Associations between hypothalamic-pituitary-adrenal (HPA) axis hormone levels, major depression features and antidepressant effects of ketamine.
Polymnia Georgiou, Cristan A Farmer, Gustavo C Medeiros, Peixiong Yuan, Jenessa N Johnston, Bashkim Kadriu, Todd D Gould, Carlos A. Zarate
Journal of Affective Disorders March 15, 2025 DOI: 10.1016/j.jad.2024.12.036 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized, placebo-controlled, crossover trial Peer reviewed |
|---|---|
| Sample size | 42 |
| Population | Participants with treatment-resistant depression following medication washout |
| Intervention | intravenous ketamine |
| Topics | Depression Ketamine Esketamine |
| Keywords | Adrenocorticotropic hormone Corticotropin releasing factor Cortisol Stress hormones Ketamine therapy Mental health biomarkers Endocrine system |
| Citations | 24 |
| Key findings | Baseline HPA axis hormone levels did not moderate ketamine's antidepressant effects, but ACTH and CRF levels were negatively associated with the duration of depressive episodes. |
Abstract
Subanesthetic doses of (R,S)-ketamine (ketamine) have demonstrated rapid and robust antidepressant effects in individuals with depression. However, individual variability in response to ketamine exists, and current biomarkers of ketamine treatment response are not entirely understood. Preclinical evidence suggests a link between hypothalamic-pituitary-adrenal (HPA) axis activation, a determinant of the stress response system, and ketamine's efficacy in stressed mice exhibiting enhanced antidepressant responses. Here, we assessed the relationship between HPA axis, major depression features, and antidepressant response to ketamine in humans. We investigated 42 participants following medication washout with treatment-resistant depression who participated in a randomized, placebo-controlled, crossover trial receiving intravenous ketamine. Plasma levels of corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline. Ketamine's antidepressant effects were assessed using the Montgomery-Asberg Depression Rating Scale. We found that baseline HPA axis hormone levels did not significantly moderate the antidepressant effects of ketamine. However, a negative association was observed between ACTH and CRF levels and the overall duration of depressive episodes, suggesting potential biomarker implications. Also, a negative correlation between baseline depressive scores and age of onset was observed, suggesting that the severity of depression might be greater if it develops at a younger age, indicating more enduring stress on the brain and body. 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.
Comparable studies
Other randomized controlled trials on ketamine for depression, most cited first.