The role of the Hypothalamic-Pituitary-Adrenal axis in depression: a focus on the hippocampus

Abstract

This research will investigate the role of the HPA axis in hippocampal function in depression and whether this might be partly mediated by effects on glutamate neurotransmission. Specific hypotheses are:

1. Patients with treatment resistant depression (TRD) will have a) decreased hippocampal responses to intravenous hydrocortisone administration b) decreased hippocampal activation during episodic and working memory tasks and c) impaired episodic and working memory; and these will be normalised by treatment with metyrapone
2. Hydrocortisone administration will increase glutamate release in hippocampal neurons

The first hypothesis will be addressed as part of an NIHR-funded clinical trial in patients with TRD using fMRI to measure hippocampal activity during memory tasks before and after treatment with the cortisol synthesis inhibitor, metyrapone. Intravenous hydrocortisone during fMRI will be used as probe of hippocampal corticosteroid receptor function, which has been developed in the first year of this project.

To test the second hypothesis healthy volunteers will receive hydrocortisone or saline infusion during magnetic resonance spectroscopy to measure glutamate concentrations and subsequent have EEG theta wave activity recorded during a memory task.

This research will help clarify the role of abnormalities in HPA axis function in depression and inform the development of novel treatment strategies for depression.

Duration of the project

3 years

Funding body

University of Manchester Biomedical Research Centre (BRC)