Comprehensive view of suicide: A neuro-immune-endocrine approach

Abstract

Suicide is defined as the act of a person attempting to take their own life by causing death. Suicide is a complex phenomenon that is influenced by a multitude of factors, including psychosocial, cultural, and religious aspects, as well as genetic, biochemical, and environmental factors. From a biochemical perspective, it is crucial to consider the communication between the endocrine, immune, and nervous systems when studying the etiology of suicide. Several pathologies involve the bidirectional communication between the peripheral activity and the central nervous system by the action of molecules such as cytokines, hormones, and neurotransmitters. These humoral signals, when present in optimal quantities, are responsible for maintaining physiological homeostasis, including mood states. Stress elevates the cortisol and proinflammatory cytokines levels and alter neurotransmitters balance, thereby increasing the risk of developing a psychiatric disorder and subsequently the risk of suicidal behavior. This review provides an integrative perspective about the neurochemical, immunological, and endocrinological disturbances associated with suicidal behavior, with a particular focus on those alterations that may serve as potential risk markers and/or indicators of the state preceding such a tragic act.

Key Words: Suicide; Neuroimmune endocrine; Neurotransmitters; Hormones; Cytokines; Hypothalamic-pituitary adrenal axis; Early life adversity; Inflammation; Genetic predisposition; Psychiatric disorders

Core Tip: The World Health Organization defines suicide as 'any act by which an individual causes injury to himself or herself, regardless of the degree of lethal intent and knowledge of the true mobile'. The etiology of suicide is multifactorial and involves complex interactions among biological, genetic, psychological, social, and environmental factors. The purpose of this manuscript is to describe the complex interactions of neuroimmunoendocrine and genetic factors associated with suicide and their relationships with environmental factors such as exposure to early life adversity, with a focus on alterations in the hypothalamic-pituitary adrenal axis and immune system.

INTRODUCTION

The term "suicide" has its etymological roots in the Latin words "sui" (oneself) and "caedere" (to kill)[1]. Suicidal ideation refers to persistent thoughts about the desire to end one's own life. In adolescents, ideation is often considered a high-risk factor. An attempt is defined as any act carried out with the intention of harming oneself or taking one's life[2].

The term "suicide" was first used in 1737 by Desfontaines. However, Émile Durkheim, a Frenchman, classified and defined suicidal behavior in 1897. In this case, the author concluded that individuals with greater social integration and whose desires and aspirations are more aligned with social norms are less likely to engage in suicidal behavior[3,4].

The concept of a 'suicidal act' was introduced in 1969 by the World Health Organization (WHO) as 'any act by which an individual causes injury to himself or herself, regardless of the degree of lethal intent and knowledge of the true mobile'. This last WHO definition includes aspects such as voluntariness, the purpose of the act, and conscious or unconscious motivations[5]. The WHO estimates that approximately 20% of global suicides are due to pesticide self-poisoning, with the majority occurring in rural agricultural areas in low- and middle-income countries. Other common methods of suicide include hanging and firearms (WHO, 2023). Due to the complex social, cultural, religious, and psychopathological implications of suicide, it is challenging to propose a universal definition that encompasses all the factors that contribute to it[6].

A suicidal crisis represents the stage at which the individual develops a structured plan for suicide and initiates its implementation. Suicidal ideation is the act of contemplating or devising a plan for suicide[7]. The term "parasuicide" is defined as any behavior that results in self-injury without the intention of ending one's life[8]. A suicide attempt is defined as any action that is intended to result in self-harm but that is ultimately unsuccessful due to the inappropriate methods employed[5]. Frustrated suicide is the term used to describe any suicidal act that is intended to result in death but is ultimately prevented by external factors beyond the individual's control. In such an act, the individual's intention is clearly to cause their own death[9]. The act of suicide is considered to be complete once the individual has taken the final steps to end his or her own life. This can involve a range of different levels of elaboration and planning, with the aim of fulfilling the purpose of the act[5].

EPIDEMIOLOGY

Suicide is a significant public health concern worldwide, with the WHO estimating that more than 700000 individuals die by suicide annually[10]. Recently, it has been observed that men over the age of 80 are more likely to commit suicide than younger people are. This is particularly evident when people are confronted with loneliness, chronic pain, and a loss of meaning in their lives[11]. Suicide is the 18th leading cause of death overall and the second leading cause of death among young people between the ages of 15 and 29[12].

The prevalence of suicide among adults in low- and middle-income countries varies by region and individual income level but is, on average, lower than that in high-income countries. Notably, young people in low- and middle-income countries have much greater rates of suicide attempts than young people in high-income countries. Additionally, women, as well as individuals with psychiatric disorders, people living with human immunodeficiency virus (HIV), and people with poor socioeconomic status, are highly vulnerable populations[10].

As reported by Zhang[13], suicide represents the seventh leading cause of lost years of potential life, surpassing liver disease, diabetes, and HIV. In the United States, one in seven young adults have presented some type of suicidal ideation during their lives, and at least five percent have attempted suicide. The financial impact on the United States healthcare system is estimated to exceed $70 billion, with significant unquantified costs borne by families affected in terms of loss of earnings.

It is estimated that for each completed suicide, there are between 100 and 200 suicide attempts by adolescents. The prevalence of suicide attempts among adolescents aged 15 to 16 years old is estimated to range from 4.1% to 23.5%[14].

THE INTRICATE NEUROBIOLOGY OF SUICIDE

The primary factors associated with a neurobiological response to suicide include anatomical and functional alterations of the central nervous system (CNS), fluctuations in neurotransmitter concentrations, genetic influences, and psychiatric disorders such as depression, schizophrenia, anxiety, personality disorders, and substance use disorders[15]. In addition to the aforementioned variables, certain mediators of inflammation, including cytokines, chemokines, hormones, and growth factors, are also implicated in the etiology of suicidal behavior[16].

Given the intricate network of factors and interactions underlying suicide, it is crucial to elucidate the endocrinological, immunological, and neurochemical alterations associated with suicidal behavior. This will facilitate a more comprehensive understanding of this challenging clinical condition. Additionally, other pertinent factors, such as genetic and anatomic factors, will be addressed. In recent years, a plethora of evidence demonstrating that the nervous, endocrine, and immune systems establish bidirectional communication, known as neuroimmunoendocrine interactions (NIEs), has been published[17]. This communication is carried out through the controlled release of soluble mediators, including hormones, cytokines, and neurotransmitters. The variation in the levels of these soluble mediators exerts a regulatory influence on physiological processes, which in turn modulates the body's response to various factors, including stress[18,19]. This neuroendocrine-immunological interaction facilitates the development of behavioral alterations.

Recently, microglia have gained significant attention in the field of suicidal behavior. It has been hypothesized that alterations in microglial function may be associated with the development of risk factors for suicidal behavior, including early life adversity (ELA), stressful events, and psychiatric disorders. As discussed below, risk factors associated with suicide are linked to inflammatory, oxidative stress, and neuroendocrine alterations. These alterations have been hypothesized to initiate microglial synaptic remodeling, leading to altered susceptibility or resistance to suicide[20].

It has been evidenced in postmortem studies that suicidal depressed subjects have increased microglial priming in the cingulum area[21]. Microglial priming is characterized by epigenetic changes that favor the overexpression of proinflammatory cytokine mRNA such as interleukin (IL)-1 in microglia, which favors an increase in the production of proinflammatory cytokines in response to stressful stimuli[22,23]. Additionally, it has been proposed that these inflammatory changes promote a disruption of the blood-brain barrier that favors leukocyte migration in the periphery. The impact of the inflammatory response on the pathophysiology of suicide will be discussed later[24]. Interestingly, it has been proposed that hormonal changes during adolescence could enhance microglial priming depending on the amount of testosterone or estrogen present during adolescence, it has been hypothesized that the higher the concentration of these hormones, the higher the risk of developing psychiatric illnesses due to microglial priming[24].

Postmortem studies have reported alterations in glial cell populations of suicidal psychiatric patients and have identified alterations in glial fibrillary acidic protein proteins or in astrocytes immunoreactive for vimentin. In addition, a higher density of glial cells was found in the dentate gyrus of the hippocampus[25]. Inflammatory changes in the morphology of astrocytes in the anterior cingulate cortex have been observed. These changes include significantly larger cell bodies, a higher number of nodes, and a reduced number of branches. Additionally, the total length of branches and the total number of spines are decreased. Furthermore, depressed suicidals exhibit more branching processes in the auditory association cortex[26]. Recently it has been described in postmortem studies that oligodendrocytes from depressed suicides have a lower expression of antioxidant molecules such as superoxide dismutase-1, superoxide dismutase-2, glutathione peroxidase-1, catalase, and alkylglycerone phosphate synthase. It has been proposed that a decrease in these antioxidant molecules favors inflammation and changes in neurotransmitter synthesis, which will be discussed below[27].

PSYCHOSOCIAL CORRELATES

It is well established that the psychosocial environment plays a pivotal role in suicidal behavior. Poverty, unemployment, and social isolation are key contributors to this phenomenon[28]. In addition, other potential risk factors for an increased likelihood of suicidal acts include psychiatric disorders, psychosocial adversity, and stressful life events[29]. Regarding pychiatric disorders, there is a strong correlation between suicidal behavior and mood states[12].

It has been hypothesized that psychosocial difficulties and neurobiological anomalies may contribute to suicidal behavior. Notably, over 90% of individuals who commit suicide have a psychiatric illness, with major depressive disorder (MDD) being the most prevalent major psychiatric condition[6]. A significant proportion of suicides are associated with mood disorders, with 60% of all suicides having a mood disorder at the time of death[12]. This can be associated with a set of characteristics or symptoms that are consistently present in mood disorders, including anhedonia and hopelessness, anxiety, agitation and panic, and impulsivity and aggression. Additionally, other factors such as excessive alcohol and drug use may contribute to this phenomenon. Other psychiatric diagnoses, including anxiety disorders, schizophrenia, and bipolar disorder, have been strongly linked to suicidal behavior. In fact, approximately 20% of individuals who have attempted or completed suicide have been diagnosed with bipolar disorder, while 15% have been diagnosed with unipolar depression[6,12,30].

In terms of gender, completed suicide is more prevalent among men, whereas suicide attempts are more common among women[6,31,32]. However, individuals who are single, divorced, or widowed are more at risk of attempting suicide in the United States than those who are married. In this context, widowed individuals are at the highest risk of suicide attempts or completed suicide, followed by those who are divorced or single. The lowest prevalence of suicide attempts or completed suicide is observed among individuals who are married with children[33]. This evidence provides support for the hypothesis that family and social support can act as protective factors in reducing the incidence of suicide.

The neurobiology of suicide is complex, so it is not yet possible to determine exactly why some patients decide to commit suicide and others do not, nor can we identify a specific triggering factor. As we have seen, there are many psychosocial factors associated with suicide, so this is an area that needs much more research. Given the high prevalence of suicidal behavior and completed suicides in patients with psychiatric disorders, it is prudent in these cases to consider suicide as the most severe phase of a psychiatric disorder, especially when completed events are considered[34,35].

EARLY LIFE ADVERSITY AND SUICIDE

Adverse events in early life strongly influence suicide rates and suicide attempts. A family history of suicide, having suffered sexual harassment, and having suffered an infection have also been found to be factors associated with suicide[36,37]. Precipitating factors in vulnerable individuals have been suggested to lead to psychological changes such as feelings of hopelessness and overwhelm, which in turn may lead to social isolation. Exposure to violence is one of the most studied risk factors for suicide. All of these biological and psychological risk factors lead to various adverse outcomes in adulthood, including an increased risk of suicide[38,39].

ELA is defined as exposure to adverse experiences during the first years of life, including adverse childhood experiences (ACEs) such as exposure to war or natural disasters, physical or sexual abuse, malnutrition, parental psychopathology, and adverse parental behaviors such as abuse, neglect, distant parent-child relationships, and unpredictable or disorganized parental care[36,40]. There is evidence that exposure to ACEs is associated with an increased risk of suicide not only in adulthood but also in children and adolescents. This has led to ACEs being an important focus of study in individuals who have attempted suicide, and ACEs have become an essential focus in the development of suicide prevention strategies[41,42].

Several studies have shown that individuals exposed to ACE have increased levels of inflammatory markers[43-46]. There is strong evidence that ACE is associated with an increased risk of disease in adulthood, characterized by chronic inflammation. Some diseases that may be triggered involve metabolic, autoimmune, or psychiatric disorders[47]. There is evidence that ELA exposure is associated with epigenetic changes in the immune system and the functioning of the hypothalamic-pituitary adrenal (HPA) axis, which modify and determine the stress response[47]. The results of some studies suggest that ELA is associated with increased hyperactivity of the HPA axis due to epigenetic changes that cause decreased glucocorticoid receptor (GR) signaling[48-53]. As described below, the stress response is regulated by the HPA axis and is accompanied by increased circulating cortisol levels, catecholamines, and proinflammatory cytokines. HPA axis hyperactivity and chronic inflammation are associated with the development of glucocorticoid resistance, which is a feature observed in individuals with MDD, a condition associated with suicide (Figure 1A)[43,54].

Figure 1 Changes caused by exposure to early life adversity or chronic stress. A: Epigenetic changes in hypothalamic pituitary adrenal axis functioning and the immune system caused by exposure to early life adversity (ELA); B: Chronic inflammation caused by exposure to ELA or chronic stress causes decreased dopamine production through the inhibition of tetrahydrobiopterin, as well as decreased serotonin production caused by the activation of indoleamine 2,3-dioxygenase. Moreover, chronic inflammation induces neuroinflammation, which increases the risk of suicide. HPA: Hypothalamic pituitary adrenal; IDO: Indoleamine 2,3-dioxygenase. Created in BioRender (Supplementary material).

On the other hand, exposure to adverse life events (ALSs) has been demonstrated to induce epigenetic changes in the immune system, resulting in the development of a chronic proinflammatory state. Long-term studies have shown that people exposed to ALSs have increased inflammatory markers such as C-reactive protein (CRP) or IL-6 during adolescence or adulthood[48,55-57]. As described below, chronic inflammation has been associated with changes in the metabolism of neurotransmitters such as serotonin or dopamine, so it has been proposed that changes in the immune system and the HPA axis increase susceptibility to developing psychopathology[58]. Finally, hyperactivity of the HPA axis and chronic inflammation modify microglial functioning, causing increased microglial activation[59,60]. These changes trigger increased proinflammatory cytokine production and decreased serotonin production. It has been proposed that microglial activation caused by chronic stress causes epigenetic changes in microglia, generating a senescent phenotype characterized by increased production of proinflammatory cytokines and increased expression of major histocompatibility complex-II, which has been proposed as a possible mechanism to explain the development of psychopathology, mood disorders, and suicide[23,61,62].

NEUROIMMUNE-ENDOCRINE AXIS

The anatomy of NIE interactions involves a complex network of molecules, cells, tissues, and organs that comprise specialized systems, all of which work together to maintain a homeostatic state[63]. The nervous system includes two large arms. The central and peripheral nervous systems primarily coordinate cognitive functions and facilitate communication with the external environment[64]. The immune system comprises a diverse array of molecules, cells, and specialized tissues that protect against various microorganisms capable of causing infections and disease[65]. The endocrine system comprises numerous glands distributed throughout the body, and its primary function is to secrete hormones that regulate various bodily functions, including temperature, mood, and metabolism[66]. As previously stated, NIE interactions are bidirectional interactions between the three major systems that maintain homeostasis in organisms. Soluble molecules, including hormones, neurotransmitters, and cytokines mediate this intricate communication. When these molecules interact with their target receptor, a cascade of intracellular signaling pathways regulates the transcription, synthesis, and production of molecules that contribute to homeostatic maintenance[67-69].

HPA AXIS

The HPA axis is of enormous relevance because it is the backbone of NIE interactions, and one of its primary roles is activating effector mechanisms to fight against any stimulus capable of generating tension in the body and reestablishing a normal state as soon as possible. When an organism experiences a stressful stimulus, whether due to the environment that surrounds it, a cognitive perception of vulnerability or a potentially pathogenic agent, the organism's physiological response is to activate the HPA axis. First, the paraventricular nucleus of the hypothalamus releases corticotropin-releasing hormone (CRH). This hormone aims to stimulate the pituitary gland to release adrenocorticotropin, which in turn travels to the adrenal glands to produce cortisol. This escalation of synthesis of the HPA axis must be regulated since its constant activation triggers alterations at the cellular, molecular, and structural level in multiple systems. For example, in the particular case of those mood disorders that have been related to a high incidence of suicidal acts, there is major depression, in which a significant increase in cortisol levels has been established due to hyperactivity of the HPA axis, which correlates with cognitive impairment, decision making, and emotional processing in patients with major depression and suicide attempts[70,71]. Another critical function of cortisol is the release of energy, increasing the mobilization of proteins and fats, as well as the regulation of inflammatory processes[72]. Recent studies evidence of alterations in the HPA axis and its association with the risk of suicide[73]. In this sense, and the search for biological markers for suicide attempt and completed suicide, the literature shows that plasma cortisol levels are elevated in patients with suicide attempts compared to healthy individuals[74]. It is also crucial to consider the clinical characteristics of patients when examining the relationship between plasma cortisol levels and suicidal behavior, as this can help to prevent misinterpretation[75]. This is because cortisol levels increase as part of the normal aging process, possibly due to a diminished activation of negative feedback mechanisms[75,76].

A review of the literature revealed that most studies exploring the potential role of the HPA axis as a risk factor in suicidal behavior have focused on individuals with major depression, physical or sexual abuse, and impulsive behavior. However, the findings of these studies are not always conclusive. For instance, while Westrin and colleagues reported elevated cortisol levels in suicidal patients compared to healthy volunteers, Lindqvist and colleagues observed the opposite result. These discrepancies may be attributed to the variability between studies, including the heterogeneity of the samples and the type of analytical method employed[77,78].

A recent meta-analysis of 2269 determinations revealed that the activity of the HPA axis varies with age. In patients under 40 years of age, there was a positive correlation between the HPA axis and suicidal behavior. The effect was reversed in samples of patients over 40 years of age, demonstrating that the role of the HPA axis is more complex than previously recognized based on the association with mood disorders: (1) In samples of patients under 40 years of age, there was a positive correlation between the increase in the HPA axis and the occurrence of suicidal acts; and (2) In samples of patients over 40 years of age, the effect was reversed, thus demonstrating that the role of the HPA axis is more complex than previously recognized based on the association with mood disorders[78]. It has been proposed that elevated plasma cortisol concentrations are associated with insensitivity of the GR and binding protein 5 (FKBP5)[77]. One proposed mechanism to increase cortisol production is based on the overexpression of FKBP5. The FKBP5 gene encodes a GR chaperone that plays an important role in intracellular signaling and is crucial for homeostatic regulation of the stress response[77,79]. Consequently, in patients who have attempted suicide, it is postulated that overexpression of FKBP5 reduces the affinity of cortisol for the GR complex, thereby increasing GR resistance and plasma cortisol levels[80]. Notably, several studies have demonstrated the presence of FKBP5 polymorphisms in various populations, which have been associated with an increased risk of suicide[81].

It is crucial to acknowledge that HPA axis hyperactivity has been linked to an elevated risk of suicide, irrespective of the presence or absence of a psychiatric condition. This suggests that the role of the HPA axis extends beyond glucocorticoid resistance, which is commonly observed in patients with MDD[82]. Exposure to ELA causes inflammation and HPA axis alterations that increase the risk of developing stress, which in turn increases the risk of suicidal behavior[82-84]. It has been postulated that alterations in the genes encoding the GR and the CRH receptor type 1 and 2 are associated with suicidal behaviors[84-86]. In postmortem studies conducted on teenagers who died by suicide, a decreased density of GR-α receptors was observed in the medial prefrontal cortex and amygdala in comparison with control subjects[87].

Furthermore, individuals who were exposed to ELA and who died by suicide exhibited reduced GR expression in the hippocampus, in addition to the expression of GR variants. This evidence suggests that ELA causes epigenetic changes in GR expression[88]. In other postmortem studies, a higher concentration of CRH and vasopressin was found in brain regions such as the forebrain, the raphe nucleus, and the locus coeruleus of suicide victims[89,90]. In addition, it has been reported that individuals who have died by suicide have a greater volume and weight of the adrenal glands, which may be due to hypertrophy resulting from chronic activation of the HPA axis[91-94].

In general, the findings align with the hypothesis of a loss or increase in allostatic load put forth by McEwen. This hypothesis posits that uncontrolled activity of the HPA axis typically results in the deregulation of various systems, including NIE interactions[95]. In conclusion, the HPA axis plays a role in the diathesis of suicidal behavior. Therefore, glucocorticoids and cortisol may be a trait biomarker for this behavior[74,76,96].

THE IMMUNE SYSTEM

In general, the immune system is responsible for protecting and preserving the integrity of the body against a wide range of potential pathogens, including bacteria, viruses, parasites, fungi, and toxins. The immune response can be divided into two major stages: The innate immune response and the adaptive immune response. In each case, characteristic cell lineages are involved, which, upon activation, secrete soluble mediators called cytokines and/or ILs. These proteins play fundamental roles as activation and signaling proteins. The role of cytokines in the pathophysiology of psychiatric disorders was postulated when observing a greater incidence of depressive symptoms in patients with an inflammatory condition, as well as in those patients therapeutically treated with cytokines[97,98]. In recent years, a considerable body of literature has been published on the role of cytokines, growth factors, and chemokines in peripheral blood and brain in the pathophysiology of behavior and suicidal acts associated with behavioral disorders (Figure 1B)[18,99,100].

Cytokine alteration in peripheral blood

Studies in individuals with suicidal ideation that evaluated the concentration of circulating proinflammatory cytokines have demonstrated alterations in the concentration of proinflammatory cytokines and CRP[18,101-105]. CRP has been demonstrated to be a dependable prognostic biomarker for predicting the risk of patients who have a history of suicide attempts[106].

IL-1: This IL family comprises 11 members. It is a cytokine considered proinflammatory. IL-1α and IL-1β are members of this family. Its synthesis is primarily by macrophages[107]. The role of IL-1α as an active proinflammatory cytokine has been evaluated in a population of patients with various psychiatric disorders who have attempted suicide. However, the results did not show a significant difference[108].

IL-2: IL-2 is a growth factor for T, B, and natural killer lymphocytes and is also involved in interferon synthesis and inflammatory reactions[109]. In patients who have attempted suicide, there is a reduction in IL-2 levels compared to those who have not attempted suicide but are depressed[101]. One hypothesis associated with this decrease in IL-2 Levels is related to the increase in sIL-2R concentrations in these patients. The sIL-2R/IL-2 complex is internalized and undergoes degradation, which explains the decrease in its levels. Furthermore, Isung et al[110] reported in a cohort with over 13 years of follow-up that a reduction in IL-2 was associated with patients who completed a suicide attempt.

IL-4: IL-4 plays a role in the differentiation of Th2 Lymphocytes and the maturation of plasma cells and is strongly associated with allergic processes[111]. The peripheral levels of this cytokine are lower in suicidal patients with major depression than in healthy volunteers[112]. These observations are preferentially associated with the depressive state because changes in levels are observed between patients with depression and those with suicidal attempts[110,113].

IL-6: The IL-6 family of cytokines consists of seven members (IL-6, IL-11, leukemia inhibitor factor, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, and cardiotrophin-like cytokine) with proinflammatory and anti-inflammatory properties and are significant players in hematopoiesis; however, they have also been implicated in inflammatory and autoimmune diseases[114,115]. According to a recent meta-analysis, IL-6 is the cytokine with the most significant relevance in suicidal behavior; its role in behavioral disorders such as depression has been reported[116]. MDD is a primary risk factor for suicide, and increased release of IL-6 has been detected in this condition; moreover, increased IL-6levels are associated with prognosis and therapeutic response in MDD patients. Drugs, herbal medications, exercise, and other interventions have been explored as potential regulators of IL-6 in inflammation-dependent depression[117]. In concordance, transgenic mice overexpressing IL-6 in the CNS display increased stress-induced glucocorticoid levels, likely inducing vulnerability to depressive-like behaviors[118].

IL-10: IL-10 is a cytokine with high activity in inhibiting inflammation and plays a crucial role in pathological processes such as cancer and autoimmune diseases[119]. The relevance of IL-10 in depression has been demonstrated in animal models. For example, in mice with learned helplessness, which results in object recognition and spatial memory impairments, reduced microglial IL-10 was observed. Intranasal administration of this cytokine restored such impairments associated with depression-like behavior[120]. However, a recent study that included 84 patients with MDD and 82 sex- and age-matched healthy controls revealed that serum levels of IL-10 were significantly greater in depressive patients. One possible explanation for this finding is that IL-10 levels are increased to cope with the inflammatory process in these patients[121]. Despite previous findings indicating the potential role of IL-10 in depression, no correlation has been identified between suicidal behavior and the serum IL-10 concentration[122].

Interferons: Interferons (IFNs) are employed as therapeutic agents in the treatment of viral infections. Additionally, they are utilized in the management of various cancers and the treatment of autoimmune disorders, such as multiple sclerosis. Most of the literature concerning interferon treatments concerns IFN-α, IFN-β, and IFN-γ[123]. Interferons are pivotal in numerous cellular processes through transcriptional regulation of immunologically relevant genes. Its functions include upregulation of pathogen recognition, antigen processing and presentation, antiviral state, inhibition of cellular proliferation and apoptosis, activation of microbicidal effector functions, immunomodulation, and leukocyte trafficking[124]. An association between alterations in mood and the administration of IFN-α was observed in patients who developed depressive symptoms[98]. This relationship occurs because IFN-α is a potent inducer of indolamine 2,3-dioxygenase (IDO-1) and tryptophan 2,3-dioxygenase, two important enzymes in the kynurenine pathway. The activation of this pathway results in the blockade of tryptophan synthesis into serotonin, thereby promoting the formation of neurotoxic metabolites[58,125]. Notably, an elevated kynurenine pathway has been observed in patients with MDD who have attempted suicide compared to those with MDD without suicidal ideation and healthy volunteers[126]. Although the number of reports is limited, it is worth noting a case series of 11 patients with multiple sclerosis who were treated with interferon beta and who presented with major depression and suicidal ideation or attempted suicide. These findings highlight the importance of being especially vigilant in interferon-treated patients[127].

Tumor necrosis factor-alpha: Tumor necrosis factor-alpha (TNF-a) is a classic proinflammatory cytokine produced by macrophages; its role in suicide is not entirely clear, although, in these patients, there is a tendency toward increased circulation; however, TNF-a polymorphisms have been reported to be associated with the development of suicidal ideation in patients with acute coronary syndrome[128,129]. Recently, it was described an increased in plasma TNF-a levels[101]. Additionally, in a study of patients with MDD and suicide attempts that there is a correlation between higher TNF-a concentrations, cognitive impairment and increased suicidal behavior[105].

Transforming growth factor-beta: This cytokine is associated with the control of cell growth, proliferation, differentiation and apoptosis; its role in the immune response is the regulation of inflammation[130]. It has been reported that transforming growth factor-beta (TGF-β) levels are elevated in suicidal patients with MDD compared to healthy volunteers, so this cytokine has been related to stressful events to counteract the deleterious effects of stress in those patients with suicidal behavior[131]. Additionally, TGF-β polymorphisms have been found to be associated with an increased predisposition to suicide[132].

Vascular endothelial growth factor: This growth factor is involved in the correct functioning of the CNS, participating in processes such as neurogenesis, neuronal patterning, neuroprotection and glial growth[133], so subtle changes in its secretion or expression become relevant in psychiatric and neurological conditions, such as decreased cognition in Alzheimer’s disease[134]. In the case of patients who have attempted suicide, a decrease in peripheral glucose levels has been observed compared to those in healthy volunteers, and these results also correlate with the severity of the depressive condition and the decreased CSF and serum glucose levels; this fact could explain the downregulation of hippocampal neurogenesis and the inadequate response to pharmacological treatment[110,135].

Cytokine alteration in brain

Cytokine and chemokine alterations have been linked to the development of psychiatric disorders such as MDD, which are associated with an increased risk of suicide. Postmortem studies have shown elevated concentrations of proinflammatory cytokines in the orbitofrontal cortex and the prefrontal cortex of suicide victims[99,136-138]. In contrast, the levels of some chemokines have been shown to be reduced in the prefrontal cortex of individuals who die by suicide[138]. Furthermore, postmortem studies have revealed elevated expression of the Toll-like receptors (TLRs) TLR2, TLR3, TLR4, TLR6, and TLR10 in the mPFC. TLRs, which recognize molecular patterns associated with damage (damage-associated molecular patterns, or DAMPs) or pathogens (pathogen-associated molecular patterns, or PAMPs), are essential components of the inflammatory response. After activation, TLRs promote the synthesis of proinflammatory cytokines. Although the participation of TLRs in suicide is not completely understood, it has been suggested that TLRs contribute to neuroinflammation[136].

Among the altered cytokines reported in the brain, an increase in IL-1 has been reported in postmortem brain samples of suicide victims, which correlates with the increase in mRNA levels in the brains of suicide victims[136]. The potential role of IL-1β is related to its biological activity at the CNS level, as it has been demonstrated to exert local effects on neuronal and glial functioning, as well as on neurodevelopment and in response to injuries[139]. In the same way, TNF-a were greater in the postmortem brains of teenager suicide victims than in those of healthy controls[136,140]. Another cytokine implicated in the pathophysiology of suicide is IL-2. It has been proposed that reduced cerebral IL-2 Levels may be linked to the loss of cholinergic neurons in the medial septum of the hippocampus, which could impair communication with the cingulate cortex[141]. In another study, increased IL-4 mRNA expression was observed in the orbitofrontal cortex in postmortem samples of suicidal patients[137].

IL-5 promotes the proliferation, activation, and differentiation of eosinophils. It is primarily produced by Th2 lymphocytes[142]. This cytokine has been explored in postmortem samples from suicidal patients in the Brodmann 11 region. However, its expression levels have not been determined. It appears that there is a significant difference in this region of the orbitofrontal cortex, which is associated with decision-making, reward processing, and long-term memory[137]. Moreover, it was reported that the plasma and CSF levels of IL-6 are greater in patients who attempted suicide than in those in the control group; in particular, the levels of IL-6 are highest in patients who attempted violent suicide[140]. Increased levels of IL-6 seem to be related to neurotransmitters, as a positive correlation was found between IL-6 Levels and 5-HIAA (5-hydroxyindoleacetic acid, a metabolite of serotonin) and HVA (homovanillic acid, a metabolite of dopamine) CSF levels in violent suicide attempts[140].

IL-13 exerts an inhibitory effect on macrophages and is an inducer of IgE, regulating numerous aspects of allergic inflammation[143]. The role of this cytokine in suicidal behavior has been observed with greater frequency in suicidal men, as indicated by a study that revealed increased mRNA levels of this cytokine in the orbitofrontal cortex in postmortem male patients. This has led to the suggestion that it may serve as a marker in suicidal behavior[137,144].

Additionally, the mRNA levels of this cytokine were found to be elevated in the prefrontal cortex region of adolescent suicide victims[136,137]. Additionally, increased plasma levels were noted in suicide attempters[101].

CHEMOKINES

Furthermore, alterations in chemokines have been observed in individuals who have committed suicide. A significant decrease in the levels of CCL1, CCL8, CCL13, CCL15, CCL17, CCL19, CCL20, and CXCL11 was observed in suicide completers[138]. The serum levels of monocyte chemoattractant protein 1 (MCP-1/CCL2) and RANTES/CCL5 were lower in patients with depression and suicidal ideation than in healthy controls, whereas the eotaxin/CCL11 ratio was elevated[145].

Finally, as previously mentioned, there is evidence that ELA exposure is associated with an increased risk of suicide due to changes in the HPA axis and inflammation in the long term. Systemic or chronic inflammation is associated with several adverse effects, including anxiety, anhedonia, fatigue, sleep disturbances, and sickness behavior. The presence of a febrile response, anorexia, lack of motivation, social deprivation, and reduced movement characterizes this latter phenomenon. These changes result from proinflammatory cytokines circulating in the bloodstream, which stimulate the brain and trigger metabolic changes in the production of neurotransmitters such as serotonin and dopamine[58]. The introduction of IFN-α for the treatment of hepatitis C led to an increase in depressive symptoms and suicidal ideation in patients receiving IFN-α treatment. This observation provided one of the earliest indications that cytokines may be linked to suicide[146,147]. The relationship between inflammation and suicide can be understood through two main pathways. The first is through the activation of microglia, previously reviewed. The second pathway is associated with an imbalance in the production of serotonin and dopamine, both of which have been linked to an increased risk of developing psychiatric disorders such as MDD in susceptible individuals which is associated with an increased risk of suicide[18,43]. This results from an increase in IDO-1 activity, which is caused by chronic inflammation. This increase in activity leads to increased kynurenine production and a decrease in serotonin production from tryptophan. On the other hand, oxidative stress induced by inflammation impairs the synthesis of tetrahydrobiopterin, a vital cofactor in dopamine production, thereby reducing dopamine synthesis (Figure 1A)[58].

NEUROTRANSMITTERS

Biogenic amines play a fundamental role in adequately maintaining metal health and homeostasis[148]. Among them are serotonin (5-HT) and dopamine. These two neurotransmitters have been shown to alter psychiatric disorders significantly. In this same sense, there is also evidence of alterations in the brains of suicide victims[149]. For many years, it has been canonically accepted that the role of neurotransmitters is strictly within the CNS; fortunately, this concept has become out of time thanks to a large number of works that have shown that their biological activity goes beyond that of nervous tissue. A transcendental activity that has been attributed to neurotransmitters is their immunomodulatory role[150,151]. In this sense, neurotransmitters play an important role in suicidal behavior since they act as dual actors, on the one hand deregulating the neurochemistry of the CNS and interacting with the immune system. As part of a neurobiological approach and because of the strong association between affective disorders and alterations in the serotonergic system, it has been hypothesized that abnormal functioning of 5-HT uptake and decreased levels of its transporter (SERT) are risk factors for suicide[152,153].

This system is critical in individuals since alterations in this system are associated with anxiety, depression, aggressiveness, and impulsivity disorders. The neurotransmission of 5-HT is mediated by at least 14 types of receptors and a transporter (SERT)[154]. Among the types of 5-HT receptors that have been associated with suicidal behaviors are 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT4, and 5-HTT; among these, 5-HT1A has generated significant interest in the investigation of suicidal acts due to its role in memory, recognition, learning memory and neurogenesis of the hippocampus, as well as its response to antidepressant treatment[155]. 5-HT2C is distributed in different areas of the brain[156], and Pandey et al[157] demonstrated a correlation between 5-HT2C mRNA and protein levels in the prefrontal cortex of suicidal patients, suggesting that 5-HT2C may play a role in suicidal behavior.

Serotonin is associated with suicide risk, with low concentrations of 5-hydroxyindoleacetic acid, a metabolite of 5-HT, in cerebrospinal fluid, potentially indicating a greater risk of suicide[6,12]. This has been corroborated in postmortem brain samples, and it is therefore proposed that a deficit in serotonin transporter binding has a significant impact on the pathophysiology of suicide[158].

Another system that has garnered significant interest in elucidating the underlying mechanisms of behavior and, in particular, emotions is dopamine. This neurotransmitter plays a key role in regulating many brain functions, including mood, aggression, and attention[159]. Dopamine is produced by dopaminergic neurons in the ventral tegmental area of the midbrain and the substantia nigra[159]. Individuals with high levels of this neurotransmitter exhibit hyperactivity and impulsive behavior. Conversely, individuals with low levels of this neurotransmitter demonstrate anhedonia. This is because nonadrenergic activity predisposes individuals to depressive events, which are associated with a decrease in the density of dopamine transporters[160,161].

THYROID HORMONES

The close relationship between thyroid hormones and psychiatric symptoms has long been explored. Recently, novel evidence has emerged showing an intriguing association between thyroid status and suicidal behavior, especially in patients with MDD or thyroid illness. With some exceptions[162], recent investigations have demonstrated that distinct alterations in thyroid status are present in MDD patients who have attempted suicide. Some authors have shown that, in comparison with nonattempters, MDD patients with suicidal attempts exhibit elevated scores in tests for depression, anxiety, or psychotic symptoms, which are accompanied by increased levels of thyroid-stimulating hormone (TSH) and anti-thyroid antibodies such as anti-thyroglobulin and anti-thyroid peroxidase (TPOAb)[163-165]. Interestingly, high TSH levels were positively correlated with elevated scores for anxiety and psychotic symptoms, and TSH and TPOAb levels were independently associated with suicide attempts[163]. Moreover, these investigations demonstrated that higher TSH and anti-thyroid antibody levels are risk factors for suicide attempts in MDD patients[163,164].

In contrast with the consistent evidence about TSH, the data on other hormones from the hypothalamus hypophysis thyroid (HHT) axis are inconclusive. Liu et al[164] and Peng et al[163] showed no significant changes in the levels of triiodothyronine (T₃) and thyroxine (T₄) in MMD patients who attempted suicide compared with those who did not attempt suicide[163,164]. In contrast, other authors reported lower or normal free T₄ levels in MDD patients with suicidal behavior[165-168], and Wang et al[167] reported that free T₄ levels are predictors of suicidal attempts in depressive patients. Regarding the participation of thyrotropin release hormone (TRH), a unique study reported reduced central TRH function in depressed patients with current suicidal behavior[166].

The high risk of suicide behavior in MDD patients with thyroid disorders is still more evident in depressive individuals who develop subclinical hypothyroidism (SCH), an endocrine disorder characterized by high TSH and normal T₃ and T₄ serum levels[169]. SCH is highly common in MDD patients, reaching a prevalence of 60%[170,171]. Interestingly, MDD patients with SCH had significantly greater suicide attempts (25.4% vs 12.2%) and a 67% greater risk of suicide than did depressive patients without SCH. Moreover, these patients exhibited higher scores for anxiety, depression, and psychotic symptoms, as well as elevated levels of TSH, than did those without suicide attempts[170].

A relationship between thyroid alterations and suicidal behavior has also been documented in patients with hyper or hypothyroidism. Three different case reports have shown that patients with hyperthyroidism (Graves’ disease) and no previous history of mental disorders present with suicidal ideation or attempts accompanied by undetectable TSH levels[172-174]. Similarly, patients with Graves’ disease have a greater risk of suicide than their controls, although this difference did not reach statistical significance[175].

Concerning hypothyroidism, Todorov et al[176] presented a case report of suicide attempts in an adult patient without a past psychiatric history but with severe hypothyroidism characterized by high TSH and anti-thyroid antibody serum levels and reduced free T₃ and T₄ serum concentrations. Similarly, patients with hypothyroidism caused by Hashimoto’s thyroiditis showed a significantly increased risk of death by suicide. Interestingly, the median time to death by unnatural causes (including suicide) was 3 years for patients with Hashimoto syndrome and 4 years for controls[177].

Most of the evidence indicates that TSH and anti-thyroid serum levels may contribute to the onset of suicidal behavior in patients with MDD or hypothyroidism. In contrast, the role of other hormones in the HHT axis is not completely clear since there are controversial results about thyroid hormone levels, and the participation of TRH has been minimally explored. Finally, we would like to emphasize the critical relationship between TSH levels and suicide, since its increased concentration is a common denominator in patients with suicide attempts, and the prevalence and risk of suicide attempts are strongly associated with the levels of TSH. Lang et al[171] demonstrated that the risk of committing suicide was 4.5 times greater in MDD patients with a TSH > 10 mIU/L than in those with a TSH < 10 mIU/L. In addition, the prevalence of suicide attempts in MDD patients with higher TSH levels was significantly greater (67.20%) that in depressive patients with TSH < 10 mIU/L (18.40%)[164]. Finally, network analysis by Peng et al[163] revealed that TSH is a key point in the onset of suicide, exhibiting substantial associations with metabolic disturbances, anxiety, and psychotic symptoms in patients with suicidal behavior.

GENETIC FACTORS

The molecular genetic basis of suicide remains incompletely understood. However, the evolution of genetic and biochemical processes is believed to be a potential avenue for further investigation. Additionally, epigenetic factors, such as negative social and environmental events (e.g., posttraumatic stress), may also play a role. The monitoring of various genetic patterns may prove valuable in identifying those responsible for alterations that could lead to a fatal outcome. With appropriate clinical follow-up and intervention, it may be possible to prevent such outcomes. Although there is evidence that diverse pathways associated with specific single-nucleotide variants could affect the same related brain regions to trigger the suicidal process, analogous to the malignant evolution of the physiological process, it is necessary to determine how to address alterations in physiological and biochemical processes. The interactome of suicide (protein-protein interactions and genetic interactions) is an important goal in this regard. Genetic studies have demonstrated the pivotal role of the serotonergic system in the genesis of suicidal ideation, suicide attempts, and suicidal behaviors, as well as impulsivity and aggressiveness[178-180]. A number of studies have indicated a correlation between specific polymorphic variants of the tryptophan hydroxylase (TPH) gene (a limiting enzyme in serotonin synthesis), the serotonin transporter (5-HTT, SERT or SLC6A4), and the serotonin receptor 2A (5-HT2A) and suicidal behaviors[181-183].

First, the gene encoding THP, an enzyme crucial for the synthesis of 5-HT, exists in two distinct isoforms: THP-1 and THP-2. A meta-analysis was conducted to investigate the correlation between the gene variants TPH-1 (A218C and A779C) and TPH2 (G-703T, A-473T and G19918A) and suicidal behavior. The findings of this meta-analysis indicate that the TPH-1 variant is associated with an increased risk of suicidal behavior, whereas no such association was observed for the TPH-2 variants[181]. In a population of patients with schizophrenia, no association was found between the 473T/A and hCV245410 variants of the TPH-2 gene and suicidal behavior[184].

The serotonin transporter (SERT) has also been investigated in patients with suicidal behavior. The results of studies on the association between the SLC6A4 (serotonin transporter) and 5-HTTLPR (serotonin-transporter-linked promoter region) and suicidal behavior have been controversial. However, a meta-analysis identified an association between the gene variant and violent suicidal behavior[185].

An association between the 5-HT2A receptor and suicidal ideation in patients with depression has been previously described. Compared with individuals with the T/C or T/7 genotype, individuals with the 102C allele exhibited a positive correlation between the item score for suicidal ideation and the C/C genotype. Additionally, the SERT gene S/L polymorphism has been linked to completed suicide. In contrast, the L/L genotype was twice as prevalent in suicide victims diagnosed with depression as in the control group[186].

Another topic worthy of further investigation is the diathesis of suicide, which is defined as a genetic predisposition toward suicidal acts. Brent and colleagues proposed the hypothesis that this phenomenon is highly familiar and may be heritable. The clinical phenotype of completed and attempted suicide is transmitted within families. Furthermore, the rates of suicide attempts are elevated in the family members of suicide completers, and completion rates are elevated in the family members of attempters[187]. In a separate study, the precursors of early-onset suicidal behavior included mood disorders, impulsive aggression, a history of suicide attempts in one's parents, and sexual abuse. The authors posit that the transmission of suicidal behavior from one generation to the next can be prevented or, at the very least, reduced among at-risk youth by attending to specific domains or factors[188].

The results of studies conducted on twins indicate that heritability estimates for suicidal behavior range from 21% to 50%, with a broader phenotype that includes suicidal ideation or planning reaching up to 55%[189]. Regarding monozygotic twins, a higher concordance rate for suicide is observed than for dizygotic twins[187]. A second group of studies that strongly reinforce the role of genetics are those in which a greater risk of suicide attempts has been observed in individuals with a family history of suicide[190].

A recent study identified potential genetic risk loci associated with suicidal ideation and behaviors. This genome-wide association study included 633778 United States military veterans with diverse ancestry and identified ESR1 (encoding an estrogen receptor), DRD2 (encoding a D2 dopamine receptor), TRAF3 (encoding TNF receptor-associated factor 3), and DCC (encoding the netrin receptor DCC) as cross-ancestry candidate risk genes. This meta-analysis identified more than 200 genome-wide significant single nucleotide variants associated with suicidal thoughts and behaviors in individuals of diverse ancestry. These variants were localized to specific regions on chromosomes 2, 6, 9, 11, 14, 16, and 18[191]. Recently, ESR1 and TRAF3 have been identified as risk loci for posttraumatic stress disorder and other disorders, including depression and anxiety, which are considered risk factors for suicidal ideation and suicidal behaviors[192]. TRAF3 is a regulator of type-1 interferon production and has been linked to MDD, antisocial behavior, and attention-deficit/hyperactivity disorder. Notably, lithium, a medication used in bipolar disorder treatment, modifies the expression of TRAF3 and several other inflammatory genes. DCC is expressed in the brain, where it regulates a number of different processes. It has been associated with a range of psychiatric phenotypes, and elevated levels have been observed in the prefrontal cortex of individuals who have died by suicide[193,194]. DRD2 is highly expressed in specific regions of the brain, has been associated with numerous psychiatric phenotypes (including suicide), and is involved as a regulator of other risk factors for suicide, including impulsive behavior, schizophrenia, and mood disorders[195-198].

ANATOMIC-FUNCTIONAL ALTERATIONS

Imaging methodology has proven to be a valuable tool for studying the anatomy and function of the brain, particularly in the context of psychiatric disorders and neurological diseases. The use of brain images from suicidal patients has facilitated the identification of structural alterations in multiple regions of the brain. These include the orbitofrontal cortex, the amygdala, the temporal-parietal-limbic networks of the hippocampus, and the putamen and cerebellum[198-200]. In addition to these findings, a meta-analysis revealed that suicidal behavior is associated with structural deficits in several brain regions, including the gyrus rectus, superior temporal gyrus, and caudate nucleus, as well as functional overactivation in the anterior and posterior cingulate cortex of patients with suicidal ideation[201].

As previously stated, the amygdala exhibits structural alterations. The significance of this region lies in its subcortical location within the medial temporal lobe and its extensive connections with the majority of the brain, including nuclei involved in emotional and anxiety-related processes[202]. Furthermore, the amygdala is connected to the prefrontal and inferotemporal cortices, which, in turn, are linked to the medial temporal memory systems, including the hippocampus and the entorhinal cortex. Another crucial connection is with the cortex. The ventromedial prefrontal cortex is linked to a range of processes, including the assessment of sensory, cognitive, and affective information, as well as decision-making. Based on this, the role of morphological alterations of the amygdala and its participation in ideation can be explained. Furthermore, the suicidal act can be understood in the context of these findings[203,204]. The prefrontal cortex and hippocampus are functionally related to emotion, stress, cognitive functions, and aspects involved in suicidal behavior.

POTENTIAL THERAPETIC TARGETS

From an inflammatory perspective, the use of non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, naproxen, celecoxib, and aspirin, has been demonstrated to reduce suicidal ideation[205]. Furthermore, the use of aspirin without concomitant administration of other NSAIDs has been associated with reduced levels of depression, anxiety, and stress in cancer patients[206].

On the other hand, the use of TNF-α antagonists has been demonstrated to reduce suicidal behaviors in patients with hidradenitis suppurativa[207]. In the case of immunotherapies such as tocilizumab (a humanized monoclonal antibody against the IL-6 receptor), a reduction in the risk of depression has been observed in patients with rheumatoid arthritis[208]. It is important to note, however, that certain treatments, such as infliximab (a chimeric monoclonal antibody that blocks TNF-α), which is commonly used for chronic inflammatory diseases[209], have been associated with an increase in suicide attempts in rheumatoid arthritis patients[210] and suicidal ideation in bipolar disorder patients[211]. Another drug of interest is minocycline, which has demonstrated efficacy in reducing depressive symptoms due to its anti-inflammatory effects. Nevertheless, further clinical studies are necessary to ascertain its efficacy in suicide prevention[212].

From a neuroendocrine perspective, levothyroxine is a commonly utilized therapeutic agent for hypothyroidism, and its use is associated with a reduction in depressive symptoms. Nevertheless, only a limited number of studies have investigated the influence of levothyroxine dosage on suicidal behavior[213,214]. Some case reports have indicated a potential correlation between levothyroxine overdose and suicidal ideation, underscoring the necessity for cautious administration and comprehensive clinical investigations to elucidate the benefits and risks associated with its use.

In this context, selenium also merits attention as a substance known to improve thyroid function and reduce inflammation in diseases such as Hashimoto's thyroiditis. Nevertheless, elevated selenium intake has been linked to an elevated risk of postpartum depression. However, adequate selenium levels have been demonstrated to mitigate depressive symptoms[215]. This highlights the necessity for precise, evidence-based dosing to prevent adverse effects.

The presence of hypercortisolemia, a condition frequently observed in individuals with a history of suicide attempts and MDD[216], suggests the potential efficacy of mifepristone as a therapeutic agent. This antagonist of progesterone and GR has been shown to have antidepressant and anxiolytic effects in preclinical studies by counteracting the effects of allopregnanolone[217]. Nevertheless, further preclinical and clinical studies are required to define its efficacy and safety in humans.

It has been established that estrogen (E2) and progesterone (P4) levels are closely associated with mood. A rise in suicidal behaviors has been documented during the premenstrual phase[218], when estrogen and progesterone levels are at their lowest[219]. Moreover, women in menopause are at an elevated risk for suicidal ideation, indicating that both hormone replacement therapy and selective estrogen receptor modulators could have a substantial impact on suicide prevention. Nevertheless, further research is essential to gain a deeper understanding of their role in this context.

NOVEL INSIGHTS INTO THE PREVENTION AND TREATMENT OF SUICIDE

Suicide prevention has been addressed through the implementation of psychosocial prevention programs and the utilization of pharmacological and clinical interventions. The implementation of prevention programs has resulted in a notable decline in the suicide rate in countries such as Japan, which has historically grappled with a high prevalence of suicide. In this country, a series of strategic government policies have been introduced gradually since 2000, including legislation aimed at reducing alcohol-related harm, promoting independent living, and supporting mental health. Given the variability of risk factors at the local level, suicide-specific prevention programs have been implemented at the municipal level[220]. Nevertheless, the efficacy of suicide prevention programs is not always evident, and enhanced collaboration between policymakers, researchers, and practitioners, along with augmented funding for suicide research, is imperative[221].

At the clinical level, there is evidence to suggest that clozapine and lithium may be effective in the prophylaxis of suicide attempts in select populations. Nevertheless, the efficacy of antidepressants, antipsychotics, electroconvulsive therapy, and transcranial magnetic stimulation remains constrained. Novel pharmacological approaches, such as the use of ketamine, are demonstrating potential efficacy[222]. Clinical studies have demonstrated that the intravenous administration of a single low dose of ketamine, an N-methyl-D-aspartate receptor antagonist, has a rapid antidepressant effect and can reduce suicidal ideation[223,224].

The antidepressant effects of ketamine have been demonstrated in preclinical studies, and new ketamine-like compounds with reduced potential for addiction are currently being investigated as treatments for depression and suicidal ideation[225,226]. Moreover, stereoisomers of ketamine have been subjected to experimental scrutiny, demonstrating that R-ketamine exhibits more efficacious antidepressant effects and a reduced incidence of adverse effects relative to S-ketamine[227]. Other novel drugs, including selective GluN2B antagonists such as CP101, 606 (Traxoprodil), CERC-301 (Rislenemdaz), and Ro 25-6981, have demonstrated promising results in both experimental and clinical studies, offering potential strategies for addressing depression and suicide risk[226].

CONCLUSION

Suicide is a significant global public health concern that is frequently overlooked and stigmatized. The intricate neurobiology of suicide encompasses a multitude of factors, including anatomical and functional alterations of the CNS, as well as abnormalities in the concentrations of neurotransmitters, cytokines, chemokines, HPA axis hyperactivity, and thyroid hormones. This intricate network of interactions between the nervous, endocrine, and immune systems, also known as NIEs, plays a pivotal role in the neurobiology of suicide. In addition, genetic factors and psychiatric disorders such as depression, schizophrenia, and anxiety are also considered potential risk factors involved in suicidal behavior.

ACKNOWLEDGEMENTS

We thank Julieta Mendoza Torreblanca for her help in preparing the figures.