Clinical Context

Glucocorticoids are some of the most commonly used medications, with between 0.5% and 3% of persons per year using these medications. Although glucocorticoids are known to promote negative adverse effects in terms of metabolism and bone health, the authors of the current study note that they are also associated with higher rates of depression, mania, and delirium. Glucocorticoids are even associated with a 7-fold increase in the risk for suicide attempt.

Glucocorticoids might exert these effects through changes in the structure and function of the brain. Previous research has found that Cushing disease is associated with global cerebral atrophy, and the use of high-dose systemic glucocorticoids has been associated with volume reduction in the hippocampus and amygdala in small studies.

The current research expands on previous work of glucocorticoids and brain structure by examining a larger cohort of adults and including more imaging parameters, as well as comparing the potential effects of systemic and inhaled glucocorticoids

Study Synopsis and Perspective

New research links the use of glucocorticoids to changes in white matter microstructure, which may explain the development of anxiety, depression, and other neuropsychiatric adverse effects related to these drugs, investigators say.

Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.

Glucocorticoids have "a whole catalogue" of adverse events, and effects on brain structure "adds to the list," coinvestigator Onno C Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, Department of Medicine, Leiden University Medical Center, the Netherlands, told Medscape Medical News.

The findings should encourage clinicians to consider whether doses they are prescribing are too high, said Dr Meijer. He added that the negative effect of glucocorticoids on the brain was also found in those using inhalers, such as patients with asthma.

The findings were published online August 30 in BMJ Open.

Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.

However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal adverse effects, as well as neuropsychiatric adverse effects such as depression, mania, and cognitive impairment.

About 1 in 3 patients exposed to "quite a lot of these drugs" will experience neuropsychiatric symptoms, Dr Meijer said.

Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.

The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease, although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.

The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).

Inhaled steroids target the lungs, whereas a steroid in pill form "travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses," Dr Meijer noted.

The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).

In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.

Imaging analyses showed that systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference [AMD], −3.7e-3; 95% CI, −6.4e-3 to 1.0e-3) and reductions in regional FA in the body and genu of the corpus callosum vs the control group.

Inhaled glucocorticoid use was associated with reduced global FA (AMD, −2.3e-3; 95% CI, −4.0e-3 to −5.7e-4) and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.

Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6) compared with the control group.

The effects of glucocorticoids on white matter were "pervasive," and the "most important finding" of the study, Dr Meijer said. "We were impressed by the fact white matter is so sensitive" to these drugs.

He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. "You could say communication between brain regions is probably somewhat impaired or challenged," he said.

Subgroup analyses among participants using glucocorticoids chronically, defined as reported at 2 consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.

Systemic glucocorticoid use was also associated with an increase in total and gray matter volume of the caudate nucleus.

In addition, there was a significant association between inhaled glucocorticoid use and decreased gray matter volume of the amygdala, which Dr Meijer said was surprising because studies have shown that glucocorticoids "can drive amygdala big time."

Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr Meijer noted.

The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is gray matter volume, "at least at the structural level," he said.

He added that longer use or higher doses may be necessary to also induce volumetric changes.

Participants also completed a questionnaire to assess mood during the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.

The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed--for example, rheumatoid arthritis or chronic obstructive pulmonary disease.

In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task compared with participants in the control group.

In light of these findings, pharmaceutical companies that make inhaled corticosteroids "should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all," which is currently the case, Dr Meijer said.

Commenting on the findings for Medscape Medical News, E. Sherwood Brown, MD, PhD, distinguished chair in psychiatric research and professor and vice chair for clinical research, Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size "impressive."

In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.

That results are in the same direction but greater with systemic compared with inhaled corticosteroids is "particularly interesting" because this might suggest dose-dependent effects, Dr Brown said.

He noted that cognitive differences were also only observed with systemic corticosteroids.

Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, "are harder to understand," said Dr Brown.

However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.

Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr Brown said.

No study funding was reported. Dr Meijer has received research grants and honorariums from Corcept Therapeutics, and a speakers' fee from Ipsen. Dr Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.

BMJ Open. Published online August 30, 2022.^[1]

Study Highlights

• Study data were drawn from the UK Biobank cohort, which includes more than 500,000 adults between the ages of 40 and 69 years. Participants included in the current study had completed magnetic resonance imaging (MRI) of the brain with diffusion tensor imaging, which provides data on microstructural architecture.
• Patients with chronic neurological conditions or certain psychiatric conditions such as schizophrenia were excluded from analysis. Patients using psychotropic medications were also excluded.
• The main study outcome included findings on brain MRI. Participants also completed 6 cognitive tasks and 4 questions about mental health. The main study variables were the use of systemic or inhaled glucocorticoids.
• The study analysis was adjusted to account for demographic data and head size, among several other variables.
• 222 adults using systemic glucocorticoids were compared with 557 adults receiving inhaled glucocorticoids and 24,106 participants who did not receive glucocorticoids. Most baseline characteristics were similar in the 3 groups, although users of systemic glucocorticoids tended to be older.

Figure. Effect of Systemic or Inhaled Corticosteroids on Brain Structure and Function

• Glucocorticoid use did not significantly affect total brain volume or subcortical volumes.
• However, glucocorticoid use was associated with significant disturbances in the microarchitecture of the brain, with a stronger effect of systemic vs inhaled glucocorticoids compared with controls. The effect of glucocorticoids was particularly pronounced in the corpus callosum.
• Moreover, a measurement of brain edema and inflammation was higher in the systemic and inhaled glucocorticoid cohorts vs the control group, with a stronger effect in the systemic vs inhaled groups.
• Areas of greater inflammation and edema associated with glucocorticoids included the corpus callosum, the uncinate gyrus, and the cingula of the hippocampus and cingulate cortex.
• Glucocorticoid users had similar results to controls in most cognitive tests, except that users of systemic glucocorticoids were associated with worse performance on the symbol digit substitution test.
• Systemic glucocorticoids were associated with higher rates of depressive symptoms, disinterest, restlessness, and lethargy compared with no glucocorticoid use, whereas inhaled glucocorticoids were only associated with more lethargy vs controls.

Clinical Implications

• The use of glucocorticoids is associated with higher rates of depression, mania, delirium, and suicide attempt. Cushing disease is associated with global cerebral atrophy, and the use of high-dose systemic glucocorticoids has been associated with volume reduction in the hippocampus and amygdala in small studies.
• The current study demonstrates that both systemic and inhaled corticosteroids can have negative effects on brain microarchitecture and inflammation. Glucocorticoids did not significantly affect total brain volume and had little effect on cognitive testing. Systemic glucocorticoids were associated with higher rates of psychological symptoms.

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