A study of individuals with treatment-resistant depression found that hormones associated with the hypothalamic-pituitary-adrenal (HPA) axis do not influence the antidepressant effects of ketamine. However, individuals with longer-lasting depressive episodes tended to have lower levels of adrenocorticotropic hormone (ACTH) and corticotropin-releasing factor (CRF). The research was published in the Journal of Affective Disorders.
The HPA axis is a complex neuroendocrine system that helps regulate the body’s response to stress. It coordinates interactions between the hypothalamus, pituitary gland, and adrenal glands.
When a person experiences a stressor, the hypothalamus releases CRF, which prompts the pituitary gland to secrete ACTH. ACTH then travels through the bloodstream to the adrenal glands, triggering the release of cortisol. Cortisol is a key stress hormone that helps maintain balance in the body by regulating metabolism, immune function, and blood pressure. The adrenal glands also release other hormones, such as adrenaline and noradrenaline, to prepare the body for a “fight or flight” response.
When the HPA axis is chronically activated, it can become dysregulated. This dysregulation has been linked to various health conditions, including anxiety, depression, and metabolic disorders. Feedback mechanisms normally help prevent overactivation; high cortisol levels signal the hypothalamus and pituitary gland to reduce CRF and ACTH production. Dysfunction in this feedback system has been implicated in stress-related conditions such as posttraumatic stress disorder.
The research team, led by Polymnia Georgiou, aimed to investigate whether the antidepressant effects of ketamine might be influenced by HPA axis hormone levels. Ketamine, originally developed as an anesthetic, has gained attention in recent years as a fast-acting treatment for people with depression that has not responded to other therapies. The researchers hypothesized that ketamine might be more effective in individuals with higher baseline levels of HPA axis hormones.
The study included 42 participants diagnosed with treatment-resistant depression. Sixty percent of the participants were women, and the average age was 36.
Each participant received two intravenous infusions, spaced two weeks apart. One infusion consisted of 0.5 mg/kg of ketamine hydrochloride, while the other was a saline solution, which served as a placebo control. Half of the participants received the ketamine infusion first, while the other half began with the placebo. Each infusion lasted 40 minutes.
To measure changes in depression, participants completed the Montgomery-Åsberg Depression Rating Scale before the infusion and on nine occasions over the following 11 days. Blood samples were also collected 60 minutes before each infusion and at several time points afterward to measure hormone levels associated with the HPA axis.
The results showed that none of the measured hormones—CRF, ACTH, or cortisol—moderated the antidepressant effects of ketamine. The therapeutic benefits of ketamine were not influenced by hormone levels at any time point, and no sex differences were observed.
However, the researchers found that participants with longer durations of depressive episodes had lower levels of ACTH and CRF. This suggests that these hormones could potentially serve as biomarkers for the chronicity of depression. In addition, participants who developed depression at a younger age tended to report more severe symptoms.
“Although we did not find a moderation effect of the plasma HPA axis hormones on the antidepressant effects of ketamine, moderation effects of the brain HPA axis hormones cannot be precluded and warrants further investigation. Importantly, our results implicate HPA axis components as potential biomarkers for the duration of depressive episodes,” the study authors concluded.
The findings add to the growing body of research on ketamine’s antidepressant effects and the biological factors that may be linked to depression severity and chronicity. But the study had limitations. Most notably, it involved a relatively small sample size, which may have limited the ability to detect smaller or more subtle effects.
The paper, “Associations between hypothalamic-pituitary-adrenal (HPA) axis hormone levels, major depression features and antidepressant effects of ketamine,” was authored by Polymnia Georgiou, Cristan A. Farmer, Gustavo C. Medeiros, Peixiong Yuan, Jenessa Johnston, Bashkim Kadriu, Todd D. Gould, and Carlos A. Zarate Jr.