This article is part of a series of articles exploring the nature, contributing factors and management of chronic & recurrent depression. This piece examines the role of stress and inflammation in the development, worsening and maintenance of depression.
It starts with the hypothalamus-pituitary-adrenal axis:
The stress response in humans is predominantly mediated by the hypothalamus-pituitary-adrenal axis (HPA), along with the sympathetic nervous system. The HPA is a major neuroendocrine system that mounts a three-step stress response when confronted with a physiological or psychosocial stressor (Smith & Vale, 2006).
This stress response begins at the (1) hypothalamus that releases two neurohormones – corticotropin-releasing factor/hormone (CRF or CRH) and arginine vasopressin (Smith and Vale, 2006). Then, this CRF travels through a special portal blood system and stimulates the (2) anterior pituitary gland to release adrenocorticotropic hormone (ACTH), which is then released into the blood (Smith and Vale, 2006). Lastly, circulating ACTH stimulates the (3) adrenal cortex to release cortisol, which is the major stress hormone that then exerts its effects on most tissues and organs (most cells have cortisol receptors) (Smith & Vale, 2006). The HPA axis is eventually shut off by cortisol itself via a negative feedback mechanism – i.e. when cortisol reaches a high enough concentration, the HPA stops producing CRF and ACTH, and homeostasis is re-established (Smith & Vale, 2006).
Cortisol can module various immune, endocrine and digestive functions, such as up-regulating inflammatory processes, increasing cardiovascular output, inducing vasoconstriction and gluconeogenesis (production of additional glucose molecules) to mention just a few. HPA axis dys-regulation has been heavily implicated in mood disorders like depression (Barden, 2004; Keller et al., 2016).
HPA axis dysregulation in depression:
The cortisol response can be measured across three phases: a baseline phase, where no stressor* is present; a reactivity phase, where a stressor is introduced and cortisol rises in response; and a recovery phase, where cortisol returns to its baseline (these phases are regulated by glucocorticoid receptor signalling during reactivity, and mineralocorticoid receptors during baseline) (Nandam et al., 2020a).
*a stressor is any event or stimulus that activates the stress response
In depression various abnormalities exist in this HPA-mediated stress response during these three distinct phases. Some depressed people exhibit stress hyperresponsiveness, which is an exaggerated reactivity phase, whilst others show a blunted cortisol response, which is a blunted reactivity phase, i.e. they produce less cortisol than average in response to a stress situation (Nandam et al., 2020b).
What is wrong with the stress response in depression?
Stress signals to the organism that there is a certain challenge that needs to be addressed or adapted to. In that sense stress is an 'adaptive response', and high-stress environments lead to certain adaptations and changes to our stress response and homeostasis. Two major adaptations in the stress system often seen in depression are a less efficient but exaggerated stress response.
One example of such adaptations, caused by high stress environments, are the changes associated with early life trauma such as childhood abuse, which is a well-known contributor to the development of depression (Raison & Miller, 2003). Early life trauma leads to a blunted cortisol increase in response to an ACTH infusion (remember ACTH is what stimulates the release of cortisol), but an exaggerated ACTH increase and CRH response to psychosocial stressors (Raison & Miller, 2003). This implies that the adrenal cortex adapts to this repeated stress by down-regulating its sensitivity to ACTH in order to deal with a sensitised (exaggerated) response at the level of the pituitary/hypothalamus. (Raison & Miller, 2003) In other words, a lot more ACTH is required to produce the same amount of cortisol (a less efficient stress response), and a lot more ACTH is produced in response to psychosocial stressors (an exaggerated stress response). ACTH is what binds to the adrenal cortex to stimulate the release of cortisol - and with repeated chronic stress from childhood trauma for example, this mechanism becomes less efficient, evident by the need for increased ACTH production (i.e. more is needed to create the same response).
This notion of a less efficient stress response is also corroborated by studies, showing that people with major depression have impaired glucocorticoid* responsiveness. In simple terms, the receptors that bind their stress hormone, don’t bind it as much. This can be measured by people’s ability to suppress further cortisol production when given a synthetic glucocorticoid called dexamethasone-CRH. Recall that cortisol production is stopped when circulating cortisol levels reach a high enough point, preventing CRF from further stimulating the HPA axis - the so-called negative feedback mechanism. Normal healthy controls suppress further production of cortisol when given dexamethasone-CRH (which mimics cortisol), but depressed individuals often do not. In general, they have much higher rates of non-suppression. (Raison & Miller, 2003).
*Glucocorticoids are the class of hormones that cortisol belongs to.
Not only is the stress response often less efficient in depressed populations, but it can also be exaggerated. In certain subgroups, such as those diagnosed with recurrent and chronic depression, cortisol is persistently elevated in response to stressors (Nandam et al., 2020a), similar to the findings of higher increases in ACTH in response to stressors.
These changes to the efficiency of the stress system can have profound effects on other systems in the body, particularly when it comes to regulating inflammatory processes, as cortisol is a powerful anti- and pro-inflammatory hormone.
Stressors, stress and the associated release of cortisol can be inflammatory:
A stressor is any event or stimuli that causes stress and stress is the adaptive response to these challenges (stressors), that results in the activation of the physiological stress pathways (i.e. the HPA axis) and the release of cortisol (Chu et al., 2019). Therefore, stressors are always associated with the release of cortisol. But cortisol does not always have the same effects - sometimes cortisol can cause inflammation. How does this make sense, given that one of the most popular anti-inflammatory medications are corticosteroids (the synthetic version of the human cortisol hormone produced by the adrenal gland)?
Cortisol can be either anti-inflammatory or pro-inflammatory - and this mainly depends on the timings of the stressors relative to other stressors and their acuity. The dumbified rule of thumb is that if a stressor shortly precedes an *inflammatory event, the cortisol will be pro-inflammatory. The implications of this for chronic or repeated stress (without proper return to homeostasis) are that the effects of stress and cortisol would be pro-inflammatory, as opposed to anti-inflammatory. Intuitively, we already knew that stress in the form of exercise or a cold bath is different from the stress of continual sleep deprivation or a toxic workplace. But now there is also some evidence to back this up (see below just one example of a paper examining this biphasic cortisol mechanism by Yeager et al. (2010)).
*What is an inflammatory event? - That can be anything from an infection to a range of psychosocial stressors that is associated with immune activation and the release of proinflammatory cytokines (e.g. TNF-a, interleukin-1, interleukin-6) (Raison & Miller, 2003).
How cortisol can exert pro- or anti-inflammatory effects on the body - below are details of the experiments from the article by Yeager et al. (2010).
Feel free to skip this section if you are not interested in the details. These experiments examine the conditions under which cortisol is pro- or anti-inflammatory - based on the timing and acuity (low to high) of the stressor (Yeager et al., 2010).
Glucocorticoid* (GC) effects on inflammation can be acute or delayed. In an acute case, GC activation (cortisol stimulation) happens during an inflammatory event, and GCs have an anti-inflammatory effect (Yeager et al., 2010). If GC activation (cortisol stimulation) happens before an inflammatory event, their effects are preparatory i.e. pro-inflammatory (Yeager et al., 2010). There is most likely an evolutionary benefit to this biphasic response because it is a way for the organism to prepare for subsequent inflammation and improve its resistance to disease.
*Glucocorticoids are the class of hormones that cortisol belongs to.
In the first experiment, participants' cortisol is depleted (using a glucocorticoid antagonist), i.e. they have less cortisol. Inflammatory markers and cortisol are measured before and after depletion. Inflammation is measured ex-vivo - monocytes (blood cell type) are taken before and after depletion, and their inflammatory properties tested ex-vivo using bacterial lipopolysacharride (which is a main constituent of gram-negative bacteria and is highly inflammatory to human cells). There was no difference in the inflammatory response between the depleted and non-depleted cells.
High acuity condition. In the second experiment, participants received a cortisol or saline infusion continuously for 8 hours. Monocytes were isolated from peripheral blood before and after treatment to measure the effects of elevated cortisol on inflammation. The mRNA of an anti-inflammatory cytokine (molecule) IL-10 was found to be regulated in a dose-dependent manner: IL-10 mRNA decreased following cortisol depletion, and it increased following cortisol exposure. The mRNA for GR alpha (main GC receptor protein), decreased following exposure to high dose cortisol, and increased following in vivo cortisol depletion. In this experiment, cortisol decreased inflammation by increasing anti-inflammatory cytokine production and decreasing the production of cortisol-binding receptors (GR alpha).
* note that how much mRNA is produced tells us how much a gene is expressed - and therefore how much a protein is synthesised. The more mRNA there is, the more this gene is expressed - mRNA transcript takes DNA and converts it into mRNA, and this mRNA is then translated into proteins (Gene Expression Is Analyzed by Tracking RNA, 2014).
Concurrent stressor timing condition. In the third experiment, cortisol was regulated during an acute systemic inflammation stimulus (heart surgery). Patients were given exogenous cortisol infusions at varying concentrations during their surgery. Cortisol suppressed inflammation in a dose-dependent manner (measured by increased anti-inflammatory IL-10 and decreased proinflammatory IL-6 cytokines). Cortisol released during an inflammatory event leads to decrease in inflammation.
Prior stressor timing condition: In the fourth experiment, cortisol was given before an acute systemic inflammation stimulus. On day 1: subjects divided into 3 groups are given either saline, intermediate cortisol, or high cortisol IV. On day 2: subjects received LPS (lipopolysaccharide), which induced an inflammatory response measured by IL-10 and IL-6. In the intermediate group, inflammatory cytokines were increased compared to both saline control and high cortisol groups, and anti-inflammatory cytokines were decreased compared to both. Cortisol released before an inflammatory event leads to an increase in inflammation. Low to moderate stress (cortisol) acuity led to more inflammation compared to high acuity or no cortisol.
Inflammation is depressogenic:
So far we have examined how the stress response, mediated by the HPA axis and cortisol, is dysregulated in depression, and that under certain conditions cortisol is pro-inflammatory (chronic or recurrent stress). The last piece of the puzzle that ties this all together is the finding that proinflammatory events can be depressogenic.
What complicates the picture is that the relationship between inflammation and a depressed mental state seems to be bi-directional, i.e. an episode of depression can induce an increase in inflammation, and inflammation can induce an episode of depression (Raison & Miller, 2012).
The strongest piece of evidence to indicate that inflammation can be depressogenic probably comes from findings that depressed mood and behaviour can be induced by both acute immune stimulation, for example a single exposure to endotoxin or typhoid vaccine, and chronic immune stimulation, such as IFN-a therapy (Raison & Miller, 2012). Furthermore, the risk of developing depression increases following significant infections and in currently non-depressed individuals increased levels of inflammatory biomarkers mark an elevated risk for future development of depression, after controlling for other variables (Raison & Miller, 2012).
It’s interesting to note that psychosocial stressors also activate inflammatory responses (Bierhaus et al., 2003). For example, the Trier social stress test, where participants have to give a personally meaningful speech and perform arithmetic in front of a judgemental panel, has been found to consistently elevate circulating levels of inflammatory cytokines (IL-6), as well as mRNA of NF-Kb (Bierhaus et al., 2003).
The implications:
The implications of all of this are wide ranging and they highlight the importance of regulating and managing stress and inflammation when dealing with depression, particularly one that has not responded to standalone treatment. In theory anything that helps re-regulate the stress response and lower inflammation could help improve symptoms. The list of possible factors that can help with this is long: lifestyle modifications, diet, supplements, exercise, sunlight, cold/hot exposure, art, meaningful connections, therapy, etc. This will potentially be discussed in a separate article.
The TL;DR summary:
Depression is defined by a dysregulated stress response - it means that cortisol is less efficient at getting its message across. This dysregulated stress response and the chronic stress associated with depression can create or worsen the inflammatory processes in the body, because cortisol is a powerful anti- and pro-inflammatory hormone. Pro-inflammatory processes have been linked to the development, worsening and/or maintenance of depression. To this end, chronic stress and a dysregulated stress response need to be addressed concomitantly with other treatments, such as therapy, in order to treat depression, especially where standalone treatments have failed.
Disclaimer: I am not a medical professional and this is not medical advice.
References:
Barden, N. (2004). Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression. PubMed, 29(3), 185–193. https://pubmed.ncbi.nlm.nih.gov/15173895
Bierhaus, A., Wolf, J., Andrassy, M., Rohleder, N., Humpert, P. M., Petrov, D., Ferstl, R., Von Eynatten, M., Wendt, T., Rudofsky, G., Joswig, M., Morcos, M., Schwaninger, M., McEwen, B., Kirschbaum, C., & Nawroth, P. P. (2003). A mechanism converting psychosocial stress into mononuclear cell activation. Proceedings of the National Academy of Sciences of the United States of America, 100(4), 1920–1925. https://doi.org/10.1073/pnas.0438019100
Chu, B., Marwaha, K., Sanvictores, T., & Ayers, D. (2019). Physiology, stress reaction. StatPearls. https://pubmed.ncbi.nlm.nih.gov/31082164/
Gene expression is analyzed by tracking RNA. (2014). nature.com. https://www.nature.com/scitable/topicpage/gene-expression-is-analyzed-by-tracking-rna-6525038/
Keller, J., Gomez, R., Williams, G., Lembke, A., Lazzeroni, L., Murphy, G. M., & Schatzberg, A. F. (2016). HPA axis in major depression: cortisol, clinical symptomatology and genetic variation predict cognition. Molecular Psychiatry, 22(4), 527–536. https://doi.org/10.1038/mp.2016.120
Nandam, L. S., Brazel, M., Zhou, M., & Jhaveri, D. J. (2020a). Cortisol and Major Depressive Disorder—Translating findings from humans to animal models and back. Frontiers in Psychiatry, 10. https://doi.org/10.3389/fpsyt.2019.00974
Nandam, L. S., Brazel, M., Zhou, M., & Jhaveri, D. J. (2020b). Cortisol and Major Depressive Disorder—Translating findings from humans to animal models and back. Frontiers in Psychiatry, 10. https://doi.org/10.3389/fpsyt.2019.00974
Raison, C. L., & Miller, A. H. (2003). When not enough is too much: The role of insufficient glucocorticoid signaling in the pathophysiology of Stress-Related Disorders. the American Journal of Psychiatry, 160(9), 1554–1565. https://doi.org/10.1176/appi.ajp.160.9.1554
Raison, C. L., & Miller, A. H. (2012). The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D). Molecular Psychiatry, 18(1), 15–37. https://doi.org/10.1038/mp.2012.2
Smith, S. M., & Vale, W. W. (2006). The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues in Clinical Neuroscience, 8(4), 383–395. https://doi.org/10.31887/dcns.2006.8.4/ssmith
Yeager, M. P., Pioli, P. A., & Guyre, P. M. (2010). Cortisol Exerts bi-phasic Regulation of Inflammation in Humans. Dose-Response, 9(3), dose-response.1. https://doi.org/10.2203/dose-response.10-013.yeager
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