Suicidal Behavior: A Distinct Psychobiology?

Over 800,000 suicide-related deaths are reported around the world every year, with one person committing suicide every 40 seconds (1). Extensive work aimed at improving suicide prevention has yet to deliver objective tools for better assessment and management of suicide risk. One of the hurdles has been a lack of full understanding of the underlying biological manifestations that lead to suicide. In order to conceptualize this complex phenomenon, the stress-diathesis model was proposed almost two decades ago and is still regarded as the most widely accepted hypothesis for understanding suicide. It describes suicidal behavior as the interplay between a stressor (e.g., an acute psychiatric condition or a negative psychosocial event) and an individual's vulnerability to experience suicidality. This vulnerability, or diathesis, potentially results from a genetic predisposition and epigenetic mechanisms related to early-life adversity (2, 3). Within this framework, substantial effort has been made to uncover the pathophysiology that would account for this diathesis. Thus far, findings are indicating that the suicide biological architecture consists of a distinct network of interrelated neural systems at play. Further study may unravel a holistic psychobiological foundation for suicidal behavior. This in turn would add support to the latter as being a discrete psychiatric disorder, a point that was suggested in DSM-5 and will be discussed in more details later. The present article reviews the most salient systems involved in the neurobiology of suicidal behavior and the interactions between them.

Serotonergic System

Owing to its major role in mediating impulsive aggression and affective instability, serotonin has already been linked to multiple psychopathologies and is heavily involved in the biological mechanism of suicide (4). Earlier studies have established a robust association between low CSF 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin and a reliable indicator of serotonin turnover, and suicide attempts, irrespective of psychiatric diagnoses (5). In contrast, suicide victims were found to have elevated tryptophan hydroxylase 2, the rate-limiting enzyme in serotonin synthesis in the brain, decreased serotonin transporter binding affinity, and increased serotonin neurons and concentration in the brainstem, perhaps compensating for low serotonergic activity (4). Taken together, these findings imply a defective transmission of serotonin (6). One proposed explanation is the elevated 5-HT1A autoreceptors binding affinity in the dorsal raphe nucleus of depressed suicide victims, which leads to decreased serotonin firing, and has been shown to predict more lethal suicidal behavior in a prospective cohort (7).

Hypothalamic Pituitary Adrenal (HPA) Axis

The HPA axis has also been heavily researched in relation to suicide, owing to its role in the stress-response system. To assess HPA axis dysregulation, the dexamethasone suppression test has been most commonly used, in which failure to suppress cortisol constitutes evidence for a hyperactive HPA axis. Several studies have found associations between dexamethasone suppression test non-suppression and a history of suicide attempts, higher hospitalization rate for suicide attempts, completed suicides, and a 14-fold higher risk for completed suicide (8–11).

Cortisol levels have also been used as a proxy measure for HPA axis activity. Both elevated and blunted levels have been associated with suicide attempts (12). Interestingly, a recent meta-analysis concluded that the direction of the association between cortisol and suicide attempts may be related to age (13), with higher levels in samples with a mean age under 40 compared with lower levels in samples with a mean age over 40 (13). While this finding may further elucidate the nature of the relationship between cortisol and suicide, it is important to remain cognizant of the marked methodological variability across studies included in this meta-analysis.

Neuroinflammation

Since the emergence of interferon-induced suicidal ideation and depression (14), the role of the inflammatory system in suicide has been garnering a lot of attention. Disturbances in cytokine levels have been associated with suicidality. The most consistent finding has been an elevated pro-inflammatory IL-6 level in blood and postmortem brain samples of individuals with suicidality compared with individuals without suicidality and healthy controls (15, 16).

Microgliosis, another indicator of neuroinflammation, has also been associated with suicide. In one study, a higher proportion of activated microglia and perivascular macrophage density was observed in the dorsal anterior cingulate white matter of postmortem brain samples from suicide deaths compared with matched nonpsychiatric deaths (17).

Additionally, large case-control studies found that omega-3 fatty acids, known for their anti-inflammatory properties, are low in individuals who attempted or completed suicide. Low levels also predicted future attempts in a prospective cohort (4). Although further studies are needed to confirm the association between omega 3 fatty acids and suicide, inflammation is nonetheless proving to be an area requiring further investigation.

Kynurenine Pathway

The kynurenine pathway, the main metabolic pathway for the degradation of tryptophan (see Figure 1), has made a relatively newer introduction to the suicide literature in the last few years. Quinolinic acid (QUIN), one of the main metabolites, is considered neurotoxic due to its activation of N-methyl-d-aspartate (NMDA) receptors, as well as the increased release of glutamate and inhibition of glutamate uptake, leading to glutamatergic neurotransmission overactivation. Another important metabolite, kynurenic acid (KYNA), is known for its neuroprotective, anticonvulsive, and antioxidant properties and acts mainly through NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors antagonism (18). A significantly higher level of QUIN in the CSF has been associated with suicide intent and attempts, with QUIN/KYNA ratio, otherwise known as the neurotoxic ratio, being 2-fold higher in suicide attempters compared with healthy controls. Furthermore, these abnormal QUIN levels were still elevated 2 years post-attempt. These findings, along with the fact that ketamine, an NMDA antagonist, has been demonstrated to have antisuicidal properties, make the kynurenine system worthy of further exploration (18).

Neuroplasticity

Neuroplasticity refers to the processes by which the brain, through neurotrophic factors, undergoes functionally necessary adaptations in response to internal or environmental stimuli. Low levels of brain-derived neurotrophic factor (BDNF), a crucial mediator for neuronal survival and growth, and its receptor tropomyosin receptor kinase B or TrkB, have been found in suicide victims irrespective of the underlying psychiatric disorder (4), in some cases as a result of epigenetic changes (19). Reduced volume in crucial areas of the brain, such as the ventrolateral prefrontal cortex, has also been reported in patients with previous suicide attempt (20). These findings indicate increased neuronal loss and decreased neurogenesis in suicide.

Interplay of Biological Systems

As previously mentioned, a common suicide diathesis irrespective of psychiatric diagnosis has been suggested. This would require an underlying coherent pathophysiological mechanism that manifests itself into suicidal behavior (6). Therefore, a closer look at the dynamic and complex interplay between the different implicated systems is crucial to a better understanding of this machinery (Figure 1).

Neuroinflammation, by way of inflammatory cytokines, may contribute to the pathophysiology of suicide through different mechanisms, including stimulation of the HPA axis and dysregulation of the serotonin system (21, 22). Inflammatory cytokines also activate the enzyme indoleamine 2,3-deoxygenase, which catalyzes the initial step of the kyrunenine pathway (23). Although yet unstudied, this may theoretically contribute to decreased tryptophan metabolism into serotonin (16, 24). Additionally, downstream along the kynurenine pathway, QUIN's neurotoxic effects through NMDA receptor agonism might offer an explanation for the antisuicidal actions of NMDA antagonist ketamine. Moreover, in recent findings, ketamine's metabolite, (2R,6R)-hydroxynorketamine, has been shown to exert antidepressant effects through AMPA receptor activation (25). This in turn leads to BDNF release (26), which makes this pathway a plausible therapeutic target for antidepressants, as well as antisuicidal agents. Neurogenesis has also been observed to be significantly affected by different systems' dysfunctions, including dysregulation of the HPA axis and impaired serotonin transmission (6). Much research needs to be conducted to understand the precise nature of these interactions and how they fit into a coherent scheme.

Conclusions

The neurobiology of suicide is a highly complex phenomenon involving multiple interconnected neural systems. However, suicide research faces many limitations: small sample sizes, absence of animal models for suicidal behavior, phenotypic heterogeneity of suicidality, and exclusion of suicidal subjects from clinical trials for safety purposes. Additionally, the interplay between biological systems remains largely unstudied.

Considerations for the addition of suicidal behavior disorder as a separate DSM-5 diagnosis were made in an effort to resolve some of the issues mentioned above. Notably, suicidal behavior fulfills the criteria for diagnostic validity determined by Robins and Guze (27) and has been demonstrated to be a reliable diagnosis (28). Reframing our concept of suicide as a separate disorder may lead to a higher screening and detection of suicidal behavior in clinical practice and a common nomenclature for a well-defined phenotype. It may also help expand suicide research to analyses of large national or insurance data sets, providing a remedy to current small sample sizes (28).

With the advances in genetics, variants associated with psychiatric disorders are being detected at unprecedented rates, shedding light on novel biological systems that could explain the phenotype in question. Neuroimaging also constitutes a valuable tool for identifying the premise of the suicide diathesis on a circuitry level. As resources continue to be allocated to genetics and brain imaging research, the future for a better understanding of suicide and its prevention looks promising.