Cortisol Hyper-Reactivity to Stress - A Putative Biomarker for Major Depressive Disorder

Lead Research Organisation: University of Cambridge
Department Name: Psychiatry

Abstract

Depression is one of the most common and disabling illnesses throughout the world. Scientists have not been able to develop tests that can help doctors reliably predict whether people will get depressed; or if they already are depressed, how soon they will get better or what the best treatment would be.

The proposed study will investigate a possible ?biomarker? or ?biological test? for depression, which we hope will be useful for doctors trying to treat and prevent depression. All people produce a hormone called cortisol. Cortisol should increase when people get stressed (this can be a physical stress, such as being starved, or a mental stress, such as a job interview). Research has suggested that cortisol increases more in people vulnerable to depression when they encounter stress. Therefore a test which measures cortisol response to stress may be a good biomarker for depression. We shall test which of two stress tests is a better potential biomarker: a physical stress [taking one deep breath of air containing a high concentration (35%) of carbon dioxide (a naturally-occurring gas in the atmosphere)] and a mental stress [participants give a talk and do some mental arithmetic in front of a mock interview panel]. Several studies have shown that these tests increase cortisol in most people, and are safe. This study will test whether cortisol reactivity is related to other known risk factors for depression; and whether it is higher in people who used to be depressed than in people who have never been depressed. Cortisol reactivity and resting cortisol will be compared as potential biomarkers.

The proposed study, by the Universities of Cambridge and Bristol, will recruit 228 Cambridgeshire 17-19 year olds who are already taking part in one of our long-term studies. We can test people?s cortisol levels from their saliva. We shall ask participants to collect their saliva 6 times per day over two days, so we can test resting cortisol. Then we shall ask them to come to our Cambridge laboratory on two occasions. At the start of the first session, while resting, they will be asked some questions about their psychiatric history and given some memory tests. In each session, they will be given one of the stress tests. After this, saliva will again be collected so cortisol can be measured. In addition, participants will be asked about how they feel, and some more memory tests will be carried out.

Technical Summary

Current potential biomarkers for unipolar major depression (MD) have low predictive power, or are too expensive or distressing for application in clinical settings. The proposed application will test whether cortisol reactivity to stress is a valid biomarker for MD in a sample of adolescents. It will compare two challenge tests (a deep (tidal) breath of 35% Carbon Dioxide and the Trier Social Stress Test) against measures of resting cortisol. The study will investigate whether cortisol reactivity to stress is:

i) Differentially present in individuals at high risk for depression.
ii) Associated with negative cognitive biases associated with depression, thus suggesting a causal pathway and biological plausibility.
iii) More strongly associated with risk factors for depression than are basal cortisol measures.

We shall compare high and low risk individuals by two designs: First we shall compare samples of individuals with no history of psychiatric disorder at high and low risk for depression as defined by 5-HTTLPR genotype and early environment. Second we shall compare never-depressed healthy individuals against those with a past history of depression. We predict that the CO2 test will be easily, rapidly and safely administered, give valid results and be the most valid potential biomarker for MD among the different measures of cortisol tested in this study.

The proposed study will be nested within a cohort of 1142 community-dwelling adolescents (aged 17-19), to maximize recruitment, minimize investigations and to ensure that participants are balanced for the aforementioned risk factors. 228 individuals will be recruited (168 never depressed, 60 past depression).

Participants will be asked to collect salivary cortisol at 6 time points on each of two consecutive days. They will be asked to attend the behavioural research laboratory on two occasions 4 weeks apart. At the start of the first session, behavioural and memory measures will be assessed. On each occasion, one of the stress tests will be administered (in random order); salivary cortisol will be collected four times over the following hour. Memory will be re-tested 25 minutes after onset of each stress test, at the cortisol peak.

Results will be published in peer-reviewed journals, presented at international conferences, put on a study web-site and communicated to appropriate user and carer groups. If the study suggests cortisol reactivity to stress is a valid biomarker for depression, future studies will test whether it reliably predicts future onset of depression, prognosis of current depression and differential response to treatment.

Publications

10 25 50
 
Description Isaac Newton Trust
Amount £18,260 (GBP)
Organisation University of Cambridge 
Department Isaac Newton Trust
Sector Academic/University
Country United Kingdom
Start 12/2009 
End 12/2010
 
Description AH Student 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Department Faculty of Psychology and Educational Sciences
Country Germany 
Sector Academic/University 
PI Contribution Research supervision of a Masters student from Maastricht University, and access to research data and facilities for this project
Collaborator Contribution Data analysis and paper writing
Impact Paper still being written Masters awarded
Start Year 2012
 
Description David Nutt 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution I have led the research project
Collaborator Contribution Prof Nutt has provided input into the design, conduct and analysis of the use of the 35% carbon dioxide test used in the study
Impact Development and award of the MRC cortisol reactivity grant
Start Year 2008
 
Description David Nutt 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution I have led the research project
Collaborator Contribution Prof Nutt has provided input into the design, conduct and analysis of the use of the 35% carbon dioxide test used in the study
Impact Development and award of the MRC cortisol reactivity grant
Start Year 2008
 
Description KF Student 
Organisation Maastricht University (UM)
Department Faculty of Psychology and Neuroscience
Country Netherlands 
Sector Academic/University 
PI Contribution Research supervision of a Masters student from Maastricht University, and access to research participants, data and facilities for this project
Collaborator Contribution Data collection and analysis. Paper writing
Impact Successful award of masters degree. Paper still being prepared for publication
Start Year 2012
 
Description Kumsta 
Organisation Ruhr University Bochum
Department Faculty of Psychology
Country Germany 
Sector Academic/University 
PI Contribution We led the research study
Collaborator Contribution Prof Kumsta advised on use of the Trier Social Stress Test, conduct of study and analysis of results
Impact Presentation of results at RCPsych International Congress 2013
Start Year 2009
 
Description Kumsta 
Organisation University of Southampton
Country United Kingdom 
Sector Academic/University 
PI Contribution We led the research study
Collaborator Contribution Prof Kumsta advised on use of the Trier Social Stress Test, conduct of study and analysis of results
Impact Presentation of results at RCPsych International Congress 2013
Start Year 2009