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 Johnston; Bashkim Kadriu; Todd D Gould; Carlos A Zarate Jr

doi:10.1016/j.jad.2024.12.036

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

J Affect Disord. 2024 Dec 12:S0165-0327(24)02022-6. doi: 10.1016/j.jad.2024.12.036. Online ahead of print.

Authors

Polymnia Georgiou¹, Cristan A Farmer², Gustavo C Medeiros³, Peixiong Yuan², Jenessa Johnston², Bashkim Kadriu², Todd D Gould⁴, Carlos A Zarate Jr⁵

Affiliations

¹ Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, MD, USA; Department of Psychology, University of Wisconsin, Milwaukee, WI, USA.
² Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
³ Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, MD, USA.
⁴ Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, MD, USA; Veterans Affairs Maryland Health Care System, Baltimore, MD, USA; Departments of Pharmacology, Neurobiology School of Medicine, University of Maryland, Baltimore, MD, USA.
⁵ Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. Electronic address: [email protected].

PMID: 39674325
DOI: 10.1016/j.jad.2024.12.036

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.