Metyrapone Fails to Benefit Patients With Treatment-Resistant Depression
Abstract
After five weeks, patients who took the cortisol synthesis inhibitor metyrapone in addition to their existing antidepressant regimen for 21 days showed no differences in depression ratings from those who took placebo.
Hypothalamic-pituitary-adrenal (HPA) axis abnormalities are often reported in patients with mood disorders, leading some researchers to believe that antiglucocorticoid augmentation of antidepressants may benefit patients with major depressive disorder (MDD). A study published December 22, 2015, in Lancet Psychiatry suggests that these benefits may not extend to patients with treatment-resistant depression.
Hamish McAllister-Williams, M.D., Ph.D., believes that more research must be done to properly identify patients with major depression who would benefit from antiglucocorticoids as an add-on to their existing antidepressant regimen.
“There is abundant evidence of abnormalities in hypothalamic-pituitary-adrenal axis function in at least a proportion of patients with major depressive disorder,” said the study’s lead author Hamish McAllister-Williams, M.D., Ph.D., of Newcastle University in the United Kingdom.
A prior double-blind, randomized, controlled trial published in Archives of General Psychiatry in 2004 found that patients with MDD who took the cortisol synthesis inhibitor metyrapone daily in addition to their serotonergic regimen for three weeks showed improvements up to two weeks after discontinuing the augmentation treatment. To see whether these benefits extended to patients with treatment-resistant depression, McAllister-Williams and colleagues randomized 165 patients aged 18 to 65 to receive 500 mg doses of metyrapone or placebo twice daily in addition to their existing antidepressant regimen for 21 days.
The analysis showed that when patients were evaluated two weeks after the augmentation was discontinued, Montgomery-Åsberg Depression Rating Scale scores did not significantly differ between the metyrapone group and placebo group. According to McAllister-Williams, “the study failed to demonstrate any beneficial effect of metyrapone augmentation at any time point on mood, anxiety, or quality of life.”
Treatment with metyrapone was well tolerated, he added. Agitation, fatigue, and nervousness were the most commonly observed adverse events among patients in the metyrapone group.
Although the researchers did notice that patients with treatment-resistant depression had slightly elevated levels of salivary cortisol compared with those taken from aged-matched, healthy controls, the differences were not significant.
“The study suggests that metyrapone augmentation of serotonergic antidepressants is not an option for treatment-resistant depression in routine clinical practice at this time,” McAllister-Williams told Psychiatric News. “This, however, does not exclude the possibility that antiglucocorticoid treatments are of relevance to some patients with MDD at some point in their treatment.”
McAllister-Williams said that the current challenge is to identify which patients with MDD might benefit from antiglucocorticoid treatments and at what stage in their illnesses should such treatments be used.
The study authors concluded that further research to clarify the extent and longitudinal course of HPA axis abnormalities in major depressive disorder and treatment-resistant depression are needed.
The study was funded by the Medical Research Council and National Institute for Health Research. ■
