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Biological bases of suicidal behaviours: A narrative review

Article  in  European Journal of Neuroscience · December 2019

DOI: 10.1111/ejn.14635

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Received: 4 July 2019 
|
  Revised: 5 November 2019 
|  Accepted: 28 November 2019

DOI: 10.1111/ejn.14635

SPECIAL ISSUE REVIEW

Biological bases of suicidal behaviours: A narrative review

Aiste Lengvenyte1,2   | Ismael Conejero3,4  | Philippe Courtet1,3  | Emilie Olié1,3

1
Department of Emergency Psychiatry &
Acute Care, CHU Montpellier, University
Abstract
of Montpellier, Montpellier, France Suicidal behaviour is a multifaceted phenomenon that concerns all human popula-
2
Faculty of Medicine, Institute of Clinical tions. It has been suggested that a complex interaction between the individual genetic
Medicine, Psychiatric Clinic, Vilnius
profile and environmental factors throughout life underlies the pathophysiology of
University, Vilnius, Lithuania
3 suicidal behaviour. Although epidemiological and genetic studies suggest the exist-
Neuropsychiatry: Epidemiological and
Clinical Research, Inserm Unit 1061, ence of a genetic component, exposure to biological and psychosocial adversities,
Montpellier, France especially during critical developmental periods, also contributes to altering the bio-
4
Department of Psychiatry, CHU Nimes, logical responses to threat and pleasure. This results in amplified maladaptive cogni-
University of Montpellier, Montpellier,
France tive and behavioural traits and states associated with suicidal behaviours. Alterations
in the cognitive inhibition and decision-making capacity have been implicated in
Correspondence
suicidal behaviours. Structural and functional changes in key brain regions and net-
Aiste Lengvenyte, Department of
Emergency Psychiatry & Acute Care, CHU works, such as prefrontal cortex, insula and default mode network, may underlie this
Montpellier, University of Montpellier, relationship. Furthermore, the shift from health to suicidal behaviour incorporates
Montpellier, France.
complex and dynamic changes in the immune and stress responses, monoaminergic
Email: aiste.lengvenyte@mf.vu.lt
system, gonadal system and neuroplasticity. In this review, we describe the major
Funding information findings of epidemiological, genetic, neuroanatomical, neuropsychological, immu-
National Institute of Health and Medical
Research; Department of Emergency
nological and neuroendocrinological studies on suicide behaviours to provide a solid
Psychiatry & Acute Care; CHU Montpellier background for future research in this field. This broad overview of the biological
bases of suicide should promote neuroscience research on suicidal behaviours. This
might lead to improved biological models and to the identification of evidence-based
biomarkers, treatment options and preventive strategies.

KEYWORDS
inflammation, neurobiology, neuroimaging, suicidal behaviour, suicide

This phenomenon has frightened and fascinated philosophers

1  |   IN T RO D U C T ION throughout history. This virtually exclusively human behaviour
has been and still is a major issue worldwide, thus explaining its
In humans, suicide overrides the basic instinct of survival place first in religious and philosophical doctrines, then in so-
that is common to the vast majority of known life forms. ciology and philosophy, and currently in biology and medicine.
Abbreviations: 5-HT, serotonin; 5-HTTLPR, regulatory region of the human serotonin transporter; ACC, anterior cingulate cortex; BDNF, brain-derived
neurotrophic factor; CRP, C-reactive protein; CSF, cerebrospinal fluid; DMN, default mode network; DNA, deoxyribonucleic acid; ELA, early life
adversity; fMRI, functional magnetic resonance imaging; GWAS, genomewide association study; HPA, hypothalamic–pituitary–adrenocortical; HuR,
human antigen R; IL, interleukin; NMDA, N-methyl-D-aspartate; PFC, prefrontal cortex; RNA, ribonucleic acid; SKA2, spindle and kinetochore-associated
complex subunit 2; TNF-α, tumour necrosis factor α; TSPO, translocator protein; WHO, World Health Organization.
Edited by Dr. Michel Barrot.
The peer review history for this article is available at https​://publo​ns.com/publo​n/10.1111/ejn.14635​

© 2019 Federation of European Neuroscience Societies     1

Eur J Neurosci. 2019;00:1–22. wileyonlinelibrary.com/journal/ejn |
and John Wiley & Sons Ltd
 |
2       LENGVENYTE et al.
Frustratingly, despite the significant progress in health systems,
suicide rates have not changed in the last decades, and they are
much higher since the start of their systemic recording. This is
partly explained by our poor understanding of the neurobiolog-
ical bases of suicide due to the lack of animal models (Gould et
al., 2017), the difficulties in accessing the brain and the human
mind complexity. The general lack of understanding about the
mechanisms underlying suicidal behaviours translates in the ab-
sence of effective prediction models, low success rates of costly
prevention programmes and the limited treatment options with
long-term benefits. Nevertheless, the significant progress in
functional brain neuroimaging, genomewide analyses and large
population epidemiological studies have contributed to improv-
ing our understanding of suicidal behaviours. These advances
and the larger accessibility to healthcare services have driven
neurobiological suicide research, from the exploration of the
genetic bases of neuroanatomical changes, gene–environment
interactions and alterations of the body regulatory systems, to
the identification of molecular and cellular changes that con-
tribute to suicidal behaviours. In this review, we describe the
current state of knowledge on suicidal behaviours, primarily
focusing on their neurobiological bases.
2  | METHODS
We performed a narrative review of studies on the neurobio-
logical bases of suicide and related behaviours. To this aim,
we searched the PubMed and PsycINFO databases to identify
articles in English or French languages and published up to 1
April 2019. First, we carried out a search using the broad terms
“suicid*” OR “self-harm” to make sure that we would not miss
the most recent and representative studies by using specific
search terms. We considered any form of suicidal outcome:
suicide, suicide attempt and suicidal ideation. Then, we carried
out individual searches for each predetermined section of the re-
view by combining “suicid*” and the following terms: “epide-
miol*,” “age,” “sex,” “mental disorder,” “illness,” “pathogen*,”
“genetic*,” “epigenetic*,” “early life adversity,” “childhood
trauma,” “stress,” “neuropsychol*,” “neurobiol*,” “neuroimag-
ing,” “endocrinol*,” “immune,” and “inflammation.” Two re-
viewers (AL and IC) screened the retrieved articles on the basis
of their title and abstract. Disagreements were solved by discus-
sion with another member of the review team. Then, we fully
read all articles deemed eligible based on the abstracts to assess
their eligibility and hand-searched the reference lists of the se-
lected original studies and review articles to identify additional
relevant articles. When multiple studies were available on one
subject, we selected the most representative to provide an up-
dated overview on the current state for that topic. Our criteria for
representativeness were as follows: recency, quality of the meth-
odology, sample size, impact factor and number of citations,
approval by the appropriate ethics committee, preregistration
in the relevant database and type of publication (we gave prior-
ity to randomized, double-blinded trials, large population-based
studies and high-quality meta-analyses, when available). After
selection and critical assessment of the articles, we performed
the qualitative synthesis.
2.1  | Epidemiology
According to the World Health Organization (WHO), the
suicide mortality rate is around 10.7 per 100,000 people
(i.e., about 800,000 completed suicides worldwide every
year). It is the second leading cause of death in young peo-
ple. Moreover, the overall male: female suicide ratio is 1.7,
thus unfavourable to men. However, regional differences are
prominent, and this ratio is higher in high than in low-mid-
dle income and in Western than in Asian/Pacific countries
(WHO, 2018). Generally, non-fatal suicide acts/behaviours
are more common among women, whereas the rate of com-
pleted suicide is higher in men, possibly due to the more se-
vere suicidal intent of their attempts (Freeman et al., 2017).
However, data are not exhaustive because most countries do
not have comprehensive vital records. Moreover, underre-
porting and incorrect classification due to religious beliefs,
stigma and legislation might be frequent. The direct link be-
tween the study quality and the reported suicide rates further
explains the paucity of robust data (Jordans et al., 2014). The
estimated rates of past-year suicidal ideation and suicide at-
tempts are around 2% and 0.3%–0.5%, respectively (Borges
et al., 2010), but information is even less reliable.
Previous suicide attempt, non-suicidal self-harm and having
a psychiatric disorder have been identified as the main vulner-
abilities contributing to suicidal behaviour (Bostwick, Pabbati,
Geske, & McKean, 2016; Carroll, Metcalfe, & Gunnell, 2014;
Gili et al., 2019). Suicidal ideation also has been linked to
higher rates of future suicide attempts, but the exact magni-
tude of this relationship is debated due to the high unexplained
heterogeneity of the existing data. Furthermore, a recent me-
ta-analysis concluded that in clinical practice, suicidal ideation
displays a modest sensitivity and low predictive value for sui-
cide (McHugh, Corderoy, Ryan, Hickie, & Large, 2019). Other
identified risk factors include prenatal and childhood problems
(Angelakis, Gillespie, & Panagioti, 2019; Orri et al., 2019), in-
terpersonal trauma (Ásgeirsdóttir et al., 2018), low socioeco-
nomic position (Batty et al., 2018), low social integration (Tsai,
Lucas, Sania, Kim, & Kawachi, 2014) and suicidal contagion,
for instance through media reporting (Sisask & Värnik, 2012).
Some risk factors for suicidal behaviour present age-re-
lated differences. In younger individuals, the risk of suicide
is associated with insomnia, burdensomeness, personality pa-
thology, substance use and recent conflicts with their entou-
rage. In middle-aged people, this risk is related to male sex,
marital/job loss, alcohol and substance abuse, anxiety and
LENGVENYTE et al.
major depressive disorder. Elderly individuals with multiple
comorbidities, low social integration and hopelessness are at
higher risk (Fässberg et al., 2012; Gobbi et al., 2019; Steele,
Thrower, Noroian, & Saleh, 2018). Functional disability has
been associated with suicide risk in both middle-aged and
elderly populations (Lutz & Fiske, 2018).
Most people (up to 9 in 10) who commit suicide have at
least one mental disorder (Arsenault-Lapierre, Kim, & Turecki,
2004). The suicide risk is higher in the presence of more than
one psychiatric illness (Holmstrand, Bogren, Mattisson, &
Brådvik, 2015). Substantial evidence shows that mood dis-
orders, posttraumatic stress disorder, borderline personality
disorder, schizophrenia, anorexia nervosa and substance use
disorders increase the risk of suicidal behaviour (Chesney et
al., 2014; Panagioti, Gooding, Triantafyllou, & Tarrier, 2015).
Indeed, it has been shown that most suicides occur after the
intake of psychoactive substances (Galway et al., 2016).
However, the existing evidence is heterogeneous, and previous
claims of a very strong effect of mental disorders on suicide
risk seem to be exaggerated. For example, while some studies
reported a robust association between depression and increased
suicide risk, a recent meta-analysis concluded that depression
and hopelessness are not strong predictors of suicidal behaviour
(odds ratios of approximately 2 for ideation, 1.6 for attempt
and 1.3 for death by suicide; Ribeiro, Huang, Fox, & Franklin,
2018). Focusing on specific symptom dimensions that are as-
sociated with suicidal behaviour, but that cross the current di-
agnostic boundaries could provide more meaningful insights.
Indeed, it has been demonstrated that anhedonia, psychological
pain (i.e., the perception of negative feelings and changes in the
Self that encompass shame, guilt, dread, fear, humiliation and
loneliness (Shneidman, 1993)) and psychotic experiences pre-
dict suicidal behaviour independently of the underlying mental
disorder (Ducasse, Holden, et al., 2018; Ducasse, Loas, et al.,
2018; Yates et al., 2019).
Besides psychiatric conditions, suicidal behaviour has
been associated also with many chronic diseases, such as can-
cer (Henson et al., 2019), asthma and allergic rhinitis (Barker,
Kãlves, & Leo, 2015; Qin, Mortensen, Waltoft, & Postolache,
2011), traumatic brain injury (Madsen et al., 2018) and con-
cussion (Fralick et al., 2019). Moreover, a long-term increase
of suicidal behaviour risk has been observed after severe infec-
tions that require hospitalization, and diseases that are treated
with anti-infective agents (Gjervig Hansen et al., 2019). Pain
and sleep disorders also are risk factors for suicidal behaviour,
independently of concurrent mental disorders (de Heer et al.,
2018; Porras-Segovia et al., 2019; Boxes 1 and 2).
2.2  |  Genetic bases of suicide
Family, twin and genetic studies support the involvement
of genetic factors in the suicide risk (Levey et al., 2019;
  
   3
|
BOX 1  Suicidal behaviours and non-suicidal self-
injury: definitions
Non-suicidal self-injury – self-injurious behaviour
with no intent to die.
Serious suicide attempt – suicide attempt that would
have been lethal without rapid emergency treatment.
Suicidal behaviour – suicidal ideation, suicide at-
tempt or completed suicide.
Suicidal ideation – thinking about, considering or
planning suicide.
Suicidality – current suicidal ideation with imminent
risk to act or history of suicide attempt.
Suicide attempt – potentially self-injurious behav-
iour associated with at least some intent to die.
Violent suicide attempt – all suicide methods with
the exception of drug overdose, poisoning and su-
perficial cutting.
BOX 2  Glossary of key terms
Cognitive control – process of selecting behaviours
according to the person's current long-term goals
and plans (often used as a synonym of executive
functions);
Cognitive inhibition – a top-down regulatory pro-
cess that allows moving the attention away from ir-
relevant cues and focusing on relevant stimuli;
Decision-making – cognitive process of selecting a
logical choice among the available options;
Default mode network – a large-scale interconnected
brain network that is involved in self-referential pro-
cessing and includes the medial prefrontal cortex,
posterior cingulate cortex, and hippocampus;
Executive functions – a set of cognitive functions
that allow planning, selecting and monitoring opti-
mal behaviours (often used as a synonym of cogni-
tive control);
Impulsivity – the combination of lack of premedi-
tation and perseverance, sensation-seeking, and
urgency;
Sensitivity to interference – inability to override ir-
relevant stimuli.
Tidemalm et al., 2011; Voracek & Loibl, 2007; see Table 1).
For example, a total population study in Sweden linked three
national registers to collect all available data on the cause of
death, psychiatric admissions and child–parent relationships
 |
4       LENGVENYTE et al.

T A B L E 1   Evidence for the genetic bases of suicide

Country/
Author, date region Study design Sample size Main findings
Levey et al. US GWAS on SA severity 6,320 GWS associations with SA severity for genes involved in
(2019) with a trans-population ­anaerobic energy production, circadian lock regulation,
meta-analysis ­tyrosine catabolism
Tidemalm et Sweden Total population study 11.4 million The OR for full siblings of suicide completers was 3.1 (95%
al. (2011) CI 2.8–3.5). Risk higher in genetically closer relatives.
Voracek and   Systematic review and 515 twin pairs 24.1% of concordance in monozygotic versus 2.8% in
Loibl (2007) meta-analysis ­dizygotic twin pairs; Hc = 21.9%.
Petersen et al. Denmark Register-based study with a 1,933 Higher SA incidence in full siblings of adoptees with SA
(2014) random sample of adoptees ­history than without SA.
Mcgirr et al. Canada Family study 718 More suicidal behaviour in relatives of probands who com-
(2009) mitted suicide than in relatives of non-suicidal depressed and
healthy probands. Impulsive-aggressive behaviour mediated
the relationship.
Hoehne et al. Canada Comparative neuropsycho- 54 Decision-making impairment in healthy first-degree relatives
(2015) logical study of first-degree of suicide completers.
relatives
Sokolowski Sweden Polygenic risk score as- 660 Modest polygenic associations of SNPs in 750 neurodevelop-
et al. (2016) sociation tests mental genes with SA.
Erlangsen Denmark Population-based GWAS, 50,264 All SNPs explained 4.6% (uncontrolled) or 1.9% (controlled
et al. (2018) case–control study for mental disorder) of SA variation.
Mullins et al. Europe GWAS of suicide attempt 23,801 Three genomewide significant loci for SA, but not replicated
(2019) in patients with psychiatric in independent cohorts.
disorders Polygenic risk scores for depression associated with SA in
mental disorders.
Abbreviations: CI, confidence interval; GWAS, genomewide association study; GWS, genomewide significant; Hc, Holsinger's index of heritability; OR, odds ratio;
SA, suicide attempt; SNP, single nucleotide polymorphism; US, United States.

with the aim of comparing suicide rates among relatives of
the 83,951 people who committed suicide between 1952 and
2003 and among relatives of the control population. This
study found that the relative risk of suicide was 2, 3 and 15
times higher in children, full siblings and monozygotic twins
of suicide descendants, respectively (Tidemalm et al., 2011).
Adoption studies also suggest genetic effects. An adoption
registry-based study from Denmark showed that the risk of
suicide was more than threefold higher among full biologi-
cal siblings of adoptees who attempted suicide than among
full siblings of adoptees who did not. However, it is worth
to note that the 95% confidence interval was wide and that
the lower limit became higher than one only after adjustment
for psychiatric hospitalization (Petersen, Sørensen, Kragh
Andersen, Bo Mortensen, & Hawton, 2014).
The existing studies suggest that the genetic risk factors of
suicide attempt partly overlap with those of psychiatric disor-
ders (Levey et al., 2019; Voracek & Loibl, 2007). Moreover,
it has been proposed that specific cognitive traits mediate the
genetic vulnerability to suicide. For example, a family study
in which 718 first-degree relatives of depressed probands
who committed or not suicide and of controls (120 families
in total) were interviewed showed that impulsive-aggressive
behaviour mediated the relationship between familial pre-
disposition to suicide and suicidal behaviours (Mcgirr et al.,
2009). Another study evaluated the cognitive performance of
healthy first-degree biological relatives of individuals who
committed suicide, or had a major depressive disorder, or
were healthy controls. It found that relatives of individuals
who committed suicide exhibited subtle decision-making
deficits, and lower effect sizes for learning effects compared
with relatives of patients with depression (Hoehne, Richard-
Devantoy, Ding, Turecki, & Jollant, 2015). However, group
differences in this study were small, indicating that there
could be more than one predisposing endophenotype, each
contributing to the increased risk of suicide behaviours. This
is in line with candidate-gene studies that show a very small
role of each gene. Studies with larger effect sizes tend to be
poorly reproducible (Zhou et al., 2018).
Similarly, polygenic risk scores for suicide attempt dis-
play a modest predictive power (Sokolowski, Wasserman,
& Wasserman, 2016). Although previous genomewide asso-
ciation studies (GWAS) failed to identify a specific genetic
profile of suicidal behaviours, recent large-scale GWAS
highlighted several specific loci associated with higher risk
of suicide attempt, supporting the genetic transmission of
LENGVENYTE et al.
suicidal behaviours (Erlangsen et al., 2018; Mullins et al.,
2019; see Table 1). A GWAS to identify quantitative traits of
suicide attempt also provided evidence for genetic risk fac-
tors of suicide attempt severity, and found associations with
genes involved in anaerobic energy production, circadian
clock regulation and tyrosine catabolism, as well as a signifi-
cant overlap with the genetic risk factors for major depressive
disorders (Levey et al., 2019).
2.3  | Gene–environment
interactions and suicide
Epigenetic studies have contributed significantly to better
understand the pathways that lead to suicide. The interac-
tion between environment and genetic makeup is mediated
through long-lasting epigenetic changes (particularly histone
modifications and deoxyribonucleic acid, DNA, methylation)
that modulate gene expression in response to environmental
stimuli (Roy & Dwivedi, 2017). It has been suggested that
these epigenetic modifications start already during the intra-
uterine and perinatal periods and continue throughout the
entire lifespan. Epigenetic modifications during the perinatal
period might, at least partly, mediate the association between
increased suicide risk during the entire lifetime and higher
birth order, teenage mothers, single mothers, low parental
education and slow foetal growth (Orri et al., 2019).
Reduced DNA methylation levels at the spindle and ki-
netochore-associated complex subunit 2 (SKA2) gene, which
is involved in the cortisol response, have been consistently
observed in prefrontal cortex (PFC) of suicide victims
(Pandey, Rizavi, Zhang, Bhaumik, & Ren, 2016). Recently,
much research has focused also on the role of non-coding
microribonucleic acids (microRNAs) that participate in neu-
ral plasticity and higher brain functioning regulation through
modulation of gene expression. For example, a post-mortem
study found that microRNA expression was downregulated
in the PFC of depressed individuals who committed suicide
compared with healthy controls (Smalheiser et al., 2012). A
recent study on the mechanisms underlying tumour necrosis
factor-alpha (TNF-α) upregulation in the dorsolateral PFC
of individuals who died by suicide suggested a complex in-
teraction of several potential mechanisms that involve the
microRNA-19a-3p and the deregulated expression of the
RNA-binding protein human antigen R (HuR; Wang, Roy,
Turecki, Shelton, & Dwivedi, 2018).
2.4  |  The stress vulnerability
model of suicide
Most explanatory models of suicidal behaviours empha-
size the interaction between predisposing and precipitating
  
|
   5
factors via the stress dimension. Many studies have focused
mostly on the stress vulnerability or stress-diathesis model
(the two terms are used interchangeably) that integrates both
clinical and neurobiological components of suicidal behav-
iours. According to this model, suicide is the outcome of
the interaction between distal factors, or trait-like diathesis,
which cause increased susceptibility, and proximal, or state-
dependent (environmental) factors, which precipitate the sui-
cidal act (van Heeringen & Mann, 2014). Both components
are required for the occurrence of suicidal behaviour.
Distal risk factors are temporally far away from the sui-
cidal crisis and confer a suicide risk by increasing the predis-
position to such behaviours. Currently recognized causes of
the suicide diathesis include genetic influences, early life ad-
versities (ELAs), chronic illnesses and dietary factors. These
factors act additively (Smith et al., 2012), and they alter the
response to environmental stimuli through epigenetic/gene
expression changes, leading to disadvantageous personality
traits and cognitive styles that mediate their association with
suicidal behaviours (Ludwig, Roy, Wang, Birur, & Dwivedi,
2017). Increased diathesis for suicidal behaviours has been
associated with dysregulated expression of genes encoding
key factors involved in regulatory body systems, such as the
stress response (O’Connor, Green, Ferguson, O’Carroll, &
O’Connor, 2017), immunity (Wang et al., 2018), serotonin-
ergic system (Mann, 2013), dopaminergic system (Ironside,
Kumar, Kang, & Pizzagalli, 2018) and neuroplasticity
(Maussion et al., 2014).
Cognitive styles and personality traits that mediate the re-
lationship between distal risk factors and suicide might be at
least partly dynamic, whereas diathesis for suicidal behaviour
is continuous (Turecki & Brent, 2016). Indeed, suicidal ide-
ation and suicide attempts have been associated with the
number and severity of negative life experiences (Buchman-
Schmitt et al., 2017). Repeated exposure to various stress-
ors gradually diminishes the resilience towards stress, such
that stressors of decreasing severity can lead to suicidal be-
haviours with stronger suicidal intent. In accordance, death at
the first attempt of suicide has been associated with the use of
more violent methods (Jamison & Bol, 2016) and requires a
less intense stressor (Buchman-Schmitt et al., 2017), suggest-
ing higher baseline diathesis in these individuals.
Proximal risk factors are temporally close to suicidal
behaviours and serve as triggers. A population-based lon-
gitudinal survey in the United States found that significant
life events were associated with suicide attempts in individ-
uals with major depressive disorder at a 3-year follow-up,
even after accounting for demographic factors and psy-
chiatric comorbidity (Wang et al., 2015). Similarly, a 25-
year review of paediatric suicides in a metropolitan area
revealed that the precipitating event could be identified
in two-thirds of teenagers who died of suicide (Molina &
Farley, 2019). Psychosocial crises and psychiatric disorders
 |
6       LENGVENYTE et al.

act through alterations in key neurotransmitter systems,
inflammatory changes and glial dysfunction in the brain
(Roy, Sarchiopone, & Carli, 2009). Furthermore, stress in
the form of a psychosocial crisis triggers a wide range of
subjective experiences that are referred to as psychological
pain. Psychological pain is characterized by a perception of
negative changes in the self, accompanied by strong nega-
tive feelings (Tossani, 2013) and independently increases
the risk of suicidal behaviours (Ducasse, Holden, et al.,
2018). Interpersonal difficulties and social exclusion also
alter the decision-making process (Jollant et al., 2007), fur-
ther increasing the risk of progression from suicidal ide-
ation to suicidal act (Figure 1).
2.5  |  Early life adversities amplify
vulnerability to suicidal behaviours
Early childhood is a critical period in human life during
which unfavourable environmental factors can have detri-
mental effects on the future neurobiological development
and psychosocial functioning. Exposure to adversity during
this period is a well-characterized risk factor of suicidal be-
haviour, and meta-analyses indicate a twofold to threefold
increase in suicidality risk following ELA (Angelakis et al.,
2019; Liu, Fang, et al., 2017; Zatti et al., 2017). In line with
the continuous diathesis model, ELA effect on later suicidal-
ity is moderated by the frequency and severity of traumatic
experiences, as well as by the victim–abuser relationship
(Brezo et al., 2008).
The underlying mechanism linking ELA and suicidality is
not entirely clear. However, several studies suggest that ELA
contributes to the suicide risk through long-term changes
in gene expression, resulting in deregulated pathways and
maladaptive responses. ELA has been associated with alter-
ations in key adaptive systems in adulthood, including the
serotoninergic (Underwood et al., 2018), oxytocin (Chang
et al., 2016), hypothalamic–pituitary–adrenocortical (HPA)
stress-response (Teicher & Samson, 2016) and immune sys-
tem (Baumeister, Akhtar, Ciufolini, Pariante, & Mondelli,
2016). Alterations in these pathways have been implicated
in suicidality (Chang et al., 2016; Pandey, Rizavi, Zhang,
Bhaumik, & Ren, 2018; Underwood et al., 2018).
Stress-induced molecular and cellular changes in the
brain interfere with the normal neurodevelopment, result-
ing in structural and functional brain alterations. Structural
neuroimaging studies have shown that cortical thickness is
decreased in people with history of ELA, whereas glial den-
sity in PFC and anterior cingulate cortex (ACC) is increased
(Underwood et al., 2019). Functional magnetic resonance
imaging (fMRI) studies in response to socio-affective cues
found state-dependent functional changes in the fronto-lim-
bic and temporo-parietal areas of the brain in individuals
with history of ELA (Heany et al., 2018). Studies in ro-
dents also show that exposure to stressors early in life leads
to defective ventral striatum-related functions, to decreased

F I G U R E 1   Path to suicide according to the stress-diathesis model. In this model, the individual's genetic interface interacts with biological
and psychological environmental factors that modify his/her capacity to adapt via alterations in key biological systems. Altered cognitive functions
and behaviours predispose to maladapted responses during psychological crises, resulting in suicidal behaviours
LENGVENYTE et al.
reward-seeking behaviours and to anhedonia (Novick et al.,
2018) that is associated with increased suicide risk in humans.
These findings underline ELA long-lasting consequences on
the structure and function of different body systems.
ELA-affected brain regions are involved in crucial cog-
nitive functions required for the normal functioning of the
individual. Inhibitory control, working memory and deci-
sion-making deficits are among the most common findings in
people with history of ELA (Cowell, Cicchetti, Rogosch, &
Toth, 2015; Guillaume et al., 2013). It has been demonstrated
that unhelpful coping mechanisms, such as social disengage-
ment and withdrawal (Stansfeld et al., 2017), impulsive-ag-
gressive behaviours, emotional dysregulation, hopelessness
and anxiety traits, mediate the relationship between ELA and
suicidal behaviours (Aas et al., 2017; Lemaigre & Taylor,
2019; Mcgirr et al., 2009; Shapero et al., 2019). Moreover,
ELA also increases the risk of other factors associated with
suicidal behaviours, such as maladaptive health and risky be-
haviours, as well as impaired financial, educational and so-
cial functioning (Copeland et al., 2018).
In conclusion, ELA can be seen as a well-documented ex-
ample of a temporally remote factor that increases the risk
of suicidal behaviours by interfering with the development
of different body systems. As these systems are pivotal for
monitoring the responses to everyday stressors, ELA ulti-
mately undermines the long-term adaptive capacities of the
individual.
2.6  |  Neuropsychology: key cognitive
impairments in suicide
Different neurocognitive impairments have been implicated
in the diathesis for suicidal behaviours. Besides lower gen-
eral intelligence quotient in young age (Andersson, Allebeck,
Gustafsson, & Gunnell, 2008), executive functions, which
normally allow planning and executing goal-directed behav-
iours, also are impaired in suicide attempters. The cognitive
impairments more frequently found in suicidal individuals
are as follows: (a) poor inhibitory control, (b) higher sensi-
tivity to interference, (c) higher attention to specific negative
stimuli, (d) impaired verbal fluency, (e) impaired decision-
making, (f) reduced memory abilities and (g) an overgen-
eral autobiographical memory (Jollant, Lawrence, Olié,
Guillaume, & Courtet, 2011; Richard-Devantoy, Berlim, &
Jollant, 2014, 2015).
Inhibition is the cognitive function most robustly related to
suicidal behaviours (Bredemeier & Miller, 2015). Inhibition
is a top-down control process that enables to override com-
peting cognitions in favour of later rewards. Impaired inhi-
bition has been identified as a specific risk factor of suicidal
behaviour in adults with different psychiatric disorders and
in depressed adolescents (Burton, Vella, Weller, & Twamley,
  
|
   7
2011; Lewis et al., 2018). Poor inhibition can lead to impulsive
behaviour, while impaired interference control results in dis-
inhibition of intrusive or irrelevant thoughts that undermines
decision-making. In a meta-analysis that compared healthy
controls and depressed patients with and without history of
suicide attempt, poorer performance in a range of executive
functions could be used to separate patients with depres-
sion from healthy controls. However, only the Stroop task,
which measures inhibition, distinguished suicide attempters
from non-attempters (Richard-Devantoy, Berlim, & Jollant,
2014). Specifically, suicide attempters tend to take more time
in the Stroop task, showing a deficit in interference process-
ing, independently of their current symptomatology (Keilp et
al., 2014). In addition to slower response times, individuals
who report higher levels of suicidal behaviours also identify
the colour of each word with less accuracy (showing diffi-
culties in inhibiting irrelevant information) compared with
those with lower levels of suicidal behaviours (Thompson &
Ong, 2018). This also indicates that the effect of inhibition on
suicidal behaviours is a gradual and not merely an “on-off”
phenomenon.
In the emotional Stroop task, which includes words with
positive and negative valence and words related to suicide,
high-risk patients tend to respond slower to the word “suicide”
(Chung & Jeglic, 2016; Thompson & Ong, 2018), suggesting
a specific attention bias towards this word. A meta-analysis
of studies based on the emotional Stroop test showed a small,
but significant attention bias towards suicide-related words,
but not towards other words with a negative valence in sui-
cide attempters (Richard-Devantoy, Ding, Turecki, & Jollant,
2016). Moreover, an attention bias towards suicide-related
words allowed predicting suicide attempts within 6 months,
after controlling for frequently used clinical predictors (Cha,
Najmi, Park, Finn, & Nock, 2010). This suggests that sui-
cide-specific attention bias is a candidate behavioural marker
of future suicidal risk. Together, these findings show that
suicide attempters have difficulties in monitoring and con-
trolling attention towards suicidal thoughts.
Impaired inhibition translates into impulsive be-
haviours that are strongly associated with suicidal be-
haviours, especially when violent means are used (Cáceda
et al., 2014; Lynam, Miller, Miller, Bornovalova, & Lejuez,
2011; Mallorquí-Bagué et al., 2018; Swann et al., 2005).
Impulsivity is defined as a combination of lack of pre-
meditation and perseverance, sensation-seeking, and ur-
gency (Whiteside, Lynam, Miller, & Reynolds, 2005). In
psychiatric patients, self-measured motor impulsivity can
distinguish between patients with and without history of
suicide attempt (Ponsoni et al., 2018) and with history
of single and multiple suicide attempts (LaCroix et al.,
2017). Furthermore, two distinct forms of impulsivity have
been identified. Cognitive impulsivity is characterized by
the tendency to prefer small immediate rather than larger
 |
8       LENGVENYTE et al.
delayed rewards (Peters & Büchel, 2011), whereas be-
havioural impulsivity refers to the difficulty to prevent and
stop a behaviour (Hamilton et al., 2015). A meta-analysis
of 34 studies on state-sensitive indices of impulsivity (go/
no-go task, stop-signal task and continuous performance
test for behavioural impulsivity; delay discounting task
for cognitive impulsivity) found small-to-medium and
medium-to-large effects for associations between suicide
attempts and behavioural and cognitive impulsivity, re-
spectively. Moreover, the strength of the association with
behavioural impulsivity was influenced by the interval of
time between the last attempt and the assessment and was
stronger when testing was performed closer to the suicide
attempt (Liu, Trout, Trout, Hernandez, Cheek, & Gerlus,
2017).
However, impulsive tendencies might not predict suicidal
behaviours, if suicide is a premeditated act, as suggested by
recent research (Smith et al., 2008). In support, it has been
shown that recent suicide attempters have poorer inhibitory
control, but better problem-solving skills than recent suicide
ideators (Burton et al., 2011). This suggests that both pattern
types are possible. Individuals with worse inhibitory control
might attempt suicide impulsively. On the other hand, good
problem-solving skills might facilitate suicide planning and
initiation of suicide attempt in individuals with long-term
suicidal ideation. Yet, it is too early to draw any firm conclu-
sion because for now, this hypothesis is based only on small
cross-sectional studies.
Decision-making, which refers to the cognitive process
of selecting a logical choice from all the available options,
is another higher-order cognitive function implicated in
suicide diathesis. Disadvantageous decision-making is a
candidate endophenotype for suicide (Courtet, Gottesman,
Jollant, & Gould, 2011). It is prone to heritability (Hoehne
et al., 2015), behaves in a trait-like manner and has a neuro-
biological substrate, as indicated by the functional PFC and
ACC changes observed in patients with history of suicidal
behaviour (Barredo et al.., 2019; Jollant et al., 2010; Olié
et al., 2015) and in relatives of suicide completers (Ding
et al., 2017). Its impairment results in decreased ability to
correctly learn to recognize the long-term risk in uncertain
situations. This increases the likelihood of choosing options
with high immediate reward, but maladaptive in the long
term. Decision-making impairment in past suicide attempt-
ers has been demonstrated using the Iowa Gambling Task,
which involves probabilistic learning via monetary rewards
and punishments (Bridge et al., 2012; Jollant et al., 2005,
2007, 2010), and the Cambridge Gambling Task, which
explicitly presents outcome probabilities entailing deci-
sion under uncertainty (Ackerman et al., 2015). Moreover,
a recent longitudinal study showed that loss aversion, a
specific behavioural component of decision-making, has
a protective role against suicidal behaviour (Hadlaczky et
al., 2018). This suggests that individuals with higher loss
aversion are less likely to carry out a suicide attempt be-
cause of a greater focus on the negative consequences of
the decision.
Decision-making defects are often more pronounced in
violent suicide attempters (Jollant et al., 2005; Wyart et al.,
2016). In a recent study, suicide attempt history was asso-
ciated with impaired value comparison during the choice
process, potentially interfering with the consideration of
alternative solutions. However, only serious suicidal be-
haviours were associated with impaired reward learning
that might hamper the search for alternative solutions
(Dombrovski, Hallquist, Brown, Wilson, & Szanto, 2019).
On the other hand, another study reported that all suicide
attempters (high and low lethality) were more likely to fail
resisting framing (i.e., responding to superficial features)
compared with healthy or depressed controls, but only
low-lethality suicide attempters could not resist sunk cost
(i.e., inability to stop an action with irrecoverable costs)
compared with both control groups and high-lethality sub-
jects (Szanto et al., 2015). These findings suggest that deci-
sion-making impairment in suicidal behaviours is nuanced
and multifaceted. Some defects are related to suicidal be-
haviour in general, whereas others are only found in spe-
cific subpopulations of suicide attempters. The phenotype
complexity might be caused by alterations in different key
neurotransmitter systems. For example, the shorter allele
of the regulatory region of the human serotonin transporter
(5-HTTLPR) has been linked to decision-making biases
in healthy populations (Crişan et al., 2009). However, the
exact underlying mechanisms of these neuropsychological
impairments and their predictive value in suicidality are
not known yet.
A major limitation to study the neuropsychological
mechanisms of suicidal behaviours is that by definition,
neuropsychological tests can only be undertaken by liv-
ing subjects. Therefore, it is possible that people who ac-
tually commit suicide represent a different group from a
neuropsychological point of view. Some of the described
impairments could be related to the reasons of the act fail-
ure rather than to the reasons of the suicide attempt. For
instance, executive functions are more severely impaired
in suicide attempters who use higher-lethality methods
(Jollant et al., 2011). Moreover, some cognitive impair-
ments might act as state markers of suicidal ideation (Pu,
Setoyama, & Noda, 2017), while others characterize a gen-
erally increased vulnerability to suicide (Richard-Devantoy
et al., 2012). A plausible approach to address this issue is
to study individuals with a history of only serious suicide
attempts (i.e., attempts that would have been lethal without
a rapid emergency treatment), a close proxy to completed
suicide. Gvion and Levi-Belz systemically summarized
studies on this group of patients and identified impulsivity,
LENGVENYTE et al.
aggressiveness, and decision-making deficits as psycho-
logical risk factors of serious suicide attempts (Gvion &
Levi-Belz, 2018). This finding suggests a continuous rather
than separate phenotype in relation to the suicide attempt
severity. However, studies on severe suicide attempts are
limited by the scarce available data and small sample sizes,
in addition to the more general problem of definition, ap-
plicable to all suicide studies.
In conclusion, despite evident gaps in the current under-
standing of the neuropsychological factors underlying sui-
cidal behaviours, impaired inhibition and decision-making
represent well-documented vulnerability factors to suicidal
behaviours, and they should be considered when managing
patients with suicidal tendencies (Box 3).
2.7  |  Suicidal behaviours and
neuroimaging findings
In the last decades, many groups have focused on the identi-
fication of neuroimaging biomarkers of suicide. The existing
evidence highlights structural and functional abnormalities in
several brain regions. A coordinate-based meta-analysis of 12
structural and functional magnetic resonance imaging (MRI)
studies that included 425 individuals (213 suicide attempters
and 262 psychiatric controls) found abnormalities in prefron-
tal, cingulate and striatal areas in individuals with history of
suicidal behaviour. This finding links suicide vulnerability
to the increased salience of negative stimuli and the inability
to control deleterious responses during cognitive processing
(van Heeringen, Bijttebier, Desmyter, Vervaet, & Baeken,
2014). A review of 33 studies on neuroimaging changes
in different psychiatric conditions, including two meta-
analyses, concluded that suicidality was consistently linked
to frontal cortex volume reduction and with insular cortex
changes in patients with major depressive disorder. However,
only few studies tried to map shared neural correlates of sui-
cidal behaviours in different disorders (Domínguez-Baleón,
Gutiérrez-Mondragón, Campos-González, & Rentería,
2018).
Generally, volume reduction of the frontal lobe grey matter
is one of the most consistent findings in structural brain im-
aging studies of suicide attempters (Domínguez-Baleón et al.,
2018; Gosnell et al., 2016; Hwang et al., 2010). Some studies
also showed a reduction of its thickness (Wagner et al., 2012).
However, studies on cortical thickness are controversial due
to the small size and high variability of the included samples
(Domínguez-Baleón et al., 2018). The PFC, a frontal lobe
region involved in executive functions, inhibition, emotion
processing, goal-directed behaviour and decision-making,
is particularly implicated. It has been suggested that the left
ventrolateral, orbitofrontal, and dorsolateral regions of the
PFC are the most affected sites in suicidal patients (Ding et
  
|
   9
al., 2015). The serotoninergic system might also be involved
because alterations of serotonin (5-HT) receptors in PFC have
been observed in people who died by suicide (Underwood et
al., 2018). Moreover, increased TNF-α expression has been
detected in the PFC of individuals who died by suicide, link-
ing alterations in this region to the pro-inflammatory state in
suicidal subjects (Wang et al., 2018).
Studies using fMRI have confirmed the role of PFC
dysfunction in suicide pathophysiology. Altered activation
patterns of PFC areas have been associated with impaired
decision-making, risk–reward assessment and social assess-
ment in patients with history of suicide attempt (Ding et al.,
2015; Olié et al., 2015; Sudol & Mann, 2017). Moreover,
the PFC activation patterns in response to exposure to angry
faces are different in individuals with suicide attempt history
compared with healthy and depressed controls (Jollant et al.,
2008). This suggests increased sensitivity to disapproval by
others and higher propensity to act on negative emotions.
Suicidal ideation has been associated with reduced PFC acti-
vation during a verbal fluency task in patients with major de-
pressive disorder (Pu et al., 2017). PFC alterations may also
lead to impaired processing of psychological pain, a known
precursor of suicidal behaviour (Meerwijk, Ford, & Weiss,
2013). For example, PFC activation is altered in individuals
who are recalling the psychological pain experienced during
a recent suicidal episode (Reisch et al., 2010).
Insular cortex is another important brain region in suicide
research. Alterations of this region have been consistently
linked to suicidal behaviours in patients with depression
(Hwang et al., 2010; Jollant et al., 2018; Nock et al., 2014;
Peng et al., 2014; Taylor et al., 2015; Wagner et al., 2012).
Insular cortex is an integral part of the salience network and
potentiates the neural response to harmful stimuli through
connections with the amygdala and cingulate cortex. The
anterior insular cortex participates in the neural network un-
derlying pain sensitivity and in the brain network related to
the acquired capability for suicide (Deshpande, Baxi, Witte,
& Robinson, 2016). Concerning pain processing, insular cor-
tex activation is associated with increased hypersensitivity to
physical pain during social exclusion (Bungert et al., 2015).
Indeed, a fMRI study found decreased functioning in the in-
sula, but not in the PFC during social exclusion modelling in
women with a history of suicidal acts (Olié et al., 2017). This
is in line with the general observation that suicide attempters
have a lower tolerance for psychological pain (Meerwijk &
Weiss, 2018). Conversely, a recent voxel-wise meta-analy-
sis found that brain activation was increased in the left in-
sula and decreased in the bilateral fusiform gyrus in patients
with depression and history of suicide attempt compared
with non-attempters. These alterations were associated with
emotional regulation, negative information processing and
self-awareness deficits, thus integrating neuropsychological
and neuroimaging findings (Li, Chen, Gong, & Jia, 2019).
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10       LENGVENYTE et al.

BOX 3  Description of neuropsychological tests

Cambridge gambling task – a computer-based test in which participants guess in which box (red or blue) a token is
hidden. Participants also choose the proportion of their score that they want to bet on their guess before each stage.
This test assesses decision-making and risk-taking behaviours.
Continuous performance test – a test in which participants must remain focused during a repetitive task to be able to
respond or inhibit responses to continuous targeted and non-targeted stimuli. It assesses sustained and selective atten-
tion, and behavioural impulsivity.
Delay discounting task – a task during which participants are presented with a set of questions that require choosing a
monetary reward based on its value (small vs. large) and temporal proximity (short vs. long delay) to the current mo-
ment. It measures the ability to delay gratification and cognitive impulsivity.
The Stroop colour and word test – a test in which participants are presented with a set of words naming colours in black
or in incongruous colours and have to correctly read the words or say the name of the ink colours as fast as possible.
The emotional Stroop test includes words with positive or negative valence. It assesses cognitive inhibition.
Go/no-go task – a computer-based test in which participants must rapidly respond to “go” stimuli and inhibit the re-
sponse to “no-go” stimuli. It measures behavioural impulsivity.
Iowa gambling task – a computer-based game in which participants must choose a card from several decks of cards in
order to win as much money as possible at the end of the game. With each selected card, participants can win or lose
money. Decks differ from each other concerning their profitability. It assesses decision-making.
Maastricht acute stress test – a laboratory test that includes a 5-min preparatory phase of test description and a 10-min
trial phase (acute physical stress) in which participants must keep their hand in ice-cold water for a randomly selected
time up to 90 s and perform a mental arithmetic task (social stressor) between the hand immersion trials. The test is
video-taped. Negative feedback is given after each math mistake, and the subject has to start over again. It measures
the responses to physical and social stressors.
Stop-signal task – a computer-based test in which participants must correctly respond to one of two stimuli or withhold
from responding in certain conditions. It measures behavioural impulsivity.
Trier social stress test – a laboratory test that includes a 5-min preparatory phase during which participants must
prepare a speech or presentation, a 5-min presentation phase and a 5-min mental arithmetic task. All test phases are
performed in front of an audience and video-taped. It measures the responses to social stressors.

Cross-sectional and longitudinal studies have suggested that
altered functioning of the insular cortex may be specifically
implicated in high-lethality suicide attempts. A grey matter
volumetric study in patients with major depression and sui-
cidal behaviours reported that grey matter volume in the insula
was higher in violent suicide attempters than in non-violent
suicide attempters (Rizk et al., 2019). Moreover, in a pro-
spective study using positron emission tomography, higher
5HT1A receptor binding potential in the insula predicted more
lethal attempts in subjects with depression within a 2-year
period (Oquendo et al., 2016).
Studies on the brain connectome represent another inter-
esting approach to understand the neurobiology of suicide.
However, this research axis is still in its infancy, and the
available data come from cross-sectional and small-scale
studies. Studies in suicide ideators highlighted abnormalities
in the amygdala–precuneus/cuneus and frontal–subcortical
functional connectivity (Wei et al., 2018), linking suicide
ideation to impulsivity and to impaired decision-making
and information integration (Bijttebier et al., 2015; Kim et
al., 2017; Myung et al., 2016). Moreover, a recent structural
connectivity network study in United States veterans found
that suicide attempters have more hub nodes, increased
global efficiency and shorter characteristic path length
compared with suicide ideators and controls (Hwang et al.,
2018). Notably, suicide attempters had greater weighted de-
gree (i.e., connectivity strength) of the left posterior cingu-
late cortex that is part of the default mode network (DMN)
involved in self-referential processing. Conversely, suicide
ideators had decreased DMN coherence and connectivity
(Chase et al., 2017; Ordaz, Goyer, Ho, Singh, & Gotlib,
2018). These findings suggest that specific changes in the
connectivity of DMN-related regions could be biological
substrates for different suicidal determinants. Indeed, the
activation of the posterior cingulate cortex has been asso-
ciated with the preference for immediate reward (Albrecht,
Volz, Sutter, & Cramon, 2013), thus possibly contributing
to impulsivity that is specifically associated with suicide
attempts. However, larger studies that will also take into
account the different comorbidities are necessary to clarify
the exact role of the brain network connectivity in suicidal
behaviours.
LENGVENYTE et al.
The existence of “neural phenotypes” has been suggested
to explain heterogeneous neuroimaging findings in suicidal
individuals. As previously discussed concerning the differ-
ential DMN connectivity in suicide ideators and attempters,
specific alterations in brain networks might be associated
with specific suicide dimensions. Furthermore, a meta-anal-
ysis of 12 different neuroimaging studies with almost 700
participants could not identify robust and consistent struc-
tural neuroimaging markers for all suicidal behaviours.
Nevertheless, it found that the volume of various brain re-
gions was decreased in individuals with family history of
suicide (independently of the violent/non-violent mean) and
that the volume of caudate nucleus and putamen was in-
creased specifically in violent suicide attempters (Jollant et
al., 2018). Some studies also demonstrated that alterations in
the striatum region could predict implicit suicidal ideation in
adolescents (Ho et al., 2018), completed suicide (Willeumier,
Taylor, & Amen, 2011) and high-lethality suicide attempts
in depressed patients (Gifuni et al., 2016). This suggests a
specific role of this brain region that cannot be detected using
traditional neuroimaging approaches, such as magnetic reso-
nance tomography. Interestingly, a recent study found higher
grey matter volume in the PFC of higher-lethality suicide
attempters, suggesting that this group of patients may have
higher attempt planning, greater response inhibition and de-
layed reward capabilities (Rizk et al., 2019). In conclusion,
these findings show that a dimensional approach to neuroim-
aging data in suicide research is relevant because changes in
cortical and subcortical brain structures could be implicated
in some dimensions of the suicidal process, such as the use of
violent means (Figure 2).
F I G U R E 2   Key functional and structural neuroimaging findings associated with suicidal behaviours
  
|
   11
2.8  |  Neuroendocrine and inflammation
biomarkers of suicidal behaviours
Alterations in various body biological systems also have been
associated with suicidal behaviours (summary in Table 2).
2.9  |  HPA axis
Dysregulation of the stress-response system is a well-
replicated finding in individuals with suicidal behaviours
and represents a major basis of the stress-diathesis model.
Specifically, the basal salivary cortisol level is lower
(Keilp et al., 2016), and evening salivary cortisol secretion
is reduced (Lindqvist, Isaksson, Lil-Träskman-Bendz, &
Brundin, 2008) in patients with depression and lifetime his-
tory of suicide attempt compared with non-attempters. It has
been suggested that age modulates the association between
basal salivary cortisol levels and suicidal behaviour occur-
rence. Specifically, a meta-analysis of studies on basal cor-
tisol levels and suicidal acts found a negative association in
individuals older than 40  years (i.e., lower level associated
with suicide attempts) and a positive association in individu-
als younger than 40 years (i.e., higher level associated with
suicide attempts; O’Connor, Ferguson, Green, O’Carroll, &
O’Connor, 2016). Moreover, in suicide attempters, cortisol
secretion is reduced in the 3 months preceding the suicidal
act compared with ideators, as indicated by the lower corti-
sol concentration in the hair of individuals hospitalized for
suicide attempt compared with those hospitalized for suicidal
ideation (Melhem et al., 2017).
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12       LENGVENYTE et al.

T A B L E 2   Neuroendocrine and immune alterations associated with suicidal behaviours

System Putative biomarker Observed change Author, date

HPA axis Cortisol in saliva ↓ basal level Keilp et al. (2016)
↓ evening secretion Lindqvist et al. (2008)
↓ in <40 years old O’Connor et al. (2016)
↑ in >40 years old
Cortisol in hair ↓ in suicide attempters compared to ideators Melhem et al. (2017)
Cortisol in plasma ↓ in relatives of suicide attempters McGirr et al. (2011)
Cortisol response to laboratory stress tests ↓ cortisol secretion O’Connor et al. (2017)
Melhem et al. (2016)
Immune CRP in plasma ↑ level Courtet et al. (2015)
system ↑ with number of suicide attempts, but not with Cáceda et al. (2018)
severity of suicidal ideation
hs-CRP in plasma ↑ increased in suicide ideators without history of Chang et al. (2017)
suicide attempts
Neutrophil-to-lymphocyte ratio ↑ ratio Ekinci and Ekinci (2017)
Ivković et al. (2016)
IL−1β in blood and post-mortem brain ↑ level Black and Miller (2015)
IL−6 in blood and post-mortem brain ↑ level Black and Miller (2015)
IL−2 in plasma ↓ level Ducasse et al. (2015)
TSPO in brain ↑ level Holmes et al. (2018)
Quinolinic acid in plasma, CSF, and ACC ↑ level Bradley et al. (2015)
Erhardt et al. (2013)
Steiner et al. (2011)
5-HT 5-HT2A receptor availability in post-mortem ↑ availability Pandey et al. (2002)
system brain
5-HT1A and 5-HT2A binding in neocortex ↑ binding Underwood et al. (2018)
Serotonin transporter binding ↓ binding Underwood et al. (2018)
Brain BDNF in brain ↓ level Dwivedi (2009)
plasticity BDNF in plasma ↓ level Salas-Magaña et al. (2017)
Gonadal Testosterone in CSF ↑ level in young men Stefansson et al. (2016)
axis Testosterone in plasma ↓ level Tripodianakis et al. (2007)
Abbreviations: 5-HT, serotonin, BDNP, brain-derived neurotrophic factor; ACC, anterior cingulate cortex; CRP, C-reactive protein; CSF, cerebrospinal fluid; HPA,
hypothalamic–pituitary–adrenocortical; hs-CRP high-sensitivity C-reactive protein; IL, interleukin; TSPO, translocator protein.

In depressed outpatients, lower plasma cortisol levels
also have been associated with family history of suicidal be-
haviours, independently of their psychopathology and previ-
ous suicide attempts (McGirr, Diaconu, Berlim, & Turecki,
2011). This suggests that malfunctioning of the stress-re-
sponse system contributes to the familial aggregation of sui-
cidal behaviours via common adverse environments and/or
genetic factors. Dynamic measures also demonstrated that the
HPA axis response to stress is modified in suicidal patients.
During a laboratory stress task (Maastricht acute stress test),
the stress response was blunted in patients who had attempted
suicide in the previous year compared with individuals with
lifetime history of suicide attempts but not during the last year
and with suicide ideators (O’Connor et al., 2017). Participants
with a past-year suicide attempt history and also family history
of suicide exhibited the lowest levels of cortisol in response
to stress, suggesting that HPA axis dysregulation is a trait and
state marker of suicidal behaviours. The results at the 1-month
follow-up supported the continuous diathesis model, because
lower cortisol level in response to the experimental stress was
associated with higher level of suicidal ideation (O’Connor
et al., 2017). Similarly, another study that used the Trier so-
cial stress test, a different experimental stress model, reported
lower cortisol secretion following stress exposure in suicide
attempters than in non-attempters (Melhem et al., 2016).
2.10  |  Inflammation biomarkers and
suicidal behaviours
Growing amount of evidence shows the involvement of
inflammation in suicide vulnerability. Concerning basal
LENGVENYTE et al.
inflammation markers, C-reactive protein (CRP) level in
plasma is increased in suicide attempters independently of
sociodemographic factors and presence of chronic diseases
(Courtet et al., 2015). Similarly, the neutrophil-to-lympho-
cyte ratio, another basal inflammatory marker, is higher in
depressive suicide attempters compared with non-attempters
(Ekinci & Ekinci, 2017), as observed also in euthymic bipolar
patients with history of suicide attempt (Ivković et al., 2016).
Furthermore, it has been reported that inflammation has a
dose-effect on suicidality (REF). Yet, it is unclear which part
of the suicidal process is the most affected by inflammation.
A study in patients with depression hospitalized for severe
suicidal ideation found a positive association between CRP
levels and number of past suicide attempts, but not with sui-
cidal ideation severity. This suggests that elevated CRP level
in plasma is a trait marker of suicidal behaviour risk, rather
that of acute suicidal crisis (Cáceda, Griffin, & Delgado,
2018). However, another study that included only unmedi-
cated patients with depression and without lifetime history
of suicidal acts reported a positive correlation between the
plasma level of high-sensitivity CRP and the intensity of
suicidal ideation (Chang, Tzeng, Kao, Yeh, & Chang, 2017).
Different explanations for this discrepancy are possible, such
as the effect of medication on inflammation (the first study
included patients that were treated as usual, while patients
in the second study were medication-free), slightly different
marker (CRP and high-sensitivity CRP) and the severity of
depression and suicidality (the first study included severely
depressed patients with imminent risk of suicide, while the
second included patients with less severe disease).
Interleukins (ILs) also are important inflammatory bio-
markers of suicide. ILs are cytokines that play a key role in
the immune response regulation. Two meta-analyses found
that IL levels are altered in patients with lifetime history of
suicide attempt. Specifically, one meta-analysis (18 stud-
ies that included 583 patients with suicidality, 315 patients
without suicidality and 845 healthy controls) showed that the
levels of the pro-inflammatory IL-1β and IL-6 are increased
in blood and post-mortem brain samples of patients with sui-
cidality compared with the other two groups (Black & Miller,
2015). The other meta-analysis (11 studies that included 494
suicidal patients, 497 non-suicidal patients and 398 healthy
controls) did not find any link between IL-6 and suicidality,
but reported that the plasma levels of the anti-inflammatory
IL-2 are reduced in suicidal patients compared with the other
two groups (Ducasse, Olié, Guillaume, Artéro, & Courtet,
2015). In addition to the relatively small sample sizes for
IL-6 quantification, the slightly different definition of sui-
cidality could have contributed to these differences. Indeed,
the meta-analysis by Black and Miller included past suicide
attempters and also patients with active suicidal ideation,
whereas the meta-analysis by Ducasse et al. included only
patients with a lethal plan for committing suicide.
  
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   13
Inflammation is also activated by social stressors that are
known triggers of suicidal behaviours. A recent study high-
lighted the differential association between basal cytokine (IL-
1β and IL-2) levels and cerebral activation during experimental
social rejection (Conejero et al., 2019). Thus, inflammation is
a way to understand suicidal behaviour through the stress vul-
nerability model. However, it remains unclear how peripheral
inflammation is related to functional and structural changes in
the brain. Several studies have suggested a relationship between
activation of microglial cells, the primary immune response
cell type in brain, and suicide, independently of the presence
of psychiatric disorders (Suzuki et al., 2019). For example, a
post-mortem study found microglia activation in individuals
who committed suicide but not in those who died from other
causes (Schnieder et al., 2014). Furthermore, a recent case–con-
trol study used a radioligand specific to the 18-kDa translocator
protein (TSPO) to visualize activated microglial cells and found
that higher TSPO availability in ACC, insula and PFC was
linked to suicidal ideation in subjects with depression (Holmes
et al., 2018). However, this study did not detect any association
between central inflammatory markers and circulating cytokine
levels, suggesting that the relationship between peripheral and
central inflammation in suicide is probably mediated by not yet
elucidated complex biological processes.
2.11  |  Pathways linking inflammation to
suicidal behaviours
An important link between inflammation and suicidal behav-
iour is the preferential metabolism of tryptophan through the
kynurenine–tryptophan pathway that entails the depletion of
serotonin and subsequently, of melatonin. It has been shown
that the level of quinolinic acid, one of the kynurenine path-
way end-products, is increased in plasma (Bradley et al.,
2015) and cerebrospinal fluid (CSF; Erhardt et al., 2013) of
suicide attempters and in ACC of depressed suicide com-
pleters (Steiner et al., 2011). Activation of the kynurenine
pathway in response to infectious agents increases the pro-
duction of cell energy (Savitz, 2019), which is vital for fight-
ing infectious agents, and reduces serotonin synthesis, which
is not essential for counteracting infection-related damage
or death. Chronic excess of pro-inflammatory cytokines, in-
duced by biological and psychological stressors, leads to the
constant over-activation of this pathway. In the brain, acti-
vated immune cells metabolize kynurenine into neurotoxic
quinolinic acid that binds to N-methyl-D-aspartate (NMDA)
receptors, resulting in glutamatergic system over-activation
and decreased production of brain-derived neurotrophic
factor (BDNF; Hardingham, Fukunaga, & Bading, 2002).
This leads to neuronal damage and related changes in cog-
nition that may favour the emergence of suicidal behaviour
(Haroon, Miller, & Sanacora, 2017). In support of this theory,
 |
14       LENGVENYTE et al.
ketamine, an NMDA-antagonist, displays specific anti-sui-
cidal effects (Wilkinson et al., 2018). Increased peripheral in-
flammation has also been linked to higher glutamate levels in
basal ganglia (Haroon et al., 2016) and decreased functional
connectivity within dopaminergic circuits that is related to
anhedonia (Felger & Treadway, 2017) and consequently to
suicidal ideation (Ducasse, Loas, et al., 2018), thus implicat-
ing the reward system in the pathway from inflammation to
suicidality.
The serotoninergic system is another essential system,
linked both to suicide (Asberg, Träskman, & Thorén, 1976)
and inflammation (Raison et al., 2009). Post-mortem studies
have demonstrated increased 5-HT2A receptor availability in
suicide victims (Pandey et al., 2002). This finding was con-
firmed by a recent post-mortem study showing lower sero-
tonin transporter and higher 5-HT1A and 5-HT2A binding in
the neocortex of depressed suicide victims compared with
controls (Underwood et al., 2018). This suggests the exis-
tence of adaptive responses to low serotonin availability in the
brain. Abnormalities in the serotonin system have also been
linked to HPA hyper-reactivity (Steinberg et al., 2019) and to
increased activity of the ventral striatum during the prediction
of immediate reward (Tanaka et al., 2007) that implicates the
stress-response and reward systems. Furthermore, a complex
relationship might exist between serotonin and BDNF activ-
ity (Popova & Naumenko, 2019). Indeed, several studies have
found decreased BDNF levels in the hippocampus and PFC
of suicide completers (Dwivedi, 2009) and in plasma of sui-
cide attempters (Salas-Magaña et al., 2017). In conclusion, the
complex relationship between chronic inflammation and sui-
cide might be favoured by disadvantageous monoamine and
neurotrophin expression modifications in the brain and dereg-
ulation of the stress-response system, resulting in the cognitive
and behavioural changes seen in suicidal individuals.
2.12  |  Testosterone and suicidality in men
Testosterone is an anabolic steroid with roles in human social
behaviours and reproduction. Both high and low testosterone
levels have been related to suicidal behaviours in men. For
example, a study on young adults found higher testosterone
level in the CSF of male suicide attempters compared with
healthy controls. This study also detected a positive correla-
tion between the testosterone/cortisol ratio and impulsivity
and aggressiveness, an important endophenotype of suicide
in young men (Stefansson et al., 2016). Furthermore, a study
in rodents found greater impulsivity and upregulation of
genes involved in the α2-adrenergic receptor–protein kinase
A signalling axis in the PFC of testosterone-treated gonadec-
tomised rats compared with the untreated gonadectomised
group (Agrawal, Ludwig, Roy, & Dwivedi, 2019). This sug-
gests that transcriptional changes in the brain might underlie
the relationship between testosterone levels and impulsivity
and consequently suicidal behaviours. However, other stud-
ies did not find any relationship between testosterone level
and suicide attempts (Perez-Rodriguez et al., 2011), and oth-
ers found an inverse relationship (Tripodianakis, Markianos,
Rouvali, & Istikoglou, 2007). A possible explanation for
these discrepancies is that the relationship between testos-
terone levels and suicidality in men could be “U” shaped.
In young men, high testosterone might be associated with
suicidality via increased aggressiveness, while in older men,
low testosterone could be implicated in suicidality by caus-
ing depressive symptoms and cognitive impairment (Sher,
2018). In conclusion, testosterone might be implicated in
male suicidality; however, the current evidence is based on
small cross-sectional studies with heterogeneous results.
Therefore, additional studies with larger samples and a wide
range of ages are required.
3  |   DISCUSSION AND FUTUR E
PERSPECTIVES
In this review, we discussed the evidence for the neurobio-
logical basis of suicidal behaviours. Briefly, data from ge-
netic and epidemiological studies show that there is some
degree of genetic predisposition for suicidal behaviours.
However, genetic studies have failed to identify genes with
large effects. In addition, environmental factors that cause
biological and psychological stress can greatly increase the
risk of suicide. The stress-diathesis model has been proposed
to explain this phenomenon. Epigenetic studies show that
adversity interacts with the genetic interface of the exposed
individual. When stress is excessive, or occurs during a criti-
cal developmental period, or in genetically predisposed in-
dividuals, maladaptive cognitive and behavioural traits and
states, such as impulsivity and decision-making impairment,
can emerge or amplify. Functional and structural changes
in key brain regions and networks, such as PFC, insula and
DMN, as well as changes in body regulatory systems, includ-
ing the immune, monoamine, stress-response and gonadal
systems, are implicated in this relationship. However, none
of the identified biological and neuroimaging markers for
suicidal behaviours has been translated in the clinical prac-
tice for the development of effective treatment options and
suicide prevention strategies. Their discovery remains crucial
for suicide understanding. Moreover, it is still unclear how
some drugs, namely lithium, clozapine (Levey et al., 2016)
and ketamine (Wilkinson et al., 2018), have anti-suicidal ef-
fects. Understanding the underlying mechanisms is essential
because it may guide the development of new interventions
and the adaptation of the current ones.
Despite considerable progress in understanding the neu-
robiological basis of suicidal behaviours in order to detect
LENGVENYTE et al.
discrete patterns, many obstacles related to the nature of
suicide, which is the voluntary termination of life, remain.
Indeed, a substantial part of the available clinical and epi-
demiological data relies on subjective patient reports of
attempted suicide and suicidal ideation. However, sui-
cidal ideation has a poor predictive value for later suicide
(McHugh et al., 2019), and many suicide attempts remain un-
reported, especially in regions where suicide is stigmatized.
Indeed, most of the high-quality data on suicidal behaviours
come from high-income developed countries (Jordans et al.,
2014), hindering our understanding of regional differences
in suicidal behaviours. For example, the “suicide paradox”
(i.e., higher rates of attempted suicide, but lower rates of
completed suicide in women; Freeman et al., 2017) is not
observed in all countries (WHO, 2018), but the reasons for
that are unclear. Furthermore, a recent GWAS demonstrated
racial differences in genetic associations with suicide attempt
severity (Levey et al., 2019), suggesting that different path-
ways to suicide have emerged in different human populations,
further underlining the need of suicide neurobiology studies
in more diverse populations.
Another important caveat to consider is the lack of di-
rect animal models in suicide research (Gould et al., 2017).
Animal models have proven their utility to understand many
medical conditions due to the possibility to create a highly
controlled environment, to select identical or genetically
modified animals and to replicate findings. In psychiatry,
many neuropsychological functions are examined by using
animal models. Yet, no animal has demonstrated the capac-
ity for such a complex behaviour as suicide. An alternative
might be to perform animal studies on suicide-associated en-
dophenotypes, such as impulsivity, hopelessness, depression
and executive functions. However, this poses the additional
challenge of translating the results to human behaviours that
are often related to multiple, and not to one single factor. For
example, hopelessness and depressive behaviours, previously
considered as key risk factors of suicide, have been recently
shown to have a poor predictive value for suicide in humans
(Ribeiro et al., 2018). Therefore, much effort should focus on
the development of complex animal models that incorporate
several different suicide-related endophenotypes, and their
translation to and back-translation from human studies.
Post-mortem studies have provided many insights for un-
derstanding the molecular changes associated with suicide,
particularly through epigenetic and transcriptional analyses
(Egervari, Kozlenkov, Dracheva, & Hurd, 2019). However,
collecting and analysing brain samples is a challenging task
due to the high costs of brain banking and rarity of suicides.
Moreover, the objectives of post-mortem studies are often
based on hypotheses generated by animal studies. Besides
the non-existence of direct animal models of suicide, the
complexity of human brain might make difficult the detec-
tion of discrete changes. Post-mortem studies can also miss
  
   15
|
individuals who, for example, had better executive functions
or empathy and concealed their suicide by staging an accident
to protect others from guilt. Moreover, although valuable for
retrospective analyses, studying brain tissue after the suicide
precludes conclusions on the biological mechanisms associ-
ated with the suicidal process onset and course. Therefore,
many studies have focused on peripheral biomarkers of sui-
cide that are easier to access. However, it is still unclear to
what extent and how peripheral changes translate into brain
alterations and vice versa. Therefore, disentangling the exact
mechanisms that connect changes in peripheral and central
systems is crucial.
In conclusion, the future understanding of suicide
would benefit from well-designed studies that focus on
dimensional approaches to suicidal behaviours and related
endophenotypes, by integrating different populations and
animal models. In addition, any study on suicide should
use a common nomenclature that will allow researchers to
better evaluate, compare and combine findings from differ-
ent studies.
ACKNOWLEDGEMENTS
The authors thank the National Institute of Health and
Medical Research (Inserm) and the Department of Emergency
Psychiatry & Acute Care, CHU Montpellier for the financial
support. AL thanks the European Commission that provided
a fellowship during the period that the manuscript was writ-
ten. All authors have no potential conflict of interest.
AUTHOR CONTRIBUTIONS
AL and IC selected, analysed relevant studies and wrote the
paper. AL revised the manuscript after peer review. EO con-
ceived the idea. AL, IC, EO and PC critically reviewed the
manuscript and agreed on the final version of it.
DATA AVAILABILIT Y STATEMENT
The data associated with this review is available on pubmed.
gov.
ORCID
Aiste Lengvenyte  https://orcid.org/0000-0001-9715-5145
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How to cite this article: Lengvenyte A, Conejero I,
Courtet P, Olié E. Biological bases of suicidal
behaviours: A narrative review. Eur J Neurosci.
2019;00:1–22. https​://doi.org/10.1111/ejn.14635​