Explain the biological mechanisms by which stress can induce depressive behaviour.
Depressive behaviour is a core feature of several major psychological disorders, most obviously major depression (MD) and depressive episodes of bipolar depression (BP). Depression is also frequently found to be co-morbid with psychotic disorders such as schizophrenia and with anxiety-related disorders (e.g. social phobia or OCD). Depression is the biggest major risk factor for self-harm and suicide, thus posing a real clinical problem to try to understand and reverse the mechanisms involved. Traditional anti-depressant treatment has only shown a modest benefit to placebos in treating the disorder; therefore, more effective drugs that target the right biological mechanisms are imminently needed. The majority of experimental research in the area has used rodents to test medication and model known psychopathological aspects of depression in humans, such as learned helplessness, cognitive deficits and increased co-morbidity with anxiety-related behaviours. There are many factors that may explain why some people (around 16% of the population) will experience a depressive episode in their lifetime and others won’t. Genetic vulnerability and epigenetic changes, psychosocial support, socioeconomic status or even climate-related factors all have to be considered in considering the right treatment for individual cases. Whilst the causal link between many of these and the onset of depression is somewhat inconclusive, the strong association between chronic mild stress (CMS) and depressive behaviour is now a huge area of research, resulting in the stress-induced model of depression. Even where there is evidence for the role of genes in depression, such as allele variants for the 5-HTT promoter region, it is shown to vary as a function of exposure to stressful life events. The mechanisms by which environmental stressors can lead to depressive behaviour have been explored thoroughly, with a strong focus on the role of the Hypothalamus-Pituitary-Adrenal (HPA) axis and its dysfunction in depression. The consequent rise in levels of the glucocorticoid hormone cortisol, following HPA activation, has been shown to become chronic increased in depressed patients. This is thought to be due to the development of glucocorticoid resistance, whereby high levels of cortisol are present in the bloodstream and peripheral tissue but negative feedback to shut down the HPA axis no longer works. Due to the numerous roles of cortisol within the body, several biological processes may be affected as a consequence of CMS that may lead to depressive behaviour. Direct and indirect effects of HPA dysfunction include changes in immune response, neuronal damage, decreased rates of neurogenesis and the serotonin pathways. These processes tend to interact and exacerbate one another; therefore, understanding each proposed biological mechanism of stress-induced depression and their impact upon each other is likely to lead to a better treatment outcome. Acute Stress and the HPA Axis
The experience of acute mild stress is a normal and adaptive process, triggered by an environmental ‘stressor’ deemed to be potentially harmful. From an evolutionary perspective, this serves to protect the individual from danger via activation of the sympathetic nervous system, preparing the individual for ‘fight or flight’ mode. Stress, as well as input from the amygdala, hippocampus and midbrain, directly activates the ‘stress response’ via the Hypothalamic-Pituitary-Adrenal (HPA) axis. The first immediate response is the release of corticotrophin releasing hormone (CRH) from the hypothalamus, which travels to the pituitary where it binds to CRH Receptor 1 (CRHR1). CRH can also act directly on other brain regions, e.g. the amygdala at this early stage. CRH1 activation stimulates the release of adrenocorticotrophin release hormone (ACTH), which travels via the bloodstream to the kidneys,...
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