Weight gain as a predictor of frontal and temporal lobe volume loss in bipolar disorder: A prospectiveMRIstudy

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A sizable fraction of people with bipolar I disorder (BDI) experience a deteriorating clinical course with increasingly frequent mood episodes and chronic disability. This is believed to result from neurobiological illness progression, or neuroprogression. Excessive weight gain predicts neuroprogression across multiple brain illnesses, but no prospective studies have investigated this in BDI. The objective of this study was to determine whether BDI patients who experienced clinically significant weight gain (CSWG; gaining ≥7% of baseline weight) over 12months had greater 12-month brain volume loss in frontal and temporal regions important to BDI. In 55 early-stage BDI patients we measured (i) rates of CSWG, (ii) the number of days with mood symptoms, using NIMH LifeCharts, and (iii) baseline and 12-month brain volumes, using 3T MRI. We quantified brain volumes using the longitudinal processing stream in FreeSurfer v6.0. We used general linear models for repeated measures to investigate whether CSWG predicted volume loss, adjusting for potentially confounding clinical and treatment variables. After correction for multiple comparisons, CSWG in patients predicted greater volume loss in the left orbitofrontal cortex (effect size [ES; Cohen's d]=-1.01, P=0.002), left cingulate gyrus (ES=-1.31, P<0.001), and left middle temporal gyrus (ES=-0.96, P=0.004). Middle temporal volume loss predicted more days with depression (β=-0.406, P=0.010). These are the first prospective data on weight gain and neuroprogression in BDI. CSWG predicted neuroprogression, and neuroprogression predicted a worse clinical illness course. Trials of weight loss interventions are needed to confirm the causal direction of the weight gain-neuroprogression relationship, and to determine whether weight loss is a disease-modifying treatment.