Neurobiology of Suicidal Behavior

The biochemical mechanisms underlying suicidal behavior in the brain are beginning to come to light, and researchers hope they may one day lead to better treatment and prevention strategies. Kees van Heeringen, who received a psychiatry internship at the physical rehabilitation unit at Ghent University Hospital in Belgium in 1980, encountered a 16-year-old girl who committed suicide by jumping off the bridge during her duty. This girl’s name is Valerie and she lost both legs when she jumped off the bridge and spent several months in the hospital. Psychiatrist Van; As she got to know this girl, she gathered events, including stressful interactions with people around her, in making the suicidal decision, and found that Valerie was constantly experiencing an accumulation of depression symptoms. Van Heeringen, who later described this experience in his 2018 book The Neuroscience of Suicidal Behavior, stated that Valerie’s story left a lasting impression on him.

In 1996, van Heeringen established the University of Ghent Suicide Research Unit. Since then he has served as his director, helping to direct many questions he and his team have about suicide into scientific research. Most of the answers are as elusive as they appeared in the rehabilitation unit that day. Suicide rates are increasing in the USA and many other countries today, and suicide is the second leading cause of death among young people worldwide after traffic accidents. The World Health Organization recently estimates that one person takes his life every 40 seconds worldwide. Suicide is as complex as it is tragic. Suicidal behaviors come in many varieties, from suicidal thoughts or ideas to suicidal attempts and completion, all of which can be associated with various levels of violence or intent. Behaviors themselves differ in incidence between genders, ethnicities, and other demographic categories. Depression or another mood disorder almost always occurs in the background, but only some people with mood disorders become suicidal.

However, no scientific research field can solve a situation as complex as suicide alone. However, van Heeringen and many scientists hope to shed light on the problem by thoroughly examining the neurobiological processes that underlie one’s thoughts of ending one’s own life, and continue to work. This study supports the idea that suicide is due to certain biochemical changes, free from mental health disorders that are often accompanied by suicide. The researchers hope that the findings from this study could help uncover new treatments and even provide opportunities to identify people most at risk for intervention. Gustavo Turecki, psychiatrist and director of suicide research, reported that the knowledge they have today is far more than they had two decades ago, and that they have made tremendous progress in understanding the complexity of the problem, neurobiology and causes.

Neurobiological Paths Linked to Suicide Risk

Scientists have identified several basic neurobiological pathways associated with suicidal behavior. Research in this area addresses only part of the complexity of this serious public health problem, and the relevant literature is complex due to the diversity in study design. However, the clues obtained point to a few interactive moderators of suicide risk.

The Role of Brain Stress Paths in Suicide

Valerie’s story is similar to the stories of many other people trying to end their lives. As van Heeringen later discovered, a family history of suicide is a known risk factor for suicidal behavior independent of depression, social stress symptoms and any psychiatric disorder. Scientists consider suicide in terms of stress diathesis models that treat suicide as a product of both accelerating factors such as high stress or mood disorders and predisposing factors (diathesis) such as family history and specific genetics. Also included are early life difficulties such as variables, abuse or neglect.

This framework has helped focus on research into biochemical pathways that regulate the brain’s response to stress and how these pathways can be modified in suicidal people. The brain has more than one stress response, but the best studied about suicide is the hypothalamic-pituitary-adrenal (HPA) axis that controls the release of the stress hormone cortisol and is known to be upregulated in clinical depression.

Initial clues to the link between the HPA axis and suicide include findings of higher concentrations of corticotropin-releasing hormone (CRH) that trigger the synthesis of cortisol and other glucocorticoids involved in the stress signal in postmortem brain samples from people who died by other means of suicide. Other studies have implied that people who die as a result of suicide enlarge their adrenal glands, that is, their cortisol production areas. However, due to the high incidence of depression and other mood disorders in self-destructive people, such studies have not attempted to determine whether the observed effects are specific to suicide or, more generally, to mood disorders. More recently, the HPA axis case, which plays a central role in suicide, has received support from studies by Turecki et al. It has long-term effects on HPA axis function in early life, which is one of the strongest risk factors for suicide even when psychiatric disorders are controlled.

In the mid-2000s, he conducted research with Turecki and McGill University geneticist Moshe Szyf. In their study, they found that rats neglected by their mothers displayed altered epigenomes and dysfunctional HPA responses to stress in the hippocampus, a brain region related to stress, learning, and memory. Turecki, Szyf, and colleagues found evidence of hypermethylation in the hippocampus of people who died of suicide and had a history of childhood abuse, and found that the expression of the gene encoding NR3C1, a glucocorticoid receptor that helps reduce cortisol signaling, decreased compared to healthy controls or humans. Studies since then have linked suicidal behaviors to methylation abnormalities in other HPA-related genes. A 2018 review of about 90 people who attempted suicide found decreased methylation in the CRH gene in blood samples from some of the study subjects, particularly those who had attempted more severe or more likely to result in death. And some studies have identified hypermethylation and codes of the SKA2 protein, which is reduced in expression when interacting with NR3C1, in people who died of suicide, compared to patients with depression, schizophrenia, or other psychiatric disorders with healthy controls. The relationship between the HPA axis and suicidal behavior is complex. For example, some studies show that the HPA axis overreacts to stress in people who died from suicide, while others show that people who attempted suicide have lower cortisol levels or dull HPA reactivity to stress compared to controls.

Stress Responses

Many studies have linked suicidal behaviors with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and other mediators of the body’s responses to stress, and these are as follows:

CRH: Higher concentrations of corticotropin-releasing hormone (CRH) have been found in the brains of people who died from suicide.

Adrenal glands: People who died as a result of suicide, and especially those who died through violence, may have enlarged adrenal glands.

Cortisol: It has been found that basal cortisol levels are low or higher than normal in people who have attempted suicide. The stress response of cortisol can also be dysfunctional in people with suicidal behavior.

NR3C1: NR3C1, also known as the glucocorticoid receptor, may be in smaller amounts in people who died by suicide, especially those with a history of childhood abuse.

Nerve Conduction

Neural communication through other neurotransmitters such as serotonin and glutamate often shows signs of disorder in people who die from suicide.

Serotonin

Disruption of serotonin signals in the brains of people who died as a result of suicide has been found repeatedly.

HARD

Levels of the serotonin transporter SERT, which sends serotonin back to the presynaptic neuron, may be lower in people who die from suicide.

Serotonin receptors

People who have attempted suicide or died may have higher levels of serotonin receptors 5-HT 1A and 5-HT 2A.

Potential Link to Neuroinflammation

Researchers in Denmark have reported a link between suicide and infectious disease. By analyzing thirty-year medical records of more than 7 million people, the team found that hospitalization for an infection was associated with a suicide probability of more than 40 percent. They found that spending more than three months in the hospital was linked to more than twice the suicide rate. While the team acknowledged that such observational data could not show causation, they calculated that the statistical risk associated with hospitalization for infections could account for about 10 percent of suicides in Denmark. There are many possible explanations for this finding. One is that treating infections with antibiotics or other hospital medications can affect mental health. However, van Heeringen and his team pointed out that the study is linked to another hypothesis regarding suicidal behavior, this hypothesis involving the role of inflammation. It has previously been reported that in people with autoimmune disorders and traumatic brain injury, conditions that typically involve inflammation, such as infections, are associated with a higher risk of suicide. Other clues come from epidemiological studies of Toxoplasma gondii, a parasite that causes chronic, low-level neuroinflammation in individuals.

A study of about 300 people in Korea in 2018 found that 14 percent of people who attempted suicide tested positive for the parasite compared to only 6 percent of healthy controls, reflecting a correlation found in several US cohorts. While depression is not thought to be an inflammatory disease, signs of neuroinflammation in the brain have been documented repeatedly in people suffering from depression, and a number of anti-inflammatory drugs show antidepressant effects. Melhem reports that Microglia, the primary immune cells and mediators of inflammation of the central nervous system, tend to show increased activation in the brains of people who die from suicide, and some studies have identified high concentrations of inflammatory cytokines such as interleukin IL-2, IL. It is -6 and IL-8 in people with fatal and non-fatal suicidal behaviors. For example, a 2019 analysis of about 2,000 Mexican-Americans found that depressed and non-depressed women who attempted suicide had elevated IL-8 blood levels.

Exactly how neuroinflammation might contribute to suicidal behavior is still unclear, and some recent epidemiological studies have raised doubts as to whether this association is independent of depression. One way researchers are investigating is the interaction of neuroinflammation with the serotonergic system. In a process thought to be mediated by microglia, neuroinflammation triggers a shift in the metabolism of tryptophan, the molecular precursor of serotonin, away from serotonin production and towards other chemical pathways. This potentially reduces the serotonin signal and triggers other suicide-related changes in the brain.

Inspiration

Epidemiological data suggest that some inflammation-related health conditions are associated with a higher risk of suicide, while those who die from suicide show signs of increased inflammation in the brain.

Microglia

The brains of people who die as a result of suicide show higher levels of microglia activation.

Cytokines

People who attempted suicide had higher levels of inflammatory cytokines in the blood, especially some types of interleukins.

Tools for Predicting and Preventing Suicide

One of the defining moments in psychiatrist David Brent’s career occurred during his medical residency nearly 40 years ago. Brent was assigned to work with teenagers who knowingly agreed to overdose at the University of Pittsburgh Medical Center Children’s Hospital. He had to determine which one would be referred to the psychiatric ward and which could go home safely. Brent, who is now a professor at Pitt, realized he didn’t really find a very good way to give that determination. As he learned more about how other clinicians made such decisions, he understood the value of the firm he was working with and realized that no one knew what he was doing. This is still a dilemma faced by anyone trying to care for people at risk of suicide. Today’s clinicians often rely on patients to inform their intentions to decide on appropriate interventions. However, the approach has its limits.

Cortisol tests can help provide predictive power to other measures of suicidality such as social and academic stress surveys. A recent analysis showed that although survey data are good indicators that among 220 young girls with mental health problems they will consider suicide in a few months, there are poor predictions of who will attempt suicide at that time. But when researchers focused on girls who showed blind cortisol responses in lab tests, the survey data predicted suicide attempts much better. Looking beyond the stress responses, other groups have attempted to identify biomarkers related to neurotransmission.

A few years ago, Mann’s group used positron emission tomographic (PET) imaging to evaluate the levels of 5-HT 1A serotonin receptors in the midbrains of 100 patients with major depressive disorder. Scientists have found that higher 5-HT 1A levels predicted more suicidal thoughts and more fatal suicidal behavior over the next two years. Last summer, a study group led by a Yale University neurophysiologist reported that glutamate receptor mGluR5 levels measured by Irina Esterlis PET are associated with individuals with current suicidal thoughts associated with post-traumatic stress disorder. However, the results obtained are not valid for patients with major depressive disorder. There are differences of opinion among researchers about the potential of such biochemical signatures to assess suicide risk.

Greg Ordway, a pharmacologist working on depression at East Tennessee State University, reported that biology can identify people prone to suicidal behavior, but it is unlikely to produce one or several biomarkers that reliably reveal whether a person will end their life. Suicide is extremely difficult to predict and people always try to do this. Some of the most promising tools for assessing immediate risk may instead come from other neuroscience areas that measure more complex, emotional signals as opposed to biochemical signatures in the brain. In 2017, Carnegie Mellon University neuroscientist Brent, Marcel Just, and team used machine learning algorithms to process this data while thinking about words such as death, trouble, and anxiety, along with a functional MRI image used in the brains of 34 people. As reported during this study, he was able to distinguish between people who thought of suicide and those who did not believe with 91 percent accuracy. The team identified people who had attempted suicide with 94 percent accuracy.

Researchers recently received $ 3.8 million from the National Institute of Mental Health to scale up the project and planned long-term follow-up of people with and without various types of mood disorders. As part of the research, the researchers hope to expand their tools to identify people who may attempt suicide in the future, not just those who thought during screening or have tried it in the past. Just to The Scientist, the team is planning to adapt the technique to a cheaper, more clinically-friendly technology than MRI, such as electroencephalography (EEG). Melhem is hopeful that combining techniques will improve predictive approaches in the coming years. In 2019, he and his colleagues published a model for predicting suicide attempts based on factors such as the severity and variability of a person’s depression symptoms over time, improving the accuracy and performance of existing models. He says that integrating such easy-to-collect clinical data with biological information from brain scans or other diagnostic tests should lead to more accurate predictions.

Investigation of such tests has important implications for suicide prevention, even beyond their potential to assess risk. Melhem reported that when biomarkers are presented, just as in other medical fields, patient-level stigma will decrease and patients are often surprised to hear that researchers are studying the biology underlying suicide. Because it is a behavioral flaw in their character and they feel guilty about it.