Loneliness has been linked to increased risk of mood disorders, but its relationship with bipolar disorder (BD) and underlying neurobiological mechanisms remain unclear.

This prospective cohort study utilized data from the UK Biobank, involving 491,472 individuals aged 38–73 years without prior BD diagnosis at baseline (2006–2010). Participants reported loneliness and provided data on demographic, socioeconomic, lifestyle factors, and polygenic risk scores (PRS) for BD. Follow-up extended until 2022, tracking incident BD cases. Neuroimaging analyses examined gray matter volume (GMV) associations with loneliness, considering genetic susceptibility.

Over 16 years, 1,316 participants developed BD. Loneliness was associated with a more than threefold increased risk of BD (hazard ratio [HR], 3.31; 95% CI, 2.97–3.69), which remained significant after adjusting for covariates (HR, 2.83; 95% CI, 2.47–3.23). Neuroimaging revealed that loneliness correlated with widespread reductions in GMV, particularly in regions involved in emotion regulation and social cognition. These neurobiological effects were more pronounced in individuals with higher BD PRS.

Loneliness is prospectively associated with a substantially increased hazard of BD and is linked to extensive brain structural changes, especially in genetically susceptible individuals. These findings highlight the importance of addressing loneliness to potentially mitigate BD risk and its neurobiological impact.