The Neurobiological Mechanisms of a Suicidal Brain

Introduction

Many of us live our lives day to day, excited to see tomorrow’s adventures or indulge in its captivating events. Others live their lives simply wishing it would end. As of 2021, suicide has been found to take a life every 11 minutes and is the ninth most common cause of death for people between the ages of 10 and 64 years [1]. This is significant, and scientists have been trying to figure out for centuries why suicide occurs. For instance, the idea of suicide being an illness has been referenced and dated back to as early as the 17th century when melancholia, a type of mental instability, was seen as a disease and could lead to suicide [2]. As we can see, suicide was originally seen as related to mental illness. Similarly, today, many people attribute suicidal ideation and behavior to external factors such as traumatic life events, abuse, poverty, or difficult medical issues. 

While external factors are a very plausible explanation for suicide, present-day scientists and technological advances have allowed us to gain important new insights into the neurobiology of suicidal ideation, opening the door for better prevention and treatments. These findings have allowed us to investigate a more holistic composition of suicidal behavior and its internal biological mechanisms from a natural science perspective. 

The Suicidal Brain

Since the late 1900s, brain imaging technology has seen a revolution. Research has identified prominent brain regions involved in regulating suicidal thoughts and negative emotions. Specifically, fMRI tests have indicated that the ventromedial prefrontal cortex (vmPFC), located in the frontal lobe at the bottom of the cerebral hemispheres, is active during the experience of negative emotions and thoughts relating to suicide [3]. fMRI is a magnetic resonance imaging test which measures brain activity through the detection of changes in blood flow. 

This particular study was conducted on adolescents with high levels of anxiety and the experience of social exclusion to explore their possible connection to suicidal ideation [3]. Two groups of 14 adolescents were studied, the first being those who demonstrated non-suicidal self injury (NSSI), the second being those who did not demonstrate NSSI. Results of the fMRI suggested that limbic brain regions such as the amygdala and hypothalamus, all connected to the prefrontal cortex, produced higher levels of activity during the experience of negative emotion in the NSSI group than those who did not demonstrate NSSI [3]. The vmPFC has been suggested to be essential due to its association with risk factors, including anxiety and depression, along with its connections with the limbic system structures that play a key role in the neural network for behavioral modulation based on emotions and drives [4]. 

Beyond the vmPFC and its role in suicidal behaviors like NSSI, It is becoming increasingly clear that cognitive processes leading up to suicidal behaviors are modulated by different brain regions, which indicates the depth and complexity of the biology of suicide. Although difficult to determine at first, social cognitive processes can now be distinguished from behavioral expression due to the insights of recent neuropsychological and neuroimaging research [5]. Thanks to these studies, we have now gained insight into the brain structures that contribute to the trait-like characteristics that develop vulnerability to suicidal behavior [5]. While no one brain region has jumped to the forefront and cognitive processes seem more distributed and complex, current research is investigating how many brain regions may work together in a network that plays a role in the social cognitive processes potentially leading up to suicidal thoughts.

Scientific studies have also shown both a genetic and environmental contribution to suicidal ideation in individuals. One study found decreased ribosomal DNA in the prefrontal cortex of people who have died of suicide [6], indicating a change in gene expression is associated with suicidal ideation [6]. Other studies have indicated mutations in serotonergic pathways that may also contribute to suicide risk, allowing scientists to use this information to further develop neurobiological tests to detect patients who are at high risk for suicide [7][8]. 

Studies focused on genetically identical twins can also identify the specific contribution of environmental factors, and they have found evidence of an increased risk of suicide in twins, providing further evidence of genetic contributions to suicide [9]. Ultimately, these identifiable genetic similarities and differences in the brain further emphasize the neurobiological components of suicide.

Neurotransmitters

Disorders involving the brain often arise from issues with how the brain communicates between regions. Studies of suicidal brains have identified some implicated neurotransmitters, which could ultimately arise from genetic, epigenetic, or environmental factors. Vast bodies of research implicate the neurotransmitters GABA and glutamate, the main inhibitory and excitatory neurotransmitters in the brain, respectively. They are involved directly or indirectly in most aspects of normal brain function, including cognition, mood regulation, memory, and learning. Particularly, GABA has been shown to lower stress, one of the most common connections to suicide [10]. Recent reports have suggested that GABA dysfunction is a widespread phenomenon in the suicidal brain, becoming evident through a significant decrease in the density of GABA neurons in the hippocampus and several neocortical areas [11][12]. As for the glutamate system, one of the three major classes of glutamate receptors, the NMDA, is believed to have altered structure in a suicidal brain. The proportion of high-affinity glycine displaceable binding sites in the suicidal brain, which are located on NMDA receptors, was assessed. Results revealed a reduction in these binding sites in suicidal brains compared to the control group [11]. Overall, biological alterations are evident in presenting suicidal ideation and behavior. However, since these neurotransmitters are widespread in the brain, direct treatments become more complicated due to the increased likelihood of side effects in other brain regions and circuits.

The Serotonergic System

In addition to more widespread neurotransmitters like GABA and glutamate, current brainstem research suggests that many biological abnormalities are present in and associated with the serotonergic system. In particular, scientists have focused on measuring serotonin metabolites, which are products of serotonin decomposition whose levels can be used to estimate serotonin levels. One in particular, 5-HIAA, is a primary metabolite of serotonin, meaning that it is the product of the first step of serotonin decomposition [14]. Early reports note a reduction in the concentration of  5-HIAA in the cerebral spinal fluid of suicidal patients [15]. There are many possible causes for these 5-HIAA reductions: reduced release of the serotonin transmitter, fewer serotonin neurons or decreased interference of target regions, impaired serotonin synthesis, or even increased self-inhibition of serotonin [16]. Additionally, under further observation, altered 5-HIAA concentrations appeared to be more strongly associated with suicidal behavior than changes in the serotonin concentration itself [15]. These reductions were discovered post mortem, with the degree of metabolite reduction correlating with the lethality of the attempt, meaning patients whose attempts were completed in the most statistically harmful methods had the lowest levels of 5-HIAA [17]. 

Based on these findings, there have been research studies conducted on the effects of medication targeting the serotonergic system, specifically under the category of antidepressants. Selective serotonin reuptake inhibitors, or SSRIs, target serotonin reuptake to increase serotonin concentration in the brain, and they are now the most common form of medication used to treat mental illness, including suicide. However, new findings are emerging about the effects of rapid-acting antidepressants, which also target the serotonergic system [18]. One drug in particular used is ketamine, a rapid-acting antidepressant that targets serotonin receptors localized in the prefrontal cortex of the brain, further enhancing the effects of serotonin and producing positive outcomes in less than 24 hours, including a rapid decrease in negative and suicidal ideation [18]. Other studies have corroborated these findings, such as research on ketamine and D-cycloserine (DCS), a partial stimulant of the NMDA glutamate receptor, the primary excitatory neurotransmitter in the brain. After several studies, such as trials involving a group who received a minimal dosage of ketamine compared to a placebo group, DCS was found capable of maintaining the antisuicidal effects enhanced by ketamine [19]. Given both our observations of suicidal patients and the results of interventions targeting the serotonergic system, we can see that serotonin is a major component of the biology of suicide. Hopefully, more research in this area can help improve the prognosis for patients and continue to support improved neuropharmaceuticals.

The Noradrenergic System

Research has also found alterations in noradrenergic neurotransmission in suicidal patients, including changes in the concentration of the neurotransmitter in deceased brain tissue. Noradrenergic innervation of the cerebral cortex is derived exclusively from neurons in the locus coeruleus (LC), located near the back of the brainstem. The LC contains norepinephrine- (another name for noradrenaline) synthesizing neurons that send axons through the central nervous system and plays a major role in arousal, attention, and most importantly, the stress response [21]. Similarly to serotonergic neurons, these noradrenergic neurons exhibit widespread innervation throughout the central nervous system, including a central part of the limbic system. Disregulation of the LC has been associated with development of pathological anxiety, which may mediate suicidal behavior [22]. Future studies should further investigate the role of noradrenergic pathways and suicide risk.

The HPA Axis

The hypothalamic-pituitary-adrenal (HPA) axis has become one of the primary locations of study behind suicide and its biological origin. Central to the human response and adaptation to stress, the HPA axis is an intricate mechanism that mediates the effects of stressors by regulating several systems. Evidence suggests that impairments of the serotonergic and noradrenergic neurotransmitter systems and structural brain abnormalities result in dysregulation of HPA stress response activity, leading to changes in levels of cortisol, our body’s most important stress hormone, and the primary output of the HPA axis. Cortisol’s association with suicidal behavior has been demonstrated through its correlation with impairments in cognitive control, decision making, and emotional processing [23]. It is no surprise that, due to the role of stress in brain dysfunction, abnormalities in the HPA axis have been found in those who have attempted suicide.

A hyperactive HPA axis has been implicated in many stress disorders such as PTSD, and is one of the most consistent psychiatric findings in depression. Corticotropin releasing factor (CRF) is produced by the hypothalamus, the most upstream regulator of the HPA axis, and is thought to play an important role in the pathophysiology of depression and suicidal behavior [24]. One of the identifiers for hyperactive CRF neurotransmission includes increased levels of CRF in cerebrospinal fluid. These levels are highest in depressed suicide victims, indicating that higher levels of CRF may be associated with greater illness severity. These results are also based on findings of CRF immunoreactive neurons in notable areas for suicidal behavior, such as the prefrontal cortex and the locus coeruleus [24]. 

High CRF levels also cause long-term issues in the regulation of the HPA axis, and recent research has focused on these changes [23]. As the upstream parts of the HPA axis, the hypothalamus and pituitary gland are normally responsible for detecting changes in cortisol and regulating them via a negative feedback loop, and the hypothalamus does so by modulating its production of CRF. When cortisol levels rise, CRF is released less to reduce cortisol production downstream, and when cortisol levels are low, the hypothalamus increases CRF secretion to produce more cortisol. These responses maintain cortisol at a homeostatic, or baseline, level, and the strength of the CRF change in response to cortisol levels is known as cortisol reactivity [23]. 

If the hypothalamus fails to respond to high levels of cortisol by reducing CRF levels, displaying a lower cortisol reactivity, CRF and cortisol may continue to remain high, contributing to increased stress associated with greater risk for suicide. One study compared cortisol reactivity between first-degree relatives of suicide victims and people not related to suicide victims [25]. The participants underwent a test called the Treir Social Stress Test (TSST), which asked them to engage in public speaking with a surprise math test. Notably, first-degree relatives of suicide victims exhibited a lower cortisol increase in response to stress than their unrelated counterparts, indicative of a lower cortisol reactivity. This finding further implies that there is a biological and genetic component to this stress response, which can have an effect on suicidal patients. Additionally, upon measuring executive function, including working memory, flexible thinking, and self control, it was concluded that participants who had a first-degree relative who had completed or attempted suicide did not improve on measures of inhibited cortisol response upon repeated testing after the first TSST, confirming lower cortisol response [26].

Based on these results, it is likely that decreased cortisol reactivity to stress is a possible trait marker of suicide risk. It is also possible that impairments of certain aspects of executive function may be a consequence of dysregulation of the HPA axis, which increases a person’s vulnerability to suicide. These findings are consistent with the idea that dysregulation of the stress system can be a heritable risk factor for suicidal behavior. This research has thus provided us with another possible biological etiology of suicide. 

Treatment

Now that scientists understand more about the biological mechanisms behind suicide, treatment specifically targeting these areas can be developed. As opposed to therapy treatments such as cognitive behavioral therapy or psychotherapy, chemical treatments are capable of adjusting hormone and neurotransmitter levels to result in an increased quality of life.

Notable psychiatric illnesses such as depression, schizophrenia, and post-traumatic stress disorder (PTSD) are now commonly associated with suicide, along with substance use disorders such as alcoholism and drug addiction [27]. Furthermore, the risk of suicide seems to be greatest during the first few months after diagnosis across all mental disorders. In schizophrenic and bipolar disorders, suicide during this timeframe is a major cause of death [28]. In certain cases, this is hypothesized to be due to specific therapeutic medications, which can improve a patient’s executive function, with the effect of giving some patients a stronger motivation to end their life [28]. Although the possibility is small, it’s imperative to consult a licensed professional on what treatment options would be likely to work for an individual case, along with frequent check-ins and being cognizant of feelings and symptoms that can be experienced while on medication. From these advances in understanding the connection between suicide and mental illness, as well as the ways in which different treatments impact them, scientists can learn more about the suicidal brain itself [29].

Prediction and Prevention

Although research for direct treatment through medications for suicidal ideation and behavior still persists and may be critical to treating biological components of suicide, advances in technology and statistics have made it possible to help predict and prevent suicide. These advances have come with the widespread use of smartphones, due to their ability to record and provide real-time ecological momentary assessment (EMA) data, which consists of real-time samples of an individual’s behavior in their natural environment. Recent technology has even allowed for wearable sensors and their integration with EMA data [30].

EMA studies have previously employed beepers, which would remind a participant to complete an assessment, but have now evolved to use smartphones, which are capable of both releasing signals and recording assessment data. Smartphone-based EMAs have been particularly important for suicide research, as suicidal ideation and risk factors can fluctuate rapidly, making a smartphone ideal to record these fluctuations as they happen [31]. Theories that may explain these fluctuations include the three-step-theory, which marks the transition from suicidal ideation to acting on those thoughts, along with the fluid-vulnerability theory, which places emphasis on rapidly changing risks for suicide [32]. This work focusing on day-to-day symptoms and factors associated with the suicide crisis illustrate why it is all the more critical to record and to record often. Since most people keep their smartphones within reach, scientists now have a better chance of capturing these risks and influencing protective factors. This can in some ways be thought of as a scientific version of BeReal, an increasingly popular social media app which asks you to post and update whatever is going on in your life at specific times.

Along with the use of smartphones, wearables such as a Fitbit or research-grade wearables such as the Empatica E4 have played a critical role in suicide research, specifically when self-reporting is not possible. Although wearables may not be able to detect ‘signatures’ of suicidal ideation or behavior, they can record behavioral and psychological alterations in the context of sleep and emotional dysregulation [33]. Although not directly evident to suicidal ideation, a study observed that shorter sleep duration was found to predict an increase in suicidal ideation the following day in adults who had recently experienced suicidal ideation and behavior [34]. In regards to emotional dysregulation, studies measuring skin conductance as an approximation for sweating responses were able to estimate the severity of suicidal ideation as it happened, along with tracking heart rate variability to determine and predict suicidal ideation and behavior [35]. 

As more predictive factors are discovered and tracked, it may soon be much easier to intervene at the right time and reduce the risk of an attempt. Thus, accurate prediction is critical, and it will revolutionize the prevention of suicide. What makes these advances particularly great is that they usually do not enhance or increase suicidal ideation and characterization as participants complete assessments and surveys. Many barriers still stand between suicide research and full detection and prevention, but these advances in technology and data are already aiding us in successfully predicting and preventing suicidal behavior.

Conclusion

Our understanding of suicide has advanced, allowing us to learn more about its complex mechanisms. Beginning with the stigma developed around mental illness and now progressing with the extensive help of modern day technology, research has broadened to focus on the biological markers which indicate suicide. Abnormalities in the HPA axis, hormones, and neurotransmitters such as cortisol and GABA, along with various brain regions, all have markers which correlate with or contribute to suicidal behavior and ideation. These new findings have opened new opportunities for the development of both chemical and physical treatments, allowing us to hone in on associated and contributing factors alongside the use of advanced technology to be able to predict and prevent suicidal ideation and behavior. Today, it remains critical to consult with professionals on the appropriate medications to take and to follow their expert advice. If suicide is a biological phenomenon, medications may be biological solutions. 

Despite these advances, suicide rates are increasing annually, hence it is important for our understanding of suicide to grow. Extensive research has been conducted, but there are still many years and discoveries that await before the mechanism of suicidal behavior is fully understood. However, what was once understood to be a psychological phenomenon is now expanding into the depth behind human biology, and armed with this new understanding, scientists have new avenues through which to treat patients and save more lives.

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