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Adverse events such as abuse in childhood are closely related to risk of psychiatric disorder in adulthood. But the effects of such experiences are modulated by genetic factors. Can we begin to understand the daunting complexity of this interaction by looking at the stress hormone system, which is often dysregulated in psychiatric disorders?
The glucocorticoid receptor is a nuclear receptor which engenders a transcriptome-wide stress response in the cell. It is now clear that exposure to the stress hormone also remodels the epigenetic landscape, mostly through a decrease in DNA methylation.
Such changes, which (among other possible effects) had implications for neuronal differentiation were evident even after a washout period of twenty days. Effects were long lasting and seem capable of altering the impact of subsequent adverse stress-related events over a lifetime.
Basic molecular mechanisms are a good place to start when trying to understand complex gene-environment interactions
Such insights prompted work on multipotent human hippocampal progenitor cells. These cells react to glucocorticoids and so may represent a good model of early exposure to stress. In this model, exposure to dexamethasone produced the expected epigenetic changes in DNA methylation.
Importantly, these changes were found to be located in gene enhancer regions that are relevant both to brain development and to risk of mood disorders. Demethylation seems to prime genes to be more reactive to future stress.
But genetic variation modulates the epigenetic response to glucocorticoid activation and to changes in transcription. And it is revealing that SNPs linked by genome-wide association studies to increased risk of schizophrenia and depression are found in the loci showing methylation changes. This association may show – at a molecular level – how the risk of stress-related disorders is determined by both environmental and genetic factors.
There are certainly many non-glucocorticoid mechanisms that influence an individual’s vulnerability or resilience to mental health problems, Professor Binder concluded. But glucocorticoids do seem able to prime an organism to respond differently to stress.
Polygenic risk factors interact with the environment to increase vulnerability to depression. Do molecular events caused by exposure to stress hormones help us understand this complex interaction?
The depth of depression in some of our patients is not well captured by MADRS and HAM-D. Even when the scores are high. Though we do use them, they do not necessarily capture the full depth of depression of emotion in some patients. Lots of emotional information is lost. Perhaps this is too much to ask of a questionnaire! But you can get the information by talking and, above all, listening. It’s about empathy.
And that’s what I try and do. Of course, it’s time consuming. But if I am on call and not too busy, I go to the acute unit and sit and talk to patients. We talk about anything – what they’re watching on TV, politics, religion, football. What they think about the world. What they think about their therapies. Anything that moves them.
I use both drugs and psychotherapy – Acceptance and Commitment Therapy (ACT). If you are anxious or depressed, most of the time you hide. You avoid things. And if you do that, slowly but inevitably, your life becomes empty. And if your life is empty it is impossible to recover from depression.
The therapy is about accepting the fact that you may not be able to control your thoughts and the feelings that come with them. But you can control your actions and the values and direction of your life. The commitment is to act according to your values to rebuild your life. To approach once again your family, your health.
I use this therapy in combination with antidepressant drugs. Ours is a private hospital, so patients are paying. And part of our job is to make sure they get the most effective combination of treatment that is possible.
Dr Jose Antonio Aguado of the Hospital Benito Menni, Valladolid, Spain, talks about his approach to the management of depression and the importance of combined treatment.