The staging model of mental illness is developing beyond the clinical level aiming to include biological processes and markers that may reflect the dynamic biological processes of stages of mental illness. The neurobiology of inflammation in mental illness has gained much attention in recent years. Since neuroinflammation has been shown to be an important possible feature of psychosis, schizophrenia and depression, in this chapter it is attempted to map changes and dysregulation of the immune system and inflammation to the different clinical stages of severe mental illness. The literature suggests that an increased inflammatory response may define a subgroup of individuals in ultra-high-risk states, in acute disease episodes and in those with severe mental illness. In addition, the literature clearly points to the dynamic nature of the immune response in mental illness and shows an involvement of both the innate and adaptive immune system in mental illness. A focus on inflammation only might be insufficient and a broader understanding of the interaction between innate and adaptive immune systems and the complex neuroimmune interaction is required.

For over a decade a transdiagnostic clinical staging framework for youth with anxiety, mood and psychotic disorders (linked with measurement of multidimensional outcomes), has been utilised in over 8,000 young people presenting to the enhanced primary (headspace) and secondary care clinics of the Brain and Mind Centre of the University of Sydney. This framework has been evaluated alongside a broad range of other clinical, neurobiological, neuropsychological, brain imaging, circadian, metabolic, longitudinal cohort and controlled intervention studies. This has led to specific tests of its concurrent, discriminant and predictive validity. These extensive data provide strong preliminary evidence that: i) varying stages of illness are associated with predicted differences in a range of independent and objectively measured neuropsychological and other biomarkers (both cross-sectionally and longitudinally); and, ii) that earlier stages of illness progress at variable rates to later and more severe or persistent disorders. Importantly, approximately 15-20% of those young people classed as stage 1b or ‘attenuated’ syndromes at presentation progress to more severe or persistent disorders. Consequently, this cohort should be the focus of active secondary prevention trials. In clinical practice, we are moving to combine the staging framework with likely pathophysiological paths (e.g. neurodevelopmental-psychotic, anxiety-depression, circadian-bipolar) to underpin enhanced treatment selection.