Home » Blogs » Leveraging Adversity » The HPA Axis, The Exaggerated Startle Response, and Epigenetic Changes – How Depression Changes Your Brain

The HPA Axis, The Exaggerated Startle Response, and Epigenetic Changes – How Depression Changes Your Brain

depression photo

When we sense stress, one of the first things our brain does is fire up all the resources. Corticotropin-releasing hormone (CRH) is released from the hypothalamus, pituitary corticotropin is secreted, and the adrenal gland releases cortisol. Heart rate and blood pressure increase, muscles tighten, and for all intents and purposes, we are ready to fight off whatever comes our way.


What is now known as the startle response has several evolutionary purposes, and is adaptive in the face of stress. The problem for depressed people, however, is that this response becomes exaggerated. Instead of propelling them to fight or flee as it is meant to, levels of CRH become chronically elevated, and the person adopts what Robert Sapolsky, acclaimed primatologist and author of, Why Zebras Don’t Get Ulcers, calls “a frozen state”. Essentially, they become paralyzed by the very resources that are meant to mobilize them.


Evidence for elevated CRH has been found in the cerebrospinal fluid in depressed subjects (Nemeroff, 2014), as well as in the limbic brain regions of depressed people who were examined post-mortem (Raadsheer, et, al, 2014), and victims of childhood trauma (Heim, 2008). There is also preliminary evidence that blocking CRH (by using CRH1 receptor antagonists) reduces symptoms of depression (Holsboer, 2012).


So the question we might ask ourselves is, just what are the effects of an exaggerated startle response (and more specifically elevated CRH)?


Well, at first, we have symptoms that resemble depression: decreased appetite, disrupted sleep, decreased libido, and psychomotor alterations. Over time, as cortisol levels remain high, we are prone to a host of physical problems, such as coronary heart disease, type II diabetes, and osteoporosis (Gold, 1999).


This chronically exaggerated startle response has also been described as an imbalance in the HPA Axis. Regulated through a dual system of mineralocorticoid (MR) and glucocorticoid (GR) receptors, in depressed people this balance gets thrown off as limbic GR receptor function decreases and MR functional activity increases (Mizoguchi, 2013). In short, the person’s brain responds as if attempting to respond to stress, while at the same time, being overwhelmed by it.


When you extend this effect over several years, what you get are changes in the brain. In what is now known as epigenetic regulation, the expression of genes that regulate the release of glucocorticoids gets effectively “turned on”, meaning that the person experiences chronic elevations in glucocorticoids. This sort of environmental programming represents just one way that early life stress, or ongoing and unresolved stress, becomes linked to increased risk of depression.


“The clinician should be aware of the potentially brain-damaging effect of depression and treat depressed patients as early and effectively as possible” (Hasler, 2017).


Given what we now know about the exaggerated startle response and its link to depression, it’s not surprising that both hypercortisolemia (high cortisol), and low cortisol seem to be predictive of depression.


Analyzing 245 patients with bipolar disorder or recurrent depressions and 258 people in a control group, researchers measured cortisol levels in participants after they had taken a so-called dexamethasone suppression test, which is used to discover early deviations in the stress system. Interestingly, when cortisol levels were found to be low, patients were more likely to also be suffering from obesity (34 per cent in comparison to 11 per cent among other patients), dyslipidaemia, i.e. high levels of fat in the blood (42 per cent compared to 18 per cent among other patients), and metabolic syndrome (41 per cent in comparison to 26 per cent among other patients) (Maripuu, 2016).


While these results seem counterintuitive, in light of what we understand about long term activation of the stress response, they make perfect sense. Stress normally leads to HPA-axis over activity, which in turn leads to increased levels of cortisol. Yet if stress is prolonged, it may lead to underactivity in the stress system, with low levels of cortisol as a result.


These disturbances in the stress regulation system (being over-activated and then under-activated) have previously been shown to be linked to several metabolic risk factors for cardiovascular diseases. Martin Maripuu, researcher at the Department of Clinical Sciences, Division of Psychiatry at Umeå University explains, “These results provide clues to better understand the high prevalence of cardiovascular diseases in people with recurrent depressions or bipolar disorder,” (Maripuu, 2016).


While bipolar disorder and recurrent depressions are associated with a 10-15 year reduction in life expectancy – due to the high prevalence of cardiovascular diseases – results such as these suggest that improving lifespan and reducing risk of depression is not so much about simply lowering cortisol, but improving cortisol regulation. As Maripuu concludes, “Cortisol regulation is linked to worsened physical health in people with bipolar disorder or recurrent depressions,” (Maripuu, 2016).


In a separate study, Maripuu and his team replicated these findings.


Examining both bipolar patients who had been on mood stabilizers throughout life, and those who had been without prophylactic mood stabilizing treatment, the researchers found that the patients who had gone without treatment exhibited lower cortisol levels. On the other hand, no increase could be seen in the proportion of hypocortisolism among bipolar patients who had been treated with the mood stabilizer lithium during a large part of their lives (Maripuu, 2016). Further, people with bipolar disorder with either high or low cortisol levels were also depressed to a near double extent than people with normal stress regulation. Low quality of life was between four and six times more common in groups with low or high activity in the stress regulation system. In people with recurrent depressions, a correlation could also be found between low cortisol levels and short telomeres, which is an indication of premature aging and a high accumulation of stress (Maripuu, 2016).


Results such as this give further evidence that it is the chronic failure to regulate stress (whether through hypercortisolemia, or hypocortisolemia), that is a risk factor for depression and long term health impairment. While hyperactivity in the hormone system with high cortisol levels is common in patients with depression, when this condition persists over time, high levels of stress can lead to hypocortisolemia in the long term. According to Maripuu, the reason is that a high accumulation of stress over time exhausts the hormone system, and when it does, the result is hypocortisolemia.


“High cortisol levels have previously been shown to be associated with poor health in people with depressions or bipolar disorder. What’s interesting about our results is that also low cortisol levels were associated with a considerable increase in negative health consequences,” (Maripuu, 2016).


Chronic stress doesn’t just predispose us to depression, it also changes the way we respond to stress. When we can’t find a ways to fight off or flee from stress, as we are designed to, the genes that regulate the release of glucocorticoids become turned on, and we become caught in a pattern of exaggerated alert. Over time, the system becomes exhausted, leaving us with low cortisol levels, poor health, and premature aging – and most likely depression. Yet, depression doesn’t just change the way our brain functions, but also how it grows.

Photo by GloWill

The HPA Axis, The Exaggerated Startle Response, and Epigenetic Changes – How Depression Changes Your Brain

Claire Dorotik-Nana, LMFT

Claire Dorotik-Nana LMFT is a licensed marriage and family therapist specializing in post-traumatic growth, leveraging adversity, and other epic human achievements. Claire has written multiple continuing education courses for Professional Development Resources, Zur Institute, and International Sport Science Association. Claire has also authored multiple books, including:
Leverage: The Science of Turning Setbacks into Springboards and On The Back Of A Horse: Harnessing The Healing Power Of The Human-Equine Bond. For more information about Leveraging Adversity or Claire, visit

3 comments: View Comments / Leave a Comment



APA Reference
Dorotik-Nana, C. (2017). The HPA Axis, The Exaggerated Startle Response, and Epigenetic Changes – How Depression Changes Your Brain. Psych Central. Retrieved on August 6, 2020, from


Last updated: 13 Oct 2017
Statement of review: Psych Central does not review the content that appears in our blog network ( prior to publication. All opinions expressed herein are exclusively those of the author alone, and do not reflect the views of the editorial staff or management of Psych Central. Published on All rights reserved.