Evidence map›Paper›PMID 39674325›Full record

Trial reportJournal of affective disorders2025

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

Abstract readRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Journal of affective disorders, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

11 citing papers in PubMed.

  1. Article
  2. The hippocampus as a central hub in ketamine's antidepressant action: from molecules to circuit rewiring.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026
    Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors.

Polymnia GeorgiouDepartment of Psychiatry, School of Medicine, University of Maryland, Baltimore, MD, USA; Department of Psychology, University of Wisconsin, Milwaukee, WI, USA.
Cristan A FarmerExperimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Gustavo C MedeirosDepartment of Psychiatry, School of Medicine, University of Maryland, Baltimore, MD, USA.
Peixiong YuanExperimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Jenessa JohnstonExperimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Bashkim KadriuExperimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Todd D GouldDepartment 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.
Carlos A ZarateExperimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. Electronic address: zaratec@mail.nih.gov.

Funding

Glutamatergic Modulators for Rapid & Sustained Antidepressant EffectZIAMH002857 · NIMH · NATIONAL INSTITUTE OF MENTAL HEALTH · PI ZARATE, CARLOS · 2009 to 2025
$55.0M
Therapeutic Efficacy of Ketamine Metabolites for Depression TreatmentR01MH107615 · NIMH · UNIVERSITY OF MARYLAND BALTIMORE · PI GOULD, TODD D · 2016 to 2025
$7.2M
BLRD VA I01 BX003631BLRD VA I01 BX006018Intramural NIH HHS ZIA MH002857NIMH NIH HHS R01 MH107615
6 · The paper itself

Abstract

backgroundSubanesthetic 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.

methodsWe 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.

resultsWe 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.

Indexed as

Adrenocorticotropic HormoneAntidepressive AgentsDepressive Disorder, Treatment-ResistantHydrocortisoneHypothalamo-Hypophyseal SystemKetamineMajor Depressive DisorderAdultCorticotropin-Releasing HormoneCross-Over StudiesFemaleHumansMaleMiddle AgedPituitary-Adrenal SystemAdrenocorticotropic HormoneAntidepressive AgentsCorticotropin-Releasing HormoneHydrocortisoneKetamineAdrenocorticotropic hormoneCorticotropin releasing factorCortisolDepressionKetamine

Identifiers

PMID39674325
PMCPMC12186659

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.