onset phase of psychotic disorder, delivered Cochrane level 1 evidence showing that the onset of full-threshold sustained psychotic disorder can be at least delayed, and is paving the way to a new generation of transdiagnostic research. Here, we document the contribution of the UHR approach to understanding the underlying mechanisms of psychosis onset as well as the long-term outcomes. Particularly, we highlight that psychosis onset can be delayed in those meeting UHR criteria and that these criteria have a higher valence for subsequent psychotic disorders and some valence for persistent non-psychotic syndromes. Critiques have helped to identify some of the limitations of this paradigm, which are acknowledged. These include evidence that psychotic disorders can emerge more acutely and from other, as yet undefined, precursor states. Rather than defending, or alternatively questioning the value of, the UHR approach, we propose a broader, transdiagnostic staging model that is consistent with the pluripotent and variably comorbid trajectories for mental disorders. This approach moves beyond psychosis to capture a wider range of subthreshold symptoms and full-threshold disorders, thus enhancing prediction for the emergence and progression of a range of mental disorders, as well as providing new avenues for early intervention and prevention.

Association of preceding psychosis risk states and non‐psychotic mental disorders with incidence of clinical psychosis in the general population: a prospective study in the NEMESIS‐2 cohort

“…Following our critical perspective papers on the CHR concept 3,5 , an intense debate has started, splitting the field into proponents 6‐8 , opponents 9‐12 , and those with ambivalent attitudes toward that concept 13‐16 .…”

Study Protocol for a Prospective Longitudinal Cohort Study to Identify Proteomic Predictors of Pluripotent Risk for Mental Illness: The Seoul Pluripotent Risk for Mental Illness Study

“…McGorry and his colleagues have already proposed a pluripotent prospective program that reflects this concept. The CHARM study encompasses schizophrenia, mood disorder, and borderline personality disorder outcomes and implements a clinical staging model along the mental health continuum (57). The CHARM study will also provide predictive and discriminant validity of the proposed criteria 16.…”

Designing and Testing of a Health-Economic Markov Model for Prevention and Treatment of Early Psychosis

“…In reality, it is likely that several phenotypic pathways leading to FEP exists outside of the UHR paradigm (e.g. in patients in which early psychotic symptoms may be absent) [40,63]. Furthermore, if a proportion of the UHR patients is not detected this would mean a reduction in the demonstrated benefits.…”

“…Patients with UHR demonstrate certain levels of intensity, severity and/or pathognomonic symptoms (e.g. a Global Assessment of Functioning-score <70) [40]. The development of this staging model in which the importance of identification and treating patients at UHR for psychosis was emphasized, boosted an interest in preventive psychiatry and it has been demonstrated that early detection and intervention in people at ultra-high risk of developing psychosis can be successful to prevent or delay a first psychosis [40][41][42].…”