01/02.2020 | THE SCIENTIST 33© ISTOCK.COM, LOFTYSTYLE
suicidal controls.^5 And one meta-anal-
ysis published a few years ago found
a positive correlation between corti-
sol levels and risk of suicide attempt in
studies of people under 40 years old,
but a negative correlation in studies of
older people.^6
Until now, “we have not been able
in the literature to capture the dynamic
nature of these pathways in relation to
suicide risk,” says Melhem, adding that
she and colleagues are beginning to
build longitudinal datasets to address
this gap. “It needs a lot more work.”Communication issues
Mann first became interested in the
neurobiology of suicide while studying
a rather different aspect of brain chem-
i s t r y. Throughout the 1980s and ’90s, he
and others found deficits in serotonin
(5-hydroxytryptamine, or 5-HT) signal-
ing and in the neurotransmitter’s main
metabolite, 5-hydroxyindoleacetic acid
(5-HIAA), in the brains of people who
died by suicide, regardless of psychiat-
ric diagnosis, compared with brains of
people with or without psychiatric dis-
orders who had died by other means.
The findings were key in the realiza-
tion that there might be biochemical
changes specific to suicide, Mann says.
Since then, the serotonergic system has
become one of several neuro transmitter
systems being probed for clues about
suicidality.
Like the H PA axis, serotonin signal-
ing appears to be modulated by early-
life adversity. For example, methylation
of HTR2A, which codes for a serotonin
receptor known as 5-HT2A, is altered in
children who have suffered early-life
adversity—although it’s not yet clear
how those methylation changes affect
HTR2A expression.^7 A 2016 study of
twins in the UK revealed that children
who were bullied had hypermethylation
at SERT—a gene coding for a 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 between the serotoner-
gic system and H PA functioning.^8
How such physiological changes
might influence suicidal behavior
remains to be seen, but groups such as
Mann’s 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 psychiat-
ric diagnoses are controlled for, levels of
the serotonin receptor 5-HT1A are corre-
lated with cortisol reactivity to stress.^9
The team has also explored levels of
serotonin receptors in depressed and
nondepressed people exhibiting sui-
cidal behaviors, and found that levels
of 5-HT1A in some regions of the cor-
tex are higher in people who attempt or
die by suicide, regardless of psychiatric
diagnosis, than in controls.10,11
Somewhat counterintuitively, higher
levels of 5-HT1A could contribute to a
deficit in serotonin signaling, Mann
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 antidepres-
sants, he adds: among other effects,
SSRIs reduce the number and respon-
siveness of 5-HT1A receptors and may
thereby quiet the negative feedback loop
that suppresses serotonin signaling.
Neurotransmitters besides sero-
tonin, including glutamate, GABA, and
dopamine, have also been investigated
in the context of suicidal behavior—
particularly following recent findings
that drugs such as ketamine and esket-
amine, which interact with the gluta-
mate receptor NMDAR, reduce suicide
risk in patients with clinical depres-
sion. However, the literature on these
neuro transmitters is fairly inconsistent,
spurring researchers to continue look-
ing for new mechanisms to explain sui-
cidal behaviors.Neural irritation
A couple of years ago, researchers in
Denmark reported a link between sui-
cide and infectious disease. Analyzing
three decades’ worth of health records
from more than 7 million people, the
team found that being hospitalized with
an infection was associated with more
than a 40 percent greater probability
of suicide. Spending more than three
months in the hospital was linked to a
more than doubled suicide incidence.
While acknowledging that such observa-
tional 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.^12There are many possible explanations
for this finding—one being that treatment
of infections with antibiotics or other
hospital medications influences mental
health. But van Heeringen and others
point out that the study ties into another
hypothesis about suicidal behavior, one
that involves a role for inflammation.
Elevated suicide risk has previously
been reported in people with autoim-
mune disorders and traumatic brain
injury—conditions that, like infections,
typically involve inflammation. FurtherIN THE US, AN
AVERAGE OF NEARLY
130 PEOPLE DIE BY
SUICIDE EACH DAY.
Source: CDC, 2017 dataIN THE US, AN
AVERAGE OF NEARLY
DIE BYIN THE US, AN
SUICIDE EACH DAY.
Source: CDC, 2017 data