Stress Hormone Dynamics Are Coupled to Brain Serotonin 4 Receptor Availability in Unmedicated Patients With Major Depressive Disorder: A NeuroPharm Study.

Abstract

BACKGROUND:

A prominent finding in major depressive disorder (MDD) is distorted stress hormone dynamics, which is regulated by serotonergic brain signaling. An interesting feature of the cerebral serotonin system is the serotonin 4 receptor (5-HT4R), which is lower in depressed relative to healthy individuals and also has been highlighted as a promising novel antidepressant target. Here, we test the novel hypothesis that brain 5-HT4R availability in untreated patients with MDD is correlated with cortisol dynamics, indexed by the cortisol awakening response (CAR). Further, we evaluate if CAR changes with antidepressant treatment, including a selective serotonin reuptake inhibitor, and if pretreatment CAR can predict treatment outcome.

METHODS:

Sixty-six patients (76% women) with a moderate to severe depressive episode underwent positron emission tomography imaging with [11C]SB207145 for quantification of brain 5-HT4R binding using BPND as outcome. Serial home sampling of saliva in the first hour from awakening was performed to assess CAR before and after 8 weeks of antidepressant treatment. Treatment outcome was measured by change in Hamilton Depression Rating Scale 6 items.

RESULTS:

In the unmedicated depressed state, prefrontal and anterior cingulate cortices 5-HT4R binding was positively associated with CAR. CAR remained unaltered after 8 weeks of antidepressant treatment, and pretreatment CAR did not significantly predict treatment outcome.

CONCLUSIONS:

Our findings highlight a link between serotonergic disturbances in MDD and cortisol dynamics, which likely is involved in disease and treatment mechanisms. Further, our data support 5-HT4R agonism as a promising precision target in patients with MDD and disturbed stress hormone dynamics.

• Authors: Gunild M Vulpius, Kristin Köhler-Forsberg, Brice Ozenne, Søren V Larsen, Arafat Nasser, Claus Svarer, Nic Gillings, Sune H Keller, Martin B Jørgensen, Gitte M Knudsen, Vibe G Frokjaer
• Journal: The international journal of neuropsychopharmacology (Int J Neuropsychopharmacol) Vol. 26 Issue 9 Pg. 639-648 (09 25 2023) ISSN: 1469-5111 [Electronic] England
• PMID: 37542733 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of CINP.

Chemical References

• Receptors, Serotonin, 5-HT4
• Hydrocortisone
• Antidepressive Agents

Topics

• Humans
• Female
• Male
• Depressive Disorder, Major (diagnostic imaging, drug therapy, metabolism)
• Receptors, Serotonin, 5-HT4 (metabolism, therapeutic use)
• Hydrocortisone (metabolism)
• Brain (diagnostic imaging, metabolism)
• Antidepressive Agents (pharmacology, therapeutic use, metabolism)