Neurobiology Eld. Suicide

Archives of Suicide Research
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Neurobiology of Elderly Suicide
S. Richard-Devantoy M.D. Ph.D., G. Turecki M.D. Ph.D. & F. Jollant M.D. Ph.D.
To cite this article: S. Richard-Devantoy M.D. Ph.D., G. Turecki M.D. Ph.D. & F. Jollant
M.D. Ph.D. (2016): Neurobiology of Elderly Suicide, Archives of Suicide Research, DOI:
10.1080/13811118.2015.1048397
To link to this article: http://dx.doi.org/10.1080/13811118.2015.1048397
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Download by: [RMIT University] Date: 13 January 2016, At: 09:32

Neurobiology of Elderly Suicide
S. Richard-Devantoy, M.D. Ph.D.
Department of Psychiatry and Douglas Mental Health University Institute, McGill University,
McGill Group for Suicide Studies, Montréal, Québec, Canada
G. Turecki, M.D. Ph.D.
Downloaded by [RMIT University] at 09:32 13 January 2016
F. Jollant, M.D. Ph.D.
Address correspondence to Stéphane Richard-Devantoy, M.D., Ph.D., Department of Psychiatry
& Douglas Mental Health University Institute, McGill University, McGill Group for Suicide
Studies, Douglas Institute, FBC building, 3rd floor, 6875 boulevard Lassalle, Montréal, Québec
H4H 1R3, Canada. E-mail: richarddevantoy@orange.fr
Sponsor's Role: None
All authors have no conflicts of interest with this text.
Abstract
Background: Suicide in the elderly is an underestimated and complex issue that has mainly been
explored in sociological, clinical and psychological perspectives. Suicide in non-elderly adults
has been associated with diverse neurobiological alterations that may shed light on future
1
predictive markers and more efficient preventative interventions. The aim of this paper was to
review studies specifically investigating the neurobiology of elderly suicidal behaviour.
Methods: We performed a systematic English and French Medline and EMBASE search until
2013. Results: Contrary to literature in the non-elderly, we found a paucity of studies
investigating the biomarkers of suicidal risk in elderly adults. Main findings were found in the
neurocognitive domain. Studies generally supported the existence of cognitive deficits, notably
decision-making impairment and reduced cognitive inhibition, in patients with a history of
suicidal act compared to patients without such history. However, replications are needed to
confirm findings. Conclusion: Due to several limitations including the small number of
available studies, frequent lack of replication and small sample size, no firm conclusions can be
drawn. The authors encourage further investigations in this field as insight in the neurobiology of
these complex behaviors may limit clichés about end of life and aging, as well as improve future
prevention of suicide in the elderly.
Keywords: biochemical, brain, cognition, elderly, genetic, suicide
INTRODUCTION
Suicidal behaviour, which refers to self-directed injurious or lethal acts carried out with
some intent to end one’s life (Mann, 2003), is a recognized public health issue (Reza, Mercy, &
Krug, 2001). What is less known is that in many countries, older adult men are at greater risk for
suicide than other segments of the population (Hawton & van Heeringen, 2009). In addition,
elderly suicidal acts show a more lethal profile than younger adults with a ratio of
attempted/completed suicide of 4:1 vs. 200:1 (Conwell & Cailting, 2008; De Leo et al., 2001;
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McIntosh, 1985). These worrisome data add to the fact that the number of suicides in later life is
expected to increase as the population ages (Reza et al., 2001).
As in younger populations, several risk factors have been associated with suicide in the
elderly, including major psychiatric illness (Dombrovski et al., 2008b; Hawton & van Heeringen,
2009; Szanto, Holly, & Reynolds, 2001), mainly major depression, (Blow, Brockmann, & Barry,
2004; Szanto et al., 2001; Turvey et al., 2002; Waern, Rubenowitz, & Wilhelmson, 2003), poor
physical health status and impaired functional capacity (Harwood, Hawton, Hope, Harriss, &
Jacoby, 2006; Paraschakis et al., 2012). Furthermore, a personal history of suicide attempt
appears to be the strongest predictive factor of future suicide completion (Hawton & van
Heeringen, 2009) although only 25% of elderly completed suicides have a history of previous
suicide attempt (Conwell, Olsen, Caine, & Flannery, 1991; Preville, Hebert, Boyer, Bravo, &
Seguin, 2005). Similarly to findings in younger populations, risk factors associated with elderly
suicidal acts confer only low predictive value (notably low specificity) and other paths need to be
explored.
Suicidal behaviours are not simple responses to stress or depression, as most people
experiencing a stressful life event or a mood episode never commit or even attempt suicide. It is
generally agreed that suicidal behaviours are best modelled as the interplay between vulnerability
factors and stress factors, including proximal stressful events, acute mental disorder like major
depression, alcohol intake or physical pain (Mann, 2003). This model has been strongly
supported in younger adults, first by clinical studies, then by cellular, molecular and genetic
studies (Mann, 2003), and more recently by neuropsychological and neuroimaging studies
(Jollant, Lawrence, Olie, Guillaume, & Courtet, 2011). In adolescents and middle-aged adults,
several investigations have pointed towards a developmental perspective of suicidal behavior
3
with genetic factors and early negative experience interacting to influence the diathesis for
suicidal acts (Turecki, Ernst, Jollant, Labonte, & Mechawar, 2012). The vulnerability to suicide
may comprise a set of biological dysfunctions such as reduced serotonergic modulation and
higher stress sensitivity (Mann, 2003), impaired decision-making (Jollant et al., 2005) and other
cognitive impairments (Richard-Devantoy, Berlim, & Jollant, 2013a), and dysfunction of the
orbitofrontal cortex and other brain regions (Jollant et al., 2008), among others. These alterations
are hypothesized to underlie the individual’s reduced ability to respond adequately to stressful
environments, leading to the risk of suicidal ideas and acts. Apart from improving our
understanding of the suicidal vulnerability, these biological and neuropsychological alterations
could be both predictive markers of suicidal risk and the target of future therapeutic interventions
aiming at reducing the long-term risk of suicidal acts.
Most of these neurobiological studies have been conducted in adolescent and adult
samples. The aim of this paper was to shed light on potential biomarkers of suicidal behaviour,
specifically in the elderly, and on the role of age-related biological changes in the diathesis to
elderly suicide. We therefore performed a systematic review of the literature aiming at
synthesizing all published articles that examined the association between biomarkers, defined as
alterations at the genetic, cellular, biochemical, brain and neuropsychological levels, and suicidal
behaviors in the elderly i.e. individuals above 60.
METHODS
Literature Search
An English and French systematic Medline literature search of controlled trials, cohort,
case-control and cross-sectional human studies published until December 31, 2013, was
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performed. The following Medical Subject Heading (MeSH) "suicide" term was combined with
selected MeSH terms and with Title and Abstract (TIAB) terms of each aspect of neurobiology
of elderly suicide. The terms were particularly chosen in reference to previous findings in
suicidal behavior and depression.
To explore the neurocognitive markers, the following MeSH terms were used:
"Cognition", "Neuropsychology", "Neuropsychological Tests", "Executive Function", "Decision
Making", "Problem Solving", "Magnetic Resonance Imaging", "Diffusion Magnetic Resonance

Imaging", "Positron-Emission Tomography", "Prefrontal Cortex", "Tomography, Emission-
Computed, Single-Photon", and "Diffusion Tensor Imaging". TIAB terms also included
"Neuropsychological functions", "Executive functioning", "Executive performance", and
"Neuroimaging".
To explore the neurochemical markers, the following MeSH terms were used:
"Serotonin", "Receptors, Serotonin", "Serotonin Plasma Membrane Transport Proteins",
"Serotonin Transporter (SERT)", "Tryptophan Hydroxylase", "Norepinephrin", "Receptors,
Adrenergic", "Dopamine", "Dopamine Transporter", "Receptors, Opioid, mu", "Acethycholine",
"Receptors, Muscarinic", "Glutamic acid", "Receptors, Glutamate", "gamma-Aminobutyric
Acid", "3,4-Dihydroxyphenylacetic Acid", "Receptors, GABA", and "Neurotrophic factors". The
following TIAB terms: "HPA", "BDNF" were also used.
Genetic markers were explored with the following MeSH terms: "Tryptophan
hydroxylase gene", "5-HT receptor gene", "alpha2A-adrenergic receptor gene", "Norepinephrine
transporter gene", "Monoamine Oxidase A (MAO A) gene", "Catechol-O-methyltransferase
(COMT)", "Tyrosine Hydroxylase", "Dopa decarboxylase", "GABA receptor gene", "glutamate
decarboxylase gene".
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The search also included the EMBASE database. An iterative process was used to ensure
all relevant articles had been obtained.
Study Selection
Abstract selection was based on the STrengthening the Reporting of OBservational
studies in Epidemiology (STROBE) (Von Elm et al., 2008) checklist which describes items that
should be included in reports of cohort studies and on the CONSORT statement for clinical trials
(Begg et al., 1996). The present review followed the STROBE statement guidelines. Abstracts
identified with the literature search were independently evaluated by two reviewers for inclusion
status (SRD and FJ).
Studies that met the following inclusion criteria were included in this systematic review
of the literature: (1) original article published in an English or French language peer-reviewed
journal; (2) including subjects aged ≥60, as justified by previous studies in the field (Grosselin et
al., 2010; Hasher, Chung, May, & Foong, 2002; Hasher, Zacks, & Cynthia, 1999; Lustig, May,
& Hasher, 2001; Connelly, Hasher, & Zacks, 1991). Studies only involving persons under age 60
were excluded; (3) including at least one group of individuals with a history of suicide attempt
(defined as any act carried out with a intent to die and different from self-mutilation (Mann,
2003)), or who completed suicide (4) using neuroimaging, neuropsychological, genetic,
biochemical (including epigenetic) or cellular investigations. From abstracts that fulfilled the
initial inclusion criteria, full articles were obtained for the final analysis. Final selection criteria
were then applied when inclusion criteria were present. The study selection is shown on a flow
diagram (Figure 1).
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Finally, we used the common definition of group of suicide attempters, suicide ideators,
patient controls, and healthy controls. Suicide attempters were defined as subjects who had a
personal history of suicidal behaviour, suicide ideators as individuals with suicidal ideations, but
no personal or first-degree family history of suicidal behaviour, and patient controls as
individuals with no personal or first-degree family history of suicidal behaviour. Finally, healthy
controls were defined as males and females with no personal or second-degree family history of
depressive disorders or suicidal behaviour and no current psychotropic treatment.

RESULTS
Genetic Studies (Table 1)
Four studies were found. Hwang et al. (2006b) found more history of attempted suicide
among depressed elderly who were carriers of the APOE 4 allele gene. Using a latent class
model to analyse depression, Bogner, Richie, de Vries, and Morales (2009) did not find any
association between APOE 4 and a class combining death and suicidal ideas.
Hwang et al. (2006a) found a significant association between the BDNF Val66Met
polymorphism and depression but not suicidal behavior in an elderly Chinese sample.
Finally, Stefulj, Kubat, Balija, and Jernej (2006) showed that elderly Croatian suicide
completers, but not younger suicide completers (below 65 years old), had higher frequencies of
the CC genotype of polymorphisms localized in intron 7 of Typtophane Hydroxylase (TPH1)
gene.
Biochemical studies (Table 2)
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Three studies explored biochemical systems in elderly suicide completers or attempters.
No between-group differences in α- and β-adrenergic receptor binding were found in anterior
prefrontal (Brodman area (BA) 10), occipital (BA 19), and temporal cortices (BA 21), or in the
hippocampus in small samples of elderly suicide completers vs. healthy controls (Crow et al.,
1984). Similarly, another study could not find any between group differences in α-adrenergic
receptor binding in the anterior frontal cortex (BA 10) of suicide completers (Ferrier et al.,
1986).
Jokinen and Nordstrom (2008) reported that in elderly patients hospitalized for mood
disorders, impaired functioning of the Hypothalamo-Pituitary-Adrenergic (HPA) axis, measured
by the inability to suppress cortisol response with dexamethasone, was a significant predictor of
later suicide.
Neuropsychological Studies (Table 3)
Several studies investigated elderly suicide attempters using neuropsychological tests.
Eight studies showed poorer cognitive performance in elderly patients with a history of suicidal
behaviour compared to patient controls. Deficits encompassed cognitive inhibition using the
Stroop test (Richard-Devantoy et al., 2011), Hayling Completing Sentence, or Reading
Distraction Task (Richard-Devantoy et al., 2012b), mental flexibility using the Trail Making Test
(TMT) (King et al., 2000; Richard-Devantoy et al., 2012b) and the Wisconsin Card Sorting Test
(WCST) (McGirr, Dombrovski, Butters, Clark, & Szanto, 2012), and global executive deficit
using the EXIT 25 scale (Dombrovski et al., 2008a; Gujral et al., 2012). One study (King et al.,
2000) reported no between-group differences at the TMT and WCST although, interestingly,
depressed suicide attempters but not non-attempter depressed patients showed larger
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performance decline with age at the TMT - part B. One study found no difference at the Stroop
test and TMT in small samples (Richard-Devantoy et al., 2011). Verbal fluency was not different
between attempters and non-attempters in two studies (King et al., 2000; Richard-Devantoy et
al., 2012b). In one study (Gujral et al., 2012), executive performance was similar between
depressed elderly suicide attempters and those with suicidal ideas only. Executive dysfunction
was positively correlated with lethality of the act in one study (McGirr et al., 2012), and
persisted regardless of confounding factors (severity of depression, effect of psychoactive
substances or exposure to psychotropic medication (Dombrovski et al., 2008a), education level

(King et al., 2000), and information processing speed (Richard-Devantoy et al., 2012b)).
More risky decision-making at the Cambridge Gambling Task (CGT) (Clark et al., 2011)
was reported in elderly suicide attempters compared to non-attempters. In addition, high-lethality
suicide attempters showed an intact ability to delay rewards whereas low-lethality attempters
tended to prefer immediate rewards (Dombrovski et al., 2011b). Suicide attempters also showed
reduced reversal learning capacities in another study conducted by the same group (Dombrovski
et al., 2010).
One study assessed (Szanto et al., 2012) the ability to recognize social emotions and
reported both reduced abilities and reduced social network in suicide attempters.
Of note, several studies were conducted by the same groups and in largely overlapping
populations (Dombrovski et al., 2010; Dombrovski et al., 2011a; Dombrovski et al., 2013).
Neuroimaging Studies (Table 4)
Five structural imaging studies have explored suicidal vulnerability in elderly. Compared
to patient controls, elderly suicide attempters showed more subcortical gray matter
9
hyperintensities (with a trend for more periventricular signals) (Ahearn et al., 2001). One study
showed that suicide attempters had more left white matter lesions, with suicide attempt history
predicting a greater growth in both left and right white matter lesions (Sachs-Ericsson et al.,
2013).
A reduction of gray and white matter volume in several brain regions including the
frontal (notably dorsomedial prefrontal), parietal, and temporal regions, as well as the insula,
lentiform nucleus, midbrain, and cerebellum (Hwang et al., 2010). The basal ganglia was also
found to be affected, with lower gray matter signal in the putamen but not caudate or pallidum of
elderly suicide attempters compared to control groups (Dombrovski et al., 2011a). The intensity
of the signal was associated with a preference for small immediate rewards rather than larger
delayed rewards (Dombrovski et al., 2011a). Interhemispheric connectivity was altered in elderly
suicide attempters (Cyprien et al., 2011), with a smaller volume of the third posterior part of the
corpus callosum in comparison to patients with no lifetime history of suicidal acts.
Only one functional imaging study has been found (Dombrovski et al., 2013). Impulsivity
and a history of suicide attempts (particularly poorly planned ones) were associated with a
weakened expected reward signal in the paralimbic cortex, which in turn predicted behavioural
insensitivity to contingency change (Dombrovski et al., 2013).
DISCUSSION
This first systematic literature review on the biomarkers of suicidal risk in elderly
patients revealed (1) a paucity of published studies, which contrasts with the accumulating data
in young or middle-aged patients (Ernst, Mechawar, & Turecki, 2009; Jollant et al., 2011;
Richard-Devantoy et al., 2012a); (2) support for the existence of some cognitive deficits in
10
patients with a history of suicidal act in comparison to patients without such history, with a
particular emphasis on executive control and to a lesser extent decision-making impairments; (3)
some structural and possibly functional brain alterations, (4) a constant lack of published
replication necessitating to remain cautious with reported positive findings.
First, we must highlight several limitations that should be taken into account when
interpreting findings reported in this review. Studies included in this review examined
heterogeneous samples in term of socio-demographic and clinical characteristics. Suicidal

behavior encompassed various populations e.g. patients with a history of suicide attempt, suicide
ideators without any history of suicide attempt, or suicide completers. Also, the first suicide
attempt may have been committed at different stages of life from onset during adolescence to a
first attempt after 60 (see below for possible interpretations). The delay between the last suicide
attempt and the neuropsychological assessment also varied, a potential confounder when
measuring vulnerability. Moreover, co-morbid depression was highly variable regarding the
status of patients (inpatient or outpatient), severity (mild, moderate or severe), recurrence and
age at first depressive episode (e.g. single late episode vs. early onset recurring depressive
disorder). Other potential confounders were not always taken into consideration e.g. age, gender,
education level, severity of depression, use of psychoactive substances, number of previous
suicide attempts, and level of suicidal intent or impulsivity. Gender is an interesting example in
this respect. Literature uncovers or reports brain and cognitive differences between men and
women (Hayat et al., 2014). However, studies usually pool men and women, and then assess a
potential gender effect with insufficient statistical power to run such analyses. In spite of the
important role gender plays in the expression of suicidal behavior, the investigation of sex
differences in brain circuitry and neurocognitive correlates of suicidal behavior has never been
11
conducted. It would also be important to perform similar studies in both sexes in the perspective
of future tailored-made therapeutic modalities.
Studies included in this review exclude suicide attempts with head injuries or brain
damage. Some authors however assessed and took into account in their results these potential
cofounders, such as anoxic-ischemic or toxic brain injury, based on medical records and clinical
interview. Besides, opposite gender ratios in frequency of suicide attempts and suicide
completions constitute an intriguing paradox. Specifically, females consistently attempt suicide

more than males (average of 2F: 1M), whereas males consistently die by suicide more frequently
than females (M:F ratio in high-income countries is 3:1 and that for middle and low-income
countries is 1.5:1) (Hawton & van Heeringen, 2009).
One major limitation remains the small sample sizes of many studies leading to a risk of
both type I and II errors, including inflated and non-replicable positive results, a global problem
in neuroscience (Button et al., 2013). Moreover, some studies (notably post-mortem studies)
included some older patients, but the number of individuals was usually too small to permit
specific analysis of this population. Only a few studies have specifically looked at the aging
processes on serotonin, norepinephrine, and dopamine systems (Crow et al., 1984; Ferrier et al.,
1986). Contrary to younger adults, no study described peripheral inflammatory markers of
elderly suicide, such as interleukins, and CRP, that may relate to vascular brain pathologies. This
review, therefore, underscores the need for more biological studies of suicide in elderly
populations, in addition to other approaches.
Neurocognition, based on neuropsychological and to a lesser extent neuroimaging
investigations, was the only domain where a significant number of studies in elderly have been
published. Here, neurocognitive deficits refer to abnormal cognitive functioning related to brain
12
dysfunction. Overall, impaired cognitive control is perhaps the most consistent cognitive deficit
found among both middle-age (Keilp, Gorlyn, Oquendo, Burke, & Mann, 2008; Keilp et al.,
2001; Malloy-Diniz, Neves, Abrantes, Fuentes, & Correa, 2009; Marzuk, Hartwell, Leon, &
Portera, 2005; Raust et al., 2007) and elderly (Dombrovski et al., 2008a; Dombrovski et al.,
2010; King et al., 2000; McGirr et al., 2012) suicide attempters, particularly among middle-age
(Keilp et al., 2001) and elderly (McGirr et al., 2012) high-lethality attempters. Similarly, deficits
have been observed in reversal learning capacities in the context of uncertain environments,
where experiential learning guides subsequent behavioural choices in young (Jollant et al., 2005)
and elderly suicide attempters (Dombrovski et al., 2010). Finally, risky decision-making seems
to be a potential candidate in both elderly (Clark et al., 2011; Dombrovski et al., 2010) and
younger adults (Jollant et al., 2005, 2007), notably in those using a violent suicidal mean (Wyart
et al. submitted). This common cognitive pathway may therefore play a crucial role in the
vulnerability to suicidal acts across ages. Additional studies investigating other cognitive
domains should be conducted to be able to draw a valid cognitive model of elderly suicidal
behaviours, and highlight common and specific features according to age.
Based on evidence from research across lifespan, the suicidal process may result from the
combined deficits in systems implicated in giving values to external stimuli, in systems of
cognitive control, verbal fluency and working memory, and in systems of long-term (notably
autobiographical) memory (Jollant et al., 2011; Richard-Devantoy et al., 2013a; Richard-
Devantoy, Berlim, & Jollant, 2014). Valuation deficits, in relation to ventral prefrontal cortex,
would lead to a higher sensitivity to social signals of reject, disapproval, threat or unfairness
(Jollant et al., 2008; Szanto et al., 2012) - which may in turn trigger many suicidal crisis - but
also to a higher tendency to choose options with immediate reward (e.g. interruption of painful
13
situation) at the expense of long-term risks (death) (Richard-Devantoy et al., 2014). Risky
decision-making in suicide attempters has also been associated with more interpersonal issues
(Jollant et al., 2007), suggesting that it may sometimes generate conditions of suicidal crisis. On
the other hand, cognitive control deficits, in relation to a prefrontal-parietal network (Richard-
Devantoy et al. submitted), do not seem to explain risky decision-making (Richard-Devantoy et
al., 2013b) but may lead to a lack of control of the provoked emotional response, a higher
tendency for ruminations and the emergence of suicidal ideas. Reduced verbal fluency is more
difficult to explain but has been shown to be associated with hopelessness (MacLeod, Pankhania,
Lee, & Mitchell, 1997). Finally, difficulties in retrieving long-term autobiographical memory
may reduce the ability to solve problems (Raes et al., 2006).
Suicide in the elderly raises also the interesting question of the developmental
mechanisms leading to suicide vulnerability. One possible pathway may be pathological aging.
This is suggested by one study (King et al., 2000) reporting a more rapid age-related decline in
cognitive flexibility performances in suicide attempters compared to patient controls. Also, the
cognitive processes and brain regions involved in suicidal vulnerability seem to be particularly
sensitive to the effects of normal aging (Hasher et al., 1999). Such aging-related alterations could
notably affect shifting, updating, and inhibition functions (Miyake, Emerson, & Friedman,
2000), non-automatic controlled inhibition processes (Darowski, Helder, Zacks, Hasher, &
Hambrick, 2008), decision-making (Eppinger, Nystrom, & Cohen, 2012), and cognitive control
(Tisserand et al., 2004). A greater impairment of prefrontal regions during aging (Wang et al.,
2011), especially the dorsolateral prefrontal and ventromedial cortices (Haug & Eggers, 1991),
may also explain suicide vulnerability. Brain atrophy during aging involves cortico-striato-
thalamic loops (Alexander, DeLong, & Strick, 1986) connecting the frontal cortex to the basal
14
ganglia. These loops play an important role in regulating behavior and complex cognitive
functions. At the biochemical level, cerebral neurotransmitters (Backman, Lindenberger, Li, &
Nyberg, 2010; Fujiwara, Zheng, Miyamoto, & Hoshino, 2011; Rieckmann et al., 2011) and
neurotrophic factors (Douillard-Guilloux, Guilloux, Lewis, & Sibille, 2012) decrease with aging
and could contribute to a lower cognitive efficacy.
An important issue could be the failure of compensatory mechanisms, such as a
decrement of cognitive reserve (Dombrovski et al., 2008a) stemming from vascular and
neurodegenerative lesions. For instance, high blood pressure has been shown to play an
important role in the progression of microvascular brain disease, which was previously
associated with functional decline in mobility and cognition of older people (White et al., 2011).
Besides, in a sample of non-demented elderly adults, subcortical infarcts contributed to an
increased risk of depressive symptoms as well as cognitive impairment (Grool, van der Graaf,
Mali, Geerlings, & SMART Study Group, 2011). In another cohort, patients having suffered a
stroke had a significantly increased risk of suicide (Stenager, Madsen, Stenager, & Boldsen,
1998), suggesting a key role of vascular factors in the aetiology of elderly suicide vulnerability.
Finally, the risk of suicide seems to be increased in dementia, which is paradigmatic of a
pathological aging brain (Sabodash, Mendez, Fong, & Hsiao, 2013). One study showed more
Alzheimer disease in a population of elderly people who committed suicide compared to a group
of age- and gender-matched control subjects who died of natural causes (Rubio et al., 2001). The
brains of individuals who committed suicide had higher modified Braak scores (a measure of
Alzheimer stages) than those of matching control subjects (Rubio et al., 2001), with a
heterogeneity of psychological presentations and neuropathological lesions in older suicide
victims (Peisah, Snowdon, Gorrie, Kril, & Rodriguez, 2007).
15
We propose here different hypothetic pathways to suicide that may inform model-based
research on elderly suicide (Figure 2). A first possibility (persistent lifetime vulnerability
pathway) is that some individuals keep high vulnerability levels across their lifespan. This
vulnerability may lead to earlier suicide attempts, unless protective factors prevent them, or some
of them, until older age. In the second possibility (decreasing lifetime vulnerability pathway),
individuals may express a high level of vulnerability at a younger age but this vulnerability may
decrease with time. This model is supported by the fact that criteria for personality disorders, a
major risk factor for suicide, tend to decrease with time in many individuals (Gutierrez, 2014). In
the third pathway (increasing lifetime vulnerability pathway), suicide vulnerability may increase
with time. This is partly supported by life trajectories in middle aged suicide completers (Seguin
et al., 2007) showing that some individuals experience few adversity early in life but seem more
reactive to later major difficulties (Seguin, Renaud, Lesage, Robert, & Turecki, 2011). This
pathway may however partly overlap with the first one as vulnerability may have been present
earlier but could express itself more strongly when the individual faces new challenges he/she
cannot overcome (e.g. job, finances, family responsibilities…). Finally, a pathological aging
pathway may explain the appearance of a late-life vulnerability, under the influence of
pathological related-aging processes including specific genes, vascular disease or degenerative
processes. This vulnerability, in combination with late life events, would increase the risk of late
life suicidal acts. This latter group may necessitate defining new, more specific risk factors.
Further investigations in elderly populations are required to shed light on the biological
basis of suicide in this age group. Collaborative initiatives bringing together cognition
neuroimaging, and biological approaches would be an important step (Szanto et al., 2013). Apart
from pathophysiological mechanisms, markers of suicide risk with significant specificity have to
16
be sought in prospective studies. Elucidating mechanisms may also shed light on potential
therapeutic targets to improve prevention. In all cases, a robust methodology would necessitate
(1) to recruit both healthy and patient control groups in order to exclude the effect of comorbidity
(2) to have a sufficient number of participants to avoid bias and inadequate conclusions (3) to
take into account potential pathways notably early onset vs. late onset (4) to examine the effect
of age.
We think that rather than regarding age as a confounding factor to control for, researchers
should view aging as an important study variable. Furthermore, we believe that the biological
investigation of suicide in the elderly may lead to less misunderstanding in the general
population, and may also reduce the fatalist acceptance of suicide in a population that should be
supported to live happily for some more years.
CONCLUSION
Although no firm conclusions can be drawn due to several limitations and the paucity of
available data, our review suggests that some neurocognitive alterations, sometimes in relation to
pathological aging, may predispose some patients to a higher risk of suicidal acts given particular
circumstances.
Acknowledgments
We would like to thank Ms Alexandra Hoehne for manuscript editing. Dr. S. Richard-
Devantoy received a fellow grant from the Canadian Institutes for Health Research (CIHR). Drs
F. Jollant and G. Turecki received a “chercheur-boursier clinicien” salary grant from the Fond de
Recherche du Québec – Santé (FRQS).
17
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Table 1. Genetic studies of elderly suicidal behavior
Reference Population Elderly patients (≥60 year) Main results
Yes/No Number
A218C intron 7 polymorphism of the Tryptophan hydroxylase 1 (TPH1) gene
Stefulj et al. Violent Suicides Yes 74 Higher frequency
(2006) completers of CC genotype
(n = 74) in older (above
Healthy Controls 65 years) victims

(n = 42) as compared to
controls. No
differences
between victims
under 65 years
and controls.
Val66Met polymorphism of Brain Derived Neurotrophic Factor (BDNF) gene
Hwang et al. Depressed Yes 110 No association
(2006a) Suicide but this
Attempters polymorphism
(n = 110; mean was significantly
age: 75.0 ± 5.3; associated with
42.7% of female) depression
Healthy Controls
(n = 171; mean
25
age: 76.0 ± 5.5
years; 45.6% of
female)
APOE 4 allele of the APOE gene
Bogner et al. Depressed with Yes NA No association
(2009) and without a between APOE 4
history of suicide allele and ideas
attempt (n = 305; of suicide

65% of female)
Hwang et al., Depressed with Yes 111 No association
(2006b) and without a between a history
history of suicide of suicide
attempt (n = 111; attempt and
mean age: APOE 4 gene
75.0 ± 5.2)
Healthy Controls
(n = 114; mean
age: 74.0 ± 8.5
years)
26
Table 2. Biochemical studies of elderly suicidal behavior
Reference Population Elderly patients (≥60 year) Main results
Yes/No Number
α-adrenergic receptor
Crow et al. Suicides Most subjects 9 No between
(1984) completers over 60 y.o. group differences
(n = 17; mean in anterior
age: 49.8 ± 20.2 prefrontal

y.o.; 58% of (Brodman Area
female) (BA) 10),
Healthy controls Occipital (BA
(n = 19; mean 19), and
age: 56.2 ± 14.6 Temporal
y.o.; 36.8% of cortices (BA 21),
female) and
Hippocampus.
Ferrier et al. Depressed Yes No between
(1986) suicide group differences
completers in anterior
(n = 9; mean age: prefrontal (BA
75 ± 6 y.o.; 55% 10) cortex.
of female)
Healthy controls
27
(n = 6; mean age:
76 ± 6 y.o.; 83%
of female)
β-adrenergic receptors in elderly suicide
Crow et al. Suicides Most subjects 9 No between
(1984) completers over 60 y.o. group differences
(n = 17; mean in anterior
age: 49.8 ± 20.2 prefrontal (BA

y.o.; 58% of 10), Occipital
female) (BA 19), and
Healthy controls Temporal
(n = 19; mean cortices (BA 21),
age: 56.2 ± 14.6 and
y.o.; 36.8% of Hippocampus.
female)
Hypothalamic Pituitary Adrenal Axis
Jokinen and Prospective Yes 99 Association
Nordstrom study between non
(2008) Patients with a suppression of
mood disorder the cortisol
(n = 99; mean response
age: 73 ± 5.8; following
75% of female) dexamethasone
28
Suicide with future
completers suicide, with a
(n = 6) higher specificity
Patient and predictive
Controls (n = 93) value in the
group with a
history of suicide
attempt.
29
Table 3. Neuropsychological studies of elderly suicidal behavior
Authors Population Suicidal Neuropsychology Main results
behaviour Cognitive Scale used
domaine
Gujral et al. In and History of Global EXIT 25 SA < PC, HC
(2012) outpatients suicide executive
with a major attempt functions
depressive (lifetime)
episode
(Unipolar
disorder):
SA (n = 83;
mean age:
69.4 y.o.;
49% F)
SI (n = 43;
mean age:
69.9 y.o.;
47% F)
PC (n = 54;
mean age:
70.7 y.o.;
67% F)
30
Healthy Current SA = SI
Controls suicidal
(n = 48; mean ideations
age: 69.1 ans; (SSI)
48% F)
Szanto et al. In and History of Social Reading the More errors in
(2012) outpatients suicide emotion ming in the SA vs.
with a major attempt recognition Eyes controls

episode
(Unipolar
disorder):
SA (n = 24;
mean age:
68.2 y.o.;
62% F)
PC (n = 38;
mean age:
70.2 y.o.;
66% F)
Healthy
Controls
(n = 28; mean
31
age: 69.6
y.o.; 39% F)
Richard- Inpatients History of Cognitive RWD SA < PC:
Devantoy et with a major suicide inhibition more semantic
al. (2012b) depressive attempt and neutral
episode: (lifetime) distractors
read
TMT SA < PC :
more
perseverations
SA (n = 20; Stroop SA < PC :
mean age: higher
77.1 y.o.; Interference
65% F) error index
PC (n = 20; Hayling SA < PC :
mean age: Sentence more penalties
75.9 y.o.; Completing
60% F) Test
Healthy Verbal Go/No-Go SA < PC :
Controls Fluency Task more
(n = 20; mean commission
age: 75.2 errors
y.o.; 60% F) SA = PC
32
Clark et al. In and History of Decision Cambridge SA < PC = HC
(2011) outpatients suicide making Gamble Task
with a major attempt
episode
(Unipolar
disorder):
SA (n = 25;
mean age:
67.1 y.o.;
48% F)
SI (n = 13;
mean age:
69.9 y.o.;
38% F)
PC (n = 35;
mean age:
70.7 y.o.;
63% F)
Healthy Current SA = SI
Controls suicidal
(n = 22; mean ideations
age: 67.8 (SSI)
33
y.o.; 37% F)
McGirr et al. In and History of Cognitive WCST High-lethality
(2012) outpatients suicide flexibility SA < Low-
with a major attempt lethality
depressive (lifetime) SA < PC < HC
episode : more
(Unipolar perseverations
disorder
High-lethality
SA (n = 14 ;
mean age:
68.8 y.o.;
50% F)
Low-lethality
SA (n = 20;
mean age:
66.8 y.o.;
50% F)
PC (n = 29;
mean age:
70.2 y.o.;
63.3% F)
Healthy
34
Controls
(n = 30; mean
age: 69.7
y.o.; 46.7%
F)
Richard- Inpatients History of Cognitive Stroop SA = PC
Devantoy et with a major suicide inhibition
al. (2011) depressive attempt

episode: (lifetime)
SA (n = 10; Test du SA < PC :
mean age: Go/No-Go more
75.3 y.o.; commission
70% F) errors
PC (n = 10; Cognitive TMT SA = PC
mean age: flexibility
72.9 y.o.;
70% F)
Dombrovski In and History of Decision Kirby’s Preference for
et al. (2011b) outpatients suicide making Monetary immediate
with a major attempt Choice rewards in
depressive (lifetime) Questionnaire Low-lethality
episode SA et SI vs.
(Unipolar PC et H:
35
disorder):
High-lethality
SA (n = 15 ;
mean age:
67.4 y.o.;
46.7% F)
Low-lethality
SA (n = 14;
mean age:
66.1 y.o.;
64.3% F)
SI (n = 12;
mean age:
69.5 y.o.;
33.3% F)
PC (n = 42;
mean age:
70.3 y.o.;
64.3% F)
Healthy Current High-lethality
Controls suicidal SA vs. three
(n = 31; mean ideations other groups
age: 68.1 (SSI) delay more
36
y.o.; 45.2% future rewards
F)
Dombrovski In and History of Affective Probabilistic SA < PC, HC
et al. (2010) outpatients suicide component of reversal-
with a major attempt decision- learning task
depressive (lifetime) making
episode
(Unipolar
disorder):
SA (n = 15 ;
mean age:
66.8 y.o.;
60% F ;
100%
hospitalized)
SI (n = 12 ;
mean age:
68.8 y.o.;
42% F ; 83%
hospitalized)
PC (n = 24;
mean age: 70
y.o.; 54% F ;
37
8%
hospitalized)
Healthy Current Affective
Controls suicidal component of
(n = 14; mean ideations decision-
age: 65.6 (SSI) making
y.o.; 14% F) impaired in
SA, but not in

SI
Dombrovski In and History of Executive EXIT 25 SA < PC
et al. (2008a) outpatients suicide functions
with a major attempt
episode
(Unipolar
disorder):
SA/SI
(n = 32; mean
age: 70.2
y.o.; 53% F ;
100%
hospitalized)
PC (n = 32; Current
38
mean age: suicidal
71.5 y.o.; ideations
62% F ; 47% (SSI)
hospitalized)
King et al. In and History of Cognitive TMT Reduced
(2000) outpatients suicide flexibility performance
with a major attempt at TMT part-B
depressive (lifetime) with age in SA

episode but not in
(Unipolar other groups.
disorder):
SA (n = 18; WCST SA = PC
mean age:
66.7 y.o.;
66% F)
PC (n = 29;
mean age:
64.2 y.o.;
69% F)
Healthy Verbal SA = PC
Controls fluencies
(n = 30; mean
age: 69 y.o.;
39
70% F)
SA: Suicide Attempters (Patient with a history of suicide attempts); SI: Suicide Ideators (Patient with current suicidal ideations
without any history of suicide attempt); PC: Patient Controls (Patient with no curent suicidal ideations and no history of suicide
attempt); HC: Healthy Controls.
HSCT: Hayling Sentence Completing Test; RWD: Reading with Distraction Task; TMT: Trail Making Test; WCST: Wisconsin
Card Sorting Test, Stroop: Stroop Task.
EXIT 25: Executive scale included number/ letter sequencing, Stroop test, fluency test, Go/No-Go, Luria’s hand sequencing.
F: Female gender; SSI: Scale for Suicide Ideation.

40
Table 4. Neuroimaging studies of elderly suicidal behavior (SA: Suicide attempters; PC: Patients
controls without history of suicide attempt; HC: Healthy controls. GM: Grey Matter; WM: White
Matter.)
Study Population Methods Main results Limitation
Dombrovski et Cross-sectional Functionnal The pregenual Medication
al. (2013) study neuroimagi cingulate
In and subregion of the
outpatients with vmPFC tracked
a major the reinforcement

depressive history less
disorder reliably in suicide
(Unipolar attempters than in
depression): the comparison
SA (n = 15; groups,
mean age: 65.9 controlling for
y.o.; 37% F) depression group
PC (n = 18; status.
mean age: 66.7
y.o.; 67% F)
Healthy controls Probabilistic Both gender
(n = 20; mean Reversal
age: 70.7 y.o.; Learning
60% F)
Sachs-Ericsson Cross-sectional Structural Suicide Suicide
41
et al. (2013) and prospective neuroimaging, attempters were evaluation
study volumetric also found to have
Outpatients MRI (T1) more left WML at
SA (n = 23; baseline and a
mean: 66.7 y.o.; greater growth in
66.7% F) both left and right
PC (n = 223; WML over time. Both gender
mean: 69.8 y.o.;

78.3% F)
Dombrovski et Cross-sectional Structural SA > PC: Lower Medication
al. (2012) study- neuroimaging putamen but not
(Sachs-Ericsson caudate or
et al., 2013) pallidum gray
matter volu
In and MRI (T1- SA: Lower
outpatients with weighted putamen gray
a major magnetization matter voxel
depressive prepared rapid counts associated
disorder acquisition with a higher
(Unipolar gradient–echo delay discounting
depression): (MPRAGE) ; 3-T but not delay
imaging system) aversion at the
SA (n = 13; Region of Cambridge Vascular and
42
mean age: 66 interest: putamen, Gamble Task degenerative
y.o.; 38.5% F) pallidum et causes of
caudate reduced regional
volume
PC (n = 20; Monetary Choice Both gender
mean age: 67.7 Questionnaire
y.o.; 65% F)
Healthy controls Cambridge

(n = 19; mean Gamble Task
age: 70.5 y.o.;
63% F)
Hwang et al. Cross-sectional Structural SA > PC: Loose VBM stats
(2010) study neuroimaging, decreased GM (no multiple
Inpatients with a volumetric and WM volume comparison
major depressive in the frontal, correction)
disorder (Late- parietal, and
Onset temporal regions,
Depression) and the insula,
(n = 70): lentiform nucleus,
SA (n = 27; midbrain, and the
mean age: 79.1 cerebellum
y.o.; 0% F)
PC (n = 43;
43
mean age: 79.6
y.o.; 0% F)
Healthy controls Voxel-Base Vascular and
(n = 26; mean Morphometry in degenerative
age: 79.5 y.o.; MRI (T1) causes of
0% F) reduced regional
Ahearn et al. Cross-sectional Structural SA > PC: More Medication
(2001) study neuroimaging, - subcortical gray

Patients with a Hyperintensity matter Both gender
unipolar signal T2 (Boyko hyperintensities
depressive Lesion et Coffey
disorder (Late- Lesion
Onset Classification
Depression): System)
SA (n = 20;
mean age: 66
y.o.; 85% F)
PC (n = 20; mea
nage: 66,4 y.o.;
85% F)
Cyprien et al. Cross-sectional Structural SA vs. PC and Heterogeneity of
(2011) study neuroimaging, HC: smaller diagnosis
volumetric posterior third
44
Outpatients MRI (T1) part of corpus Patients not
SA (n = 21; callosum depressed at
mean:72.2 y.o.; evaluation
76.2% F)
PC (n = 180;
mean: 71 y.o.;
65% F)
Healthy controls Region of Both gender

(n = 234; mean: interest: corpus
71 y.o.; 38% F) callosum
45
Figure 1. Flow chart of the selection process.
46
Figure 2. Hypothetical pathways of suicide vulnerability.
47

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Archives of Suicide Research

ISSN: 1381-1118 (Print) 1543-6136 (Online) Journal homepage: http://www.tandfonline.com/loi/usui20

Neurobiology of Elderly Suicide

To link to this article: http://dx.doi.org/10.1080/13811118.2015.1048397

Accepted author version posted online: 08

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Download by: [RMIT University] Date: 13 January 2016, At: 09:32

S. Richard-Devantoy, M.D. Ph.D.

McGill Group for Suicide Studies, Montréal, Québec, Canada

G. Turecki, M.D. Ph.D.

McGill Group for Suicide Studies, Montréal, Québec, Canada

F. Jollant, M.D. Ph.D.

McGill Group for Suicide Studies, Montréal, Québec, Canada

Address correspondence to Stéphane Richard-Devantoy, M.D., Ph.D., Department of Psychiatry

H4H 1R3, Canada. E-mail: richarddevantoy@orange.fr

Sponsor's Role: None

All authors have no conflicts of interest with this text.

explored in sociological, clinical and psychological perspectives. Suicide in non-elderly adults

review studies specifically investigating the neurobiology of elderly suicidal behaviour.

2013. Results: Contrary to literature in the non-elderly, we found a paucity of studies

decision-making impairment and reduced cognitive inhibition, in patients with a history of

prevention of suicide in the elderly.

Keywords: biochemical, brain, cognition, elderly, genetic, suicide

expected to increase as the population ages (Reza et al., 2001).

several investigations have pointed towards a developmental perspective of suicidal behavior

understanding of the suicidal vulnerability, these biological and neuropsychological alterations

aiming at reducing the long-term risk of suicidal acts.

elderly suicide. We therefore performed a systematic review of the literature aiming at

behaviors in the elderly i.e. individuals above 60.

suicidal behavior and depression.

"Cognition", "Neuropsychology", "Neuropsychological Tests", "Executive Function", "Decision

Making", "Problem Solving", "Magnetic Resonance Imaging", "Diffusion Magnetic Resonance

Imaging", "Positron-Emission Tomography", "Prefrontal Cortex", "Tomography, Emission-

"Neuropsychological functions", "Executive functioning", "Executive performance", and

"Serotonin", "Receptors, Serotonin", "Serotonin Plasma Membrane Transport Proteins",

"Serotonin Transporter (SERT)", "Tryptophan Hydroxylase", "Norepinephrin", "Receptors,

Adrenergic", "Dopamine", "Dopamine Transporter", "Receptors, Opioid, mu", "Acethycholine",

"Receptors, Muscarinic", "Glutamic acid", "Receptors, Glutamate", "gamma-Aminobutyric

Acid", "3,4-Dihydroxyphenylacetic Acid", "Receptors, GABA", and "Neurotrophic factors". The

following TIAB terms: "HPA", "BDNF" were also used.

hydroxylase gene", "5-HT receptor gene", "alpha2A-adrenergic receptor gene", "Norepinephrine

transporter gene", "Monoamine Oxidase A (MAO A) gene", "Catechol-O-methyltransferase

(COMT)", "Tyrosine Hydroxylase", "Dopa decarboxylase", "GABA receptor gene", "glutamate

all relevant articles had been obtained.

Abstract selection was based on the STrengthening the Reporting of OBservational

status (SRD and FJ).

2003)), or who completed suicide (4) using neuroimaging, neuropsychological, genetic,

diagram (Figure 1).

no personal or first-degree family history of suicidal behaviour, and patient controls as

depressive disorders or suicidal behaviour and no current psychotropic treatment.

Genetic Studies (Table 1)

the CC genotype of polymorphisms localized in intron 7 of Typtophane Hydroxylase (TPH1)

Biochemical studies (Table 2)

No between-group differences in α- and β-adrenergic receptor binding were found in anterior

disorders, impaired functioning of the Hypothalamo-Pituitary-Adrenergic (HPA) axis, measured

Neuropsychological Studies (Table 3)