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How to Save a Life
[Disclaimer: This article talks about suicidality and recent research into how the brain is altered in individuals experiencing it, so it may be triggering to some.]
The world loses more than 700,000 people to suicide a year, and the amount of suicide attempts per year is astronomical: there are more than twenty times more suicide attempts each year than those who die by suicide (1,2). Moreover, with the recent attacks on LGBTQ individuals, especially the legislation attacking LGBTQ youth in schools in the U.S., suicide rates for LGBTQ youth are increasing. Furthermore, The Trevor Project–a suicide prevention organization that’s mission is to end suicide for the LGBTQ youth population–conducted a survey and found that 41% of LGBTQ young people seriously considered attempting suicide in the past year (3).
For those who suffer from these sorts of thought patterns and behaviors (e.g. nonsuicidal self-injury), life’s adversities and stressful situations can seem overwhelming and leave them feeling hopeless. The system in their body that is responsible for the stress response is on overdrive, which can sometimes lead to dire outcomes.
Although similar to depressive behavior, suicidal ideation does not require an individual to suffer from depression or other psychiatric illnesses. They share similar causes, but depression and suicidality are distinct. Many studies have implicated a collection of structures known as the hypothalamic-pituitary-adrenal (HPA) axis in both of these conditions, which affect the structures in similar but distinct ways. In fact, recent research has found that the system in your brain and body responsible for the stress response is hyperactive in individuals who suffer from various psychiatric illnesses, as well as those who attempt suicide (1,4,5,6).
The Stress System
The HPA axis is a collection of anatomically distinct structures in the body: the hypothalamus and pituitary gland are both situated within the brain, fairly close to each other, whereas the adrenal glands rest on top of the kidneys. The HPA axis is an essential part of the neuroendocrine system, a subsystem of the body which is responsible for the regulation of hormones for maintaining homeostasis, the body’s internal balance, growth, reproduction, metabolism, and other bodily functions. The HPA axis plays a major part in our body’s stress response, each part of it working together to prepare the body for perceived danger.
The hypothalamus and the pituitary gland are the brain’s components of the HPA axis. The hypothalamus is essential for keeping the body in homeostasis by releasing compounds known as neurotransmitters and hormones (which are basically the same thing, except hormones are released in the bloodstream to act on the body, and neurotransmitters act only within the nervous system between its fundamental cells, neurons). It is responsible for what is known as the “Four Fs” of survival: Fight, Flee, Feed, and Fu–I mean Fornicate (reproduce). A portion of the hypothalamus that initiates the stress response in our brain is known as the paraventricular nucleus (PVN), which releases a hormone to stimulate the next region in the stress response, the pituitary gland.
The pituitary gland lies underneath the hypothalamus, and it is divided into two lobes, which are creatively named the anterior (front) pituitary and the posterior (back) pituitary. The pituitary is both a part of the brain and a gland; because of this, it is known as “the master gland”. It is responsible for the production and secretion of many of the body’s hormones, such as the creatively named ‘growth hormone”–responsible for, well, growth. In the stress response, the anterior portion of this master gland is stimulated by a hormone released by the PVN called corticotropin-releasing hormone (CRH). This begins the final step of kicking the body into gear for perceived danger, where the anterior pituitary communicates with the adrenal glands.
Our final stop on our stressful journey is at the adrenal glands, which are a ways away from the brain, but crucial nonetheless. The adrenal glands are important for producing — you guessed it — adrenaline (and noradrenaline), an important hormone for getting the body moving and ready to fight or flee (for instance, it increases your heart rate and elevates your blood pressure). Thus, these glands are what make your body begin the stress response. The adrenal glands both play a crucial role in our body’s stress response. They are stimulated by adrenocorticotropin hormone (ACTH) released by the anterior pituitary during the stress response. Once stimulated by ACTH, the adrenal glands release cortisol–known as “the stress hormone”–and adrenaline/noradrenaline, and thus complete the stress response, and your body is ready to respond to impending doom.
Suicide’s Origins
So why is it important for us to understand how the stress response is produced in the body? As it turns out, the HPA axis is dysregulated in people who suffer from a variety of stress-related disorders, including depression and suicidality. In fact, many studies have linked hyperactivity of the HPA axis to depression (4,5,6).
Although hyperactivity of the HPA axis has been linked to psychiatric illnesses extensively, not all of those who suffer from suicidal ideation and/or behaviors have any comorbid mental health diagnoses; however, there are noticeable trends that point to a correlation between dysregulation of the HPA axis and eventual suicide. In one study conducted in 2001, researchers used a diagnostic tool known as the dexamethasone suppression test (DST), which measures the response of the adrenal glands to ACTH to assess the functioning of the HPA-axis (7,8). DST results were collected from 78 patients with psychiatric disorders and were then followed up with 15 years later. DST results in this study seem to point us in the right direction to better understand and predict suicidality: 32 of the 78 patients had abnormal DST results at the beginning of the study. When followed up 15 years later, the estimated risk for eventual suicide in the group with abnormal results was 26.8%. In comparison, the group with normal DST results (normal functioning of their HPA axis) had a risk of only 2.9%. This comparison shows us that the functioning of the HPA axis seems to correlate with suicide risk. (7).
Even more recently (August 2022), researchers used a slightly different test to determine how HPA axis regulation (or dysregulation) differed with respect to the participants’ history of suicide attempts (SA; none versus multiple) (2). Researchers made this alteration because they found it to be a better indicator of HPA axis function. Known as dex-CRH, this test combined DST with another test used to assess HPA axis functioning (CRH stimulation test), which does so by measuring the levels of cortisol in the blood after administration of synthetic CRH.
For this study, participants took two dex-CRH tests in the study: one upon admission for acute depression, and one upon recovery from acute depression (completion of antidepressant treatment) (2). The researchers found that participants with no history of suicide attempts showed a normalization (decrease) of the stress hormone response (ACTH) after recovery from acute depression, but patients with multiple SA had an increase in the response of ACTH. Those that reported only one past suicide attempt had no change in HPA axis reactivity (neither increase nor decrease in ACTH response). Put simply, it seems that an increase in the HPA axis during acute depression treatment (e.g. antidepressants) may be a “biological characteristic for individuals with a history of SA”, as well as a possible predictive factor for future SA (2).
With such a large population of MDD patients who are resistant to current treatments which focus on serotonin and norepinephrine transmission, we should wonder: what other MDD-related changes in the brain may be targeted for future treatments? With research pointing in the direction of cortisol and the HPA axis, maybe there is an opportunity to intervene at the source of the increased stress.
A New Wave of Treatments
With the insights from this body of research into how the HPA axis and cortisol affect those with psychiatric conditions and suicidal ideation, it begs the question: why aren’t the mainstream antidepressant medications targeting the HPA axis and hormones affecting cortisol levels in the brain/body? Take, for instance, that with the current antidepressants on the market, 50% of those with Major Depressive Disorder (a condition that affects approximately 20% of people in their lifetime) do not respond to the first antidepressant they are prescribed, and 30% are treatment resistant after multiple drug options are exhausted (5). Is there something better than our current treatments that takes this research on the HPA axis into account?
As it turns out, there are a few options researchers believe would target the HPA axis and hormones related to the stress response directly and have desired antidepressant effects. One category of drugs, known as glucocorticoid receptor (GR) antagonists, prevents cortisol (a glucocorticoid) from binding to the relevant receptors, balancing out hyperactivity of the HPA axis by decreasing the number of receptors available to be activated by cortisol. There have been several studies (10, Figure 1) that indicate that patients who took the GR antagonist mifepristone showed significant improvements in depressive symptoms as opposed to placebos.
Another category of drugs that show promise as antidepressants are known as CRH1 receptor antagonists. As discussed earlier, CRH is the hormone that the PVN releases to get the pituitary gland to release ACTH (which then drives the adrenal glands to produce cortisol). Like GR antagonists, CRH1 antagonists block some of the CRH receptors so that there is less of a response in the HPA axis. This time, however, the drug’s effects result in less cortisol being produced. Research into this class of drugs as antidepressants and for stress-related disorders is a little less promising, though. Some researchers believe that CRH1 antagonists do work to help with depression and stress-related conditions, but only when used with other treatments (9). Others think these are promising agents for some stress-related conditions, but may not be suited for others (11).
How to Save a Life
There has been a lot of research into the HPA axis and psychiatric illnesses over the years, especially important is the finding that there is a link between hyperactivity in the HPA axis and psychiatric illnesses. Recently, however, with research showing that hyperactivity in the HPA axis also correlates with a higher likelihood of those individuals to die by suicide, the tests used in these studies might be ways in which we can predict suicidality in individuals; as well, we could have better treatments for both psychiatric disorders and suicidality, as opposed to the current antidepressants on the market. This means the 700,000 deaths by suicide and millions of suicide attempts annually could possibly dramatically decrease, as well as making those with psychiatric illnesses have a better quality of life.
As it seems prejudice, bigotry, and laws targeting the LGBTQ community are not going away soon, (as disheartening and cynical as that may sound) exploring alternative avenues to improve and save the lives of those affected by this bigotry seems like our next best option. As someone who believes in the power of medicine, as well as a suicide survivor, I fully support the exploration of the HPA axis as a target for improved antidepressant treatment.
Just imagine: millions of lives saved and improved, just with a test and/or new medications.
Well, what are we waiting for?
If you or someone you know is experiencing suicidal thoughts, behaviors, or any form of crisis, please refer to and/or share the resources and helplines below:
- 988: the national suicide hotline in the U.S.
- 1-800-662-4357: SAMHSA’s National Helpline
- 741741: Crisis Text Line
- 44357: TXT 4 HELP, a free, confidential text message helpline for youth in crisis
- https://www.thetrevorproject.org/get-help/: The Trevor Project, a suicide prevention organization with a free, confidential crisis phone line, text line, and online chat service with counselors who have competency with issues affecting LGBTQ+ youth in the U.S.
References
- https://www.who.int/news-room/fact-sheets/detail/suicide
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9412752/
- https://www.thetrevorproject.org/survey-2023/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313380/
- https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00101/full
- https://www.sciencedirect.com/science/article/pii/S0022395698900565
- https://pubmed.ncbi.nlm.nih.gov/11329397/
- https://www.uclahealth.org/medical-services/surgery/endocrine-surgery/patient-resources/patient-education/endocrine-surgery-encyclopedia/dexamethasone-suppression-test#:~:text=What%20is%20a%20Dexamethasone%20Suppression,to%20the%20administration%20of%20dexamethasone.
- https://www.sciencedirect.com/science/article/pii/S0006322317317298
- https://www.tandfonline.com/doi/full/10.3109/15622975.2014.916414?casa_token=O6lF0ShkfTQAAAAA%3ApQll_XvTJjkzKgXAyHMn1Mu6lzhhXLMK0nF-Lo3GTcezOBjpVEszCGIO44iwMZdYe1j3Q5yo7ZTJJg
- https://doi.org/10.1016/j.biopsych.2017.10.012
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