Chronic exposure to high levels of endogenous or exogenous glucocorticoids can lead to neuropsychiatric symptoms and is associated with changes in brain volume and white matter. However, most clinical studies investigating the effects of glucocorticoid overexposure on the brain have been performed in small, selected populations with chronic glucocorticoid excess, and it remains unknown whether these consequences can also be observed in a general sample of people using glucocorticoids, including inhaled glucocorticoids. Therefore, we investigated whether oral or inhaled glucocorticoid use are associated with changes in with grey matter volumes and white matter microstructure in the population-based cohort of the UK Biobank.

In this cross-sectional study, imaging data were available for 222 oral glucocorticoid users, 557 inhaled glucocorticoid users, and 24106 controls after exclusion based on neurological, psychiatric, or endocrine history, and use of psychotropic medication. Both oral and inhaled glucocorticoid use were associated with reduced white matter integrity (lower fractional anisotropy and higher mean diffusivity), with larger effect sizes in oral users than inhaled users, and largest effect sizes in chronic oral glucocorticoid users. In addition, oral glucocorticoid use was associated with larger volumes of the caudate nucleus, while inhaled glucocorticoid users had smaller amygdala volumes. As for secondary outcomes, oral glucocorticoid users scored significantly lower on one cognitive task (symbol digit substitution) and both oral and inhaled glucocorticoid users had significantly worse scores on all four investigated emotional outcomes (depression, disinterest, tenseness, and tiredness), compared to controls.

In conclusion, both oral and inhaled glucocorticoid use are associated with decreased white matter integrity and volumetric changes in several brain regions. These effects may contribute to the neuropsychiatric side effects of glucocorticoid medication.