New research from the Leiden University Medical Center shows that both systemic and inhaled glucocorticoids — a class of synthetic steroids — are associated white matter integrity and limited changes in gray matter volume; this association may contribute to the neuropsychiatric side effects of glucocorticoid medication, especially with chronic use.
van der Meulen et al. show that both systemic and inhaled glucocorticoid use are associated with an apparently widespread reduction in white matter integrity, which may in part underly the neuropsychiatric side effects observed in patients using glucocorticoids. Image credit: Steve Buissinne.
Due to their immunosuppressive properties, glucocorticoids are among the most prescribed drugs on the market, with an estimated annual prevalence of systemic glucocorticoid use between 0.5% and 3%.
Although efficacious, both systemic and local (especially inhaled) glucocorticoids are associated with many potentially serious metabolic, cardiovascular and musculoskeletal side effects.
Besides these physical side effects, the use of synthetic glucocorticoids is also associated with neuropsychiatric symptoms and disorders, including depression, mania, delirium and even a sevenfold increased suicide (attempt) rate.
Previously published research suggests that long term medical steroid use is associated with structural abnormalities and shrinkage of certain areas of the brain. But most of these studies have involved only small numbers of people with specific conditions.
In a bid to find out, Merel van der Meulen and her colleagues from the Department of Medicine at the Leiden University Medical Center drew on data from the UK Biobank, comprising half a million 40-69 year olds from the general population, to see if there were any detectable differences in brain volume and structure between users and non-users of systemic and inhaled steroids.
The researchers also wanted to know if steroid use might be associated with differences in processing speed and emotional responses.
The MRI brain scans of 222 people using systemic steroids and 557 using inhaled steroids were compared with those of 24,106 non-users.
None of the study participants had previously been diagnosed with neurological, psychiatric or hormonal (endocrinological) disorders or was taking mood altering drugs, such as antidepressants.
Participants filled in a questionnaire to assess certain aspects of mood over the previous fortnight.
Comparison of the MRI scan results showed that both systemic and inhaled steroid use was associated with less intact white matter structure than was seen on the scans of those not on these drugs. White matter has a role in neuronal connectivity and signaling in the brain.
The effects were greater in systemic users than in users of inhaled steroids. And further detailed analysis suggested that the effects might be even larger among long term users.
Systemic use was associated with a larger caudate compared with no use, while use of inhaled steroids was associated with a smaller amygdala.
Both the caudate and amygdala are gray matter structures in the brain involved in cognitive and emotional processing.
Systemic steroid users also performed worse on a test designed to measure processing speed than non-users, and they reported significantly more depressive symptoms, apathy, restlessness and fatigue/lethargy than non-users.
Inhaled steroid users reported only more tiredness/lethargy, and to a lesser degree than systemic steroid users.
“Although a causal relation between glucocorticoid use and changes in the brain is likely based on the present and previous studies, the cross-sectional nature of this study does not allow for formal conclusions on causality,” the scientists said.
They also point to certain limitations: only a few indicators of mood change were assessed, and only for the preceding 2 weeks; and the reported changes might have been related to the condition for which steroids were prescribed rather than to steroid use itself.
Nor were the authors able to differentiate between steroid tablets and infusions for systemic users, all of which may have influenced the findings.
“While it remains unclear whether the observed effect sizes have clinical consequences for the population of glucocorticoid users as a whole, these findings are remarkable given the common neuropsychiatric side effects of synthetic glucocorticoids,” they said.
“This study shows that both systemic and inhaled glucocorticoids are associated with an apparently widespread reduction in white matter integrity, which may in part underlie the neuropsychiatric side effects observed in patients using glucocorticoids.”
“Given how widely used these drugs, both doctors and patients need to know about the possible effects on the brain.”
The results appear in the journal BMJ Open.
Merel van der Meulen et al. 2022. Association between use of systemic and inhaled glucocorticoids and changes in brain volume and white matter microstructure: a cross-sectional study using data from the UK Biobank. BMJ Open 12: e062446; doi: 10.1136/bmjopen-2022-062446