The neuroscience of suicidal behaviors: what can we
expect from endophenotype strategies?
P Courtet1, II Gottesman2,3, F Jollant4and TD Gould5
Vulnerability to suicidal behavior (SB) is likely mediated by an underlying genetic predisposition interacting with environmental
and probable epigenetic factors throughout the lifespan to modify the function of neuronal circuits, thus rendering an individual
more likely to engage in a suicidal act. Improving our understanding of the neuroscience underlying SBs, both attempts and
completions, at all developmental stages is crucial for more effective preventive treatments and for better identification of
vulnerable individuals. Recent studies have characterized SB using an endophenotype strategy, which aims to identify
quantitative measures that reflect genetically influenced stable changes in brain function. In addition to aiding in the functional
characterization of susceptibility genes, endophenotypic research strategies may have a wider impact in determining
vulnerability to SB, as well as the translation of human findings to animal models, and vice versa. Endophenotypes associated
with vulnerability to SB include impulsive/aggressive personality traits and disadvantageous decision making. Deficits in
realistic risk evaluation represent key processes in vulnerability to SB. Serotonin dysfunction, indicated by neuroendocrine
responses and neuroimaging, is also strongly implicated as a potential endophenotype and is linked with impulsive aggression
and disadvantageous decision making. Specific endophenotypes may represent heritable markers for the identification of
vulnerable patients and may be relevant targets for successful suicide prevention and treatments.
Translational Psychiatry (2011) 1, e7; doi:10.1038/tp.2011.6; published online 10 May 2011
The increased use of pharmacological treatments for psy-
chiatric diseases over the previous decade has had limited
effect on decreasing the overall rates of attempted and
completed suicides.1Thereis a pressingpublic health need to
revisit existing strategies and notably to promote preventive
action specifically directed toward those most at risk for
suicide. To achieve this goal, suicide prevention strategies
require the identification of at risk individuals, and the
development of specific and targeted interventions for those
individuals, independently of any coexisting psychiatric
The term suicidal behavior (SB) refers to a heterogeneous
outcome of suicide attempts and suicide completions.2
Support for SB as an entity is multifold. Although it is well
known that the nature of a suicidal act (suicide attempt or
completed suicide) may be influenced by gender, age,
availability of a lethal mean and specific suicidal dimensions,
such as suicidal intent and medical lethality, these behaviors
seem to have more in common and are often distinguished
namely, suicidal ideation. The clinical profiles of suicide
attempters and completers overlap.3In addition, previous
of the suicidalprocess,
suicide attempt is an important predictor of future suicide.4
attempts and completed suicides may share a common
genetic basis.5Furthermore, there is limited support that
suicidal thoughts run in families, or that they are predictive of
suicide attempts or completions within families.6Finally,
suicide attempts and suicide completions share many
An historic turning point in suicidology resulted from the
demonstration that psychobiological abnormalities are asso-
ciated with vulnerability to SB, independently of co-occurring
psychiatric disorders.7On the basis of cumulative results, a
general model has been proposed postulating that vulner-
ability to SB is mediated in part by an important underlying
genetic predisposition interacting with environmental and
probable epigenetic factors throughout the lifespan; this
combination of risk factors then modifies the function of
neuronal circuits, thus rendering an individual more likely to
engage in a suicidal act.9,10A number of identified biological
impairments are coincident with personality traits related to
impulsivity, aggression, neuroticism or hopelessness, which
confer vulnerability to SB that is expressed in the context of
aversive life events.11–13
Received 22 March 2011; accepted 23 March 2011
1Department of Emergency Psychiatry, CHRU Montpellier, Inserm U1061, University of Montpellier I, Montpellier, France;2Department of Psychiatry, University of
Minnesota Medical School, Minneapolis, MN, USA;3Department Psychology, University of Minnesota, Minneapolis, MN, USA;4Douglas Mental Health University
Institute, McGill Group for Suicide Studies, McGill University, Montreal, Quebec, Canada and5Departments of Psychiatry, and Pharmacology and Experimental
Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA
Correspondence: Dr TD Gould, Department of Psychiatry, and Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Room 934D
MSTF, 685 West Baltimore Street, Baltimore, MD 21201, USA.
Keywords: animal models; biomarker; decision making; emotions; orbitofrontal cortex; suicide
Citation: Transl Psychiatry (2011) 1, e7, doi:10.1038/tp.2011.6
& 2011 Macmillan Publishers Limited All rights reserved 2158-3188/11
These ideas about SB further stimulate research aimed at
identifying the etiological factors and their effects on the
processes of brain and psychological development, leading to
a better understanding of the pathophysiology and phenom-
enology of SB. Hopefully this will help to create tools for the
early detection of SB and new strategies for targeted
prevention. With this aim in mind, the search for endopheno-
types represents a valuable emerging strategy for the
identification of susceptibility genes and should improve
insight into relevant biological systems, sub-classification of
patients and treatment approaches.14,15
The endophenotypic approach
Endophenotypes were originally described as internal phe-
notypes that mediate on the path between genes and the
diseases genes moderate.16,17Their fundamental relevance
was related to, but not necessarily dependent on, the
assumption that endophenotypes represent less complex
clues to genetic underpinnings than the disease syndrome
itself, promoting the view that psychiatric diagnoses can be
successful genetic analysis.17,18
The most commonly accepted criteria for a genetically
influenced endophenotype include trait identification in an
objective and quantitative manner in patients before onset of
the disorder and/or periods of remission. State independence
or longitudinal stability should be further established in
longitudinal studies with repeated measures. Finally, epide-
miological studies should be examined to determine whether
the endophenotype co-segregates with SB in family members
and is also found in non-affected family members at a higher
rate than that in the general population. The endophenotype
should therefore run in families and be associated with an
increased risk of clinical illness. Such criteria are useful to
distinguish endophenotypes from biological markers; the
latter meet few of the above mentioned criteria and for this
reason would likely not direct clinical research in psychiatry
toward genetically meaningful conclusions. Our armamentar-
ium used to assess endophenotypes includes, though is not
limited to, neurophysiological, biochemical, endocrinological,
neuroanatomical/imaging, cognitive and neuropsychological
As a heuristic model, one can consider a cascade from
the studied phenotypic syndrome to the genes, with different
levelsof analysis: syndrome-mediating
self-report measure/clinical interview; laboratory behavioral
task performance; cognitive task performance; psychophy-
neurochemical imaging; postmortem neurochemistry, cell
structure, mRNA expression; genotype.19These complemen-
tary approaches, when used in the identification of endophe-
notypes for SB may provide convergent validity for the most
promising endophenotypes,17,19–21while noting that predict-
ing rare events such as SB (especially completed suicides)
adds to the difficulties of such research.22,23
It is known from twin studies that genetic susceptibility
factors, independent of an additional psychiatric diagnosis,
modify the risk of SB.6,24,25Therefore, it is probable that
genetically delineated endophenotypes exist that are asso-
ciated with such behaviors.14,26Although there are many
potential endophenotypes that are associated with SB,27
we selectively provide a brief review of some associations
(Figure 1). As reviewed previously, additional putative
endophenotypes may be considered for further researches.14
Specific psychiatric disorder
early onset major depressive disorder) and personality
dimensions or disorders (for example, borderline personality
disorder) have also been linked to SB.14Few of the reported
alterations fulfill the complete definition of an ideal endophe-
notype. As such, a majority of the studies reported below
should be seen as promising, but not yet definitive, areas of
subtypes (for example,
ciations between suicide and personality measures are with
indicators of aggression and impulsivity, which meet most, if
not all, stringent endophenotype criteria (as detailed in Mann
et al.14and Kovacsics et al.28). These endophenotypes can
be readily quantified using self-report data from suicide
attempters and their relatives, or by psychological autopsy
methods.12,14Impulsivity and aggression are related and
many studies have also examined ‘impulsive aggression’ in
populations with SBs. Specifically, a number of studies have
found that both impulsivity and aggression meet criteria for
endophenotypes such as being heritable, associated with
suicide, state independent and co-segregating with SB in
families.29–33The data suggesting that aggression and
impulsivity are valid candidate endophenotypes of SB
include case–control, retrospective (psychological autopsy),
prospective longitudinal and family studies.32,34Laboratory
assessments of impulsive aggression may be more reliable
than clinical assessments, promoting the use of neuro-
psychological tools.14It is a promising approach to move
from personality dimensions defined at the complex level of
the psychopathology derived from self or clinician reports, to
more subtle traits with presumably more precisely definable
neurobiological underpinnings. Neuropsychological tools may
help to avoid the pitfalls related to the use of personality
dimensions, yielding ‘stronger’ endophenotypes.35Although
there is overwhelming evidence to support the role of
impulsive–aggressive behaviors in suicide, not all suicides
are mediated by impulsive–aggressive behaviors. Thus,
subgroup of patients with SB, and there remain a number of
other vulnerability factors.
Disadvantageous decision making. Decision making, as
quantitatively defined in the Iowa gambling task36that
compares choosing between disadvantageous choices for
which a lot of money is won but even more is lost (resulting in
a net loss) and advantageous choices where less is won
but even less is lost (resulting in a net gain), shows
associations with SB. A significantly higher tendency
toward disadvantageous choices was found in patients with
a history of SB compared with patients without any such
history and to healthy controls.37Patients were euthymic at
the time of assessment, suggesting a trait, rather than state,
finding. This impairment was not related to comorbid axis-I
disorders.37Similar alterations in suicide attempters were
Endophenotypes of suicidal behaviors
P Courtet et al
recently reported in patients suffering from major depressive
disorder,38bipolar disorder39,40and also in self-harming
Most recently, disadvantageous decision
making was found deficient in elderly suicide attempters
versus elderly suicide ideators, non-suicidal depressed and
non-depressed subjects in a reward/punishment-based
task.42Although decision making has not been formally
studied in relatives of suicide attempters/completers, one
study reported decision-making alterations in unaffected
relatives ofalcoholics suggesting
dysfunction may be heritable.43Jollant et al.44reported that
genetic polymorphisms previously associated with SB
includingthe serotonin transporter
(5HTTLPR), tryptophan hydroxylase 1, and monoamine
oxidase A modulated the learning process necessary in the
Iowa gambling task for making advantageous choices in
suicide attempters. The 5HTTLPR association has also been
confirmed in an obsessive-compulsive disorder population45
and in healthy individuals.46
that this cognitive
Altered skin conductance. An association has been found
(hyporeactivity), as measured by skin conductivity, and SB in
several studies (see Thorell47for meta-analysis). Moreover,
electrodermal activity during decision making seems to implicate
key brain regions associated with SB (see below), such as the
ventral and medial prefrontal cortices.48Electrodermal reactivity
is under genetic influence, with a heritability of B50% in healthy
twins,49and is state independent.50In addition, an electrodermal
response has been correlated with decision making in the Iowa
gambling task in healthy subjects.51
physiological hyporesponsivity may be an endophenotype
partially linked with poor decision-making abilities.
Neuroimaging. At the neuroanatomical level, postmortem
studies have implicated involvement of the prefrontal cortex,
particularly themost ventral
orbitofrontal cortex.52These regions have been reported to
be different from controls in structural neuroimaging studies
regions including the
genes and regions
genetic,epigenetic and environmental factors that produce cumulative liability to suicidal behaviors. Although attempted suicide does not always predate a completed suicide
unmentioned here because of our focus on genetic and neurobiological correlates. Similarly, there are many gene loci, genes and candidate endophenotypes that were
not included because of the conceptual limitations of this Figure. Modified from Kovacsics et al.28See the following reviews for additional discussion: refs 7, 12, 14, 25, 28,
96–98. r II Gottesman and TD Gould and used with permission.
Candidate gene regions, genes and endophenotypes implicated in suicide research. The upper portion of the figure indicates the dynamic interplay among
Endophenotypes of suicidal behaviors
P Courtet et al
Pharmacological neuroimaging studies have highlighted the
particular importance of the prefrontal cortex. Two studies
showed reduced prefrontal 5HT2A receptor binding in
SB.54,56Cannon et al.57found increased binding of the
serotonin transporter in the anterior cingulate gyrus of bipolar
patients with a history of suicide attempts compared with
those without a past history of attempts. Finally, Leyton
tryptophan in the ventral and lateral prefrontal cortex of
high-lethality suicide attempters compared with healthy
controls. These findings support the idea that altered
serotonergic modulation may modulate prefrontal cortex
dysfunctions, though their genetic basis is unclear.
Using functional neuroimaging, previously depressed male
suicide attempters, in comparison with previously depressed
male patients with no history of suicide attempts, were found
to have higher activation of the right orbitofrontal cortex in
response to viewing angry versus neutral faces.59This
activation was not found when happy faces were presented.
Of note, all patients were euthymic at the time of scanning. It
was hypothesized that patients with a vulnerability to SB may
have a particular sensitivity to rejection and disapproval
(expressed by angry faces), modified by orbitofrontal cortex
dysfunction. Other findings suggest lower activation of the left
lateral orbitofrontal cortex in suicide attempters versus non-
attempters during risky versus safe choices as measured in
the Iowa gambling task.60Decision-making impairment in
suicide attempters is therefore associated with the decreased
ability of these patients to correctly learn to recognize long-
term risk in uncertain situations.
Positron emission tomography imaging has shown that
there is reduced activation of the medial prefrontal cortex in
high versus low lethality suicide attempters,61a difference
accentuated by fenfluramine, a serotonergic agonist. This is
consistent with the reproduced finding that the prolactin
response to fenfluramine is decreased in individuals with a
past history of SB.62,63In addition, activity in these brain
regions was associated with intent and lethality of a previous
suicidal act.61See Jollant et al.64for a more complete review
of neuroimaging findings.
Previous studies in other populations combining neuroima-
ging and genetics suggest that the brain regions involved in
vulnerability to SB are modulated by genetic polymorphisms
previously associated with SB. For instance, the 5HTTLPR
variant known to regulate expression of the 5HT transporter
was found to modulate activation of the medial prefrontal
cortex and amygdala during the resting state,65and the
amygdala or amygdala–prefrontal coupling during aversive
The findings described above suggest that neuropsycholo-
gical, neurophysiological and neuroimaging alterations may
represent valuable endophenotypes in SB (Figure 1), but with
the exception of impulsive aggression do not currently meet
stringent endophenotype criteria including heritability, state
independence and familiar aggregation both in affected and
unaffected relatives. Altered cognitive and emotional pro-
cesses, modulated by specific genetic polymorphisms, were
found in patients, even in the euthymic phase. These
alterations may decrease the ability of some individuals to
different populations ofsuicide attempters.53–55
respond with resilience to life stressors or facilitate acting on
emerging suicidal ideas. A number of other potential
endophenotypes for SB exist as well, including hypothala-
mic–pituitary–adrenal axis hyperfunction.10,68
Future directions, including animal model approaches
to study the neurobiology of SB
Future areas of research should include the simultaneous
assessment of cognitive and emotional functions, neural
activation and genetic polymorphisms, structural and func-
tional connectivity, and pharmacological studies with different
ligands. The biological differences between men and women
vis-a `-vis SB should be investigated, as well as the effects of
age (adolescents, adults and elderly). Moreover, a practical
model should be developed that includes a correlation
betweencognitive and neuroanatomical
and the various steps of the suicidal process comprising
psychological pain, suicidal ideation and the suicidal acts
A major advantage of the endophenotype approach is that
the neurobiology underlying SB may be translated success-
fully from humans to other species.68Animal models or tests
are designed to reproduce some aspect of the disease, rather
than the disease itself, thereby excluding dubious anthro-
pomorphizing. Thus, although SB per se will never be
modeled in non-human animals, it may be possible to
reproduce some aspects of the underlying neurobiology.
Approaches used to validate animal models or tests can be
grouped into three categories: face validity (do animals
behave similar to humans who have the illness), construct
validity (do processes that result in human pathology also
result in the abnormal animal behavior) and predictive validity
(is the model responsive to effective medications).70–72A
successful example can be taken from schizophrenia re-
search. Modeling endophenotypes such as impaired prepulse
inhibition and impaired working memory in rodents has been
successful in schizophrenia research, in regards to under-
standing the neurobiology underlying the disease, assessing
thefunctionofrisk alleles, andindeveloping noveltherapeutic
approaches. However, just as it is not possible for rodents to
be ‘psychotic’, it is not possible for a mouse to be ‘suicidal’.
Indeed,itis notpossible to developanimal modelswith face
validity to human suicide. However, construct-valid ap-
proaches including those reliant on neurobiology, genetics
and in particular endophenotypes, such as those discussed in
this review, can be used.28,73,74Some examples would be the
behavior of mice in tests that assess their decision-making
process, or levels of impulsive aggressive behavior, for
example, a rodent version of the Iowa gambling task exists
where the profile in choice behavior retains many of the key
characteristics of the human task.75,76Serotonin transporter
levels have been shown to modulate long-term decision
making in this task in the rat (as it has been previously shown
in humans)77and Iowa gambling task impairment has been
associated with a decrease in 5-HIAA levels in the orbito-
frontal cortex in a rat chronic pain model.78The proposed link
betweenthis main metabolite of serotonin, orbitofrontal cortex
function and decision making is significant, as deficiencies in
these three parameters are implicated in suicide vulnerability.
Endophenotypes of suicidal behaviors
P Courtet et al
Drugs with recognized antisuicidal or prosuicidal effects
provide a mechanism to assess the predictive validity of a
potential model. In this regard, extensive evidence indicates
that lithium is effective in the prevention of suicide in patients
with mood disorders.28,79–81Administration of lithium, com-
pared with drugs equally effective at stabilizing mood, but less
effective at reducing the risk of suicide such as valproate79,82
Interestingly, lithium was found to modify activation of the
orbitofrontal cortex in pathological gamblers.83The endophe-
notypic approach may be useful for the identification of
potential mechanisms underlying the antisuicidal effect of
Relevance and limits of the endophenotypic approach
There have been many discussions about the most appro-
priate criteria for evaluating the validity of potential endophe-
notypic markers; some of these criteria are widely accepted,
whereas others are more controversial.17,85,86Other terms
such as ‘intermediate phenotype’ or ‘biological marker’ are
sometimes used interchangeably, whereas they differ in their
meanings; endophenotypes include the idea that a heritable
quantitative phenotype is closer in the chain of causality to the
genes underlying the disease, but the latter terms do not
necessarily reflect genetic underpinnings, and a minority of
the too casual use of non-valid endophenotypes, which would
lead to invalid genetic studies and disappointments in
In a recent heuristic, paper Flint and Munafo85performed
severalmeta-analysesaimedatexamining thebasic assump-
tion that effect sizes of genetic loci contributing to endophe-
notypes are larger than those contributing to disease
susceptibility. By investigating several neuropsychological
and schizophrenia, the authors concluded that the genetic
basis for potential (cognitive) endophenotypes might be as
genetically complex as the related psychiatric disease. This
idea is close to the concept of fractality or scale invariance, in
which the shapes remain complex irrespective of the scale.88
However, faced with psychiatric disorders, including SB,
characterized by a high level of complexity, the endopheno-
typic strategy currently represents a valuable approach to
enhance our understanding of the link between genes and
neurobiological processes. This may ultimately provide trait
markers of susceptibility to disease, models of the disease
process, improvements in classification and diagnosis,
elucidation of new therapeutic targets, and improvements in
the development of animal disease models. However,
although it was an original aim of this strategy, the
endophenotype approach may not be most appropriate to
robustly enhance our ability to discover new genetic poly-
morphisms related to disease. In other words, using en-
dophenotypes to link the different levels of understanding
(from genes to behavior through biochemistry and cognition)
may be more useful than using endophenotypes to make de
novo discoveries of new susceptibility genes.
Leadingcandidate endophenotypesforSB include impulsive/
aggressive personality traits, neuropsychological and neuro-
physiological responses, and functional changes in circuit
activity as observed by brain imaging. Among these, only
impulsive/aggressive personality traits meet all stringent
endophenotype criteria. It is critical that future research
efforts define the extent to which findings beyond impulsivity
and aggression meet stringent endophenotype criteria
including heritability, state independence and familial aggre-
gation both in affected and unaffected relatives. Such
putative endophenotypes may represent new and innovative
outcomes that can be targeted to reduce the risk of SB, and
future research efforts should be directed to defining the
degree to which such traits are specific for SB and genetic in
origin. Endophenotypes should help us to discover the
pathophysiology-related mechanisms involved in SB, and
lead to the identification of potential new biological systems
as therapeutic targets.
Considering endophenotypes, tested first in animals and
then in humans, as potential targets for new treatments may
enable us to circumvent the obstacles in pharmacological
studies, represented by ethical concerns as well as issues
with obtaining adequate sample sizes. Clinical trials could
potentially aim to investigate the effects of a new compound,
not on the rare SB directly, but on the related endopheno-
types, measurable quantitatively, which would address the
validity of assessing outcomes with low base rates in the
general population, potentially avoiding false positives. This
is now the case with the MATRICS and related programs
aimed at cognition in schizophrenia.89Moreover, measuring
the same endophenotypes in unaffected relatives of cases
will enhance the statistical power of such studies. Evaluation
of new treatments for SB could be based on the involvement
of identified cognitive and emotional processes, related to
dysfunction of the orbitofrontal cortex in the pathophysiology
of SB.Improving decision making and emotions, that is to say
focused psychotherapeutic interventions, can be proposed to
complement additional strategies. For example, it has been
demonstrated that stimulation of the prefrontal cortex
(ventromedial or dorsolateral) using repetitive transcranial
magnetic stimulation in healthy volunteers may induce
alterations in decision making and in the generation of
emotional signals.90–92Such findings may be translatable
into therapeutic studies in SB, as has been carried out for
craving in patients with addictions.93–95
We also conclude that it is possible to use animal models to
study crucial aspects of the neurobiology underlying SB.
Though SB cannot be reproduced in animals, suicide
endophenotypes, risk alleles and neurochemical findings
may be successfully translated from humans to other
species. Emerging neuroscience data provide a better
understanding of the factors leading to SB, independently
of co-occurring psychopathology labeled in the diagnostic
manuals. Additional neuropsychological and brain imaging
studies, linked to genetic and environmental factors, are
necessary to better understand vulnerability to SB, to identify
vulnerable patients and to develop more specific therapeutic
Endophenotypes of suicidal behaviors
P Courtet et al
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements. This work was support by the American Foundation
Health (R01 MH091816-01 to TDG), and the Gralnick Prize from the American
Psychological Foundation and the NARSAD Lieber Prize for Outstanding
Schizophrenia Research (to IIG).
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Endophenotypes of suicidal behaviors
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