vesicles, and glia, all of which have been reported to be
abnormal in individuals who die by suicide or who have
mood disorders.
A possible role for polyamine-mediated
apoptosis (so-called programmed cell death) in suscep­
tibility to suicidal behaviour via a neuro­degenerative
reduction of grey-matter volumes has been proposed.
Adversity in childhood might be linked to suicide risk in
adulthood via epigenetic modifications in specific
neurotransmitter systems that cause downstream
modification of brain circuitry involved in mood
regulation and decision making. There is some
disagreement about specific findings, and the molecular
mechanisms that link these factors are not yet clear.
However, results of many studies using various designs
and post-mortem and in-vivo techniques in diverse study
groups indicate important roles for serotonin
transmission, noradrenergic transmission, and the
hypothalamic–pituitary–adrenal axis in the diathesis for
suicidal behaviour.
About 30 years ago, deficits in serotonin function such as
low CSF concentrations of 5-hydroxyindoleacetic acid
(5-HIAA; the major metabolite of serotonin in the brain)
were first associated with suicide attempts in people with
major depression, bipolar disorder, schizophrenia, and
personality disorders in many, but not all, studies. In
parallel, changes were noted in serotonin and 5-HIAA
concentrations in cell bodies of serotonin neurons in the
brainstem of individuals who died by suicide, which was
independent of psychiatric diagnosis.
investigators reported that low 5-HIAA concentration in
CSF predicted the risk of suicide in patients with
depression with an odds ratio of 4·6.
The excess of
serotonin neurons and even serotonin concentrations in
the brainstem of people who died by suicide does not seem
to be reflected in a proportional increase in 5-HIAA
concentrations in cell bodies or in serotonin terminals. In
fact, low 5-HIAA concentrations in the CSF suggest a
deficiency in serotonin release and that the other changes
(more TPH2, more serotonin neurons, less serotonin
transporter binding, etc) are potentially compensatory.
One explanation for this finding is that serotonin
somatodendritic 5-HT
autoreceptors are upregulated, as
noted in post-mortem studies of individuals who died by
suicide and in in-vivo studies of patients with depression.
Such an effect, which might be due to a
promoter polymorphism, would reduce serotonin neuron
firing and result in decreased serotonin release and
signalling. The increase in autoreceptors, perhaps due to a
gene variant, and the resultant lower serotonin release,
might result in homoeostatic upregulation of serotonin
biosynthetic capacity.
Another possibility is that childhood
adversity, or even adult adversity, upregulates the serotonin
system, as occurs in adult rodents when stressed in infancy
(more serotonin neurons) or when stressed in adulthood
(more TPH2 in the raphe nuclei).
There seems to be a deficiency
of noradrenergic
neurons in the locus coeruleus in people who die by
suicide, and low 3-methoxy-4-hydroxy-phenylglycol
(MHPG) con­centrations in the CSF seem to predict risk
of suicide attempts in people with major depression and
the degree of lethality of those suicide attempts.
Childhood adversity in rodents, and possibly also man,
sensitises norepinephrine release in response to a
stressor in adulthood.
Perhaps this excessive
norepinephrine release, when combined with fewer
noradrenergic neurons, is more likely to result in a
depletion of norepinephrine and this is manifested by
lower concentrations of MHPG in the CSF of people at
risk of suicide attempts.
Hypothalamic–pituitary–adrenal axis abnormalities are
known to be related to the risk of suicide, but little is
known of the mechanisms involved and how those
abnormalities can change mood and cognition to affect
suicide risk.
Maternal deprivation in infant rats causes
DNAmethylation of the glucocorticoid receptor, resulting
in less expression, impaired feedback inhibition, and
hence an excessive stress response (release) of cortisol
after adult stress.
Of individuals who died by suicide,
those who reported childhood adversity had more DNA
methylation of glucocorticoid receptor promoter and less
glucocorticoid receptor gene expression in the
hippocampus than did those who did not report
childhood adversity, which might explain why resistance
to dexamethasone (a glucocorticoid receptor agonist)
predicts risk for suicide.
People who die by suicide who
did not report childhood adversity do not differ from
healthy controls without childhood adversity in levels of
hippocampal DNA methylation and expression of
glucocorticoid receptor, indicating that this candidate
biological phenotype of suicide might be part of an
environment-dependent epigenetic pathway.
related to suicide include
a deficit of the glucocorticoid
receptor chaperone protein, FKBP5, impairing trans­
location of glucocorticoid receptor to the nucleus.
Animal studies show that chronic stress can produce this
deficit in FKBP5, which is ameliorated by anti­depressant
Excessive concentrations of cortisol might be
neurotoxic and downregulate 5-HT
receptor expression
in the hippocampus, which might diminish the trophic
effect of this receptor on the brain.
Early-life adversity might affect risk of suicide through
the moulding of neural circuitry. Stress–reactivity
dysregulation with potential cytotoxic effects from
excessive concentrations of increased corticotropin-
releasing hormone and glucocorticoids might have a
role. A deficit of non-neuronal cells might occur, which
could be partly a result of stress during a crucial period of
childhood development.
Since glial cells control the
extracellular concentrations of glutamate through uptake
and glutamate is potentially neurotoxic, when combined
with possible neurotoxic effects of excessively elevated
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