Investigating the Differential Impact of Hydrocortisone on Depressive Symptoms: A Double-Blind, Placebo-Controlled, Crossover Study

Abstract

Research Question: The study investigates: "Will depressed patients experience a reduction in depressive symptoms, measured by the Quick Inventory of Depressive Symptomatology (QIDS), when treated with hydrocortisone as opposed to a placebo?"

Background and Significance: Major depressive disorder (MDD), characterized by altered cortisol levels, has been a subject of extensive research. Recent studies, such as those conducted using the UK Biobank data, have shown that both systemic and inhaled glucocorticoid use is associated with changes in brain volume and white matter microstructure, impacting cognitive and emotional outcomes. This study is an interim, secondary analysis of a double-blind, placebo-controlled clinical trial with treatment crossover, examining the effects of hydrocortisone on the human hippocampus (NCT03896659). This manuscript is focusing on an interim secondary analysis of a larger trial. While the main study is interested in understanding whether hydrocortisone has a differential effect on the hippocampus of depressed versus non-depressed individuals, we are investigating if depressed patients will experience a reduction in depressive symptoms, measured by the Quick Inventory of Depressive Symptomatology (QIDS), when treated with hydrocortisone as opposed to a placebo. A meta-analysis highlighted the importance of HPA axis dysregulation in the onset and maintenance of depressive symptoms, suggesting that targeting this dysregulation could advise therapeutic strategy. The manipulation of cortisol levels has been shown to have a significant impact on depression symptoms. According to DeBattista et al. (2000), acute hydrocortisone infusion significantly reduced the severity of depression in patients with major depression, suggesting that cortisol modulation may be of therapeutic benefit in depression.

Materials and Methods: This study is an interim, secondary analysis of an NIH-funded (5R01MH115932-05) double-blind, placebo-controlled clinical trial with treatment crossover, examining the effects of hydrocortisone on the human hippocampus (NCT03896659). Eligible participants were allocated into two groups based on their baseline QIDS-C: the ¿depressed¿ arm (QIDS-C 11-20), consisting of individuals diagnosed with Major Depressive Disorder (MDD), and the ¿healthy control¿ arm (QIDS-C ? 5), individuals with no history of MDD diagnosis. Of the 54 potentially eligible participants, 12 participants were lost to follow up or screen failed. Therefore, a total of 42 participants were included in this study. For each group, participants were randomized by a statistician to receive either hydrocortisone (160 mg tablet) or a matching placebo tablet for three days, followed by MRI and cognitive testing, with a subsequent washout period and treatment cycle repeat. The study was conducted over a total of five visits.

Results: Building on existing research indicating altered brain structures and cognitive functions in glucocorticoid users, this study's preliminary insights suggest a nuanced response to hydrocortisone in the modulation of depressive symptoms. The expected outcomes, based on initial data, indicate that depressed patients might exhibit a more significant change in QIDS scores following hydrocortisone treatment compared to placebo, aligning with clinical trial findings. However, our results revealed no significant difference in QIDS-C scores when treated with hydrocortisone versus the placebo among the depressed cohort.

Conclusion: This study aims to augment the understanding of cortisol's role in depression. While final results are pending, the interim secondary analysis may enhance understanding of the role cortisol plays in depression. Our results highlight the complexity of the HPA axis feedback mechanism and its role in depression. This is further supported by evidence suggesting variability in glucocorticoid receptor sensitivity among individuals. Additionally, both high and low cortisol states have been associated with depressive disorders. The study's design is anticipated to yield robust, generalizable data, influencing future clinical practices and psychoneuroendocrinology research.