Suicide, neuroinflammation and other physiological alterations

To talk about suicide is also to talk about its risk factors, as they have a significant influence on suicidal behaviour. These can be classified into biological (including familial), mental and physical health (psychological) and social (including environmental) factors (Fig. 1).

Fig. 1figure 1

Age is one of the risk factors to be highlighted, as it represents the second leading cause of death in the 15–29 age group. We also found that the age group with the highest rate of people who take their own lives is the over-70s, with a higher rate in the over-75s [20]. According to the WHO, suicides increase with age. This may be partly explained by a decrease or lack of interpersonal relationships and a decrease in daily activity. In terms of suicide attempts, suicide attempts are more frequent in women aged 15–24, while in men, they are more frequent in the 25–34 age group [20].

Regarding gender, we found that women have more suicidal ideation and attempts, 3–4 times more than men. However, more men commit suicide, 2–4 times more [20]. In both men and women, the risk of committing suicide is substantially increased in schizophrenia, substance abuse and affective disorders, with schizophrenia being of particular relevance in men and substance abuse in women [20]. In addition, some events that are considered protective factors for both sexes are pregnancy and having a son or daughter [5].

For genetic factors, an association has been found between genetic polymorphisms and suicidal behaviour. In addition, it has been found that the odds of suicide are ten times higher in those who have had family members who committed suicide. It is also estimated that approximately 43% of suicidal behaviour can be explained by genetics [5]. Reviewing family history is important, as those children who have had parents who have committed suicide are up to four times more likely to take their own lives. Some studies point to the age of the child when a parent commits suicide, noting that the younger the age of the child, the greater the likelihood of suicide in the future. The reason for this is currently unknown. It could be a genetic issue or parental imitation [18]. In addition, reviewing family history may also involve parental neglect or physical or sexual abuse, which may increase the risk of children taking their own lives [7]. It is believed that those who suffered sexual or physical abuse in childhood may be the cause of suicide in 50% of cases in females and 30% in males [8], which should also be taken into account.

Studies linking suicidal behaviour and molecular genetics are now trying to find specific genes that explain it. Some point to specific loci in chromosomes that play an important role in suicide. Others point to the importance of mental disorders and their heritability, which would link the two phenomena and could thus be explained. Others argue that behavioural factors such as impulsivity or aggressiveness could play a role in genetic factors [16]. However, the studies conducted so far use small population samples and, for the most part, do not differentiate whether people have psychiatric disorders or not, which makes it difficult to provide a concrete explanation of the relationship between suicidal behaviour and genetics [16].

Regarding mental health disorders, if we look at the percentages linking a mental disorder and the phenomenon of suicide, we find that 90% of people who commit suicide have a mental disorder [24]. It is estimated that in higher income countries, the most frequent mental disorders are major depression, bipolar disorder and post-traumatic stress disorder. However, in developing countries, substance abuse disorder and post-traumatic stress disorder are found to be the most prevalent [24].

Some remarkable data are that people with major depression have up to 20 times more risk of committing a suicidal act and up to 80% more risk of suicidal ideation than those who do not have it. If we look at individuals with bipolar disorder, we find that 20–60% attempt suicide. And, in the case of people with schizophrenia, the risk of suicide is 30–40 times higher than in healthy individuals, and 25–50% will attempt suicide. Other studies, however, suggest that people with schizophrenia have an 8.5 times higher risk of suicide [5]. Looking at the average age of people with schizophrenia who commit suicide, we find that they are on average 33 years old [20]. In addition, it has been found that approximately 20% of people who are socially distressed will attempt to take their own life at least once [5].

Other findings point to a close link between eating disorders and suicide, with an eight-fold increased risk of suicide appearing in anorexia nervosa and up to five-fold in bulimia nervosa. There is also a link between attention deficit hyperactivity disorder (ADHD) in men aged 5–24 years, showing a three-fold increase in the likelihood of suicide [20, 29].

Another disorder that could be related to suicidal behaviour is borderline personality disorder (BPD), finding that 10% of people with this disorder will end up committing suicide. Some studies claim that a person with this disorder will have up to three suicide attempts in their lifetime, in most cases due to substance intoxication. A characteristic feature of BPD is chronic suicidal ideation, with increasing intensity of stressful events, which becomes frequent on a daily basis [36]. One of the issues being investigated in relation to this risk factor is the psychotic experience which, although it can be defined as an experience full of hallucinations and delusional moments, is believed to be close to the suicidal act, finding a three-fold increase in the probability of attempting suicide. However, psychotic experiences may be a reflection of suicidal thoughts that already exist in the person and not the cause of it. So far, there is no scientific consensus that clearly supports this relationship [49].

Previous suicide attempts are the most important risk factor for suicide. Some findings that show this close relationship are that 50% of those who committed suicide had made previous suicide attempts or that a suicide attempt increases the risk of attempting suicide again by 32%. Some studies point to a 100 times higher risk of suicide in those who make a suicide attempt compared to those who do not [20].

Regarding personality, two of the most prominent personality traits are hopelessness and impulsivity. The former appears in up to 90% of those who commit suicide [20]. Regarding impulsivity, there are studies that strongly support that this trait influences the transition from suicidal thinking to action, while other studies cast doubt on this [24]. Other related traits are emotional instability (which may increase the risk by 2.3 times), perfectionism and high demands [20].

Alcohol and other substances use/abuse are implicated in 25–50% of suicidal acts and 70% of suicides in adolescents [9, 47]. If we look at the different substances that are related to suicide, we find that those who consume alcohol are 8.5 times more likely to commit suicide [20], which may be involved in an increase in aggressiveness and impulsivity, as well as influencing the use of more radical methods to take their own lives [47]. In recent years, both phenomena have been increasing simultaneously. If we delve deeper into this relationship, we find that acute alcohol intoxication and chronic alcohol consumption increase the likelihood of suicidal behaviour and suicidal ideation. The day after substance abuse, the probability of dying from a suicidal act increases sevenfold [41]. A link has also been found between alcohol intoxication and the use of more lethal methods of suicide, which would increase the likelihood of death. In addition, more than 30% of people who die by suicide had consumed alcohol, 63% of whom were intoxicated [41].

Tobacco has also been associated with suicide and increased impulsivity and aggressiveness, as have marijuana, cocaine and amphetamines. Other substances such as heroin (14 times more likely to be suicidal) or MDMA (9 times more likely than non-users) have also been linked [20]. Finally, studies suggest that LSD, due to its effects such as well-being, optimism and mood enhancement, may be excluded from the other risk factor substances, although this is not a clear-cut statement [9].

Regarding physical illness, several studies suggest that it was present in 25% of cases of suicide and in 80% of cases if the person is elderly. It is believed that there is an increased risk of suicide within six months of being diagnosed with the illness. In addition, it is essential to consider pain as a companion to physical or disabling illness.

Cases are more frequent in patients with HIV and multiple sclerosis. In the latter, mortality rates are twice as high and are more frequent in young men [20].

Several social factors are also included as risk factors. A notable risk factor is a person's marital status, with up to three times the risk of suicide found in divorced or widowed men. Living alone or lacking a social support structure may increase the risk. Some studies point to marriage as a protective factor against suicide [5].

An increased risk of suicide in both unemployment and in some professions has been found. If we look at unemployment, we find that there is a two to three-fold increase in the likelihood of suicide, as well as in those who do not have stability in this area such as the 25–34 age group. In addition, some professions have a higher risk of taking their own lives, such as farmers, police or health workers, as they have access to lethal means [18]. If we focus on health care workers, we find that they are considered to be a group at high risk of taking their own lives, especially women. Factors that may play a role include workload, working hours and schedules, anxiety, communication of bad news, stress during the working day and access to lethal means. Some specialties also have an increased risk of suicide such as anaesthesia, psychiatry, general medicine or surgery [14].

In addition, some studies mention religious beliefs as a protective factor for suicide [5].

Finally, suicide is also affected by the twenty-first century and the use of technology in all areas. Cyberbullying in particular has become a risk factor for suicide, with studies indicating that approximately 20% of adolescents are at risk of taking their own lives, and that 78% of those who have done so have been cyberbullied [5].

The influence of COVID-19 on suicide

A recent historical event such as the COVID-19 pandemic has set the path for new studies that bring a new field of vision in science. It had repercussions in the field of mental health, as the authorities ordered the isolation and the confinement of the population. This, together with the fear of contagion and daily deaths, caused a turning point in scientific literature and in the lives of millions of people around the world. This is why it affected all areas of life, from the psychological to the physical to the economic, among many others. In this section, we will look at the mental health consequences of COVID-19, the groups at risk, its relationship with suicide and the scientific evidence that exists today.

According to studies in the United States, about 40% of adults experienced anxiety or depression in the first months of the COVID-19 pandemic [1]. Considering the repercussions that this pandemic has had on the mental health of the world's population, it has been found that the most frequent symptoms have been stress, anxiety, depression and insomnia. This can be explained by the impact of this virus on all areas of daily life, from home confinement to fear of infection or deaths that occurred when transmission was unknown. This led to a state of social unrest that forced many to be alone, which was a determining factor in the appearance of some symptoms such as anxiety or the risk of suicide. In addition, there was an increase in self-harm [17]. There was also an increase in the number of patients admitted for an intensification of psychiatric symptoms, anxiety and obsessive–compulsive disorders, while at the same time increasing the risk of dying by suicide [3, 12].

It is of particular relevance to note that the impact of COVID-19 on people's mental health occurred both in people who were infected by this virus and those who were not. Because this pandemic affects so many areas, symptoms and complications in the field of mental health can develop in any person. This makes the magnitude of the problem very important and requires global action.

The risk factors for suicide that emerged during the pandemic include: (1) loneliness and isolation. This was due to the isolation required by the authorities, quarantines and mobility restrictions [3]; (2) fear of contagion. This is because in the first few months there was a lack of knowledge about the transmission of the virus, how it affected people and what to do to stop it. Due also to social media, sometimes false or unscientific news appeared, which increased the lack of knowledge and anxiety. As it was an unknown virus, there were no vaccines or treatments that were effective. It was not until months later that health workers were able to decide on one type of treatment or another. In addition, the development of several vaccines against the virus led to a significant drop in the number of people infected [3]; (3) prejudice. Those who were infected by this virus were socially stigmatised, which is a risk factor for mental health [3]; (4) intensified mental health disorders. As noted above, anxiety, stress, depression, substance abuse disorders, among others, appear to have intensified. In addition, due to the overload of work for health personnel, the authorities urged citizens to avoid going to hospitals or primary care centres in order to avoid the collapse of the health system. This meant that many pathologies could not be properly treated or diagnosed, and some intensified their symptoms [3]; (5) employment and economic changes. The isolation of the population and the halt in employment caused many people to lose their jobs or to stop earning an income. Unemployment is believed to have caused an increase in the number of suicides. There were also sectors that forced their workers to work from home, via the internet. Most countries experienced a decline in economic growth, which led to the symptoms mentioned above [3]; (6) increased access to lethal means. Some studies point to the decrease in vigilance due to the pandemic situation to explain the increase in access to metal means of suicide [3].

Also, those groups that were at risk during the first months of the COVID-19 pandemic include: (1) people who were on the front line. The health professionals are particularly important, as they were and are the ones in charge of diagnosing the infection, monitoring and treating the symptoms of the patients, as well as providing support to their families. Working conditions were affected by the situation and health workers had to face a lack of material, longer working hours, fear of contagion, stress, anxiety, loneliness or voluntary isolation in their homes to avoid infecting their relatives. This led to an increase in hopelessness, one of the key aspects in identifying suicide risk [3]. One of the indicators among healthcare workers that indicated an increased risk of developing suicidal ideation was burnout. The healthcare category showing the highest rates of burnout during the pandemic was nursing staff, according to the scientific literature [1]; (2) people in old age. Older age has been associated with both the risk of suicide and the risk of having complications from COVID-19. In this group of people, loneliness, isolation and depression play important roles in the development of suicide risk. A large percentage of them require help with daily activities and, due to home confinement, could not be properly cared for, increasing frailty in this age group [3]; (3) people in adolescence This age group also presents various suicide risks. It should be noted that technology and the social environment play a very important role for adolescents. During the pandemic, there was a disruption of the social environment and an isolation which made increase symptoms affecting mental health. The development of an individual's identity is largely created in this age range, so that in many cases, there was an imbalance due to home confinement. This led to an increased risk of suicide [3]; (4) victims of domestic violence. Because of house confinement, many families were forced to live together for months at a time without being able to leave their homes. This led to an increased risk of violence in families, as in the case of gender-based violence. This group is among the most vulnerable to confinement, as it increases the risk of death by suicide. Psychological support units were also restricted, making victims' coping with these situations more complex [3, 10]; (5) homelessness. This group is at high risk of increased economic, psychological, social and other impacts. An increased risk of suicide has also been reported in this group due to COVID-19.

Despite the need for more scientific evidence on the relationship between suicide and COVID-19, it can begin to deduce that there has been an increase in suicide risk. Sher [43] found that the mental health consequences of the COVID-19 crisis including suicidal behaviour are likely to be present for a long time and peak later than the actual pandemic. Other authors found that despite the initial alarming predictions for an increase in suicide rates due to the COVID-19 pandemic, the majority of published studies to date suggest that experienced difficulties and distress do not inevitably translate into an increased number of suicide-related deaths, at least not in the short-term [15]. A recent meta-analysis found that increased event rates for suicide ideation (10.81%), suicide attempts (4.68%), and self-harm (9.63%) during the COVID-19 pandemic when considered against event rates from pre-pandemic studies [13]. On the other hand, it has been found that by increasing the risk of isolation, fear, stigma, abuse and economic fallout, COVID-19 has led to increase in risk of psychiatric disorders, chronic trauma and stress, which eventually increase suicidality and suicidal behaviour [3]. These findings suggest that the COVID-19 pandemic may lead to an increase in suicide rates.

However, more studies and reviews are needed to provide a more scientifically rigorous coverage of this phenomenon. The lack of cause-of-death records during the pandemic makes it difficult to draw conclusions and study this relationship.

Suicide risk assessment

Just as it is important to understand the phenomenon of suicide, it is also important to assess a person's risk of committing suicide. This would make it possible to predict, or at least estimate, a person's likelihood of taking his or her own life.

In order to approach assessment, it is necessary to know that there are more subjective strategies such as questionnaires or scales, and more objective ones such as biomarkers, which will be discussed later.

Firstly, objective strategies include the collection of data on the person, the analysis of the family history, the pathologies they present, among others. In short, the assessment of the individual's risk factors through interviews carried out by the professional [21, 48]. Tools have been created to facilitate the access of professionals to the identification of the risk of suicidal behaviour, such as scales or questionnaires. These tools have been approved by the European Psychiatric Association, although the scientific evidence is not high [18]. Some of them are the Beck Hopelessness Scale, the Suicidal Ideation Scale or the Columbia Suicide Severity Rating Scale [18, 47]. These scales focus on identifying the person's suicidal ideation and the risk factors that may accompany it. However, the cooperation of the person is needed to know the reliable results of these tools. This is why previous suicide attempts become one of the most important factors in this phenomenon, as they make it easier to assess suicide risk [47].

Secondly, objective strategies such as biomarkers of inflammation are gaining importance in the scientific community and in methods of suicide assessment and prediction [30, 45]. We will focus on them below and analyse the mechanisms of neuroinflammation that accompany suicidal behaviour. Over the years, more and more scientists have been supporting research into biomarkers of inflammation, as they could be used to reveal to healthcare professionals which individuals are at higher risk of suicide or even who are more likely to commit suicide. Other physiological alterations, which will be discussed below, would also shed light on the mechanisms of suicide. If the subjective strategies discussed above fail to fully unravel this phenomenon, will inflammatory biomarkers allow us to tailor prevention and treatments to combat death by suicide?

Physiological alterations in suicide

The path that leads to suicide is accompanied by physiological alterations in the body. One of the alterations that stands out from the rest is neuroinflammation. This phenomenon has a large repertoire of scientific literature, so we will focus specifically on inflammatory cytokines and their direct relationship with suicide, and on the kynurenine pathway. Other striking changes reported in numerous studies and to which we will give space in this review are the hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis, changes in serotonin levels, the relationship between suicide and immune and infectious disorders, and the relationship between suicide and other notable alterations. Although there are several areas that could be addressed in this phenomenon, we will focus on the above-mentioned alterations, as they could lead to major scientific breakthroughs. Some of these disorders may also appear in major depression, as it shares certain characteristics and mechanisms with suicide [8, 34, 46].

Some changes that occur in people who make suicide attempts take place in specific regions such as the hypothalamus, the cortex and prefrontal areas or the hippocampus. Changes in cognition, emotions and decision-making occur in these areas. The anterior cingulate cortex, where the creation of negative self-conceptions is located, is also of importance [47].

Neuroinflammation

In order to talk about biomarkers of inflammation and their relationship with suicide, we must first talk about neuroinflammation, a concept that has been studied extensively in recent years. Neuroinflammation is defined as an inflammatory response mechanism of the central nervous system to an alteration produced inside or outside the system, such as trauma, neoplasms, infections, ischaemia or alterations in the immune system, among others. Neuroinflammation is considered a normal mechanism of the brain that contributes to the proper functioning of its structures as long as it is transitory, thus creating a neuroprotective effect. If neuroinflammation spreads over time, creating chronic inflammatory disorders, it could lead to significant damage to the system [27].

The discovery of new findings in this field has brought with it the knowledge that the central nervous system is not isolated. Years ago, the scientific community spoke of the brain as a privileged organ that was isolated by the blood–brain barrier. However, numerous studies have shown that it is in constant communication with the immune system. This is also made possible by the involvement of inflammatory mediators (which can be pro-inflammatory or anti-inflammatory), neurotransmitters or hormones. It is important to know that when inflammation occurs in the central nervous system, glial cells are activated and inflammatory cytokines are released. This is related to the various dysfunctions in the system [27, 32].

Taking a brief look at glial cells, some of them are of particular interest in the field of neuroinflammation. They carry out neuronal support functions. This is the case with microglia, which are a fundamental pillar of central nervous system immunity, bearing certain similarities to macrophages. They go to the sites where inflammation is occurring and, therefore, play an important role in this phenomenon. Astrocytes also contribute to the proper functioning of the immune system, as well as providing neurons with metabolic support and controlling the permeability of the blood–brain barrier. Oligodendrocytes are also involved in neuroinflammation and have receptors for various interleukins. Several studies point to a close communication between microglia and oligodendrocytes, which would offer a more dynamic explanation for inflammation in the nervous system, but further studies are needed to confirm this [27, 32].

As mentioned above, microglia and astrocytes produce inflammatory cytokines. These are messenger proteins that are released in order to regulate immune and inflammatory responses, carry out intercellular communication, as well as participate in cognitive, emotional and behavioural domains that are regulated in the hypothalamus, hippocampus and prefrontal cortex [6, 47]. These particular areas have been found to have a higher number of cytokine receptors [19]. They may be pro-inflammatory, such as IL-1β, IL-6, tumour necrosis factor (TNF-α) or anti-inflammatory, such as IL-10 and IL-4 [19, 32, 42].

Neuroinflammation and suicide

In the late 1980s and early 1990s, interferons were being used for the treatment of cancer, hepatitis B and hepatitis C. Soon, health care workers working with these patients discovered a link between interferon treatment and increased depression and suicidal behaviour. The percentage of patients who had depression and were treated with interferon-α in those studies was as high as 30%. This fact attracted the attention of the scientific community, who decided to continue research in this area and discover the relationship between both of them [6, 22,

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