The Link Between Weight Gain and Hippocampal Atrophy in Bipolar Disorder: A Longitudinal Investigation in 934 Participants

Background Obesity, which is common in bipolar disorder (BD), is associated with smaller hippocampal volumes. We do not know the role of weight/weight gain in relation to longitudinal hippocampal changes among individuals with BD. Methods In collaboration with the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis)-BD Working Group, we obtained T1-weighted magnetic resonance imaging and clinical data from 233 participants with BD and 701 healthy control participants (HCs) scanned twice, 2.84 ± 1.63 years apart on average. We estimated subcortical volumes using FreeSurfer longitudinal image processing stream and used linear mixed models to assess the bidirectional relationship between baseline body mass index (BMI) or BMI change and hippocampal volume or volume change. While the hippocampus was our a priori region of interest, we repeated these analyses in other subcortical regions. Results Baseline BMI predicted future hippocampal atrophy, but baseline brain structure did not predict future weight changes. BMI increased significantly over time ( F 1,1085 = 15.98, p < .001). Individuals with lower baseline BMI experienced greater weight gain ( F 1,922 = 105.12, p < .001). Greater weight gain was associated with greater hippocampal atrophy over time ( F 1,899 = 16.33, p = .001), more so in participants with BD than HCs ( F 1,898 = 6.91, p = .009). Consequently, lower baseline BMI predicted greater future hippocampal volume loss ( F 1,904 = 14.77, p < .001). These associations were not observed in other subcortical regions. Conclusions Our findings suggest that weight gain is a modifiable risk factor for hippocampal atrophy, especially in individuals with lower BMI and those with BD. Prevention of weight gain in general, but especially in people with BD, could provide neuroprotective benefits.