Psychology and Neuroscience of Affective Disorders PDF - King's College London

Module: Psychology and Neuroscience of Affective Disorders Week 3 Cognitive and biological alterations of affective disorders Topic 2 The neurobiological aspects of stress response - part 2 of 3 Dr Patricia Zunszain Senior Lecturer, Department of Psycho...

Module: Psychology and Neuroscience of Affective Disorders Week 3 Cognitive and biological alterations of affective disorders Topic 2 The neurobiological aspects of stress response - part 2 of 3 Dr Patricia Zunszain Senior Lecturer, Department of Psychological Medicine Lecture transcript Slide3: If we are chased by a lion, an acute stress response is ideal. And this has a role for this type of situation and is very adaptive. It allows the mobilisation of glucose and other energy molecules to fuel muscles for flight or fight. Now being chased by a lion is not a common situation nowadays. If we consider public speaking, a situation which many people find stressful, there will be increased blood flow to the brain which helps facilitate cognition and increased alertness, we may have faster breathing and an increase in blood pressure, digestion will slow dramatically, and perspiration would increase to cool the body. If we measure cortisol in saliva of these individuals, levels would be increased, resulting in increased energy mobilisation. Muscle tension can increase to prepare for this fight or flight, and some of you may have experience these effects of stress. Slide 4: In modern life, stressors are more likely to be chronic, and they can be imagined, such as when we anticipate events in the future. And at some point, this stress response can become more damaging than the stressor itself. Chronic stress can cause digestive problems, increases stomach acids, increased cholesterol and fatty the acids, and increase blood pressure and blood sugar, contributing to the development of hypertension and diabetes. It can also cause menstrual cycle irregularities in women, reduced sperm count and reduced testosterone levels in men, and increased chances of developing infections. And if the levels are more severe, we may see depression. Slide 5: Stress and depression are highly correlated. While the relationship between stressful life events and the risk of onset of depression has been repeatedly demonstrated, the effects of stress depend on the individual, so we can consider some vulnerability factors. In an interesting study of over 7,500 individual twins from a population-based sample, a group of researchers used a proportional hazard model to predict onsets of episodes of major depression, assessing neuroticism and adversity during the past year. As you can see on the slide, stress increase the hazard ratio for all, but those with low levels of neuroticism, as presented in green, are less sensitive to the depressogenic effects of adversity than those with high levels of neuroticism, as seen in orange. Slide 6: We know through animal studies that chronically high glucocorticoid levels, which can either be induced by stress or by direct administration of glucocorticoids, cause depression-like behaviour, decreased neurogenesis, monoamine dysfunction, impaired synaptic plasticity, and reduce volume of the hippocampus in animals, and these are all changes thought to be present in Week 3 © King’s College London 1.  the brains of depressed patients. Interestingly, patients receiving high dose glucocorticoids are initially prone to develop manic symptoms, but after weeks of treatment they are more likely to demonstrate depressive symptoms. These synthetic glucocorticoids are powerful anti- inflammatory agents and are used to treat many inflammatory conditions, like asthma, and autoimmune diseases. In Cushing’s syndrome, a disorder caused by over production of cortisol, which can happen for various reasons including tumours, the rates of depression are also high. Slide 7: As introduced in the previous part, stress is regulated by the HPA axis. The hypothalamus secretes corticotropin releasing hormone and arginine vasopressin, which stimulates the secretion of adrenal cortical hormone from the pituitary. ACTH travels to the adrenal glands to promote the synthesis and release of cortisol, and in conditions of high stress cortisol levels increase. Slide 8: So let's focus on the mechanisms underlying an increase in cortisol production. As presented in the previous part, under normal conditions there is a negative feedback inhibition of the HPA axis, meaning that cortisol produced in response to a stressor would signal back to the hypothalamus and pituitary to stop its production. However, this feedback inhibition does not always work. When the feedback inhibition does not work, we have a phenomenon known as glucocorticoid resistance believed to be related in part to an impaired function of GR, the glucocorticoid receptor. A failure in GR function as hypothesised to take place in depression may result from reduced glucocorticoid binding to GR or from reduced GR expression. If this happens, increased levels of cortisol cannot signal back to the brain to stop the release of CRH and ACTH, and so the production of cortisol continues. Slide 9: Many depressed patients, specifically in more severe cases, show increased cortisol levels, and we talk about hypercortisolism and hyperactivity of the HPA-axis. This happens in classic depression or in the melancholic subtype of depression, both of which are characterised by an unreactive mood. However, we need to remember that depression is a very heterogeneous disorder, and in atypical depression, a subtype that has a reactive mood normally with increased appetite and moods that are strongly reactive to environmental circumstances, HPA axis hypoactivity and hypocortisolism have been reported. We will focus on what happens when there is hypercortisolism. In the following topic, you will learn about the coexistence of two opposite phenomena. In depressed patients, cortisol which we said, is the most potent anti-inflammatory hormone increased in inflammation instead of being decreased, is also elevated as evidence in both cerebrospinal fluid and the periphery. Week 3 © King’s College London 2.