What Neurobiology Can Tell Us About Suicide

27. 12. 2020.
What Neurobiology Can Tell Us About Suicide | The Scientist Magazine®
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What Neurobiology Can Tell Us About Suicide

The biochemical mechanisms in the brain underlying suicidal behavior are beginning to come
to light, and researchers hope they could one day lead to better treatment and prevention
strategies.
Catherine O ord
Jan 13, 2020
T
he rst time Kees van Heeringen met Valerie, the 16-year-old girl
had just jumped from a bridge. It was the 1980s and van ABOVE: © LYNN SCURFIELD
Heeringen was working as a trainee psychiatrist at the physical
rehabilitation unit at Ghent University Hospital in Belgium. As he got to
know Valerie, who’d lost both legs in the jump and spent several months at the hospital, he pieced together the
events leading up to the moment the teenager tried to end her life, including stressful interactions with people
around her and a steady accumulation of depression symptoms.
Van Heeringen, who would later describe the experience in his 2018 book The Neuroscience of Suicidal Behavior,
says Valerie’s story le a permanent impression on him. “I found it very di cult to understand,” he tells The
Scientist. He asked himself why anyone would do “such a horrible thing,” he recalls. “It was the rst stimulus fo
me to start studying suicidal behavior.”
In 1996, van Heeringen founded the Ghent University

Unit for Suicide Research. He’s been its director ever
since, helping to drive scienti c research into the ma
questions he and others have about suicide. Many of
answers remain as elusive as they seemed that day in
rehabilitation unit. Suicide rates are currently climbi
in the US and many other countries, and suicide is no
the second leading cause of death among young peop
globally, a er tra c accidents. The World Health
Organization recently estimated that, worldwide, one
person ends their own life every 40 seconds.
Suicide is as complicated as it is tragic. Suicidal

behaviors come in many varieties, ranging from suic
thinking, or ideation, to suicide attempt and
completion, all of which may be associated with vario
levels of violence or intent. The behaviors themselve
di er in incidence among genders, ethnicities, and ot
demographic categories, and almost always occur
Source: American Foundation for Suicide Prevention, 2017 data
against a background of depression or some other m
THE SCIENTIST STAFF
disorder—although only a fraction of people with mo
disorders become suicidal.
https://www.the-scientist.com/features/what-neurobiology-can-tell-us-about-suicide-66922?_ga=2.153822456.1761513644.1609095922-867588… 1/13
27. 12. 2020. What Neurobiology Can Tell Us About Suicide | The Scientist Magazine®
No eld of scienti c inquiry can single-handedly untangle a phenomenon as complex as suicide. But van
Heeringen and many other scientists are hoping to shed light on the problem by digging into the neurobiolog
processes underlying thoughts about ending one’s own life and attempts to do so. This work is building suppo
for the idea that suicide is tied to speci c biochemical changes that can be measured and targeted independen
of, and possibly in parallel with, the mental health disorders they o en accompany. Findings from this work,
researchers hope, could help reveal new treatments, and perhaps even opportunities to identify the people mo
at risk in time to intervene.
“The knowledge we have today is way larger than what we had twenty years ago,” says Gustavo Turecki, a
psychiatrist at McGill University and the director of the McGill Group for Suicide Studies at the Douglas
Research Centre in Montreal. “[We’ve] made tremendous advances . . . in terms of understanding the complex
of the problem, understanding the neurobiology, understanding the causes.”
NEUROBIOLOGICAL PATHWAYS LINKED TO SUICIDE RISK
Scientists have identi ed several key neurobiological pathways with ties to suicidal behaviors. Research in th
eld addresses only a fraction of the complexity of this serious public health problem, and the literature on
the topic is complicated by variation in study design, but the clues point to several interacting moderators of
suicide risk. Three of the systems best-studied in relation to suicide are depicted below.
NOTE: The ndings shown in these graphics come from studies with very di erent approaches to investigating suicide. Some studies
control for psychiatric disorders, others don’t; di erent studies focus on di erent brain areas; and many of the ndings are preliminary.
© LISA CLARK
See full infographic: WEB | PDF
The role of the brain’s stress pathways in suicide
Valerie’s account shared elements with the stories of many other people who have attempted to end their lives
She showed signs of depression and social stress, and, as van Heeringen later discovered, she had a family hist
of suicide—a known risk factor for suicidal behaviors, independent of any psychiatric disorders.
Scientists now think about suicide risk in terms of stress-diathesis models, which treat suicide as a product of
both so-called precipitating factors such as elevated stress or mood disorders and predisposing factors—the
“diathesis”—such as family history, particular genetic variants, or early-life adversity such as abuse or neglect.
“Suicide is more than . . . being very depressed,” explains Columbia University’s John Mann, a psychiatrist and
translational neuroscientist who helped develop the conceptual framework with Columbia neurobiologist
Victoria Arango.
This framework has helped focus research on biochemical pathways that regulate the brain’s response to stres
and how those pathways could be altered in people who become suicidal. The brain has multiple stress
responses, but the best-studied in relation to suicide is the hypothalamic-pituitary-adrenal (HPA) axis, which
controls the release of the stress hormone cortisol and is known to be upregulated in clinical depression.
Early clues regarding the link between the HPA axis and
suicide include ndings of higher concentrations of
corticotropin-releasing hormone (CRH), which triggers
the synthesis of cortisol and other glucocorticoids
involved in stress signaling, in postmortem brain
samples from people who died by suicide than in
samples from people who died by other means. Other
research has hinted that people who died by suicide
have enlarged adrenal glands—sites of cortisol
production. Due to the high incidence of depression
and other mood disorders among people who end their
own lives, however, studies such as these didn’t attempt
Source: CDC, 2017 data
to determine whether the observed e ects were speci c
© ISTOCK.COM, LOFTYSTYLE
to suicide or to mood disorders more generally.
More recently, the case for a central role for the HPA axis in suicide has gained support from work led by Ture
and others revealing that early-life adversity, one of the strongest risk factors for suicide even when psychiatri
disorders are controlled for, can have long-term e ects on HPA axis function. In the mid-2000s, Turecki team
up with McGill University geneticist Moshe Szyf, who had shown that rats neglected by their mothers exhibit
altered epigenomes in the hippocampus—a brain region involved in stress, learning, and memory—and
dysfunctional HPA responses to stress. In the hippocampi of people who have died by suicide and had a histor
of childhood abuse, Turecki, Szyf, and their colleagues found evidence of hypermethylation and reduced
expression of the gene coding for NR3C1, a glucocorticoid receptor that helps dampen cortisol signaling,
compared with healthy controls or people who died by suicide but hadn’t experienced abuse.
Research since then has linked suicidal behaviors to methylation abnormalities in other HPA-related genes. O
2018 assessment of nearly 90 people who had attempted suicide identi ed reduced methylation at the CRH ge
in blood samples from some of the study’s subjects—speci cally, those who made attempts that were more
violent or more likely to result in death. And several studies have identi ed hypermethylation and reduced
expression of SKA2, which codes for a protein that interacts with NR3C1, in people who died by suicide
compared with healthy controls and with nonsuicidal patients with depression, schizophrenia, or other
psychiatric disorders.
The relationship between the HPA axis and suicidal behavior is complicated. For example, while some studies
imply that the HPA axis overreacts to stress in people who die by suicide, others indicate that people who
attempt suicide have lower baseline cortisol levels and/or blunted HPA reactivity to stress compared with
controls. “It is a confusing literature,” says Nadine Melhem, a psychiatric genetic epidemiologist at the Univers
of Pittsburgh School of Medicine who found a few years ago that, among around 200 people whose parents h
mood disorders, those who attempted suicide had overall lower HPA activity. “Almost every [possible] nding
been reported.”
Part of this inconsistency likely stems from small study samples and variations in experimental design, Melhe
notes. But variability may also come from di erences in the drivers of suicidal behavior in di erent groups of
people. Mann’s group reported last year that, of 35 people who attempted suicide, only those who scored high
for impulsive aggression in personality tests had signi cantly elevated cortisol responses to stress compared w
nonsuicidal controls. And one meta-analysis published a few years ago found a positive correlation between
cortisol levels and risk of suicide attempt in studies of people under 40 years old, but a negative correlation in
studies of older people.
Until now, “we have not been able in the literature to capture the dynamic nature of these pathways in relation
suicide risk,” says Melhem, adding that she and colleagues are beginning to build longitudinal datasets to addr
this gap. “It needs a lot more work.”
STRESS RESPONSES
Many studies have linked suicidal behaviors to dysregulation of the hypothalamic-pituitary-adrenal (HPA)
axis and other mediators of the body’s responses to stress.
CRH
Corticotropin-releasing hormone (CRH) has been found in higher concentrations in the

brains of people who die by suicide.
Adrenal glands
People who die by suicide, and particularly those who die by violent means, may have
enlarged adrenal glands.
Cortisol
Basal cortisol levels have been found to be both higher and lower than normal in people wh
have attempted suicide. The reactivity of cortisol to stress may also be dysfunctional in
people with suicidal behaviors.
NR3C1
NR3C1, also known as the glucocorticoid receptor, may be in lower abundance in people wh
die by suicide, particularly those with a history of childhood abuse.
© LISA CLARK
The e ect of serotonin and other neurotransmitters
Mann rst became interested in the neurobiology of suicide while studying a rather di erent aspect of brain
chemistry. Throughout the 1980s and ’90s, he and others found de cits in serotonin (5-hydroxytryptamine, o
HT) signaling and in the neurotransmitter’s main metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in the brai
of people who died by suicide, regardless of psychiatric diagnosis, compared with brains of people with or
without psychiatric disorders who had died by other means. The ndings were key in the realization that ther
might be biochemical changes speci c to suicide, Mann says. Since then, the serotonergic system has become
one of several neurotransmitter systems being probed for clues about suicidality.
Like the HPA axis, serotonin signaling appears to be modulated by early-life adversity. For example, methylat
of HTR2A, which codes for a serotonin receptor known as 5-HT2A, is altered in children who have su ered ea
life adversity—although it’s not yet clear how those methylation changes a ect HTR2A expression. A 2016 stud
of twins in the UK revealed that children who were bullied had hypermethylation at SERT—a gene coding for
protein that helps transport serotonin from the synapse back into the presynaptic neuron—compared with
children who weren’t. Bullied children also showed blunted cortisol responses to stress, hinting at a link betwe
the serotonergic system and HPA functioning.
How such physiological changes might in uence suicidal behavior remains to be seen, but groups such as Man
are working to disentangle some of the details. For example, he and his colleagues recently published a more
concrete link between serotonin and HPA-axis activity: even when psychiatric diagnoses are controlled for, lev
of the serotonin receptor 5-HT1A are correlated with cortisol reactivity to stress. The team has also explored
levels of serotonin receptors in depressed and nondepressed people exhibiting suicidal behaviors, and found t
levels of 5-HT1A in some regions of the cortex are higher in people who attempt or die by suicide, regardless o
psychiatric diagnosis, than in controls.
Somewhat counterintuitively, higher levels of 5-HT1A could contribute to a de cit in serotonin signaling, Man
explains, because the receptor is part of a neural feedback response that inhibits further serotonin release into
synapses. Accordingly, it seems that in people who are suicidal, “the problem is not the capacity to make
serotonin but . . . the capacity to use that serotonin,” he says. This role for 5-HT1A could also help explain why
selective serotonin-reuptake inhibitors (SSRIs) do a better job of dampening suicidal thoughts and behaviors
than some other antidepressants, he adds: among other e ects, SSRIs reduce the number and responsiveness
5-HT1A receptors and may thereby quiet the negative feedback loop that suppresses serotonin signaling.
See “Antidepressant Approvals Could Herald New Era in Psychiatric Drugs”
Neurotransmitters besides serotonin, including glutamate, GABA, and dopamine, have also been investigated
the context of suicidal behavior—particularly following recent ndings that drugs such as ketamine and
esketamine, which interact with the glutamate receptor NMDAR, reduce suicide risk in patients with clinical
depression. However, the literature on these neuro-transmitters is fairly inconsistent, spurring researchers to
continue looking for new mechanisms to explain suicidal behaviors.
NEURAL TRANSMISSION
Neural communication via serotonin and other neurotransmitters such as glutamate o en shows signs of
dysregulation in people who die by suicide.
© LISA CLARK
Serotonin
Disruption of serotonin signaling has repeatedly been found in the brains of people who die by suicide.
SERT
Levels of the serotonin transporter SERT, which shuttles serotonin back into the presynaptic neuron, may b
lower in people who die by suicide.
Serotonin receptors
Levels of the serotonin receptors 5-HT1A and 5-HT2A may be higher in people who attempt or die by suicid
A potential link to neuroin ammation
A couple of years ago, researchers in Denmark reported a link between suicide and infectious disease. Analyzi
three decades’ worth of health records from more than 7 million people, the team found that being hospitaliz
with an infection was associated with more than a 40 percent greater probability of suicide. Spending more th
three months in the hospital was linked to a more than doubled suicide incidence. While acknowledging that
such observational data can’t demonstrate causation, the team calculated that the statistical risk associated with
hospitalization for infections could account for about 10 percent of the Denmark’s suicides.
There are many possible explanations for this nding—one being that treatment of infections with antibiotics
other hospital medications in uences mental health. But van Heeringen and others point out that the study ti
into another hypothesis about suicidal behavior, one that involves a role for in ammation.
Elevated suicide risk has previously been reported in people with autoimmune disorders and traumatic brain
injury—conditions that, like infections, typically involve in ammation. Further clues come from
epidemiological studies of Toxoplasma gondii—a parasite that causes chronic, low-level neuroin ammation in
humans. A 2018 study of nearly 300 people in Korea found that 14 percent of people who attempted suicide
tested positive for the parasite, compared to just 6 percent of healthy controls—mirroring a correlation found
several US cohorts. Together, the ndings paint a compelling picture that neuroin ammation “is part of the
story,” says Melhem.
While depression is not thought of as an in ammator

disease, signs of neuroin ammation in the brain have
been repeatedly documented in people who su er fr
depression, and a number of anti-in ammatory drug
show antidepressant e ects. Microglia, the central
nervous system’s primary immune cells and mediato
of in ammation, tend to show increased activation in
the brains of people who die by suicide, Melhem add
and several studies have identi ed elevated
concentrations of in ammatory cytokines such as
interleukins IL-2, IL-6, and IL-8 in people with fatal a
nonfatal suicidal behaviors. One 2019 analysis of nea
2,000 Mexican-Americans, for example, found that
blood levels of IL-8 were elevated in depressed and
nondepressed women who had attempted suicide.
Source: WHO, 2016 data How exactly neuroin ammation might contribute to
© ISTOCK.COM, MATSABE suicidal behavior is still unclear, and some recent
epidemiological studies have raised doubts about
whether the association exists independently from depression. One route that researchers are exploring is
neuroin ammation's interaction with the serotonergic system. In a process thought to be mediated by microg
neuroin ammation triggers a shi in the metabolism of serotonin’s molecular precursor, tryptophan, away fr
the production of serotonin and towards other chemical pathways—potentially reducing serotonin signaling a
triggering other suicide-related changes in the brain.
That’s just one hypothesis, says Melhem, who recently won a grant with Mann to investigate the suicide-
in ammation link. These pathways haven’t “been interrogated enough,” Melhem says. “We’ll be looking more
into that in future work.”
INFLAMMATION
INFLAMMATION
People who die by suicide show signs of increased in ammation in the brain while epidemiological data
reveal that some in ammation-related health conditions are associated with higher suicide risk.
© LISA CLARK
Microglia
The brains of people who die by suicide show higher levels of microglia activation.
Cytokines
Blood levels of in ammatory cytokines, particularly some types of interleukins, have been found at higher
levels in people who attempt suicide.
Tools to predict and prevent suicide
One of the de ning moments in psychiatrist David Brent’s career happened during his medical residency som
40 years ago. Brent had been assigned to work with young people admitted for intentional drug overdoses at t
University of Pittsburgh Medical Center Children’s Hospital. He had to determine who should be referred to a
psychiatric ward and who could safely go home. “I found that I really didn’t have a very good way of making t
determination,” says Brent, now a professor at Pitt. As he learned more about how other clinicians made such
decisions, “I realized I was in good company—that nobody really knew what they were doing.”
It’s still a dilemma facing anyone attempting to provide care for people at risk of suicide. Today’s clinicians o
rely on patients to report their intentions in order to decide on appropriate interventions. But the approach h
limitations. One 2019 meta-analysis of studies on suicidal ideation found that around 60 percent of people wh
ended their lives had denied having suicidal thoughts when asked by a clinician or doctor in the weeks or mon
before their death.
This problem has led some researchers to look for ways to translate ndings from neurobiology, however
preliminary, into the identi cation of biomarkers to predict the onset of suicidal behaviors. Given its strong
association with suicide, the HPA axis has long been a focus of this work, and there’s some evidence that
abnormal cortisol levels—higher or lower than normal—in blood or saliva could hold promise as a biomarker
few months ago, for example, Melhem, Brent, and colleagues published ndings from a long-term study of
teenagers that suggested a person’s baseline cortisol levels might be used to predict future suicidal thinking, w
higher cortisol associated with increased ideation within the next couple years.
Cortisol tests may help provide predictive power to

other measures of suicidality, such as questionnaires
about social and academic stress. One recent analysis
showed that while survey data were good predictors of
who among 220 teenage girls with mental health
concerns would be thinking about suicide within the
next few months, they were poor predictors of who
would attempt suicide during that period. But when the
researchers focused only on girls who had shown
blunted cortisol responses in lab tests, the questionnaire
data predicted suicide attempts much better.
Looking beyond stress responses, other groups have

attempted to identify biomarkers related to
neurotransmission. A few years ago, Mann’s group used
positron emission tomographic (PET) imaging to assess
levels of 5-HT1A serotonin receptors in the midbrains of
100 patients with major depressive disorder. The
Source: NATIONAL ALLIANCE ON MENTAL ILLNESS, various
scientists found that higher 5-HT1A levels predicted datasets
© ISTOCK.COM, KADIRKABA
greater suicidal ideation and more-lethal suicidal
behavior within the next two years. Last summer, a team led by Yale University neuropsychologist Irina Esterl
reported that levels of glutamate receptor mGluR5, as measured by PET, was linked to current suicidal ideatio
in patients with post-traumatic stress disorder—though the results didn’t hold for patients with major depress
disorder.
Opinions di er among researchers about the potential of such biochemical signatures to assess suicide risk. G
Ordway, a pharmacologist studying depression at East Tennessee State University, says that while biology mig
identify people predisposed to suicidal behavior, it’s unlikely to produce one or a handful of biomarkers that
reliably reveal whether a person is about to end their life. “Suicide is extremely di cult to predict,” he says.
“People are always trying to do it—people like me are looking for markers. But in reality, I don’t think we’ll
probably ever nd that.”
Some of the most promising tools for assessing immediate risk might instead come from other areas of
neuroscience that measure more-complex, emotional signals in the brain as opposed to biochemical signature
In 2017, Brent, along with Carnegie Mellon University neuroscientist Marcel Just and other colleagues, used
functional MRI to image the brains of 34 people as they contemplated words such as “death,” “trouble,” and
“carefree.” Using machine learning algorithms to process the data, the team could distinguish between people
who were thinking about suicide, as self-reported during the study, and those who weren’t with 91 percent
accuracy. Among those who were, the team identi ed people who’d already attempted suicide with 94 percent
accuracy.
The researchers recently received $3.8 million from the National Institute of Mental Health to scale up the
project and are planning long-term monitoring of people with and without various types of mood disorders. A
part of the study, the researchers hope to extend their tool to identify people who might attempt suicide in th
future, not just those who are thinking about it at the time of the scan or who have attempted it in the past. Jus
tells The Scientist that the team also plans to adapt the technique to a cheaper, more clinic-friendly technology
than MRI, such as electroencephalography (EEG).
Melhem says she’s hopeful that combining techniques will improve predictive approaches in the coming year
In 2019, she and colleagues published a model that improved on the accuracy and performance of existing
models to predict suicide attempts based on factors such as the severity and variability of a person’s depressio
symptoms over time. Integrating this sort of easy-to-collect clinical data with biological information from bra
scans or other diagnostic tests should lead to more-accurate predictions, she says.
The search for such tests has important consequences for suicide prevention even beyond their potential to
assess risk. “When we introduce biological markers, just like [for] any other area of medicine, then stigma will
reduced at the level of the patient,” Melhem says. Patients are o en surprised to hear that researchers are
studying the biology underlying suicide “because they’ve been thinking that this is a behavioral aw in their
character, and they feel guilty about it. That’s part of the stigma that we want to break.”
Preventing suicide
Medical professionals consider suicide a preventable public health problem. In the US, agencies such as
the Centers for Disease Control and Prevention and the Substance Abuse and Mental Health Services
Administration oversee initiatives designed to help assess and respond to suicide risk in the general
population, and particularly in communities considered to be at high risk, including among people with
mood disorders, substance abuse problems, or a family history of suicide.
Many nonpro t organizations also work to raise awareness of the problem, fund research on suicide, and
provide resources for people a ected by suicide. Find information about suicide warning signs, treatment,
and other resources at the American Foundation for Suicide Prevention website. For help, call the
con dential, free 24/7 National Suicide Prevention Lifeline at 1-800-273-8255.
Catherine O ord is an associate editor at The Scientist. Email her at co ord@the-scientist.com.
Keywords:
cortisol, depression, HPA, in ammation, mental health, microglia, neurobiology, neuroscience, neurotransmitters, serotonin,
serotonin receptors, stress, stress response, suicide

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27. 12. 2020.

What Neurobiology Can Tell Us About Suicide | The Scientist Magazine®

Home / Archive / January/February 2020 / Features

In 1996, van Heeringen founded the Ghent University

Suicide is as complicated as it is tragic. Suicidal

NEUROBIOLOGICAL PATHWAYS LINKED TO SUICIDE RISK

See full infographic: WEB | PDF

The role of the brain’s stress pathways in suicide

Corticotropin-releasing hormone (CRH) has been found in higher concentrations in the

The e ect of serotonin and other neurotransmitters

See “Antidepressant Approvals Could Herald New Era in Psychiatric Drugs”

See full infographic: WEB | PDF

A potential link to neuroin ammation

While depression is not thought of as an in ammator

See full infographic: WEB | PDF

Tools to predict and prevent suicide

Cortisol tests may help provide predictive power to

Looking beyond stress responses, other groups have

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