How does stress lead to depression?
Updated: Feb 2, 2021
The stress response is regulated by the HPA axis and involves the release of cortisol.
An acute stress response is beneficial, however chronic stress can be harmful and lead to elevated levels of cortisol.
In depressed people, there may be elevated levels of cortisol which correlates with the severity of depressive symptoms.
The underlying mechanisms is unclear however scientists believe it may involve the immune system, neuronal degeneration or changes to the levels and function of glucocorticoid receptors.
Therapies that have the ability to regulate glucocorticoid function and reduce cortisol levels may be effective in treating people with elevated cortisol and depression.
So what is stress?
The stress response causes physical changes in the body such as increased heart rate, muscle tension, blood vessel constriction and improved short-term memory. The response is acute and is known as the fight or flight response.
Research suggests that acute stress is beneficial to us. However, chronic stress can prevent our bodies returning to normal after a stressful event. When chronic stress occurs this can negatively impact attention and memory and it is this response that may contribute to mental illness .
The HPA axis and cortisol
The stress response is regulated by the hypothalamic pituitary adrenal (HPA) axis. It is made up of the hypothalamus, pituitary and adrenal glands. The HPA axis releases glucocorticoids, which are central to the stress response. Some glucocorticoids can exert an autoregulatory effect on HPA activity .
Cortisol is a glucocorticoid released from the HPA axis. It is the overall stimulant involved in the fight or flight response. The effects of cortisol are mediated by specialised glucocorticoid receptor subtypes (GR and MR) . Short-term increases in cortisol can aid in survival but long-term elevations may do the opposite.
The link between cortisol and depression
When there is prolonged stress, this can cause hyper-activity of the HPA axis leading to constantly elevated levels of cortisol . This can cause dysfunction of the HPA axis, which has been associated with depression [3-5].
The link between depression and cortisol was first described in the 1960s . Many studies report increased cortisol levels in depressed people [7, 8]. Normally, in those without depression, the level of cortisol in the bloodstream peaks in the morning and decreases as the day progresses. In people with depression, studies suggest that cortisol levels peak earlier and do not decrease in the afternoon .
Interestingly, people with more severe subtypes of depression have higher levels of cortisol in their bodies than those with mild depression . Levels of cortisol may be able to predict the severity of depressive behaviour . It has also been suggested that elevated cortisol may be responsible for the psychotic symptoms and cognitive impairment of severe depressive disorder .
Scientists have also found that prolonged increase in cortisol may lead to reduced levels of neurotransmitters such as serotonin and dopamine , which have both been implicated in depression. These neurotransmitters are normally responsible for regulating mood and emotions.
What are the underlying mechanisms?
The mechanisms by which chronic stress leads to depression remains largely unknown. However, here are a few hypotheses:
Cortisol and the immune system
One possible mechanism involves the immune system. During the stress response, the immune system is activated. However, chronic stress and activation of the immune response may have negative effects on the brain and lead to depression in some people (see previous blog post to read more).
Cortisol and neuronal degeneration
Some studies suggest that chronic stress can change the structure of the brain, especially in areas involved in learning and memory. It can affect the neurons (grey matter) and the connections between them (white matter). Chronic release of cortisol can lead to learning and memory formation deficits and a reduction in grey matter of the brain regions including the hippocampus and frontal lobe [13-15]. Both of these brain regions have been shown to be altered in depression (see previous blog post on neuroplasticity). Chronic release of cortisol may also inhibit the growth of new neurons and induce neurotoxicity . It is these changes that may be responsible for increasing the likelihood of developing depression.
Cortisol and receptors
The association between cortisol and depression may be explained by changes to glucocorticoid receptors. Brains of depressed people demonstrate abnormalities in the signalling and number of GR receptors [2, 16]. Decreased GR receptor number and function may underlie excessive cortisol secretion through an inability to produce the negative feedback pathway to regulate the HPA axis .
Furthermore, high cortisol levels can negatively impact mood and cognition via action on GR receptors. It may be that the GR receptor subtypes in the hippocampus and hypothalamus, that are associated with the negative feedback mechanism to regulate the HPA axis, are reduced and those in other brain regions are normal. Therefore, increased cortisol levels may result in an increase in the negative effects of cortisol and reduced inhibition of cortisol release .
Another suggestion is that the effect of cortisol on mood and cognition is largely mediated by the MR receptor subtypes. It may be that it is a change in the balance between MR and GR receptor subtypes that underlies the depressive symptoms induced by elevated cortisol .
Treatments that have the ability to regulate GR receptor expression and binding may have greater therapeutic effect in patients with elevated cortisol levels. Some anti-depressants exert their effect through altering GR receptors. Studies in neuronal cells show that tricyclic anti-depressants can increase GR receptor mRNA, which translates to increased GR receptor protein and binding [17, 18]. Interestingly, these changes do not occur with selective serotonin reuptake inhibitor (SSRI) anti-depressants.
Measuring the level of cortisol in the bloodstream may act as an important biomarker of treatment response. For example, in a study with patients with depression who responded well to SSRI’s, they presented decreased levels of cortisol .
Psychedelics and cortisol
Psychedelic drugs may exert an effect on cortisol levels. One psychedelic, ayahuasca, has been shown to have anti-depressant affects . In a recent clinical trial, ayahuasca, was able to alter levels of cortisol in depressed people so they were comparable to the levels in healthy people .
Scientists are keen to understand why some people are much more affected by stress then others. It is thought that investigating genetics, early life events, personality and social factors may reveal underlying mechanisms. Understanding this would potentially lead to the development of better treatments to combat stress and mental health problems.
1. Schimelpfening, N. The Role of Cortisol in Depression. 2020; Available from: https://www.verywellmind.com/cortisol-and-depression-1066764.
2. Mackin, P.Y., H;. The Role of Cortisol and Depression: Exploring New Opportunities for Treatments. 2004; Available from: https://www.psychiatrictimes.com/view/role-cortisol-and-depression-exploring-new-opportunities-treatments.
3. Mello, A.F., et al., Update on stress and depression: the role of the hypothalamic-pituitary-adrenal (HPA) axis. Braz J Psychiatry, 2003. 25(4): p. 231-8.
4. Qin, D.D., et al., Prolonged secretion of cortisol as a possible mechanism underlying stress and depressive behaviour. Sci Rep, 2016. 6: p. 30187.
5. Shively, C.A., et al., Social stress-associated depression in adult female cynomolgus monkeys (Macaca fascicularis). Biol Psychol, 2005. 69(1): p. 67-84.
6. Gibbons, J.L. and H.P. Mc, Plasma cortisol in depressive illness. J Psychiatr Res, 1962. 1: p. 162-71.
7. Young, E.A., N.E. Carlson, and M.B. Brown, Twenty-four-hour ACTH and cortisol pulsatility in depressed women. Neuropsychopharmacology, 2001. 25(2): p. 267-76.
8. Ferrari, F. and R.F. Villa, The Neurobiology of Depression: an Integrated Overview from Biological Theories to Clinical Evidence. Mol Neurobiol, 2017. 54(7): p. 4847-4865.
9. Dienes, K.A., N.A. Hazel, and C.L. Hammen, Cortisol secretion in depressed, and at-risk adults.Psychoneuroendocrinology, 2013. 38(6): p. 927-40.
10. Posener, J.A., et al., 24-Hour monitoring of cortisol and corticotropin secretion in psychotic and nonpsychotic major depression. Arch Gen Psychiatry, 2000. 57(8): p. 755-60.
11. Keller, J., et al., HPA axis in major depression: cortisol, clinical symptomatology and genetic variation predict cognition. Mol Psychiatry, 2017. 22(4): p. 527-536.
12. Nandam, L.S., et al., Cortisol and Major Depressive Disorder-Translating Findings From Humans to Animal Models and Back. Front Psychiatry, 2019. 10: p. 974.
13. Lee, A.L., W.O. Ogle, and R.M. Sapolsky, Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord, 2002. 4(2): p. 117-28.
14. Lupien, S.J. and B.S. McEwen, The acute effects of corticosteroids on cognition: integration of animal and human model studies. Brain Res Brain Res Rev, 1997. 24(1): p. 1-27.
15. Young, A.H., et al., The effects of chronic administration of hydrocortisone on cognitive function in normal male volunteers. Psychopharmacology (Berl), 1999. 145(3): p. 260-6.
16. Webster, M.O.G., JM; Orthmann, J; Weickert, CS; , Decreased glucocorticoid receptor mRNA levels in individuals with depression, bipolar disorder and schizophrenia. Schizophrenia Research, 2001. 41(1): p. 111-112.
17. Pepin, M.C., S. Beaulieu, and N. Barden, Antidepressants regulate glucocorticoid receptor messenger RNA concentrations in primary neuronal cultures. Brain Res Mol Brain Res, 1989. 6(1): p. 77-83.
18. Seckl, J.R. and G. Fink, Antidepressants increase glucocorticoid and mineralocorticoid receptor mRNA expression in rat hippocampus in vivo. Neuroendocrinology, 1992. 55(6): p. 621-6.
19. Piwowarska, J., et al., Serum cortisol concentration in patients with major depression after treatment with fluoxetine. Psychiatry Res, 2012. 198(3): p. 407-11.
20. Palhano-Fontes, F., et al., Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med, 2019. 49(4): p. 655-663.
21. Galvao, A.C.M., et al., Cortisol Modulation by Ayahuasca in Patients With Treatment Resistant Depression and Healthy Controls. Front Psychiatry, 2018. 9: p. 185.