Brain Age in Bipolar Disorder: Impact of Model Selection and Clinical Factors

Bipolar disorder (BD) has been associated with accelerated aging, but studies investigating brain age have yielded mixed results. This may reflect differences in methodology and model sensitivity.

We compared 3 publicly available brain age models (ENIGMA [Enhancing Neuro Imaging Genetics through Meta Analysis], PyBrainAge, Pyment) using T1-weighted magnetic resonance imaging (MRI) scans from 352 individuals with BD type I and 327 control participants across 4 sites. Predicted age difference (PAD) was calculated as brain age minus chronological age. We examined group differences, medication effects, and age-related patterns using linear mixed-effects models controlling for chronological age, sex, and scanner.

PAD was higher in participants with BD than in control participants across all models (PyBrainAge: +3.03 years; ENIGMA: +2.78 years; Pyment: +1.43 years; Cohen's d = 0.26-0.36; all ps < .001), with group differences being more pronounced in participants ≥40 years of age. In region-based models, thalamic and ventricular volumes contributed most consistently to elevated PAD in BD. Across all models, lithium-treated participants with BD showed no significant PAD elevation compared with control participants (all ps > .5), while non-lithium-treated participants exhibited significant elevation (+1.47 to 3.24 years; all ps < .01). Within participants with BD, mixed modeling of any current medication status, lithium treatment, and illness duration/severity measures showed that any current medication status was associated with increased PAD (+2.03 to 4.48 years; all ps < .05), whereas lithium use was associated with a 1.87- to 3.67-year reduction in PAD (all ps < .05), and no associations were found with duration/severity metrics.

Our findings support the presence of elevated brain age in BD and lithium's suggested neuroprotective profile and highlight the influence of the brain age model, MRI scanner, and other confounders on predictions.