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

Int J Neuropsychopharmacol. 2023 Sep 25;26(9):639-648. doi: 10.1093/ijnp/pyad041.


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.

Keywords: Major depressive disorder; SSRI; cortisol awakening response; serotonin 4 receptor; stress hormone dynamics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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