G Collerone
Glucocorticoids and Suicide
“The most evident fact about suicidology and suicidal events is that they are multidimensional, multifaceted, multidisciplinary–containing as they do, concomitant biological, sociological, psychological (interpersonal and intrapsychic), epidemiological, and philosophic elements (Shneidman, 1996, p. 633).”
In 2022, there were 49,449 suicides, and it was the 11th leading cause of death in the United States (NSDUH, 2022). There is no one cause of suicide, but researchers have tried to pinpoint one. Suicide is defined as “a conscious act of self-induced annihilation, best understood as a multidimensional malaise in a needful individual who defines an issue for which suicide is perceived to be the best option”(Shneidman, 1993). A suicide attempt is defined as a “self-destructive act with some intent to end one’s life that was not self-mutilating in nature” (Roy et al., 2010). I have quoted these words because the nomenclature is not fully defined across all research and practices (O’Carroll et al., 1996). The language of suicide has changed over the years. Most places are no longer using “committed suicide” and have opted instead to use, death by suicide. This is also challenged in the O’Carroll paper (1996). The fact remains that despite more resources to hotlines and even the addition of the 988 suicide crisis line, suicide rates have not decreased. This remains a major problem for suicide prevention researchers. Most of the research has involved talk therapy to deal with crises. We are still of the mindset of having individuals come forward to seek help. However, what if it was in their physiology? The latest research shows a link between the Hypothalamus-Pituitary-Adrenal Axis (HPA) and childhood trauma along the glucocorticoid receptors (Roy et al., 2010).
Cortisol is the primary effector hormone of the HPA axis stress response system. The HPA axis is regulated by a negative feedback system, whereby the hypothalamus and the pituitary gland have receptors that detect changes in cortisol levels (O’Connor et al., 2020). This loop begins when the amygdala in the brain senses stress, therefore activating the hypothalamic-pituitary-adrenal (HPA) axis. At that point, the hypothalamus releases corticotropin-releasing hormone (CHR). The CHR then activates the pituitary gland causing it to release adrenocorticotropic hormone (ACTH). At this point, the ACTH activates the adrenal glands which then release cortisol, a glucocorticoid hormone. In normal negative feedback loops the presence of cortisol in the bloodstream activates the negative feedback mechanism that halts the stress response by inhibiting the hypothalamus from generating CRH (Harvard Health, 2024) For example, cortisol secretion will be inhibited when circulating levels rise or stimulated when levels fall. However, if the HPA axis is repeatedly activated, this will trigger increased cortisol output, thereby exposing bodily tissues to excessive hormone concentrations (O’Connor et al., 2020). Childhood trauma can potentially make the amygdala hypervigilant effecting the HPA negative feedback loop (Harvard Health, 2024).
Studies have shown that for those over 40 years of age, lower cortisol was associated with suicide attempters. Conversely, people under the age of 40 higher cortisol levels are associated with suicide attempts. This is thought to be attributed to the stress of cortisol in younger adults versus older adults. These findings suggest that a reversal in the association between cortisol and suicide attempts occurs when the average age of the sample is approximately 40 years of age or older.
Additionally, this does not imply that the shift in cortisol levels happens at exactly 40 years of age; in meta-analysis studies, the mean age of the sample (O’Connor et al., 2020). In O’Connor’s paper, he also looked at the dexamethasone suppression test. He found a very small sample that showed significant prediction in suicide completion but did not show significant prediction in suicide attempts (four attempts vs eight complete). In another study by O’Connor et al. (2018), higher levels of childhood trauma were associated with blunted HPA axis activity in vulnerable populations, and these effects were independent of a family history of suicide. The challenge for researchers is to elucidate the precise causal mechanisms linking trauma, cortisol, and suicide risk and to investigate whether the effects of childhood trauma on cortisol levels are amendable to psychological intervention (O’Connor et al., 2018). Glucocorticoid stress hormones are produced in response to HPA axis activation. Glucocorticoids are essential for physiology and exert numerous actions via binding to the glucocorticoid receptor (GR; (Viho et al., 2023).
Another study of post-mortem brains found that the amygdala of undiagnosed and untreated suicide completers, FKBP5 protein, and mRNA were decreased (Rizavi et al., 2023). FKBP5 is known to be an inhibitor of glucocorticoid sensitivity; therefore, elevated levels of FKBP5 might result in impairment of the HPA axis negative feedback loop (Roy et al., 2010). The FKBP51-bound glucocorticoid receptor (GR) complexes have low cortisol affinity with reduced nuclear translocation. The FKBP5 gene is strongly upregulated by stress, creating an ultrashort negative feedback loop of cortisol release and, thus, prolonged cortisol elevations following a stressor. This maladaptive prolonged stress response may render individuals to be more vulnerable to suicide (Hernandez-Diaz et al., 2021).
I became interested in suicide in 2006 for personal reasons. While working on a psychometrics paper, I learned about the field of suicidology and became a part of it. Additionally, studying the works of the founding father of American suicidology, Dr. Edwin Shneidman, as well as a few of his followers through his organization, the American Association of Suicidology. His philosophy was “no psychache, no suicide”(Shneidman, 1993). I have focused my research primarily on the treatment of suicidal ideation o the idea that psychache causes suicidality. Suicidality has become an all-inclusive term to capture the full range of suicidal thoughts and behaviors just short of death by suicide; however, the National Strategy for Suicide Prevention (2001) defined it as “a term that encompasses suicidal becomes difficult, if not impossible, to define thoughts, ideation, plans, suicide attempts, and completed suicide” (p. 203). This paper has focused on death by suicide and attempts by following the Hippocampal-Pituitary-Adrenal (HPA) Axis pathway and how stress from childhood abuse can cause disruption in this pathway, leading to suicidal behavior (Roy et al., 2010). We know millions attempt suicide each year, and millions more think about suicide. The typical schema is ideation followed by a plan followed by intent followed by action on the plan.
Herein lies two critical questions. Could cortisol levels and other hormones contribute to the intent part? And could it make life unbearable to make a person want to die? According to Shneidman’s cubic model of psychache, there is lethality, perturbation, and psychache. A 5-5-5 means a suicide is imminent (Shneidman, 1994). Could cortisol cause perturbation along the HPA axis? It is an interesting theory, one that has not been explored. Childhood trauma certainly plays a role in the heightened response level. Could the hypervigilance seen in trauma be a cause of the cortisol disruption? I am glad there is research looking at the blood work for suicide.
Maybe there will one day be a test to determine someone’s suicidal tendencies. I do not think it will be that easy, however. There are undoubtedly other factors that play a role. However, over the eighteen years I have been studying this, I never really looked at the biology of suicide. I did not think it existed. I thought it was primarily a psycho-social condition that needed a form of therapy to be treated. I think it is great that there are genes and possible DST tests that could predict suicide with more research. I just hope it does take away the human factor of the individual’s suffering while going through this. We also need to reach those who are thinking about suicide and those who attempt it because the best indicators we have right now are those factors.
References
Harvard Health, P. (2024). Understanding the Stress Response. Retrieved 12/14/2024 from https://www.health.harvard.edu/staying-healthy/understanding-the-stress-response#:~:text=If%20the%20brain%20continues%20to,tissue%20and%20to%20weight%20gain
Hernandez-Diaz, Y., Gonzalez-Castro, T. B., Tovilla-Zarate, C. A., Juarez-Rojop, I. E., Lopez-Narvaez, M. L., Perez-Hernandez, N., Rodriguez-Perez, J. M., & Genis-Mendoza, A. D. (2021). Association between polymorphisms of FKBP5 gene and suicide attempt in a Mexican population: A case-control study. Brain Res Bull, 166, 37-43. https://doi.org/10.1016/j.brainresbull.2020.11.002
NSDUH. (2022). Annual National Report. https://www.samhsa.gov/data/report/2022-nsduh-annual-national-report
O’Carroll, P. W., Berman, A. L., Maris, R. W., Moscicki, E. K., Tanney, B. L., & Silverman, M. M. (1996). Beyond the Tower of Babel: A Nomenclature for Suicidology. Suicide and Life-Threatening Behavior, 26(3), 237-252.
O’Connor, D., Gartland, N., & O’Connor, R. C. (2020). Stress, Cortisol, and Suicide Risk. International Review of Neurobiology, 152, 101-130. https://doi.org/https://doi.org/10.1016/bs.irn.2019.11.006
O’Connor, D., Green, J., Ferguson, E., Ocarroll, R., & O’Connor, R. (2018). Effects of Childhood Trauma on Cortisol Levels in Suicide Attempters and Ideators. Psychoneuroendocrinology, 88, 9-16. https://doi.org/https://doi.org/10.1016/j.psyneuen.2017.11.004
Rizavi, H., Khan, O., Zhang, H., Bhaumik, R., Grayson, D., & Pandey, G. N. (2023). Methylation and expression of glucocorticoid receptor exon-1 variants and FKBP5 in teenage suicide. Translational Psychiatry, 13(53). https://doi.org/https://doi.org/10.1038/s41398-023-02345-1
Roy, A., Gorodetsky, E., Yuan, Q., Goldman, D., & Enoch, M.-A. (2010). Interaction of FKBP5, a Stress-Related Gene with Childhood Trauma Increases the RIsk for Attempting Suicide. Neuropsychopharmacology, 35, 1674-1683. https://doi.org/https://doi.org/10.1038/npp.2009.236
Shneidman, E. S. (1993). Suicide as Psychache: A Clinical Approach to Self-Destructive Behavior. Jason Aronson, Inc.
Shneidman, E. S. (1994). Definition of suicide (1st softcover ed.). J. Aronson.
Shneidman, E. S. (1996). Suicide as psychache. In J. T. Maltsberger & M. J. Goldblatt (Eds.), Essential papers on suicide (pp. 633-638). New York University Press.
United States. Public Health Service. (2001). National strategy for suicide prevention : goals and objectives for action. U.S. Dept. of Health and Human Services, Public Health Service. http://www.mentalhealth.org/suicideprevention/nsspfullreportfinal.pdf
Viho, E. M. G., Kroon, J., Feelders, R. A., Houtman, R., van den Dungen, E. S. R., Pereira, A. M., Hunt, H. J., Hofland, L. J., & Meijer, O. C. (2023). Peripheral glucocorticoid receptor antagonism by relacorilant with modest HPA axis disinhibition. J Endocrinol, 256(2). https://doi.org/10.1530/JOE-22-0263
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