22
Series
cortisol, glutamate excess could contribute to the deficit
in neurons reported in people with depression who died
by suicide.
77
Another cause of fewer neurons might be
impairment of trophic effects due to impaired serotonin
transmission via the 5-HT
1A
receptor (less serotonin
release caused by lower firing rates due to greater
autoreceptor expression; less trophic effect in the
hippocampus owing to reduction of
5HT1A
gene
expression by excessive levels of glucocorticoids) and
reduction in brain-derived neurotropic factor (BDNF)
and its receptor TrkB (NTRK2). Studies done in mice and
man show that stress depletes BDNF concentrations in
the brain and blood, and deficits
in the protein have been
noted in the brains of people who die by suicide and the
blood of patients with depression.
78
Researchers are
beginning to discover specific windows of susceptibility
during development of a person that determine the
negative effects of exposure on regional brain volumes.
The hippocampus seems to be most susceptible to
maltreatment in girls when aged 3–5 years, whereas the
prefrontal cortex in women
is affected by abuse that
occurs later in life.
79
Childhood adversity creates diathesis
in early childhood, then in later adolescence and
adulthood stressors trigger suicidal behaviour and major
depression.
Genetic factors might also be involved in the changes
in brain circuitry observed in people who attempt suicide
or die by suicide because brain volume, particularly
volume of frontal lobes, is strongly heritable.
Frontostriatal volumetric changes in people who attempt
suicide are similar to those noted in first-degree relatives
of individuals with a history of fatal or non-fatal suicidal
behaviour.
80,81
Effects of suicide-related genes on regional
brain volumes have been shown in people with mood
disorders, people who die by suicide or attempt suicide,
and individuals without mental illness. For example, an
association between alleles for lower expression of the
serotonin transporter gene
5HTTLPR
and greater
thalamic volumes is noted in people who die by suicide.
82
Other studies report that the same alleles are associated
with impaired connectivity between the prefrontal cortex,
amygdala, and anterior cingulate, including decreased
functional coupling between the amygdala and anterior
cingulate cortex in carriers
of the S allele of
5HTTLPR
,
decreased functional coupling between the amygdala and
perigenual anterior cingulate cortex in S allele carriers,
but more coupling with medial prefrontal cortex, and
abnormalities in white-matter left uncinate fasciculus in
carriers of S or L
G
alleles compared with L
A
allele
carriers.
82–86
These findings could point to a functional
uncoupling between the amygdala and anterior cingulate
cortex in in low-expressing-allele carriers.
Thus, early-life adversity and genetic factors might
increase suicide risk through a moulding effect on brain
circuitry and chemistry involved in reactivity to particular
stressors. However, many questions remain unanswered.
For example, this paper identifies roles for serotonin and
certain brain areas in the diathesis for suicidal behaviour,
but how serotonin system function in childhood, or even
in utero, changes the formation of brain circuits related to
decision making and mood regulation, and thereby, the
risk for suicidal behaviour, is not yet known. Post-mortem
studies done in mice and human brain indicate that
serotonin can regulate neurogenesis, process extension,
and synapse formation, but the way in which this effect
extends to brain regions such as dorsal or ventral
prefrontal cortex, anterior cingulate, and amygdala is not
understood. Imaging studies show thinner cortex and
anterior cingulate in people with depression who attempt
suicide and people with depression who have a family
history of suicidal behaviour than in people without
depression and people with depression but without a
personal or family history of suicide attempts.
81
Lower
blood flow in the dorsal lateral prefrontal cortex predicts
suicide in patients with depression, indicating a
functional outcome of thinner cortex.
87
Such an outcome
is also suggested by increases in risky decision making in
men on a gambling task during inhibition of cortical
function with use of transcranial magnetic stimulation.
88
Examination of the anterior cingulate (which has a role in
decision making during a response inhibition task)
reveals a different activation in adolescents with
depression with a history of suicide attempts when
compared with those without suicide attempt history,
indicating that part of this circuit might differ during
response inhibition.
45
Separate from its trophic effect on brain structures,
serotonin is also a neurotransmitter. Serotonergic neurons
in the dorsal raphe are activated by stress-related stimuli.
68
These neurons control behavioural responses through
bidirectional connections to forebrain structures, crucial
in reactivity to particular stressors (ie, evaluation and
response selection). Figure 2 shows the components of
the serotonergic brain circuitry involved in this reactivity,
in which post-mortem and neuroimaging studies have
shown changes in association with suicidal behaviour.
Through changes to the firing rate of serotonin neurons,
the medial prefrontal cortex regulates serotonergic
innervation of the circuitry. Potential outcomes of
serotoninergic disturbances in this circuitry include the
overvaluation of social signs of rejection, deficiencies in
control of emotional responses (ie, emotional pain), and
the low number of choices in the decision-making
process. Serotonergic genes modulate crucial components
of this process in people who attempt suicide.
89
From symptom control to management of risk
Susceptibility to suicidal behaviour and risk assessment
Prevention of suicide needs not only the adequate
management of suicide risk as a symptom of an acute
psychiatric disorder such as major depression, but also
the treatment of the underlying and enduring
susceptibility to suicidal behaviour. With regard to acute
situations, identification of predisposition to suicidal
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