Bipolar Disorder Integrative Staging: Incorporating Biomarkers Into Progression Across Stages

Rationale Bipolar Disorder (BD) is a highly prevalent (approximately 1% in the general population) and disabling condition, characterized by a chronic and progressive course. The natural history of BD typically includes an initial asymptomatic phase, followed by a prodromal stage, and subsequently the onset of a first syndromic episode (depressive or manic), which is usually followed by recurrent episodes, often in the absence of full inter-episodic recovery. A growing body of evidence supports the notion that the longitudinal course of BD is associated with an active process of neuroprogression, characterized by progressive brain alterations and functional impairment. Several clinical factors may influence the trajectory of the disorder, including the number of affective episodes, the presence of psychiatric and medical comorbidities, exposure to stressful life events, and a family history of psychiatric disorders. Neuroimaging studies have consistently supported the neuroprogressive hypothesis in BD, demonstrating structural and functional brain alterations that progressively emerge as the illness advances. Abnormalities have also been described at the level of large-scale neural networks. In particular, the Default Mode Network appears to exhibit altered patterns of hyper- and hypo-connectivity with affective, fronto-parietal, and attentional systems, involving key hubs responsible for efficient large-scale brain communication. Moreover, structural and functional alterations have also been identified in unaffected relatives of patients with BD. Studies investigating additional biomarkers in BD have further provided evidence supporting a stage-related progression of the disorder, particularly with respect to Brain-Derived Neurotrophic Factor (BDNF) and inflammatory cytokines. Overall, recent advances in the field of clinical staging of BD, together with progress in the identification of biological markers (e.g., gene transcription modulation, neurotrophic signaling, immuno-inflammatory pathways, microbiota) and neuroimaging (structure and function of large-scale brain systems), provide a strong rationale for the development of a multidimensional staging model. Such a model would integrate clinical and neurobiological data, allowing for greater diagnostic, prognostic, and therapeutic precision.

Specific aims and experimental design

BOARDING PASS study has the following objectives:

1. to longitudinally assess BD clinical progression over an 18-month period using the Kupka & Hillegers' staging model;
2. to investigate the role of biological and neuroimaging markers in BD stage transitions (i.e. gene transcription regulation, inflammation, microbiotic, structural and functional neuroimaging measures);
3. to implement a predictive ML model based on the integration of clinical, biological, and neuroimaging data, in order to provide an individualized and data-driven prediction of BD stage transitions.

The study involves the consecutive recruitment of 120 subjects enrolled at three of the four participating centers: UO1 (ASST Fatebenefratelli-Sacco, Milan), UO2 (ASST Papa Giovanni XXIII, Bergamo), and UO3 (ASL 2 Abruzzo, Lanciano-Vasto-Chieti). Inclusion and exclusion criteria are detailed below.