Two established staging models outline the longitudinal progression in bipolar disorder (BD) based on episode recurrence or inter-episodic functioning. However, underlying neurobiological mechanisms and corresponding biomarkers remain unexplored. This study aimed to investigate if global and (sub)cortical brain structures, along with brain-predicted age difference (brain-PAD) reflect illness progression as conceptualized in these staging models, potentially identifying brain-PAD as a biomarker for BD staging.

In total, 199 subjects with bipolar-I-disorder and 226 control subjects from the Dutch Bipolar Cohort with a high-quality T1-weighted magnetic resonance imaging scan were analyzed. Global and (sub)cortical brain measures and brain-PAD (the difference between biological and chronological age) were estimated. Associations between individual brain measures and the stages of both staging models were explored.

A higher brain-PAD (higher biological age than chronological age) correlated with an increased likelihood of being in a higher stage of the inter-episodic functioning model, but not in the model based on number of mood episodes. However, after correcting for the confounding factors lithium-use and comorbid anxiety, the association lost significance. Global and (sub)cortical brain measures showed no significant association with the stages.

These results suggest that brain-PAD may be associated with illness progression as defined by impaired inter-episodic functioning. Nevertheless, the significance of this association changed after considering lithium-use and comorbid anxiety disorders. Further research is required to disentangle the intricate relationship between brain-PAD, illness stages, and lithium intake or anxiety disorders. This study provides a foundation for potentially using brain-PAD as a biomarker for illness progression.

Bipolar Disorder (BD) is a life-course illness with evidence of a progressive nature. Although different staging models have been proposed from a theoretical perspective,longitudinal studies are scarce.

The aim of the present study was to apply four staging models in a sample of BD patients and to observe their progression in 10 years of retrospective evaluation.

In a naturalistic sample of 100 BD patients, a retrospective assessment of clinical stages across 10 years of observation at six time points (T0: 2010; T1: 2013; T2: 2015; T3: 2018; T4: 2019; T5:2020) was performed according to the BD staging models (Berk et al., 2007; Kapczinski et al., 2009; Kupka et al., 2012 and Duffy et al., 2014). Socio-demographic and clinical variables were collected and the staging progression across time was analyzed.

A significant progressive staging worsening emerged over 10 years of BD observation for each examined model (p<0.001). Moreover, for all considered staging approaches, stage values were lower over the time points for BD II, lower number of lifetime episodes and hospitalizations (p<0.05). Finally, the stage increase was associated with a lower age at first elevated episode (p<0.05).

Present preliminary results confirm the relevance of illness onset and early intervention in BD, given their role in patients classified into worse clinical staging. There is an emerging need of a standardized universal staging model in order to better characterize BD patients, their treatment and their clinical course.

No significant relationships.