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Randomized Controlled Trial
. 2025 Mar 15:373:126-132.
doi: 10.1016/j.jad.2024.12.036. Epub 2024 Dec 12.

Associations between hypothalamic-pituitary-adrenal (HPA) axis hormone levels, major depression features and antidepressant effects of ketamine

Polymnia Georgiou  1 , Cristan A Farmer  2 , Gustavo C Medeiros  3 , Peixiong Yuan  2 , Jenessa Johnston  2 , Bashkim Kadriu  2 , Todd D Gould  4 , Carlos A Zarate Jr  5
Affiliations
Randomized Controlled Trial

Associations between hypothalamic-pituitary-adrenal (HPA) axis hormone levels, major depression features and antidepressant effects of ketamine

Polymnia Georgiou et al. J Affect Disord. .

Abstract

Background: 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.

Methods: 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.

Results: 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.

Discussion: 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.

Keywords: Adrenocorticotropic hormone; Corticotropin releasing factor; Cortisol; Depression; Ketamine.

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Conflict of interest statement

Declaration of competing interest Dr. Zarate is listed as a coinventor on a patent for the use of ketamine in major depression and suicidal ideation. Dr. Zarate is listed as coinventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. Drs. Zarate, and Gould are listed as co-inventors on a patent application for the crystal forms and methods of synthesis of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine and the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. Dr. Zarate have assigned their patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. Dr. Gould has assigned his patent rights to the University of Maryland. All other authors have no conflict of interest to disclose, financial or otherwise.

Figures

Figure 1:
Figure 1:. Baseline levels of HPA-axis reactivity prior to placebo or ketamine infusion.
Plasma levels of (A) CRF, (B) ACTH, and (C) cortisol prior to the first infusion with either ketamine or placebo. Logarithmic normalization of plasma levels of (D) CRF, (E) ACTH, and (F) cortisol prior to the first infusion with either ketamine or placebo in males and females.
Figure 2:
Figure 2:. Spearman Correlation analysis of baseline measurements.
Correlation matrix analysis of baseline measure of (A) both sexes combined. (B) females, and (C) males. Values represent the Spearman R. *p<0.05; **p<0.01, ***P<0.001.
See this image and copyright information in PMC

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