32 THE SCIENTIST | the-scientist.com
THE SCIENTISTSTAFFago,” 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 complexity
of the problem, understanding the neuro-
biology, understanding the causes.”Pressure points
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 dis-
covered, she had a family history of sui-
cide—a known risk factor for suicidal
behaviors, independent of any psychi-
atric 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 “diathe-
sis”—such as family history, particular
genetic variants, or early-life adver-
sity such as abuse or neglect. “Suicide
is more than... being very depressed,”
explains Colum bia University’s John
Mann, a psychi atrist and translational
neuroscien tist who helped develop the
conceptual framework with Columbia
neurobiolo gist Victoria Arango.This framework has helped focus
research on biochemical pathways that
regulate the brain’s response to stress,
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 sui-
cide is the hypothalamic-pituitary-
adrenal (HPA) axis, which controls the
release of the stress hormone cortisol
and is known to be upregulated in clin-
ical depression.
Early clues regarding the link
between the H PA axis and suicide
include findings of higher concen-
trations of corticotropin-releasing
hormone (CRH), which triggers the
synthesis of cortisol and other glucocor-
ticoids 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 adre-
nal glands—sites of cortisol production.
Due to the high incidence of depression
and other mood disorders among peo-
ple who end their own lives, however,
studies such as these didn’t attempt to
determine whether the observed effects
were specific to suicide or to mood dis-
orders more generally.
More recently, the case for a cen-
tral role for the H PA axis in suicide
has gained support from work led by
Turecki and others revealing that early-
life adversity, one of the strongest risk
factors for suicide even when psychi-
atric disorders are controlled for, can
have long-term effects on H PA axis
function. In the mid-2000s, Turecki
teamed up with McGill University
geneticist Moshe Szyf, who had shown
that rats neglected by their mothers
exhibit altered epigenomes in the hip-
pocampus—a brain region involved in
stress, learning, and memory—and dys-
functional H PA responses to stress.^1 In
the hippocampi of people who have died
by suicide and had a history of child-
hood abuse, Turecki, Szyf, and their col-
leagues found evidence of hypermeth-
ylation and reduced expression of thegene coding for NR3C1, a glucocorti-
coid receptor that helps dampen cor-
tisol signaling, compared with healthy
controls or people who died by suicide
but hadn’t experienced abuse.^2
Research since then has linked sui-
cidal behaviors to methylation abnor-
malities in other HPA-related genes.
One 2018 assessment of nearly 90 peo-
ple who had attempted suicide identi-
fied reduced methylation at the CRH
gene in blood samples from some of the
study’s subjects—specifically, those who
made attempts that were more violent
or more likely to result in death.^3 And
several studies have identified hyper-
methylation 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 H PA
axis and suicidal behavior is compli-
cated. For example, while some studies
imply that the H PA axis overreacts to
stress in people who die by suicide, oth-
ers indicate that people who attempt sui-
cide have lower baseline cortisol levels
and/or blunted H PA reactivity to stress
compared with controls. “It is a confus-
ing literature,” says Nadine Melhem, a
psychiatric genetic epidemiologist at
the University of Pittsburgh School of
Medicine who found a few years ago
that, among around 200 people whose
parents had mood disorders, those who
attempted suicide had overall lower H PA
activity.^4 “Almost every [possible] find-
ing has been reported.”
Part of this inconsistency likely
stems from small study samples and
variations in experimental design, Mel-
hem notes. But variability may also
come from differences in the drivers
of suicidal behavior in different groups
of people. Mann’s group reported last
year that, of 35 people who attempted
suicide, only those who scored highly
for impulsive aggression in personality
tests had significantly elevated cortisol
responses to stress compared with non-IN THE US, MORE THAN
3.5 TIMES AS MANY
MEN AS WOMEN DIE
BY SUICIDE.
Source: American Foundation
for Suicide Prevention, 2017 dataIN THE US, MORE THAN
3.5 TIMES
MEN AS WOMEN DIESource: American Foundation
for Suicide Prevention, 2017 dataMEN AS WOMEN DIE
BY SUICIDE.
Source: American Foundation
for Suicide Prevention, 2017 dataIN THE US, MORE THAN
3.5 TIMES
MEN AS WOMEN DIE
BY SUICIDE.IN THE US, MORE THAN
AS MANY
MEN AS WOMEN DIE
BY SUICIDE.3.5 TIMES AS MANY
MEN AS WOMEN DIE