Modern-day life appears to be more stressful than ever before – with COVID-19, lockdown living, economic uncertainty, and impending Brexit being superimposed upon a decade of austerity, all contributing to immeasurable hardship over recent years. The uncertainty that we have, and are continuing, to face is a stressful experience for millions of people within the UK, and beyond. But, what is ‘stress’, and why is this important when considering our health? There is no doubt that our acute stress response offers an innate survival instinct that is critical within the evolution of our mammalian species. This mechanism continues to permit our survival and continued evolution from our shared ancestors, such as Lucy (australopithecus afarensis) to our current evolutionary state, and will continue to shape our ongoing evolution.
While it is accepted that our acute stress response is a critical factor in permitting our ongoing survival as a species, what about longer-term, or chronic, stress? Twelve years on from the financial crash of 2008, levels of both relative and absolute poverty within the UK have escalated significantly. This can develop into a much longer form of toxic stress, and exposure to such experiences is evidenced to be associated with poorer health outcomes across multiple domains, including both ‘mental’ and ‘physical’ disorders (I use these terms with caution for fear of perpetuating Cartesianism). This is evidenced from subjection to chronic stress leading to inflammatory responses within the body – which contributes to multiple health conditions, with examples ranging from depression to cancer and diabetes to autoimmune disorders. While the argument is strong that acute stress is very good for us, chronic stress, along with the accompanying inflammatory response, certainly is not.
The human ‘stress axis’, the hypothalamic-pituitary-adrenal (HPA) axis, is a complex set of negative feedback loops responsible for the human stress response. When an individual is exposed to chronic stress (or, life events that one perceives as being stressful), there is an allostatic alteration leading to the HPA axis becoming hyperactive, which consequently can lead to a vicious cycle of inflammation. The hormones secreted by the HPA axis, among others, include cortisol and corticotrophin-releasing factor (CRF), which, when expressed at excessive levels, have a deleterious effect upon the central nervous system. However, CRF may play a critical role within future therapeutics, as a potential target for new antidepressant agents. Antagonism of CRF1 may offer relief from the vicious cycle of stress and inflammation frequently observed within those who are depressed. Researchers have been exploring this area in recent years, and advances in this area would be a very welcome addition.
Cortisol is probably the most well-known of these hormones and is evidenced to accumulate excessively during exposure to chronic stress. This is associated with impaired long-term potentiation, which is critical within learning and memory, as well as adversely impacting upon neuroplasticity and reducing adult neurogenesis in the dentate gyrus area of the hippocampus. These factors contribute to poorer cognition and motivational states, features often observed within those who are depressed. In addition, animal models demonstrate that exposure to chronic stress leads to reduced neuronal branching within the hippocampus, as well as a reduced number of synaptic contacts. In addition, there is also evidence that chronic and excessive cortisol leads to shrinkage of the hippocampus, the human ‘memory centre’.
Essentially, it is clear (and becoming increasingly clearer still) that chronic stress, along with the excessive inflammatory response, is very bad for us. It is also noteworthy that some endocrinological conditions – such as Cushing’s syndrome – display chronic hypercortisolemia. There is evidence of secondary depressive illness for between 30–50% of individuals with the syndrome. Might it be that the knowledge gained from better understanding cortisol and inflammation leads to clinical advances within the detection and treatment of depression? Perhaps, particularly with the possibility of salivary cortisol levels or hair cortisol levels being recorded to assist within the diagnostic process, potentially offering a valuable biomarker.
While we know that depression is very common – and is now considered the most common cause of disability globally – the precise aetiological mechanism remains unclear. However, it is accepted that the risk factors that predispose individuals to develop depression are legion; these are a delicate blend of genetic factors, epigenetic modifications, and life experiences. However, it may be fair to state that the more we learn of depression, the more questions arise.
Recovery from depression is possible with recommended treatment strategies, including lifestyle adaptions, the use of antidepressant agents (selective serotonin reuptake inhibitors, or SSRIs, are first-line choices), along with psychological interventions, such as cognitive behavioural therapy. However, it is accepted that those who have experienced depression are likely to have a higher-than-average probability of relapse in the future – this being very often precipitated by escalating levels of psychosocial stressors. SSRIs act by enhancing the quantity of serotonin (5HT) available at the post-synaptic receptor by blocking the reuptake at the pre-synaptic receptor and increasing the available 5HT within the synaptic gap.
These commonly used medications are lifesaving interventions for many who are prescribed these. SSRIs are also evidenced to increase brain-derived neurotrophic factors (BDNF), which promotes neuronal and glial cell survival and promotes adult neurogenesis within the hippocampus. These mechanisms are considered crucial in the treatment of depressive illnesses.
While progress is being made related to understanding the interface between stress and health, there is still much to understand. We know that a nurturing environment can protect against subsequent stress, as well as that stressful experiences (particularly during development) may precipitate long-lasting alterations of the HPA axis and influence subsequent emotional reactivity. Many of these alterations persist long after the initial stress has been removed. But, what can we do now, today, to best manage our own stress levels? As you’d expect, try to minimise your stress, but of course, this isn’t always possible. Some small changes may assist; maybe commence with a reduction of alcohol consumption, along with an introduction to sleep hygiene and exercise. Exercise, considered to be just as effective as SSRIs in mild depression, is also evidenced to enhance adult neurogenesis within the hippocampus – potentially mitigating the effect of depression.
As we move forward in a time of increasing uncertainty, it may be that we have even more reason to assist each other in recognising, managing, and reducing chronic stress for the benefit of us all.
Joel Petch is a senior lecturer at Kent and Medway Medical School. Joel tweets @joelpetch
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