Series

Suicide 1
The neurobiology of suicide
Kees van Heeringen, J John Mann

The stressdiathesis model posits that suicide is the result of an interaction between state-dependent (environmental) Lancet Psychiatry 2014
stressors and a trait-like diathesis or susceptibility to suicidal behaviour, independent of psychiatric disorders. Published Online
Findings from post-mortem studies of the brain and from genomic and in-vivo neuroimaging studies indicate a May 2, 2014
http://dx.doi.org/10.1016/
biological basis for this diathesis, indicating the importance of neurobiological screening and interventions, in
S2215-0366(14)70220-2
addition to cognitive and mood interventions, in the prevention of suicide. Early-life adversity and epigenetic
This is the rst in a Series of
mechanisms might explain some of the link between suicide risk and brain circuitry and neurochemistry three papers about suicide
abnormalities. Results from a range of studies using diverse designs and post-mortem and in-vivo techniques show Unit for Suicide Research,
impairments of the serotonin neurotransmitter system and the hypothalamicpituitaryadrenal axis stress-response Department of Psychiatry and
system in the diathesis for suicidal behaviour. These impairments manifest as impaired cognitive control of mood, Medical Psychology, Faculty of
pessimism, reactive aggressive traits, impaired problem solving, over-reactivity to negative social signs, excessive Medicine and Health Sciences,
Ghent University, Ghent ,
emotional pain, and suicidal ideation, leading to suicidal behaviour. Biomarkers related to the diathesis might help to Belgium
inform risk-assessment procedures and treatment choice in the prevention of suicide. (Prof K van Heeringen PhD); and
Molecular Imaging and
Neuropathology Division,
Neurobiology of suicide: introduction prevention of suicide. Therefore, in this Series paper we
Department of Psychiatry,
Prediction of risk of suicide and identication of describe the neurobiological basis of suicide, and focus Columbia University, NY, USA
treatment and prevention targets beyond major on clinical and cognitive manifestations that might be (Prof J J Mann MD)
psychiatric illnesses are objectives to improve suicide related to impairments in mood regulation and decision Correspondence to:
prevention. Available clinical predictors are scarce and no making, involving serotonergic, hypothalamicpituitary Prof Kees van Heeringen, Unit for
biomarkers have been established to help clinicians to adrenal axis, noradrenergic, and other neurobiological Suicide Research, Department of
Psychiatry and Medical
predict suicidal behaviour or to target with treatment. A abnormalities. Psychology, Faculty of Medicine
proposed stressdiathesis model of suicidal behaviour and Health Sciences, Ghent
describes it to be the result of an interaction between From cells to circuits University, University Hospital,
stressors and a susceptibility to suicidal behaviour Cells Ghent 9000, Belgium
cornelis.vanheeringen@ugent.
(diathesis). The biological correlates of the traitdiathesis Post-mortem studies of people who have died by suicide be
could provide biomarkers for suicide risk that are show changes in several cell types (neurons and glial
distinguishable from biomarkers of co-occurring cells such as astrocytes and oligodendrocytes) in cortical
psychiatric disorders and that might help to predict risk and subcortical areas of the brain. In the brainstem,
after exposure to stressors such as an acute psychiatric suicide seems associated with more serotonin neurons
disorder or adverse psychosocial events.1,2 Although and more tryptophan hydroxylase 2 (TPH2; the rate-
suicidal behaviour is heterogeneous and varies in degree limiting enzyme in the synthesis of serotonin) gene
of intent and amount of clinical damage done, suicide expression and protein per neuron, and possibly higher
deaths and non-fatal but highly lethal suicide attempts serotonin concentrations, compared with individuals
are similar from demographical, clinical, and who have died suddenly from causes other than suicide
neurobiological perspectives, and therefore probably and who did not have a psychiatric illness.8 People with
have a common diathesis (gure 1).3 untreated depression who have died by suicide had fewer
Most people with major psychiatric disorders never mature granule neurons in the hippocampus (specically
manifest suicidal behaviour, indicating the importance in the dentate gyrus) than had people with depression
of diathesis in addition to a disorder. About 50% of the given selective serotonin-reuptake inhibitors before their
risk of suicide due to diathesis is inherited, and this
percentage is possibly higher in women than in men.4,5 Genetics; childhood traumatic Psychiatric disorders;
Epigenetic eects of childhood adversity (eg, life-events events psychosocial adverse events
such as physical or sexual abuse) might also increase an
individuals risk of suicidal behaviour through an eect Diathesis Stress
on their diathesis and an increase in their risk of mood Sensitivity to social stress; Financial or marital problems;
disorders.6 Genetic and epigenetic pathways to suicidal impulsivity; pessimism or exacerbation of psychiatric
hopelessness disorder; emotional pain
behaviour might therefore link genes and the clinical
and cognitive manifestations of biological-intermediate
phenotypes.7 The stressdiathesis model provides an Suicidal behaviour
opportunity to integrate neurobiological phenotypes with
clinical and cognitive perspectives in the study and Figure 1: The stressdiathesis model of suicidal behaviour

www.thelancet.com/psychiatry Published online May 2, 2014 http://dx.doi.org/10.1016/S2215-0366(14)70220-2 1

 Series
death by suicide or had people without a psychiatric
disorder who died a sudden death that was not due to
suicide. In parallel, in people with depression who died
by suicide, the volume of the dentate gyrus is smaller,
and there is less angiogenesis, in people not treated than
in those who were treated before death.9 In the
noradrenergic system, there seems to be a deciency of
noradrenergic neurons in the locus coeruleus of people
who have died by suicide compared with individuals
without psychiatric disorders who have died a sudden
death.10 In mood disorders, three patterns of
morphometric cellular changes are notedcell loss
including loss of glia (in the subgenual prefrontal cortex),
cell atrophy or lower neuronal density (dorsolateral
prefrontal cortex and orbitofrontal cortex), and increased
numbers of serotonin cells (dorsal raphe nucleus).11
Circuits
Neuroimaging studies link brain circuitry and localised
changes in neurochemistry to mood regulation, reactive
aggression, and decision making components of the
diathesis. Functional MRI allows imaging of activity in
certain brain regions, and use of molecular neuroimaging
techniques can quantify specic neurotransmitter
systems in people who have attempted suicide but not
died and compare them with those in control individuals
with psychiatric disorders to investigate directly the
diathesis for suicidal behaviour.
Most molecular imaging studies have focused on the
serotonin system. Two brain regions, one in the anterior
cingulate and medial prefrontal cortex, and one in the
lateral prefrontal cortex, were shown to have activity that
was correlated with lethality (degree of medical injury
sustained as assessed with the Beck Medical Damage
Scale) of suicidal behaviour in people with major
depression. This relation, as measured by relative
F-uorodeoxyglucose (FDG) uptake on PET, was
mediated by degree of suicidal intent (positive correlation
between degree of intent and medical injury due to the
attempt) and severity of impulsive trait (negative
correlation between impulsivity and medical injury). The
regional dierence in brain activity between people who
had made high-lethality suicide attempts and those who
had made low-lethality suicide attempts was more
pronounced in individuals given fenuramine, a drug
that causes a robust release of serotonin. Prefrontal
localised hypofunction and impaired serotonergic
responsivity in people who have attempted suicide was
proportional to the lethality of suicide attempts.12 Later
imaging studies showed that the uptake of
C-methyltryptophan (an analogue of the essential
aminoacid tryptophan needed for synthesis of serotonin)
is low in the orbital medial prefrontal cortex of people who
have attempted suicide and in proportion to the degree of
suicide intent.13 PET studies show a decit of serotonin
transporter binding in the serotonin neurons of people
with depression who have attempted suicide compared
2 www.thelancet.com/psychiatry Published online May 2, 2014 http://dx.doi.org/10.1016/S2215-0366(14)70220-2
with those of people with depression who did not attempt
suicide or those of healthy individuals.14,15 This nding is
similar to that of the decit in serotonin-transporter
expression and binding reported in post-mortem studies
of people who have died by suicide. Conversely,
investigators have noted higher brainstem 5-HT1A binding
in people with depression who have attempted suicide,
which was greatest in people who had higher intent and
did more medical damage. These ndings are consistent
with lower transporter binding and higher 5-HT1A binding
in the prefrontal cortex and brainstem people who have
died by suicide.16 Two studies showed no dierence in
dopamine-transporter binding between people who
attempted suicide and control individuals with depression,
but more studies of other neurotransmitter systems are
needed in relation to suicidal behaviour.17,18
A further molecular imaging study investigated brain
activity associated with the emotional pain of major
depression that might lead to suicide.19,20 Greater
emotional pain in individuals with depression was
associated both with risk of suicide and with changes in
activity in several brain areas, including the dorsolateral
prefrontal cortex and the inferior frontal gyrus.20 Thus,
despite the limited anatomical distribution of tracer
targets and insucient sensitivity to quantify the
receptors in all of the brain regions where they are
present, molecular imaging studies have begun to
identify the neural circuitry of suicidal behaviour, and
particularly, to implicate an abnormal serotonin system
in more lethal suicidal behaviour.
Imaging studies have explored further with use of MRI
the neural circuitry of individuals who show non-fatal
suicidal behaviour (tables 1 and 2).21 Structural ndings
(table 1) include mainly right-sided decits in volumes of
grey matter in cortical areas (orbitofrontal, dorsolateral
prefrontal, insula, and superior temporal gyrus) and
basal ganglia (caudate and globus pallidus). The volumes
of thalamus and right amygdala seem to be greater in
suicide attempters. Findings of white-matter hyper-
intensities (particularly periventricularly), increased
bilateral volumes of inferior frontal white-matter tracts
(particularly in the uncinate fasciculus and inferior
orbitofrontal fasciculus), and lower anisotropy in the left
orbitofrontal area and the left anterior limb of the internal
capsule, indicate that there are structural connectivity
impairments linked to suicidal behaviour.
Functional neuroimaging ndings (table 2) associated
with suicidal behaviour include changed reactivity to
several stimuli, noted mainly in bilateral orbitofrontal,
right ventromedial and anterior cingulate, and left
dorsolateral prefrontal cortex areas. Functional
connectivity is decreased between anterior cingulate and
posterior insula, and connectivity increased in a striatal
motorsensory network.
Although the identied structural and functional
correlates of suicidal behaviour could serve many
alternative functions, they are components of brain
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Ahearn et al,22 2001
Ehrlich et al,23 2004
Ehrlich et al,24 2005
Pompili et al,25 2007
Pompili et al,26 2008
Monkul et al,27 2007
Aguilar et al,28 2008
Rsch et al,29 2008
Hwang et al,30 2010
Jia et al,31 2010
Matsuo et al,32 2010
Vang et al,33 2010
Benedetti et al,34 2011
Cyprien et al,35 2011
Spoletini et al,36 2011
Dombrovski et al,37 2012
Mahon et al,38 2012
Nery-Fernandes et al,39 2012
Solo et al,40 2012
Giakoumatos et al,41 2013
Lopez-Larson et al,42 2013
Study population Measurement Main ndings for people who attempted suicide
compared with controls
Disorder People Psychiatric Individuals
who had controls without
attempted (n) mental
suicide (n) illness (n)
Major depression 20 20 0 Grey-matter hyperintensities More subcortical grey-matter hyperintensities
Miscellaneous* 43 110 0 White-matter hyperintensities More suicide attempts among individuals with both major
depression and white-matter hyperintensities
Major depression 62 40 0 White-matter hyperintensities More periventricular white-matter hyperintensities
Major depression 29 36 0 White-matter hyperintensities More white-matter hyperintensities
and bipolar disorder
Major depression 44 55 0 White-matter hyperintensities More periventricular white-matter hyperintensities,
and bipolar disorder similar deep white-matter hyperintensities
Major depression 7 10 17 Regions of interest: orbitofrontal Lower volume of bilateral orbitofrontal cortex and right
cortex, anterior cingulate cortex, amygdala
amygdala, hippocampus
Schizophrenia 13 24 0 Voxel-wise grey-matter density Lower density in left orbitofrontal cortex and superior
temporal gyrus
Schizophrenia 10 45 55 Whole-brain voxel-based Higher bilateral volume of inferior frontal white matter
morphometry (uncinate fasciculus and fasciculus orbito-frontalis)
Major depression 27 43 26 Whole-brain voxel-based Lower grey-matter and white-matter volume of
(aged >65 years) morphometry (particularly dorsal medial) frontal and parietal areas
Major depression 16 36 52 Diusion tensor imaging; Lower fractional anisotropy in left anterior limb of
whole-brain voxel-based analysis internal capsule and right lentiform nucleus
Bipolar disorder 10 10 27 Region of interest: corpus callosum No dierences
Adjustment disorder 7 0 6 Region of interest: subcortical Smaller bilateral globus pallidus; smaller right caudate
and major depression volume
Bipolar disorder 19 38 9 Whole-brain voxel-based Lower grey-matter volume of dorsolateral prefrontal
morphometry cortex, orbitofrontal cortex, anterior cingulate cortex,
superior temporal gyrus, parieto-occipital cortex, and
basal ganglia
Major depression 21 180 234 Region of interest: corpus callosum Smaller posterior third of the corpus callosum
Schizophrenia 14 36 50 Region of interest: subcortical Higher volume of right amygdala
volume
Major depression 13 20 19 Regions of interest: basal ganglia Smaller putamen
(aged 60 years) volume
Bipolar disorder 14 15 15 Diusion tensor imaging fractional Lower fractional anisotropy in left orbitofrontal white
anisotropy matter
Bipolar disorder 19 21 22 Region of interest: corpus callosum No dierences
Borderline personality 44 24 0 Region of interest: voxel-based Smaller volume of left insula; high-lethality attempters
disorder morphometry; lethality of suicidal had smaller right superior temporal gyrus, orbitofrontal
behaviour cortex, insula, fusiform gyrus
Psychotic disorders 148 341 262 Grey-matter volumes Lower volume of bilateral inferior and superior temporal
cortices, and left superior parietal, thalamus, and
supramarginal regions, right insula, superior frontal and
rostral middle frontal regions; high-lethality attempters
had smaller left lingual gyrus and right cuneus
Traumatic brain injury 19 40 15 Regions of interest: thalamus Increased thalamic volume; increased fractional
volume; diusion tensor imaging anisotropy in anterior thalamic radiations
fractional anisotropy

*Individuals with mood disorder, psychosis, conduct disorder, or attention decit hyperactivity disorder (plus 10% other).

Table 1: Structural MRI studies done in people who have attempted suicide

circuitry that is involved mainly in reappraisal, mood
regulation, and particularly decision making, more
specically, the prediction of reward and punishment.52
Structural abnormalities might constitute a biological-
trait susceptibility that explains maladaptive responses to
stressors including an acute psychiatric illness or episode
and adverse psychosocial events. Findings from a 2013
meta-analysis of neuropsychological studies indicate an
association between susceptibility to suicidal behaviour
and impairments in cognitive control and decision
making.53 Reports from neuroimaging and neuro-
psychological studies suggest that susceptible individuals

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Study population Measurement Main ndings for people who attempted suicide compared
with controls
Disorder People Psychiatric Individuals
who had controls without
attempted (n) mental illness
suicide (n) (n)
Jollant et al,43 2008 Major depression 13 14 16 Response to Greater reactivity to angry faces in right orbitofrontal cortex; decreased
emotional faces reactivity in right dorsolateral prefrontal cortex
Jollant et al,44 2010 Major depression 13 12 0 Iowa Gambling Task Decreased activation during risky choices in left lateral orbitofrontal
cortex and occipital cortices
Pan et al,45 2011 Major depression 15 15 14 Go or no-go task Dierential activation of right anterior cingulate cortex during
(adolescents) response inhibition
Marchand et al,46 2012 Major depression 6 16 0 Putamen functional Association with striatal motorsensory network
connectivity
Pan et al,47 2013 Major depression 15 14 13 Iowa Gambling Task No dierence during learning in the context of risk
(adolescents)
Pan et al,48 2013 Major depression 14 15 15 Response to Greater reactivity to angry faces in right dorsal anterior cingulate cortex
(adolescents) emotional faces and left dorsolateral prefrontal cortex, decreased functional
connectivity between right anterior cingulate cortex and bilateral
posterior insulae
Dombrovski et al,49 2013 Major depression 15 18 20 Reward prediction Weakened expected reward signal in ventromedial prefrontal cortex
(aged >65 years) (pregenual anterior cingulate cortex)
Fan et al,50 2013 Major depression 27 10 57 Amplitude of low- Amplitude of low-frequency uctuation increased in right superior
frequency uctuation temporal gyrus and decreased in right ventromedial prefrontal cortex
Marchand et al,51 2013 Major depression 7 13 21 Motor-activation Association with functional connectivity in striatal motor circuit
paradigm

Table 2: Functional MRI studies done in people who have attempted suicide

overvalue signs of social rejection, as indicated by hyper-
reactivity to angry faces.43,47 This susceptibility resembles
sensitivity to signals of defeat, which has been formulated
For the Series paper by in cognitive models of suicide.54 The involved brain
OConnor and Nock see circuitry determines the processes that individuals use to
http://dx.doi.org/10.1016/
S2215-0366(14)70222-6
control cognitively which emotions they generate and
then to decide how to deal with these emotions.
Susceptible individuals might experience intense mental
pain that they nd dicult to control. Deciencies in
decision-making processes might restrict the extent of
choices so that suicide might be considered the only way
to stop the intense, unrelenting, emotional pain.53
From causes to pathophysiology
Causes
Stressors such as life events and psychiatric disorders are
important risk factors for suicide, but the diathesis
concept explains why only few individuals exposed to
these stressors will take their own life. Early-life adversity
and epigenetic mechanisms seem to be related to causal
mechanisms for this diathesis.55 Findings from cross-
sectional and longitudinal studies have shown that early-
life adversity is one of the strongest risk factors for
suicide, even after adjustment for other major risk factors
such as psychopathology.56 The experience of repeated
acts of abuse, particularly physical and sexual abuse,
increases risk of suicidal behaviour throughout life.
Epigenetic mechanisms could explain the association
between childhood experiences and reactivity to stressors
in later life, mediated in part by the hypothalamic
pituitaryadrenocortical axis.57
About 50% of the risk for suicide or suicide attempts is
heritable. The specic genes are not conrmed. One
genome-wide study of individuals who had attempted
suicide did not show a signicant link between attempts
and any single nucleotide polymorphism.58 Another
study identied a region within ABI3BP, but this nding
was not replicated in a second cohort.59 Data from a meta-
analysis (8700 individuals with mood disorders)
identied four candidate regions, one of which included
the protein kinase C- (PRKCE) gene.59 Investigators of a
later study did not report any single nucleotide
polymorphisms that reached the traditional p<5 10
threshold for signicance, but when they used gene
expression data from people who died by suicide to
screen their ndings, they identied a cluster of genes
involved in neuroimmune functions.60 A genome-wide
association study of individuals with bipolar disorder
reported an association signal on 2p25 at a threshold of
genome-wide signicance.61
Antidepressant-treatment-emergent suicidal ideation
might reect a susceptibility to suicidal ideation in
individuals, but no reports of genome-wide association
studies have noted any variant associated with it that
reached genome-wide signicance.62 Investigators using
a genome-wide expression prole have identied genes
associated with glutamate and GABA cortical neuro-
transmitters, growth factors, polyamines, synaptic

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vesicles, and glia, all of which have been reported to be
abnormal in individuals who die by suicide or who have
mood disorders.63 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.64
Pathophysiology
Adversity in childhood might be linked to suicide risk in
adulthood via epigenetic modications in specic
neurotransmitter systems that cause downstream
modication of brain circuitry involved in mood
regulation and decision making. There is some
disagreement about specic ndings, 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
hypothalamicpituitaryadrenal axis in the diathesis for
suicidal behaviour.
About 30 years ago, decits in serotonin function such as
low CSF concentrations of 5-hydroxyindoleacetic acid
(5-HIAA; the major metabolite of serotonin in the brain)
were rst 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.8 Subsequently,
investigators reported that low 5-HIAA concentration in
CSF predicted the risk of suicide in patients with
depression with an odds ratio of 46.65 The excess of
serotonin neurons and even serotonin concentrations in
the brainstem of people who died by suicide does not seem
to be reected 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
deciency 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 nding is that serotonin
somatodendritic 5-HT1A autoreceptors are upregulated, as
noted in post-mortem studies of individuals who died by
suicide and in in-vivo studies of patients with depression.66,67
Such an eect, which might be due to a 5HT1A gene
promoter polymorphism, would reduce serotonin neuron
ring 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.67 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).68
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Series
There seems to be a deciency 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.10,69
Childhood adversity in rodents, and possibly also man,
sensitises norepinephrine release in response to a
stressor in adulthood.70 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.
Hypothalamicpituitaryadrenal 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 aect
suicide risk.3 Maternal deprivation in infant rats causes
DNA methylation of the glucocorticoid receptor, resulting
in less expression, impaired feedback inhibition, and
hence an excessive stress response (release) of cortisol
after adult stress.71,72 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.57 People who die by suicide who
did not report childhood adversity do not dier 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.73 Other
hypothalamicpituitaryadrenal axis abnormalities
related to suicide include a decit of the glucocorticoid
receptor chaperone protein, FKBP5, impairing trans-
location of glucocorticoid receptor to the nucleus.74
Animal studies show that chronic stress can produce this
decit in FKBP5, which is ameliorated by antidepressant
drugs.74 Excessive concentrations of cortisol might be
neurotoxic and downregulate 5-HT1A receptor expression
in the hippocampus, which might diminish the trophic
eect of this receptor on the brain.75,76
Early-life adversity might aect risk of suicide through
the moulding of neural circuitry. Stressreactivity
dysregulation with potential cytotoxic eects from
excessive concentrations of increased corticotropin-
releasing hormone and glucocorticoids might have a
role. A decit of non-neuronal cells might occur, which
could be partly a result of stress during a crucial period of
childhood development.57 Since glial cells control the
extracellular concentrations of glutamate through uptake
and glutamate is potentially neurotoxic, when combined
with possible neurotoxic eects of excessively elevated
5
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cortisol, glutamate excess could contribute to the decit
in neurons reported in people with depression who died
by suicide.77 Another cause of fewer neurons might be
impairment of trophic eects due to impaired serotonin
transmission via the 5-HT1A receptor (less serotonin
release caused by lower ring rates due to greater
autoreceptor expression; less trophic eect 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 decits 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 specic windows of susceptibility
during development of a person that determine the
negative eects of exposure on regional brain volumes.
The hippocampus seems to be most susceptible to
maltreatment in girls when aged 35 years, whereas the
prefrontal cortex in women is aected 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 rst-degree relatives
of individuals with a history of fatal or non-fatal suicidal
behaviour.80,81 Eects 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 LG alleles compared with LA allele
carriers.8286 These ndings 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 eect on brain
circuitry and chemistry involved in reactivity to particular
stressors. However, many questions remain unanswered.
For example, this paper identies roles for serotonin and
6 www.thelancet.com/psychiatry Published online May 2, 2014 http://dx.doi.org/10.1016/S2215-0366(14)70220-2
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 eect
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 ow 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 dierent 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 dier during
response inhibition.45
Separate from its trophic eect 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 ring 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, deciencies 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, identication of predisposition to suicidal

behaviour might contribute to the assessment of suicide
risk, and translational results of neurobiological research
are beginning to be realised. Childhood adversity and a
familial history of suicide are associated with a
susceptibility to suicide, and a personal history of non-
fatal suicide attempts might show the existence of such a
diathesis to suicidal behaviour and thus need to be
assessed. This assessment can include measurement of
biological responses to ecologically relevant stimuli
related to mood, suicidal ideation, or emotional pain, and
characterisation of decision-making processes.
Treatment or prevention?
New treatments are emerging from early clinical trials for
the acute management of suicide risk. In the past, a
course of electroconvulsive therapy might have had a
short-term life-saving eect in suicidal patients with
severe or drug-resistant depression. More recently, a
subanaesthetic dose of ketamine was reported to have an
acute antisuicide eect that lasted for about 1 week.90,91
Because of the association between suicidal behaviour and
serotonergic and noradrenergic disturbances, and because
most antidepressant drugs enhance serotonergic or
noradrenergic function or both, an antisuicidal eect
would be expected for these drugs. Direct evidence of such
an eect has not been shown, although one randomised
clinical trial of suicidal patients showed that a selective
serotonin-reuptake inhibitor had a better antidepressant
eect and greater reduction in suicidal ideation than did a
noradrenergicdopaminergic drug, and that this thera-
peutic advantage is greatest in patients with the most
severe suicidal ideation.92 A prosuicidal eect for anti-
depressant drugs in younger adults, adolescents, and
children, for which direct evidence was scarce, seems less
likely after ndings from recent studies.9396 The probability
of serotonergic antidepressant drugs having benecial
eects is supported by the discovery of plausible
underlying neurobiological mechanisms. Mouse studies
show that stress impairs neurogenesis in the one locus in
the human brain in which adult neurogenesis takes
placethe dentate gyrus of the hippocampus. In mice,
this eect can be blocked or corrected by giving them a
selective serotonin-reuptake inhibitor and is partly
mediated via hippocampal 5-HT1A receptors.97 Findings
from post-mortem studies of the human brain conrm
that neurogenesis takes place in adulthood and that it
might have been enhanced in individuals with depression
who were treated with a selective serotonin-reuptake
inhibitor shortly before their death.9
Investigators have also debated the eects of mood
stabilisers, lithium, and antipsychotic drugs on risk of
suicidal behaviour. The possibility that antiepileptic drugs
have adverse eects on risk of suicide might have been
overestimated.98 A large amount of evidence now exists
that lithium reduces the risk of suicide and non-fatal
suicidal behaviour.99 In addition to its serotonin-
enhancing eects, lithium has antiapoptotic eects, and
www.thelancet.com/psychiatry Published online May 2, 2014 http://dx.doi.org/10.1016/S2215-0366(14)70220-2
Series
Medial prefrontal cortex and
anterior cingulate cortex
Orbitofrontal cortex Dorsolateral prefrontal cortex
Insula
Ventral and dorsal Inferior parietal cortex
Striatum
Ventral and dorsal
Globus pallidus,
substantia nigra
pars reticulate
Thalamus
Dorsal raphe
Figure 2: Regions shown in neuroimaging and post-mortem studies to have structural or functional changes
associated with suicidal behaviour
Dotted lines indicate cortical-to-cortical connections; blue lines and arrows indicate the serotonergic pathways
from the dorsal raphe. Adapted from Tanaka and colleagues,52 with permission from Macmillan Publishers.
its use in long-term treatment might be associated with
increased grey-matter volume, eects that might decrease
suicide risk.34 Clozapine is an antipsychotic drug that
blocks D2 and 5-HT2A receptors and, in patients with
schizophrenia, it has a protective eect against suicidal
behaviour compared with olanzapine.100 The antisuicidal
eects of lithium are independent of its eectiveness as a
mood stabiliser and the antisuicidal eect of clozapine is
independent of its eectiveness as an antipsychotic drug.
Therefore, both drug types could exert their antisuicidal
eect on some aspect of the diathesis.
The future
Since clinical predictors of suicide risk have poor
eectiveness, genomics and brain imaging are the most
promising new directions for detection of patients at
high risk for suicide. Because serotonergic abnormalities
can be detected in living patients, brain imaging might
help to identify people at risk of a more lethal suicide
attempt or suicide. Suicide prevention depends on
detection of such patients. Since a third of people who
die from suicide die from their rst attempt, the aim for
prevention is to detect these patients before any attempt
is made. Neuroimaging could delineate brain regions
and networks involved in suicide risk and could be a way
to track the eect of interventions, which target such
specic brain regions and neural networks. Given the
association between biochemical disturbances and
lethality of suicidal behaviour, further studies might
7
 Series
Search strategy and selection criteria
We searched Medline for articles published in English from
Jan 1, 1990, to Dec 31, 2013, with the term suicide and
neurobiology, genetics, and neuroimaging. We selected
mainly articles published in the past 5 years, but we did not
exclude frequently referenced and highly regarded older
articles. We also searched the reference lists of articles
identied with use of this search strategy and chose papers
that we judged to be relevant. We also considered articles
suggested by the peer reviewers. We cited review articles due
to space considerations.
subclassify suicidal behaviour in terms of lethality
and intent. Imaginggenetic approaches, combining
genomic study (eg, of serotonergic, glutaminergic,
GABAergic, neurotrophic and apoptotic systems) and
neuroimaging, might help to elucidate the association
between circuitry-related changes and gene function and
suicidal behaviour. Techniques for comprehensive
mapping of the functional connectomeie, detailed
maps of complex neural systemsare now available to
study genetic eects on brainbehaviour associations.
High-throughput resting-state functional MRI could
provide quantitative phenotypes for molecular genetic
studies and biomarkers of developmental and
pathological processes in the brain. Machine-learning
techniques might enable the combined use of inform-
ation from such neuroimaging techniques, genomics,
and from medical non-image records for assessment,
determining prognosis of individual patients.
New approaches for prevention include repetitive
transcranial magnetic stimulation directed at the
dorsolateral cortex to modify functional activity in the
orbitofrontal cortex, which might aect decision-making
processes to decrease the likelihood of risky decisions and
protect against suicide. Novel psychopharmacological
compounds that might reduce susceptibility to suicidal
behaviour include drugs that aect the hypothalamic
pituitaryadrenal axis, neuroprotective factors, and
ketamine-like drugs. Genomic markers and neuroimaging
might identify patients at high risk of suicide and help to
identify personalised interventions for the prevention of
suicidal behaviour.
Contributors
We both planned, wrote, and edited this Series paper and we take joint
responsibility for its contents.
Declaration of interests
JJM receives royalties for commercial use of the Columbia Suicide Severity
Rating Scale from the Research Foundation for Mental Hygiene and has
stock options in Qualitas Health. KvH has no competing interests.
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