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Are all stressors of equal measure?

Depression is a serious condition that interferes with your ability to work, sleep, to interact with friends and family. In fact, it profoundly affects almost all aspects of your life. To me, perhaps one of the most striking ways in which depression has been described is that “it is like drowning. Except you can see everyone else around you breathing”.

@Tina. Adobe Stock

Of increasing concern is that depression is exceptionally common and has been recognised as one of the leading causes of disability worldwide but unfortunately the development and implementation of effective treatments for depression is struggling to keep pace.

To add to an already highly complicated issue, not all types of depression are the same and the biological causes can be widely different. Currently, the most common treatment for depression involves prescribing antidepressants, which essentially target one biological system and, thus, cause of depression. Unfortunately, this treatment strategy does not work for all forms of depression and treating depression has, therefore, become exceptionally challenging given the complexity of finding the most suitable treatment for an individual and the significant risks posed by the delay this may cause in treatment. Combating the burden imposed by depression has undeniably become a major global challenge for psychiatry.

But why do some people go on to develop depression, while others remain well?

There are many theories to account for this and one leading theory is linked to a dysfunctioning immune system, which leads to increased inflammation throughout the body and in the brain, that can subsequently lower mood. Another important theory concerns the body’s diminished ability to appropriately respond to stressors (such as financial concerns and worries, mounting work pressures, family tensions), so much so that the stress system either remains constantly active and in overdrive or, alternatively, does not respond to stressful stimuli as it should and becomes blunted. Both outcomes have been linked to depression as we have described before in this blog, but importantly these changes in the stress system can change the immune system, which, as already mentioned, the dysfunction of which has been linked to depression in its own right.

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However, it is important to point out that not everyone that experiences stress — as ultimately, we all do — goes on to develop depression.

One potentially important factor might relate to the nature of the type of stress we are exposed to — an idea reinforced by research showing how different forms of trauma, neglect and abuse (which are in fact severe forms of stress) can promote distinct psychological profiles. And this is where my work comes in.

I am a mental health neuroscientist keen to further understand the way in which stress (and inflammation) can lead to depression, hopefully, with a view to help develop more effective treatments for this debilitating condition. In this blog, I will discuss the work I have done trying to disentangle the effect of different stressors on depression and anxiety.

For the most part, research has not dissected the effects of different types of chronic (prolonged and constant) stress but has instead focused on the overall effects of stress (both physical and psychosocial in nature) on the causes of depression. This is largely because of the exceptionally difficult task of cleanly defining and disentangling stressor types like physical stress (e.g., pain or illness) from psychosocial stress (e.g., social isolation and deprivation). But the distinction between the effect of different types of stress on behaviour and physiology may have some important implications.

Indeed, why should we apply a one-size-fits-all approach when for the most part this has been widely deemed inappropriate in psychiatry. Although different stressors may promote several comparable behavioural outcomes (such as low mood, loss of pleasure or interest, loss of concentration, weight and sleep changes), the biological changes leading to these aberrant behaviours, for different types of stress, may be starkly different. So, based on this, I set myself the challenge of determining whether all types of stress are of equal measure using rodent models of stress and depression.

Animal models are not only essential for furthering our understanding of depression and for identifying and developing much needed new treatments, but they make it somewhat easier to practically define and distinguish between stressors. My work, therefore, focused on understanding whether starkly different stressors could promote different depression outcomes in mice by investigating the effects of physical stress and psychosocial stress. This challenge became the sole basis of my doctoral research and from which stemmed two publications, one in Frontiers in Neuroendocrinology and another in Translational Psychiatry, forming the emphasis of this blog.

To kick start my journey, I first reviewed just over 300 hundred animal studies on stress and depression to determine whether there was any evidence to support that different types of stress can indeed promote different depression outcomes in rodents — the results of which are published in Frontiers in Neuroendocrinology.

Through this process, I found some evidence to indirectly support that different types of chronic stress may promote different behaviours and physiological responses. For example, I found how increased inflammation and less hippocampal neurogenesis (i.e., the birth of new brain cells that are needed for learning and memory and regulating mood) was more strongly linked with psychosocial and combined stress (both physical and psychosocial stress) in male rodents, whereas increased brain inflammation was more closely related to psychosocial stress in female rodents. I also found that reduced overall activity was more closely associated with psychosocial and combined stress but was not affected in response to physical stress. And a similar pattern was seen for body weight in female rodents, which was reduced only in mice exposed to combined stress and not psychosocial stress. Therefore, there appears to be some indirect evidence to support that different types of stress may provoke subtly different depression outcomes, ones that may have subtly different underlying biological mechanisms in male and female rodents.

However, one of the main limitations to the research on stressor type thus far is the lack of directly comparable research, that is, studies that directly compare and evaluate the effects of different types of stress. Addressing this issue become my next priority and so I designed an animal experiment that did just this and directly compared the chronic effects of physical stress (in the form of a repeated injection) against the chronic effects of psychosocial stress (represented by permanent social isolation) — as published in Translational Psychiatry.

Du Preez, A., Law, T., Onorato, D. et al. The type of stress matters: repeated injection and permanent social isolation stress in male mice have a differential effect on anxiety- and depressive-like behaviours, and associated biological alterations. Transl Psychiatry 10, 325 (2020).

Here, I now show direct evidence to support the idea that different forms of chronic stress may lead to different depression outcomes. For example, I found that physical stress promoted anxiety, decreased inflammation, overactivated the stress system, increased brain inflammation, and decreased hippocampal neurogenesis. While in contrast, psychosocial stress promoted depression, increased inflammation, blunted the stress system, decreased brain inflammation and increased hippocampal neurogenesis. Interestingly, combining the two stressor types did not have a more severe effect, and in fact did not alter the stress system or change levels of brain inflammation, but resulted in yet another profile, one characterised by increased anxiety, decreased inflammation and decreased hippocampal neurogenesis.

Although this work helps shed light on my own research aspirations, it importantly highlights the need to now continue to explore the effects of different stressors in other animal models, so that we can understand more fully why this is happening, determine if this could influence treatment responses and, crucially, begin to apply this in a clinical setting.

At the end of my journey, which has ultimately raised further questions and opened up more research avenues to explore, I bring to light that the type of stress may indeed matter when it comes to depression. Being able to more precisely identify the impact of different types of stress on depression could help to identify vulnerable individuals, help practitioners and individuals to monitor and report their experience of stress, and ultimately may aid in the discovery of new therapeutic treatments.

Much like in other areas of psychiatry, we should move away from a one-size-fits-all approach to understanding the impact of stress on depression as all stressors may indeed not be of equal measure.


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