Progress in Neurobiology 89 (2009) 315–333

Contents lists available at ScienceDirect

Progress in Neurobiology
journal homepage: www.elsevier.com/locate/pneurobio

Suicide neurobiology
Carl Ernst, Naguib Mechawar, Gustavo Turecki *
McGill Group for Suicide Studies, McGill University, Montreal, Quebec, Canada

A R T I C L E I N F O A B S T R A C T

Article history: In this review, we examine the history of the neurobiology of suicide, as well as the genetics, molecular
Received 21 May 2009 and neurochemical findings in suicide research. Our analysis begins with a summary of family, twin, and
Received in revised form 26 August 2009 adoption studies, which provide support for the investigation of genetic variation in suicide risk. This
Accepted 1 September 2009
leads to an overview of neurochemical findings restricted to neurotransmitters and their receptors,
including recent findings in whole genome gene expression studies. Next, we look at recent studies
Keyword: investigating lipid metabolism, cell signalling with a particular emphasis on growth factors, stress
Suicide
systems with a focus on the role of polyamines, and finally, glial cell pathology in suicide. We conclude
with a description of new ideas to study the neurobiology of suicide, including subject-specific analysis,
protein modification assessment, neuroarchitecture studies, and study design strategies to investigate
the complex suicide phenotype.
ß 2009 Published by Elsevier Ltd.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
2. Historical perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
3. Genetics of suicide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
3.1. Family studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
3.2. Twin studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
3.3. Adoption studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
3.4. Genes for suicidal behavior? Conceptualizing genetic effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
3.5. Association studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
3.6. Epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
4. Neurotransmitters and their receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
4.1. Serotonin (5-HT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
4.2. Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
4.3. Adrenaline and noradrenaline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
4.4. Glutamate and GABA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
4.5. Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
4.6. Acetylcholine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
5. Cell signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
6. Lipid metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
7. Stress systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
7.1. Hypothalamic–pituitary–adrenal axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
7.2. Polyamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
8. Astrocytes and oligodendrocytes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
9. Future outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
9.1. Whole genome association studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
9.2. Individualized genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
9.3. Deep sequencing and large-scale methylation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
9.4. MicroRNA analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327

* Corresponding author at: McGill Group for Suicide Studies, Douglas Hospital Research Institute, 6875 LaSalle Blvd, Montreal, QC H4H 1R3, Canada.
E-mail address: gustavo.turecki@mcgill.ca (G. Turecki).

0301-0082/$ – see front matter ß 2009 Published by Elsevier Ltd.

doi:10.1016/j.pneurobio.2009.09.001
316 C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333

9.5. RNA editing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327

9.6. Protein modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
9.7. Brain circuitry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
9.8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328

1. Introduction only on clinical and sociological relationships to suicide, yet the

age of genetics impacted the study of suicide as well. Kallman and
Suicide or suicide completion is the act of taking one’s own life others recruited twin pairs and only-children to better understand
voluntarily, and usually intentionally. Suicidal behavior is a general the heredity of suicide (Kallmann et al., 1949), i.e. if one twin
term used to refer to suicide and suicide attempts. Under the latter we commits suicide, does the other twin also suicide?
refer to the actions taken to end one’s life, irrespective of the degree of Research into suicide in the first half of the 20th century was
intentionality, but not resulting in death. While the majority of largely restricted to clinical variables that associated with suicide
individuals who attempt suicide will never die by suicide, about 50% and different methods of death selected by the subject. A succinct
of suicide completers made a previous nonfatal suicide attempt summary of the literature at this point is provided below (Sifneos
(Isometsa and Lonnqvist, 1998). As there is important variability in et al., 1956):
suicide intent among suicide attempters, these are regarded as a more
heterogeneous group than suicide completers (Turecki, 2005). ‘‘The literature on suicide is voluminous. Summaries of some of
The purpose of this review is to present evidence that a the findings follow. The role of social sciences in the study of
relationship exists between changes in the brain and suicidal suicide cannot be overemphasized. Dynamic formulations are
behavior. First, we will present an historical perspective of the very important in individual cases. In ‘‘successful’’ suicides, men
neurobiology of suicide. Our goal with this section is to understand outnumber women in a ratio of 3 to 1. In attempted suicides,
how and when the neurobiology of suicide came to be studied men are outnumbered by women in a ratio of 1 to 3. In age, the
independently from the study of mood disorders. Next, we will peak for men is from 25 to 29 years; and for women, from 20 to
address major brain systems (e.g., glutamate metabolism, astrocyte 24 (William Blake, ‘‘Auguries of Innocence.’’). Northern
function) that have been implicated in suicide. Finally, we will Europeans outnumbered Southern Europeans. Negroes attempt
conclude with a future outlook where we will describe some of the suicide less frequently than any other race. More Protestants
technologies that could be used to assess suicide neurobiology. Fig. 1 than Catholics try to kill themselves. Marriage seems to be a
summarizes the different approaches and major lines of investigation protective influence; the more people in the family, the fewer
in the research of the neurobiology of suicide and related behaviors. the suicides. Attempts increase in May and June in the Northern
hemisphere and in January and February in the Southern
hemisphere. Suicide is rare in the morning, frequent in the
2. Historical perspective
afternoon. With war it decreases, and with peace it increases.
Poison (iodine was first of the poisons years ago) is the favorite
Published record of the study of suicide began by statistical
method, with gas second. Slashing, firearms, hanging, leaping,
accounts of cause-of-death in different communities. The earliest
and drowning follow in that order in men; leaping, slashing,
reports of the kind appeared in the early 19th century by the
firearms, drowning, and hanging, in women. Physical incap-
American Board of Health (Board of Health, 1809). From the late
ability was the major motivating factor in 8 out of 200 patients.
1830s, more detailed statistical data about suicide became
The incidence of a history of broken homes is higher among
available. For instance, a study conducted by health departments
suicidal individuals than among those with any other type of
in England over a 24-year period included information on age and
adult nervous or mental illness.’’
sex of suicide completers as well as the month and method of
suicide (London, 1838). The book, Suicide (1897), by the sociologist In the 1950s, research on suicide took a distinctly more complex
Emile Durkheim helped lay a foundation for understanding the approach. Instead of focusing on raw population statistics,
sociological elements of suicide, for example, in the relationship investigators began to focus on clinical variables that relate to
between religious beliefs and suicide. Most early studies focused suicide such as psychopathology (Simon and Gilberstadt, 1958;

Fig. 1. Research topics in suicide neurobiology. Abbreviations: DA: dopamine ADR: adrenaline, 5HT: serotonin, ACH: acetylcholine, OPI: opioids, GLU: glutamate, WGAS:
whole genome association study.
 C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333
Walton, 1958). In one noteworthy case, researchers used the
Minnesota Multiphasic Personality Inventory to classify person-
ality types to determine who may commit suicide (Litman et al.,
1961). The early 1950s studies largely concluded that personalities
did not differ between attempters and a non-attempter psychiatric
control group, but that there did appear to be personality trait
differences between people who threatened suicide and those who
actually attempted it. These findings led scientists to suggest that
suicidal behavior should be sub-grouped into suicidal ideation/
threats and suicide attempters, to reduce the heterogeneity in the
samples (Rosen et al., 1954). The results from these studies, where
questionnaires were heavily influenced by the psychoanalytic
model of psychiatry popular at the time, suggested that suicide
was a result of poor masculine identification, narcissism, and poor
psychosexual development (Finn, 1955).
In the mid-1960s, the concept of suicide as a neurobiological
entity emerged. To this point, it was unclear exactly what the
relationship was between psychopathology and suicide. Debates
were ongoing about the causes of suicide, in particular whether most
people were reacting to a situation (e.g., break-up, lost job) or
whether there was an intrinsic, biological explanation why people
committed suicide. Studies investigating the biology of suicide
specifically had to use a within group design, where a particular
variable was measured at different time points in the subject
manifesting suicide behavior, anticipating that these subjects would
die by suicide. One of the first studies of this kind to be attempted was
done using urine samples collected from individuals prior to suicide.
Bunney and Fawcett observed that levels of 17-hydroxycorticoster-
oid, a breakdown product of cortisol, was elevated prior to suicide
(Bunney and Fawcett, 1965). The ability to possess samples from
patients who will commit suicide is an extremely difficult endeavor
because only a minority of patients will die by suicide (5% lifetime
risk in clinical populations) and that most people who die by suicide
are not followed by medical services. This difficulty is emphasized in
the Bunney and Fawcett study (1965) where it was only possible to
recruit three subjects. Later studies used postmortem brain tissue to
analyze neurotransmitter and hormone metabolism where suicide
cases could be studied independently from psychopathology,
provided a matched psychopathological control group was recruited
as well. This study design was employed with an investigation
measuring levels of the main metabolite 5-Hydroxyindoleacetic acid
(5-HIAA) of serotonin (5-HT), and noradrenaline (NA) in the
hindbrain of suicide and control subjects (Bourne et al., 1968). This
study showed reduced levels of 5-HIAA in the brains of suicide
completers compared to control subjects. Two subsequent studies of
significance assessed levels of 5-HIAA and other electrolytes in the
brain of suicide completers (Shaw et al., 1967, 1969). During the late
1960s, Pare and collaborators performed a comprehensive compara-
tive analysis of 5-HT, NA and dopamine (DA) levels in three different
brain regions of suicide and control subjects (Pare et al., 1969). These
studies were limited, however, by having to have previously assessed
subjects for psychopathology and other clinical variables ante-
mortem. Also, they investigated limited sample sizes as it was
difficult to obtain pre-mortem information. This was changed by the
psychological autopsy method (Barraclough et al., 1974) which
allowed the assessment of suicide cases that were previously
unknown to researchers and elicit pre-mortem diagnoses based on
proxy-based interviews. This permitted the expansion of postmor-
tem studies in suicide, most of which will be discussed in this review.
3. Genetics of suicide
3.1. Family studies
The notion that suicide aggregates in family is not new, as
indicated by Moore in 1790 in a book entitled A Full Enquiry Into The
317
Subject Of Suicide. In this publication, Moore indicates that suicide
has a propensity to affect successive generations of the same
family. A number of family and family history studies have shown
that suicidal behavior runs in families (reviewed in Baldessarini
and Hennen, 2004; Turecki, 2001). While most studies have shown
that biological relatives of adolescent and adult suicide completers
or attempters have higher rates of suicidal behavior as compared
with the relatives of control subjects (Brent et al., 1996; Cheng
et al., 2000; Johnson et al., 1998; Malone et al., 1995; Murphy and
Wetzel, 1982; Pfeffer et al., 1994; Roy, 2000; Tsuang, 1983), a
question that remained of critical importance is the potential
overlap between the familial liability to suicidal behavior and that
conferring predisposition to psychiatric disorders. In other words,
as suicide is frequently associated with psychopathology, and
primarily mood disorders, the question that researchers have been
trying to address over the last decades is to what extent familial
aggregation of suicide is conditional on the familial aggregation of
psychopathology.
One of the first studies that was able to disentangle familial
transmission of psychiatric disorders from familial aggregation of
suicide was the study carried out by Egeland and Sussex (1985) in
the Old Order Amish, a conservative religious community in
southeastern Pennsylvania. Although suicide is rare in the Amish,
they have kept extensive genealogical and medical records,
enabling the identification of all suicides that occurred during a
100-year period (1880–1980). In all, there were 26 suicides. These
suicides were clustered in only four families that also aggregated
mood disorders, while no suicides occurred in many other families
that also segregated mood disorders with the same density, illness
severity and overall clinical characteristics. This finding was
strongly suggestive that genetic factors increasing predisposition
to suicide are different from those increasing predisposition to
affective disorders. However, as families did not segregate suicide
in the absence of mood or other psychopathology, it seemed also
clear that familial transmission of suicidal behavior was
independent, but also conditional, on the liability for psycho-
pathology.
The formal test of this hypothesis was first made in a study
carried out by Brent et al. (1996), which investigated familial
aggregation of suicide and measures of aggression in adolescent
probands who had committed suicide, and compared these
measures with those of a sample of demographically similar
controls who had never exhibited suicidal behaviors. A higher rate
of suicide attempts was found in the first-degree relatives of
suicide probands compared with the relatives of controls. This
finding persisted even after controlling for increased rates of Axis I
and II disorders in probands and families, supporting the notion
that a genetic liability to suicide may be transmitted by a
mechanism separate from the familial transmission of psychiatric
disorders. Of further interest is their finding that a higher familial
loading of suicide attempts among suicide probands was
associated with higher scores on aggression measures in the
probands, even after controlling for family loading of aggression.
This suggests that the genetic transmission of suicidal behavior
and aggressive traits are related. In a methodologically similar
study in adult probands, our own group found that relatives of
suicide completers were over 10 times more likely than relatives of
comparison subjects to attempt or complete suicide after
controlling for psychopathology (Kim et al., 2005). Similarly, other
studies corroborate the notion that factors accounting for familial
transmission of suicidal behavior act, at least in part, indepen-
dently from factors accounting for liability to psychopathology. In
two studies investigating high risk offspring of parents with
suicidal behavior, Brent and colleagues (Brent et al., 2002, 2003)
found that offspring of mood-disordered attempter parents were
more likely to attempt suicide themselves relative to the children
318 C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333
of mood-disordered non-attempting parents, despite having
similar Axis I and II profiles.
3.2. Twin studies
Twin studies investigating suicide completion, given its
relatively infrequent nature, have been limited to case reports
on concordance between twin pairs, according to zygosity. Studies
focusing on suicide attempts, on the other hand, have investigated
epidemiologically representative samples and are methodologi-
cally more robust. Regardless of the design, however, twin studies
suggest that genes account for at least part of the familial
aggregation of suicidal behavior, consistently indicating that
concordance rates for MZ twins are higher than for DZ twins
(Roy et al., 1991, 1995; Glowinski et al., 2001; Statham et al., 1998).
Roy et al. (1991) looked at concordance rates in a sample of 176
twin pairs in which at least one twin from each pair had committed
suicide. Seven of the 62 MZ twin pairs (11.3%) were found to be
concordant for suicide, while concordance was observed for only
two of the 114 DZ twin pairs (1.8%). In a separate study, Roy et al.
(1995) examined the frequency of attempted suicide in a sample of
living twins whose co-twins had committed suicide and found that
38% of MZ co-twins had a history of attempted suicide, while none
of the DZ twins did. Thus, higher concordance rates are again
observed in MZ twins, particularly when a broader spectrum of
suicidal behavior is considered.
A large epidemiological and genetic study conducted in an
Australian community-based sample of MZ and DZ twin pairs
examined suicidal behavior and considered a number of important
risk factors, including psychiatric history, personality traits,
traumatic life experiences and certain socio-demographic vari-
ables (Statham et al., 1998). It was found that even following
adjustment for these risk factors, history of suicidal behavior in one
MZ twin remained a powerful predictor of suicidal behavior in the
other MZ co-twin, while failing to be consistently predictive in DZ
twin pairs. Furthermore, this genetic liability was determined
using a genetic model-fitting approach to account for approxi-
mately 55% of the variance in serious suicidal behavior.
In a sample of male twins, Fu et al. found that a suicide attempt
in one MZ twin was predictive of suicide attempt or ideation in the
co-twin, even after controlling for other risk factors, including
psychiatric history, and concluded that the genetic liability to
suicidal behavior is likely independent of the genetic predisposi-
tion to psychiatric illness (Fu et al., 2002). Glowinski et al. (2001)
reported similar findings in an adolescent female twin sample.
3.3. Adoption studies
Adoption studies have produced data largely consistent with
the findings from twin studies. The first adoption study on suicide
was carried out by Schulsinger et al. (1979) using the Danish case
registry of adoptions. There were 57 cases found of adoptees that
had committed suicide. These were matched to a control sample of
57 adoptees. Examination of the biological relatives of these
adoptees revealed significantly more suicides among the biological
relatives of the suicide adoptees compared with the biological
relatives of the control adoptees. There were 12 suicides out of the
269 biological relatives of the suicide adoptees, while there were
only 2 cases of suicide among the 269 biological relatives of the
control adoptees. There were no cases of suicide found among the
adoptive relatives of either the suicide or control adoptees. These
findings provide evidence that the tendency to suicide is
influenced by genetic factors.
Wender et al. (1986) selected 71 index adoptees with affective
disorders and 71 control adoptees from the same Danish adoption
registry, and examined the frequency of psychiatric disorders
among the biological and adoptive relatives. Particularly remark-
able was their finding that the frequency of suicide among the
biological relatives of the index adoptees was 15 times higher than
that of the biological relatives of the control adoptees, with no
differential risk between the adoptive relatives of index and
control adoptees. Moreover, they noted an especially high
frequency of suicide among the biological relatives of a subset
of index adoptees who were characterized as ‘‘affect reaction’’ type
(i.e. more prone to make an impulsive suicide attempt in response
to an emotional setback). In addition to providing further robust
evidence for a genetic predisposition to suicide that is transmitted
independently of the genetic liability to psychopathology, this
study goes one more step forward to suggest that the genetic
element in suicide may be related to impulse control.
Family, twin and adoption studies provide consistent evidence
that there is an underlying genetic predisposition to suicidal
behavior which is distinct from, although perhaps contingent on,
the genetic liability to psychiatric illness. Suicidal behavior, as a
complex trait, is likely to be the result of a combination of
numerous environmental factors and the effect of multiple genes.
3.4. Genes for suicidal behavior? Conceptualizing genetic effects
As reviewed above, there is strong support for familial and
genetic factors increasing vulnerability for suicidal behavior. It is
unlikely, however, that genes have direct effects on suicide risk.
More precisely, genetic effects are believed to act through
intermediate phenotypes (Turecki, 2005), which are conceptua-
lized as the link between genes and suicidal behavior. In other
words, intermediate phenotypes, are factors that mediate the
relationship between genes and suicidal behaviors. There is
considerable data suggesting that cluster B personality disorders
and impulsive-aggressive personality variants may act as inter-
mediate phenotypes of suicidal behavior (Brent et al., 1994;
Duberstein et al., 2000; Dumais et al., 2005a,b; Isometsa et al.,
1996). Accordingly, several studies suggest that suicide completers
and attempters have higher levels of these behaviors (Brent et al.,
1994; Brezo et al., 2007; Dumais et al., 2005a; McGirr et al., 2007a).
High levels of impulsive-aggressive behaviors appear to be related
to increased suicide risk among patients with the same psychiatric
diagnosis, such as major depression (Dumais et al., 2005a) and
borderline personality disorder (McGirr et al., 2007a), as well as
when, in the course of the illness, suicide is more likely to occur
(McGirr et al., 2008a). More importantly, high scores of impulsive-
aggressive behavior in probands predict increased familial loading
of suicidal behavior (Brent et al., 1996; Kim et al., 2005), history of
suicidal behavior is associated with increased levels of impulsive-
aggressive behaviors among psychiatric patients (Diaconu and
Turecki, 2008), and finally, familial aggregation of suicidal behavior
co-segregates with (Brent et al., 1996; Kim et al., 2005), and seems
to be partly explained by (McGirr et al., 2007b), familial
transmission of impulsive-aggressive behaviors.
3.5. Association studies
In light of the considerable support from genetic–epidemiolo-
gical studies for the role of genetic factors in suicidal behavior,
many case–control association studies have been conducted
exploring the effect of genetic variation on suicidal behavior.
We have generated a database, updated quarterly that catalogues
all genetic association studies in suicide (available through
www.douglasrecherche.qc.ca/suicide). To date, however, the
identification of putative susceptibility genes remains elusive.
As with other psychiatric phenotypes, association-based searches
for genes with small-to-moderate effects in complex diseases are
plagued by insufficient power, population stratification, and
 C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333
phenotype heterogeneity (Craddock and Forty, 2006) Additionally,
the effects of some variants may only be obvious when considered
in the context of other genes and environments (Caspi et al., 2003;
De Luca et al., 2006). Along with methodological improvements,
future research in the field should benefit from better character-
ization of final and intermediate phenotypes, quantification of
both main and interactive genetic effects within and across
systems, and consideration of environmental and epigenetic
factors.
3.6. Epigenetics
Epigenetic effects are non-heritable changes to the genome or
changes to those factors that regulate the genome. Some examples
of epigenetic changes include histone acetylation, phosphoryla-
tion, and methylation, but by far the best studied example of
epigenetics in suicide and psychiatry is DNA methylation. This is
the addition of a methyl group to DNA and can alter DNA structure
or DNA binding protein accessibility. These changes can repress
gene transcription affectively turning a gene on or off. DNA
methylation has long been known to be important in cell specific
functioning (DNA is identical in every cell, yet neurons are
different from hepatocytes) and X chromosome inactivation in
women.
DNA methylation is suggested to be involved in psychiatry as an
explanation for the apparent reductions in RNA or protein that may
be related to some mental disorders. For example, if a disease is
caused by reduced function of GABA-A receptor, than the
methylation of the GABA-A receptor gene may be the cause of
this reduction.
The first suggestion that a methylation-related mechanism was
involved in psychiatric illness was probably by Osmond and
Smythies (1952), when they observed that some hallucinogens
(e.g., mescaline) are methylated versions of catecholamines—
major neurotransmitters in the brain. They proposed that
psychosis was due to abnormal methylation (in this case of an
amine) of catechols in the brain. They termed this the ‘‘trans-
methylation hypothesis’’ (Osmond and Smythies, 1952).
Methylation of DNA and its effects on gene transcription may
have a role in psychiatric disorders. The epigenome (the pattern of
methylation throughout the genome) is programmed during
development, but recent data suggests that it could be responsive
to environmental cues during life. Signaling pathways activated by
neuronal and environmental stimuli could target DNA methylation
to specific loci, resulting in inter-individual epigenetic alterations
that would cause changes in gene expression. It is these inter-
individual differences in methylation that may mediate the
interaction between the genome and the environment that may
predispose people to the development or persistence of a mood
disorder. Recent work has implicated altered methylation patterns
of a number of different genes in a psychiatric context. In an animal
model of early life environmental influences, a recent study has
suggested that mice raised in environments with poor maternal
care have increased methylation at a CpG nucleotide that forms a
transcription factor binding site in the glucocorticoid receptor gene
(Weaver et al., 2004). This data suggests that early life events can
alter methylation status and affect gene transcription of an
important gene in stress reactivity. This finding has recently been
translated by our group to humans, by studying the epigenetic
regulation of the glucocorticoid receptor in hippocampus tissue
from suicide completers with a history of severe childhood
adversity (McGowan et al., 2009). A number of different genes
have also been investigated in humans in relation to psychiatric
illness, mostly schizophrenia, including reelin (Grayson et al.,
2005; Tochigi et al., 2008a), COMT (Abdolmaleky et al., 2006),
Sox10 (Iwamoto et al., 2005). In relation to suicide, such genes as
319
rRNA (McGowan et al., 2008), GABAA (Poulter et al., 2008), the
glucocorticoid receptor (McGowan et al., 2009), and TrkB (Ernst
et al., 2009) have implicated a role of DNA methylation on reduced
expression in suicide.
While DNA methylation is cell specific, it is not clear how
important DNA-region specificity is, in terms of dysfunction
possibly leading to suicide. Having an increased methylation
pattern on certain genes in DNA extracted from hippocampal cells
and no methylation change between cases and controls on, for
example, DNA extracted from cells from the frontal cortex may not
be as important as the actual molecules involved in methylation;
the expression of ‘methylation molecules’ may be region specific.
The possible mechanism regulating these methylation molecules is
unknown, but it may be related to external stimuli. That is, that
some environmental stimulation (e.g., divorce) leads to the up-
regulation of a methylation molecule in a particular brain region,
leading to altered DNA methylation of specific genes.
Epigenetic analyses in psychopathology offer a possible
explanation for the difficulty geneticists have experienced trying
to link genetic polymorphisms to disease. Epigenetic effects alter
gene expression without altering the genome and there is some
evidence that environmental factors can influence methylation
status. More work is required in this area to clarify the role of
epigenetic modification to DNA or histones and the relationship to
psychopathology.
4. Neurotransmitters and their receptors
4.1. Serotonin (5-HT)
The 5-HT system has been the most widely investigated
neuromodulatory system in studies of suicide attempters and
completers. The idea of a dysfunction in 5-HT transmission leading
to depressed mood and possibly suicide emerged from the clinical
benefits of antidepressants acting on serotonergic neurotransmis-
sion, as well as to two studies where CSF-5HIAA was correlated
with depression and suicide (Asberg et al., 1976a,b).
The dense 5-HT innervations pervading all brain regions
originate exclusively from projection neurons located in the
brainstem’s raphe nuclei. Tryptophan hydroxylase (TPH), the
enzyme of synthesis of 5-HT, has been widely used as a marker of
5-HT activity. Quantitative immunocytochemical and immunoau-
toradiographic studies in the dorsal raphe nucleus (DRN), which
projects mainly to the cerebral cortex and hippocampus, have
shown significantly higher numbers and densities of TPH-
immunoreactive (TPH-IR) neurons in MDD subjects (Underwood
et al., 1999), depressed suicides (Boldrini et al., 2005) and alcohol-
dependent depressed suicides (Bonkale et al., 2004) compared to
controls. In accordance with these studies, Bach-Mizrachi and
colleagues (2006) reported a 33% increase in expression (mRNA) of
TPH2 in the raphe of suicide victims compared to controls. Given
the multiple lines of evidence indicating an overall reduction in 5-
HT transmission in both cortical and subcortical regions of MDD
and suicide subjects (see below), increased TPH expression could
constitute a compensatory mechanism to alleviate central 5-HT
transmission, and/or a response to increased stress, which has also
been associated with alterations of TPH protein and mRNA levels
(Azmitia et al., 1993; Chamas et al., 2004). Alternatively, a
predisposing neurodevelopmental phenomenon may exist which
increases the number of 5-HT neurons in the DRN, as suggested by
the observation of significantly higher numbers of TPH-IR neurons
documented across the lifespan, even at a young age, in suicide
subjects (Underwood et al., 1999). A possible mechanisms
accounting for such an increase would be an alteration in the
programmed cell death normally occurring during brainstem
development.
320 C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333
A large number of studies investigated 5HT receptor binding in
postmortem brain tissue from suicides or platelets from attemp-
ters and controls. Arango et al. (2001) examined [3H]-paroxetine
binding to the 5-HT transporter (SERT) in the DRN of suicides and
matched controls, and reported fewer SERT-expressing neurons
accompanied by a greater expression of SERT per neuron. This
study also reported a decrease in 5-HT1A binding, thus suggesting
a loss of receptors in the raphe, in contrast to earlier data from an
independent group (Stockmeier et al., 1998). With regards to 5-HT
innervations in terminal fields, Mann and colleagues reported a
decrease of [3H]-paroxetine binding in prefrontal cortex (Mann
et al., 1996) and ventro-lateral prefrontal cortex (Arango et al.,
1995) of suicide subjects. Although these data were not
consistently reproduced by others (Bligh-Glover et al., 2000;
Hrdina et al., 1993; Lawrence et al., 1990) SERT-immunocyto-
chemistry has supported the notion of a decrease in densities of 5-
HT innervations in prefrontal cortical areas (Austin et al., 2002).
A few 5-HT receptor binding studies have compared terminal
fields between suicides and controls. Cheetham and collaborators
reported no difference in 5-HT2 binding sites (Cheetham et al.,
1988a) in cortex and amygdala, nor in 5-HT1A and 5-HT1B binding
(Cheetham et al., 1990) in frontal and temporal cortex of suicides
versus matched controls. They did, however, report a reduction in
the number and affinity of 5-HT1 binding sites in the hippocampus
and amygdala, respectively (Cheetham et al., 1990). A subsequent
study found a significant increase in [3H]-ketanserin (5-HT2
receptors) binding in both PFC and amygdala (67% and 96%,
respectively) (Hrdina et al., 1993). However, using a very large
sample of 73 suicides and 70 controls, no difference between
groups was observed in [3H]-ketanserin binding in any of six brain
regions assessed (Lowther et al., 1994). In a similar sample, these
investigators found no difference in [3H]8-OH-DPAT (5-HT1A)
binding either (Lowther et al., 1997).
Neuroendocrine challenges have also been used to understand
the role of serotonin in suicide. Fenfluramine, the most commonly
used serotonin challenge agent, causes the release of serotonin
from pre-synaptic storage granules, inhibits its reuptake, and may
also stimulate post-synaptic serotonin receptors (Rowland and
Carlton, 1984). The serotonergic activation leads to a dose-
dependent increase in prolactin (Quattrone et al., 1983). Decreased
prolactin responses are believed to reflect reduced serotonergic
activity. Blunted prolactin responses to fenfluramine challenge
have been observed in patients with major depression and a
history of suicidal behavior (Mann et al., 1995).
Correa et al. (2000) found significantly lower prolactin
responses to fenfluramine challenge in psychiatric patients with
a history of attempted suicide compared with healthy controls and
patients without such a history, and propose that the blunted
serotonergic response may represent a marker for suicidality
specifically, rather than depression. Furthermore, reduced prolac-
tin responses to fenfluramine challenge have also been seen in
psychiatric patients with diagnoses other than depression, such as
personality disorders (New et al., 1997; Soloff et al., 2003).
Malone et al. (1996) found a significantly lower prolactin
response to fenfluramine in patients with a history of a higher
lethality suicide attempt, suggesting that high-lethality suicide
attempters are more closely related to completed suicides not only
behaviorally but also at a biochemical level. Keilp et al. (2008)
analyzed prolactin output after fenfluramine challenge and
followed subjects for a 2-year period. Suicide attempters and
psychiatric patients demonstrated a lower prolactin output.
Microarray expression studies offer the possibility to assess
transcription levels of most known genes and 5-HT related genes
can also be assessed in this way. A number of microarray studies in
human frontal cortex have been produced in recent years for both
the study of suicide and major depression (Choudary et al., 2005;
Kim et al., 2007; Sequeira et al., 2006; Sibille et al., 2004; Tochigi
et al., 2008b).
Sibille et al. (2004) produced the first comprehensive micro-
array study in the depressed suicide brain. In this study, 19
depressed suicides were matched to controls and RNA extracted
from two frontal cortical regions was processed by microarray.
After stringent microarray statistical processing, the authors found
no significant differences between groups. A follow-up analysis
examining only genes of the 5-HT system yielded no results of
significance. Our own group using microarray data from 17
different brain regions from 14 controls and 30 suicide completers,
most of whom had depression, also failed to detect any differences
in expression of any genes in the serotonergic system (Ernst et al.,
2009; Klempan et al., 2007; Sequeira et al., 2006, 2007). In another
study (Kim et al., 2007), suicide completers were compared to
other subjects with the same Axis I diagnosis (either schizophrenia
or bipolar disorder). Despite the large sample size used, not one
serotonergic-related gene was detected as significant between
groups. The negative evidence of 5-HT gene expression was further
solidified by the Tochigi study, where 99 differentially expressed
genes were identified, but none of which were serotonergic. The
Pritzker group (Atz et al., 2007) did not provide detailed analysis of
gene expression differences between groups, so it is impossible to
say whether any serotonergic genes were detected as differentially
expressed between suicide and non-suicide groups in that
microarray study. It seems reasonable to suggest though, that
the lack of presentation of any serotonergic gene expression data
likely signifies that there were no differences.
It is not clear exactly why protein studies of serotonergic
function have been mostly positive and RNA studies mostly
negative (i.e. no differences in expression between groups). One
possible explanation is that the dysfunction in serotonergic
function occurs post-translationally. In that, RNA levels between
suicides and controls are similar, but some dysfunction after
protein synthesis leads to altered levels of the serotonergic protein
product. It would be curious to see whether these protein findings
would be substantiated if non-hypothesis-driven approaches were
used, as the RNA analyses were.
While some neuroanatomical studies have suggested a link
between serotonergic receptor up- or down-regulation in depres-
sion and suicide, this has not been supported by microarray
studies. While microarray studies have been criticized for lack of
accuracy (Geller et al., 2003; Pavlidis et al., 2003), these studies
have the initial benefit of being exploratory studies, which allow
experimenters to assess many possible leads without committing
to any one in particular in the initial analysis. While involvement of
the serotonergic system cannot be ruled out, it has been suggested
that more energy needs to be spent investigating other biological
systems (Rujescu et al., 2007).
4.2. Dopamine
The major dopaminergic innervations in the brain take their
origin in the ventral tegmental area and substantia nigra in the
mesencephalon. To date, very little evidence has implicated
dopaminergic transmission in suicide. Measurements of dopamine
concentrations in cortical and subcortical regions in suicide versus
matched control subjects did not reveal any significant difference
between groups (Allard and Norlen, 2001). However, it has been
hypothesized that mesolimbic dopaminergic transmission is
reduced in depression and suicide (Bowden et al., 1997), which
could account for the dopaminergic-based antidepressant phar-
macotherapies. In support for this, radioligand binding data have
shown that there is a significant reduction in dopamine transport
coupled with an increase in D2/D3 receptors in the amygdala of
major depressed subjects. It is thus conceivable that regional
 C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333
changes in dopaminergic transmission may be involved in mood
disorders (e.g., by contributing to anhedonia) and lead to suicide.
4.3. Adrenaline and noradrenaline
Adrenaline (epinephrine) is synthesized from tyrosine and
phenylalanine in both the adrenal gland and the brain, and is
considered both a hormone and a neurotransmitter. Adrenaline is
an activator molecule well known to induce several physiological
effects (e.g., increased heart rate) and general cognitive enhance-
ment (e.g., increased awareness and attention). Although adre-
nergic transmission has been hypothesized to play a role in mood
and possibly suicide (Lipinski et al., 1987), no study has examined
in suicide the morphological features of the small adrenergic nuclei
located in the brainstem. Instead, most of the attention has been
devoted to central noradrenergic transmission, including the
adrenaline- and noradrenaline-binding adrenergic receptors; a
system also known to interact with the stress response through a
feed-forward mechanism.
Noradrenaline-synthesizing neurons are located in the locus
coeruleus (LC) of the brainstem and project to all brain regions
(Moore and Bloom, 1979). The LC has been reported to present
neurochemical alterations in MDD and suicide subjects (Merali
et al., 2006), but there is no compelling evidence in the literature
suggesting that LC cells display morphological signs of altered
plasticity in these conditions. Thus, most studies have failed to find
differences between MDD suicides and control subjects in the
number of neuromelanin containing (NA-producing) cells in the LC
(Baumann et al., 1999; Syed et al., 2005). One report has indicated
significant reductions in the total number and average density of
pigmented LC neurons (left hemisphere only) in suicide com-
pleters (Arango et al., 1996), and another the inverse trend
(Ordway et al., 1994). In general, no differences have been reported
in the numbers of LC TH-immunoreactive neurons (TH-IR)
between depressed suicides and control subjects. Interestingly, a
secondary analysis by Baumann and colleagues (1999) revealed
that the patients with mood disorders not committing suicide had
significantly fewer TH-IR neurons. Arguably, this observation
suggests that the LC undergoes similar increases in local
neurotransmitter synthesis than those in the DRN in subjects
with mood disorders which are prone to suicide. In line with this
argument, increased levels of TH protein have been observed in the
LC of suicide subjects.
In the CNS, the metabotropic adrenergic receptors are
subdivided into a- and b-subtypes (Hein, 2006). The a2-
adrenergic receptors have received the most attention with
regards to suicide. At the time of these adrenergic studies, the
reduced monoaminergic (serotonin and noradrenaline) function-
ing theory of depression was under intense investigation and
epinephrine, or the catabolic products of epinephrine, reductions
had received little support from brain studies in depression and
suicide to date (Moses and Robins, 1975; Riederer et al., 1980) The
inhibitory presynaptic a2-adrenergic receptors then, represented
a different player in the adrenergic system to study with regard to
the monoaminergic theory of depression. Until 1992, a2-
adrenergic receptors had been investigated in depressed brain
in hippocampus, frontal cortex, and occipital lobes—with no
significant differences between cases and controls (Crow et al.,
1984; Ferrier et al., 1986).
Garcia-Sevilla and colleagues therefore performed a large study
of multiple brain regions specifically in depressed suicides and
controls assessing the level of a2-adrenergic receptors (Meana
et al., 1992) and reported increases in a2-adrenergic receptor
densities in the hypothalamus and frontal cortex of depressed
suicides compared to matched controls, with no changes in
binding affinity, which supported some of their earlier work
321
(Meana and Garcia-Sevilla, 1987). These data were supported by
subsequent findings obtained with a similar sample set, where
increased a2-adrenergic receptor binding (Callado et al., 1998) and
mRNA levels (Garcia-Sevilla et al., 1999) were described in frontal
cortex of depressed suicides compared to controls. Employing the
a2-adrenergic agonist [3H]UK-14304, these authors further
reported a significant increase in [35S]GTPgs binding in hippo-
campal and frontal cortical tissues of suicides and depressed
suicides compared to controls (Meana et al., 1992). More recent
studies by this group have provided further evidence that a2-
adrenergic receptor expression is altered in the brains of depressed
suicides (Escriba et al., 2004; Gonzalez-Maeso et al., 2002).
However, a number of negative studies by independent groups
suggest that this may not be the case (Arango et al., 1993; De
Paermentier et al., 1997; Gross-Isseroff et al., 2000). Other studies
suggest that a2-adrenergic receptors may be involved in non-
frontal cortical regions (De Paermentier et al., 1997; Ordway et al.,
1994).
It is difficult to accurately assess a2-adrenergic receptor studies
because of the disparate nature of the studies from the
independent groups. Different groups tend to use different brain
areas for their studies and sometimes different technologies to
assess the idea that a2-adrenergic receptors are increased in
suicide brain, thereby supporting the monoaminergic reduction
theory of depression and suicide. If the number of current a2-
adrenergic studies is any indication though, it seems that most
groups see little evidence for a2-adrenergic receptor increases in
suicide.
4.4. Glutamate and GABA
Glutamate and GABA are respectively the main excitatory and
inhibitory neurotransmitters in the mature brain. As a rule of
thumb, glutamate is mainly synthesized by projection neurons,
whereas GABA is the fast-acting transmitter used mainly by
interneurons. Glutamine is a core requirement for the synthesis of
both glutamate and GABA. In nerve terminals, the enzyme
glutaminase converts glutamine to glutamate, and the latter can
be used for the synthesis of GABA via the enzymatic actions of GAD.
In glial cells, glutamine synthetase is the enzyme required to
synthesize glutamine from the re-uptake of either glutamate or
GABA (Weiler et al., 1979).
Recently, it was reported that a highly significant increase in
density of GABA neurons (GAD 65/67-immunoreactive (-IR))
occurs in the hippocampus and in several neocortical areas in
MDD suicide subjects versus controls (Bielau et al., 2007),
suggesting GABA dysfunction as a widespread phenomenon in
the brain. However, these results need to be further investigated as
studies using different methodologies have indicated a somewhat
opposite trend. Recently, Rajkowska et al. (2007) focused on
subpopulations of cortical GABA interneurons based on the co-
expression of GABAergic markers with calcium binding proteins
and found significant reductions in both neuron somal size and
density for BA9 calbindin (CB)-IR neurons in MDD (majority of
suicides) versus control subjects. In contrast, these authors found
no differences in the density and somal size of parvalbumin-
immunoreactive (PV-IR) interneurons in the same sample (Raj-
kowska et al., 2007).
There are three major classes of glutamate receptors: AMPA,
NMDA, and metabotropic glutamate receptors. AMPA receptors are
composed of 4 subunits (GluR1–GluR4; Wisden and Seeburg,
1993), whereas NMDA receptors are composed of one NR1
receptor and one of NR2A, NR2B, NR2C, NR2D subunits (Wenthold
et al., 2003). The family of metabotropic receptors comprises
mGluR1-mGluR8 (Conn and Pin, 1997). One study of NMDA
receptors with the ligand MK-801 showed no difference between
322 C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333
suicide and control subjects (Holemans et al., 1993). Functional
activation of NMDA receptors requires co-binding of glycine and
glutamate at distinct sites. To test the hypothesis that glycine
displaceable sites may be altered in suicide brains, Nowak et al.
(1995) assessed the proportion of high affinity glycine displaceable
[3H]CGP-39653 binding sites in the brain, and found that binding
was reduced from 45  5% in controls to 27  6% in suicide victims. A
later study also suggested that the density of AMPA receptors may be
increased in the caudate nucleus of suicide subjects (Noga et al.,
1997).
Despite a slight difference observed in the hypothalamus,
regional GABA levels in the brain do not seem to differ between
suicide and control brains (Korpi et al., 1988). Similarly, assessing
binding to GABA transporter-1 (GAT-1) with the ligand [3H]-
tiagabine in frontal cortex and anterior cingulate cortex of suicide
and control subjects led to no significant difference between
groups (Sundman-Eriksson and Allard, 2002). GABAA and GABAB
receptors, the two GABA receptor subtypes (Macdonald and Olsen,
1994), have received significant attention from suicide research-
ers, and studies have largely come up negative. Manchon et al.
(1987) conducted one of the first GABA receptor binding studies in
suicide brains. These authors reported an increase in the number
of type I benzodiazepine binding sites in the hippocampus of
suicides versus controls. This increase was accompanied by a
slightly greater binding affinity (Manchon et al., 1987). Using a
larger sample, the same group later reproduced these results
(Rochet et al., 1992). However, an independent study using the
same radioligand with hippocampal and amygdalar tissues found
no difference between subject groups (Stocks et al., 1990).
Similarly, investigating GABAA receptor binding with [3H]-
flunitrazepam at three anatomically defined levels of the locus
coreleus revealed no significant difference between depressed
suicides and controls (Zhu et al., 2006). A subsequent study of
benzodiazepine receptors in BA10 using [3H]-RO15-1788 realized
in schizophrenic suicides, non-schizophrenic suicides and con-
trols found a small increase in benzodiazepine receptors in the
suicide group, although this seemed mostly due to neuroleptic
treatment (Pandey et al., 1997). Similarly, Cheetham and
colleagues (1988b) reported an increase in GABAA binding in
the frontal (but not temporal) cortex of suicides versus controls.
Two studies investigating metabotropic GABAB binding sites in
the brain found no difference between suicide and control
subjects (Arranz et al., 1992; Cross et al., 1988).
GABA- and glutamate-associated dysregulations have been the
most consistent finding in microarray studies in psychiatry.
Choudary et al. (2005) used tissue from BA9 and anterior cingulate
cortex from 7 controls, 9 MDD subjects and 6 BPD to generate
microarray data—these subjects appear to be identical to those
subjects used in the paper by Evans et al. (2004). In subjects with
MDD, this group showed that SLC1A2, SLIC1A3, and glutamine
synthase (GS) were all down-regulated in the sample of MDD
compared to controls in both regions, while GABAAa5 was
upregulated. The findings of SLC1A2, SLIC1A3, and GS down-
regulation are of interest as they are all glia specific genes,
suggesting support for a glial hypothesis of mood abnormalities
(Coyle and Schwarcz, 2000). With regards to GABAAa5, Kim and
colleagues also showed an upregulation of GABAAa5 in a large
microarray sample (>50 microarray chips for both controls and
suicides) in frontal cortex of suicide completers with mixed
phenotype and controls subjects (Kim et al., 2007). This study also
found SLC1A3, and GLUL to be significantly down-regulated in
suicide brain. Our own group has conducted a series of studies
using microarray data generated from suicide completers and
controls using brain tissues from the Quebec Suicide Brian Bank.
Our data has implicated GABA and glutamate dysfunction
(Klempan et al., 2007; Sequeira et al., 2007), and the same gene
transcripts identified by Choudary et al. (2005) as down-regulated
are found in the samples we analyzed.
While glutamate-associated findings show some consistency
across microarray studies, as well as other studies assessing MDD
and suicide, future work will need to be performed cautiously as
glutamate has a known role in brain cell death (Nicholls, 2008).
Therefore, it will be important in future postmortem studies to
control carefully for method of death and agonal state. For both
glutamate and GABA associations with psychopathology, the lack
of specificity to a particular mental illness is of some concern. For
example, is glutamate/GABA dysfunction consistently present in
schizophrenia, MDD, and bipolar disorder? Given the differing
phenotypes, this would be surprising, although glutamate/GABA
systems may be involved in different CNS systems or perhaps at
the level of different receptor subunit stoichiometry for different
diseases. In this perspective, subtle differences in the glutamate/
GABA system, beyond analysis of up–down-regulation, will need to
be investigated.
4.5. Opioids
Opioids have long been known to have an effect on mood, but
not since the discovery of endogenous opioids and opioid receptors
(Cox et al., 1975; Goldstein, 1976; Hughes et al., 1975), and their
effects (Belluzzi and Stein, 1977) have these molecules been
examined as potential etiological factors in mood disorders (Ball,
1987). The first study to examine the relationship between opioid
receptors and suicide was performed with quantitative [3H]-DAGO
autoradiography to assess m-opioid receptors in the brain (Gross-
Isseroff et al., 1990). This group reported that younger suicide
completers had a higher density of m-opioid receptors in frontal
and temporal cortex than matched controls. These results were
later independently replicated with the same technique on a
comparable sample (15 subjects per group) (Gabilondo et al.,
1995). In this study, a 40% increase in m-opioid receptors was
observed in frontal cortex and thalamus. Interestingly, a recent
investigation employing the same approach found no difference in
m-opioid density or affinity in prefrontal cortex or pre-post central
gyrus of suicide completers compared to matched controls
(Zalsman et al., 2005). This may be attributable to smaller sample
size (n = 9/group). No study has yet addressed the distribution and
affinity of other opioid receptor subtypes in the brain of suicide
subjects.
4.6. Acetylcholine
Acetylcholine (ACh) innervations in the brain originate from the
basal forebrain, the pedunculopontine tegmentum, and from a
population of giant interneurons in the striatum. ACh has been
implicated by several studies in cognitive states and functions,
such as attention and memory (Sarter et al., 2003). There are two
main types of acetylcholine receptors: nicotinic (nAChRs) and
muscarinc receptors (mAChRs) (Berg et al., 1989; Birdsall and
Hulme, 1976; McCarthy et al., 1986). Cholinergic dysfunction was
first considered in psychiatric disorders when sleep disturbances
in mood disorders were related to myasthenia gravis, an
autoimmune disorder where antibodies attack nAChRs and
generate weakened states (Gillin et al., 1979; Sitaram et al.,
1982). To our knowledge, no study has ever examined the
morphology of ACh neurons and their axonal projections in
suicide, and none have reported in this context on changes in
nAChR binding in the brain. In contrast to Meyerson et al. (1982)
who reported that [3H]-quinuclidinyl benzilate binding to mAChRs
increased by 47% in the cerebral cortex of suicide completers
compared to homicide victims (Meyerson et al., 1982), two
subsequent studies using the same approach reported no
 C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333
difference in mAChR binding affinity nor density between groups
in the frontal cortex (Stanley, 1984) as well as in the pons and
hypothalamus (Kaufmann et al., 1984). An investigation using
[35S]-GTPgS binding to G-proteins largely supported the view that
mAChRs are generally unaltered in suicide brains (Gonzalez-Maeso
et al., 2002). More recently, however, using [3H]-pirenzepine, a
ligand specific to M1 and M4 receptors, an effect of suicide on
binding was reported (Zavitsanou et al., 2004) in one patient
population (SCZ) but not in others (bipolar and major depressive
disorders). It remains to be seen if this result will be replicated in
other samples.
5. Cell signaling
Extra- and intra-cellular signaling refers to the interaction and
resulting effector cascade between proteins inside or outside the
cell. The processes can be seen as continuous in the sense that
nuclear effects generate gene products which can be exported from
the cell to stimulate receptors on other cells’ membranes which
can then activate an intracellular signal cascade which stimulates
nuclear effectors. In suicide research, the study of signaling
molecules is largely restricted to either measuring the quantity of
an RNA or protein molecule postmortem known from basic
neuroscience studies to be involved in cell signaling or, in some
cases, from the attempt to measure activity of a protein extracted
from suicide brain (Shelton et al., 2009).
Neurotrophic factors are extracellular signaling molecules and
have emerged as candidate molecules in the neurobiology of
suicide. Neurotrophins are well known for their roles in neuronal
survival and plasticity, and their altered expression could underlie,
at least in part, changes in plasticity observed in the brains of
suicides. Neurotrophic receptors, meanwhile, are mostly found on
the cell membrane and, after binding the ligand, can stimulate
intracellular effects. While the major neurotrophic factors include
NGF, NT3/4, FGF, and BDNF, only BDNF, FGF, or their respective
receptors have been associated with suicide or major depression
by multiple investigators.
FGF is an important molecule for cell and organ development
throughout the body, including the brain (Turner et al., 2006;
Vaccarino et al., 1999). Two different studies have implicated the
fibroblast growth factor (FGF) system in depression and suicide.
Using brains collected as part of the Pritzker consortium, Evans
et al. (2004) used frontal cortical tissue from 14 controls, 6 bipolar,
and 13 MDD subjects, of which 6 were female. The most robust
findings from their work were that two FGF receptors (FGFR2 and
FGFR3) are down-regulated in both DLPFC and anterior cingulated
cortex specifically in MDD subjects. The FGF system is of interest to
studies of suicide and depression and has received some support
from other research groups. For example, microarray data derived
from BA10 from Stanley subjects (15 bipolar, 15 depressed, 15 SCZ,
and 15 controls donated by Stanley Foundation) yielded alterations
in the FGFR1, NCAM1, and CAMK2A (Tochigi et al., 2008b). The
FGFR3 gene was also shown to be reduced in frontal cortex in
suicide brain in the Kim et al. microarray expression study (Kim
et al., 2007). Using our own microarray data, we confirmed that
FGFR3 and FGFR2 are down-regulated in multiple brain regions of
suicide completers (unpublished observations). In support of
human gene expression studies, animal studies have also
suggested that the FGF system may be involved in chronic defeat
stress. In these studies, chronic defeat stress decreased expression
of multiple genes of the FGF system and this effect was sometimes
reversible by continuous antidepressant treatment (Bachis et al.,
2008; Mallei et al., 2002; Turner et al., 2008a,b).
TrkB is a trans-membrane receptor capable of high affinity
binding to BDNF, a growth factor that acts to stimulate cell
signaling cascades to affect cell growth and proliferation in the
323
CNS. The TrkB gene has three main splice products, where full-
length TrkB and TrkB.T2 expression are mostly restricted to
neurons and TrkB.T1 expression is restricted to astrocytes. A
number of brain postmortem studies as well as serum BDNF level
studies have been performed both in suicide completers and
subjects with major depression. Much of this work, that
demonstrates a decrease in the BDNF/TrkB system, has been
supported by the animal literature.
Antidepressants increase the expression of BDNF in human.
Early reports in rodent suggested that treatment with antide-
pressants or electro-convulsive therapy led to an increase in BDNF
expression (Nibuya et al., 1995), and it was these studies that
encouraged studies in human psychopathology to move forward.
While the conceptual model suggesting that individuals with
depression have chronic under expression of TrkB/BDNF is difficult
to test, testing the effect of antidepressants on TrkB/BDNF
expression in human brain is more feasible. These studies followed
a general procedure where postmortem brain sections were
obtained from a particular brain region, usually hippocampus or
frontal cortex, and assessed for gene expression level (Chen et al.,
2001). These studies showed increased expression of BDNF mRNA
after pharmacological treatment. Other studies addressing the
effects of antidepressants on BDNF collected serum from treated
patients, largely with similar results to the postmortem studies
(Matrisciano et al., 2009). The idea that antidepressants can up-
regulate BDNF expression seems clear and a meta-analysis of this
effect has been conducted (Sen et al., 2008); the role of
antidepressants on TrkB expression is less clear, however (Linden
et al., 2000).
If antidepressants up-regulate BDNF mRNA, might a chronic
decrease in BDNF/TRKB mRNA be an underlying cause of major
depression? To assess this idea, a number of studies have been
performed in both depressed people and suicide completers. Some
studies have suggested that both BDNF and full-length TRKB are
down-regulated in different brain regions of suicide completers,
most of who were diagnosed with major depression (Dwivedi et al.,
2003; Pandey et al., 2008). A number of serum studies suggest,
controlling for medication effects, that BDNF is down-regulated in
subjects with major depression (Brunoni et al., 2008).
Microarray expression studies have not observed differences in
BDNF mRNA in either depressed patients or suicide completers, but
have detected decreased expression of TrkB mRNA. As mentioned,
there are three main variants of TrkB and most microarray
platforms are able to detect all three variants. To date, three
different microarray studies have implicated TrkB decrease in
depressed mood (Aston et al., 2005; Ernst et al., 2009; Nakatani
et al., 2006), yet only one of these studies, performed by our group,
disclosed which variant was analyzed. Interestingly, in our own
study it was the T1 variant that was down-regulated in suicide
brain with no alteration in either other TRKB variants. The T1
variant is mostly specific to astroglial cells and plays a role in
calcium signaling (Rose et al., 2003), suggesting a role for
astrocytes and TRKB in depression and suicide. As astrocytes are
the neural stem cell of the adult CNS (Doetsch et al., 1999), and it is
these cells that are implicated in the neurogenesis hypothesis of
depression (Duman et al., 1997; Kempermann and Kronenberg,
2003), a decrease expression in TrkB.T1 could have an affect on
astroglial growth, signaling, and differentiation.
Intracellular signaling cascades often involve second messenger
systems where an external signal is transduced in the cell by a
series of enzymatic reaction that can significantly amplify a signal.
This can come in the form, for example, of the addition of
phosphate groups or from protein conformational changes. Other
signaling cascades involve the influx of ions in the cell, such as
calcium, which can generate numerous downstream effects.
Molecules in intracellular signaling cascades that relate to
324 C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333
extracellular signaling cascades have received recent attention in
thorough reviews so we refer the reader to reviews that summarize
the relation of different signals to mood disorders and suicide
which have largely focused on the cAMP second messenger system
(Dwivedi and Pandey, 2008; Sulser, 2002).
6. Lipid metabolism
The interest in cholesterol as a possible biological correlate of
suicide and related behaviors goes as far back as 1979, when
Virkkunen demonstrated that male subjects with antisocial
personality disorder—a high risk group prone to violence and
suicide—had lower levels of serum cholesterol than the control
group of male patients with other personality disorders (Virkku-
nen, 1979). Interest in cholesterol also relates to its relationship to
the stress system, where it is the building block of cortisol. It was
only after concerns were raised over the safety of using
cholesterol-lowering medications that specific attention was paid
to the seeming relationship between cholesterol and violent
behavior. In particular, two large randomized, double-blind lipid-
lowering trials (Frick et al., 1987) revealed that although
decreasing serum cholesterol with lipid-lowering medications
was effective in reducing mortality from coronary heart disease,
the overall mortality rate was not significantly different. The
reduction in cardiac-related deaths appeared to be offset by an
increase in violence-related deaths including suicide, accidents
and homicide. Muldoon et al. (1990) combined the results of
primary prevention trials using meta-analytic techniques and
concluded that there was a significant increase in non-illness-
related mortality (i.e. deaths from accidents, suicide or violence) in
groups receiving treatment to lower cholesterol concentrations
compared with controls. However, as many of the more recent
primary prevention trials have not had similar outcomes as the
first ones (Muldoon et al., 2001), the issue of whether or not there is
a relationship between the lowering of cholesterol and violent
behaviors, including suicide, remains controversial. In part, lack of
observation of significant increases in violent-related deaths in
more recent statin trials can be explained by a modification of
inclusion and exclusion criteria of these trails, which began
excluding individuals at risk of suicidal behavior.
Support for a relationship between peripheral cholesterol and
violent deaths also come from other lines of evidence. A few
epidemiological studies, some of which conducted in large
samples, reported significant associations between low, or
lowered, serum cholesterol and violence or suicide (Ellison and
Morrison, 2001; Lindberg et al., 1992; Neaton et al., 1992; Partonen
et al., 1999; Zureik et al., 1996). For instance, mortality and
cholesterol data from over 350,000 men screened for the Multiple
Risk Factor Intervention Trial (MRFIT) and followed up for an
average of 12 years revealed that the risk of death by suicide was
significantly greater in the men with serum cholesterol levels less
than 4.14 mmol/L compared with those in each of the upper three
cholesterol level strata (Neaton et al., 1992). Similar results were
observed in epidemiological cohorts from other populations, such
as those from Canada (Ellison and Morrison, 2001) and Finland
(Partonen et al., 1999). The association between low cholesterol
and high relative risk of suicide has not been replicated in every
cohort study (Iribarren et al., 1995), adding to the controversy. One
possible reason for the inconsistency is that suicide is relatively
rare in the general population and may represent an event rate too
small to be detected in these studies.
This relationship has also been investigated in clinical popula-
tions at risk of suicide. Although not demonstrated by every study
(Apter et al., 1999; Tanskanen et al., 2000), the majority of studies
have frequently demonstrated an association between low
cholesterol level and violent, impulsive-aggressive or suicidal
behavior, providing consistent evidence in support of this
relationship. Golier et al. (1995) found that male patients with
low cholesterol were two times as likely to have ever made a
serious suicide attempt than male patients with cholesterol levels
in the highest 25th percentile. In a large sample of psychiatric
inpatients, Modai et al. (1994) showed that the mean cholesterol
level of those who had attempted suicide at least once was
significantly lower than that of the non-suicidal psychiatric
inpatients. Kunugi et al. (1997) found that the mean cholesterol
level of patients admitted to an emergency ward following a
suicide attempt was significantly lower compared with both non-
suicidal psychiatric and normal controls. Garland et al. (2000)
reported similar findings, and additionally, demonstrated that
higher impulsivity scores were associated with low cholesterol.
Among suicide attempters, Alvarez et al. (1999) found that the
mean cholesterol level of violent attempters was significantly
lower than that of the suicide attempters who used less violent
means.
How could serum cholesterol influence suicide risk? Studies in
humans (Ringo et al., 1994; Steegmans et al., 1996, 2000) and non-
human primates (Kaplan et al., 1991, 1994; Muldoon et al., 1992)
demonstrating a relationship between low or lowered cholesterol
and low measures of serotonergic activity—which has been linked
to impulsive-aggressive and suicidal behaviors. Kaplan et al.
(1994) showed that juvenile cynomolgus monkeys fed diets low in
cholesterol displayed lower serotonergic activity (as determined
by lower CSF 5-HIAA measures), lower cholesterol levels, less
affiliative interaction and higher levels of aggression in comparison
with monkeys fed high-cholesterol diets. These results are
suggestive of an association among low cholesterol, low seroto-
nergic activity and impulsive-aggressive behaviors, but they do not
reveal the mechanisms behind this apparent association.
A hypothesis involving a more direct role for cholesterol in the
brain as a factor influencing suicide risk requires an under-
standing of how serum cholesterol levels relate to brain
cholesterol levels. This is certainly worth examining more closely,
particularly given the growing evidence demonstrating essential
roles for cholesterol in the brain. Cholesterol is crucial for normal
development of the central nervous system, and is a major
component of brain cell membranes and of the myelin sheath that
surrounds the axons of nerve cells (Dietschy and Turley, 2004).
Glia-derived cholesterol has been shown to be necessary for the
formation of new synapses in the adult brain (Mauch et al., 2001).
This presents the possibility that a deficient supply of cholesterol
in the brain could limit synaptic plasticity, and hence, have
important neurobehavioral consequences (Pfrieger, 2003). A key
step that must be taken in further studies is to determine whether
the low serum cholesterol levels reported to be associated with
suicidal behavior actually reflect reduced cholesterol in the brain.
Data from our lab is relevant in this regard. Our findings suggest
that the relationship between peripheral cholesterol and suicidal
behavior also holds true at central levels, as we observed inverse
correlations between frontal cortex cholesterol levels and violent
suicide. Similarly, we have shown that the association with
suicidal behavior may have developmental origins, as we found
that carriers of a mutation involved in Smith–Lemli–Opitz (SLO)
syndrome, all of whom are phenotypically normal but have levels
of cholesterol in the low percentiles, are more likely than normal
carriers of mutations involved in other inborn errors of
metabolism not related to cholesterol metabolism to manifest
suicidal behaviors (Lalovic et al., 2004). SLO is an autosomal
recessive syndrome comprising multiple malformations and
characterized by abnormally low cholesterol levels resulting
from mutations in the gene coding for the enzyme 7-dehydro-
cholesterol reductase (DHCR7), which is involved in cholesterol
biosynthesis (Lalovic et al., 2004).
 C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333
In summary, considerable amount of evidence suggests that
low serum cholesterol is associated with suicidal behavior,
however more thorough investigation is required. While sub-
stantial amount of data has been produced suggesting a relation-
ship between peripheral cholesterol levels and violent/suicidal
behaviors, it remains unclear if this is a primary or secondary
association, and more importantly, what are the mechanisms
mediating this association.
7. Stress systems
7.1. Hypothalamic–pituitary–adrenal axis
The hypothalamic–pituitary–adrenal (HPA) axis is the major
biological infrastructure of the human stress system with
interconnections between the structures by the hormones CRH,
ACTH, and cortisol. It is the over- or under-activity of these
hormones that is often tested in suicidal behavior and depression
studies and how their long-term effects can alter brain structures.
In particular, the stress-related theory of depression postulates
that long-term chronic activation of the HPA axis leads to
detrimental effects on hippocampal neurons (Duman et al.,
1997; McKinnon et al., 2009).
The dexamethasone suppression test is used to assess HPA axis
functioning. Dexamethasone is an exogenous synthetic glucocor-
ticoid hormone that provides negative feedback on the HPA axis,
thereby suppressing the release of ACTH from the hypothalamus
and consequent release of cortisol from the adrenal gland. Cortisol
can be easily measured.
While there is very strong data suggesting that cortisol non-
suppression to the dexamethasone challenge is a strong predictor
to suicide completion (Coryell and Schlesser, 2001), there is a lack
of consensus in studies assessing suicide attempters compared to
controls. This has been reviewed in detail elsewhere (Currier and
Mann, 2008; Westrin, 2000). Hypoactivity of cortisol in suicide
attempters after dexamethasone has been interpreted as a ‘burnt-
out’ HPA axis; that is, that chronic stress has over-exerted the
system and cortisol can no longer be released properly. Alter-
natively, hyperactivity of cortisol in suicide attempters after
dexamethasone challenge has been interpreted as an HPA axis that
releases too much cortisol leading to detrimental brain effects and
feelings of chronic stress. How can these divergent findings and
explanations be interpreted? Most likely, these discrepancies
result from phenotypic and etiological heterogeneity in the suicide
attempt group, differences in sampling procedure, analysis
methodology, and time of the suicide attempt in relation to the
dexamethasone challenge. Also, recent data from our group
suggest that the expression regulation of the hippocampal GR
receptor, a key component of the HPA axis, is decreased primarily
among suicides with history of childhood adversity (McGowan
et al., 2009). Therefore, given the frequent history of childhood
abuse among individuals displaying suicidal behavior, it is possible
that suicidal behavior acts as a proxy variable of childhood
adversity in its relationship to HPA dysregulation. An alternative
explanation is that there is genuinely some dysfunction the HPA
system in suicide completers at a base infrastructure level, but that
the manifestation could come in different forms (e.g., hypo- or
hyper-activity) of this dysfunction is not necessarily in specific
changes of particular markers.
7.2. Polyamines
Polyamines are ubiquitously expressed, highly regulated
compounds found in all organisms and contain two or more
amine (NH2) groups (Tabor and Tabor, 1984). While their function
in cells in not entirely clear, they are known to bind DNA through
325
an intermediary and play a role in cell stress system response
(Moinard et al., 2005). Inhibition of the most widely studied
polyamines, which include spermidine, putrescine, and spermine,
leads to cell death (Gilad and Gilad, 2003). A number of these
compounds or the rate-limiting enzymes in the metabolic path-
ways, have been related to psychiatric illness, particularly
schizophrenia, anxiety, and major depression (Gilad et al., 1995).
Both human and animal studies have associated polyamine
dysfunction with psychopathology. In animal models of depres-
sion, levels of putrescine, spermine and spermidine have been
shown to be down-regulated (Genedani et al., 2001) and
antidepressant effects of different medications have been shown
to alter the polyamine system, particularly the interaction of
agmantine or putrescine on NMDA receptors (Aricioglu and
Altunbas, 2003; Li et al., 2003; Zeidan et al., 2007; Zomkowski
et al., 2006). Stress has also been shown to have an effect on the
polyamine system in rodents, including stress-increased putres-
cine levels in frontal cortex (Gilad and Gilad, 2002; Lee et al., 2006;
Sohn et al., 2002), as well as non-human primate models of
depression (Karssen et al., 2007b). In human, most studies involve
only assessments of the rate-limiting enzymes in polyamine
metabolic pathways; these include spermidine/spermine N1-
acetyltransferase (SSAT), ornithine decarboxylase (ODC), and
polyamine oxidase (PAO). Dahel et al. (2001) found an increase
in PAO in serum of depressed patients which returned to more
normal levels after electro-convulsive therapy. Our own group has
demonstrated in multiple brain regions of suicide completers that
SSAT expression is down-regulated in frontal cortex of suicide
completers with or without major depression (Sequeira et al.,
2006). Other reports have also emerged indicating a possible role
of SSAT in animal models of depression (Karssen et al., 2007a), and
in independent human samples (Guipponi et al., 2008; Klempan
et al., 2009b).
8. Astrocytes and oligodendrocytes
Glia includes primarily astrocytes, oligodendrocytes, and
microglia and the understanding of their role and importance in
the central nervous system continues to expand (Barres, 2008).
Microglial progenitor cells are derived from mesodermal origins,
unlike oligodendrocytes and astrocytes which are derived from
ectodermal origins (Chan et al., 2007). Microglia are mononuclear
phagocytes in the CNS, and one of their key roles is to clear cell
debris and to support cell survival (Gonzalez-Scarano and Baltuch,
1999). They are the housekeepers of the resting nervous system,
continuously surveying the brain with small mobile processes
(Nimmerjahn et al., 2005). Oligodendrocytes are the myelin
generating cells of the CNS and myelination of axonal membranes
allows for action potential functioning in neurons (McTigue and
Tripathi, 2008; Peters, 1960). More recent work also expands the
role of oligodendrocyes to receptor clustering on the neuronal
membrane and neuron survival (Wilkins et al., 2003). Astrocytes
are a heterogeneous group of cells with many functions (Wang and
Bordey, 2008) and this category of cells is likely the most diverse of
glial cells. Astrocytes release and take-up neurotransmitters,
propagate calcium waves, play a role in synapse development
and maintenance, and are involved in the immune response
(Kettenman and Ransom, 2005), among many other roles not least
of which is acting as the neural progenitors cells in the adult brain
(Bonfanti and Peretto, 2007; Doetsch, 2003). Glial cells, particularly
astrocytes and oligodendrocytes have been implicated in major
depression and suicide.
Astrocytes were first implicated in depression and suicide
through neuro-anatomical and hypothesis-driven gene expression
studies. Using postmortem brain sections, initial anatomical
studies reported less glial cells in brain of people with depression
326 C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333
(Bowley et al., 2002; Cotter et al., 2001; Ongur et al., 1998;
Rajkowska, 2003; Rajkowska et al., 1999). Due to the type of
staining techniques used it was impossible to distinguish which
type of glial cell that was reduced, but still independent reports
suggested that the frequency of non-neuronal cells in the brain was
less in depressed subjects than in controls. These findings suggest a
general decrease in astrocytes, oligodendrocytes, and microglia in
brains from depressed subjects but the lack of cell-type specificity
as well as the difficulty in accurately counting cells in postmortem
brain (Gundersen et al., 1988) left a requirement for more evidence
to demonstrate global glial reduction in depression. Investigating
expression levels of astrocyte-specific genes is a different way to
assess a reduction in astrocytes. The glial fibrillary acidic protein
(GFAP), an astrocyte-specific marker, has been used in studies
using frontal or anterior cingulate tissue from depressed subjects.
These studies have suggested that astrocyte levels are normal or
increased in the depressed brain, with the exception possibly in
younger suicides where a slight reduction in astrocytes has been
observed (Davis et al., 2002; Miguel-Hidalgo et al., 2000; Si et al.,
2004; Webster et al., 2005).
Astrocyte dysfunction, without reduction in cell number, may
be a factor in major depression and suicide. Microarray studies
have implicated a number of genes that are specific to astrocytes
and a number of these genes have been replicated by independent
groups. Astrocyte expressed genes that are detected across
multiple microarray studies using frontal cortical tissue from
depressed subjects or suicide completers include FGFR2/3, SLC1A3,
SLC1A2, and GLUL. We note the distinct glutamate involvement of
some of these astrocyte-specific genes (Choudary et al., 2005; Ernst
et al., 2009; Evans et al., 2004; Kim et al., 2007). Given the role of
glutamate in mood disorders and the role of astrocytes in
glutamate metabolism, astrocytes may be mediators of glutamate
dysfunction detected in major depression and suicide. Astrocytes
have a number of roles in the brain and slight alterations in
functioning could affect mood. Two roles of distinct curiosity are
astrocyte glutamate release at the synapse and the long-range
propagation of calcium waves throughout the brain.
Oligodendrocytes and myelin-related disturbances have been
noted in multiple psychiatric disorders, particularly schizophrenia,
but also in major depression. A number of histochemical studies of
oligodendroglia in depression, (Regenold et al., 2007) used a
detection technique that stains all cells, requiring experimenters to
make challenging cell-type decisions based on cell morphology.
These studies found a consistent decrease in oligodendrocytes in
brain areas of depressed subjects; however, the interpretation is
difficult due to the staining technique used (Uranova et al., 2004;
Vostrikov et al., 2007). One study done in amygdala that suggests
reduction in cell number is due to oligodendrocytes used
immunochemical stains for astrocytes and microglia and a general
stain for all cells. By detecting an overall cell number deficit in
depressed subjects, with non-significant differences in cell number
of astrocytes or microglia this data points to the idea that cell
number reduction is due to oligodendrocytes (Hamidi et al., 2004).
Other studies using specific chemical stains for myelin observed
decreased myelin in the depressed brain (Regenold et al., 2007).
The suggestion that oligodendrocyte dysfunction plays a role in
depression and suicide have been recently supported by a study of
a molecular signature of depression in amygdala (Sibille et al.,
2009), where some oligodendroglial genes were down-regulated,
and in rodent models of depression and the effects of antide-
pressant treatment (Surget et al., 2009).
White matter (myelin) scarring, as detected by hyper-
intensities using magnetic resonance imaging, is suggested to
be increased in people with depression (Dupont et al., 1995).
While this appears to be due to cerebrovascular disease risk
(Lenze et al., 1999), there does appear to be an increase in white
matter scarring in people with late-life depression (Herrmann
et al., 2008).
A number of gene expression studies have implicated
oligodendroglial genes in depression and suicide. One exploratory
gene expression study found a large number of oligo-specific genes
to be down-regulated in postmortem brain of depressed subjects
(Aston et al., 2005). Research from our group also suggests down-
regulation of multiple oligodendroglial genes, particularly the RNA
binding protein QKI (Klempan et al., 2009a). In a mouse study of
depression using unpredictable chronic stress, a gene set enriched
with oligodendroglial genes was observed to be significantly
down-regulated. Because of the wide variety of confounding
factors that can affect gene expression studies done using human
brain such as postmortem interval or pH (Vawter et al., 2006), an
animal study such as this supports oligodendrocyte involvement in
chronic stress/depression and suggests that oligodendroglial
reduction is not due to postmortem artifacts.
9. Future outlook
Early on, studies of the neurobiology of suicide explored levels
of a particular gene or protein in specific brain areas, blood, or CSF
of suicide completers and control subjects. While more technically
advanced, studies of this nature continue to be performed in the
form of proteomics and transcriptomics. While valence studies
(more or less of a certain product in affected subjects compared to
controls) may turn-out to be informative, it is not clear whether
this is the only approach that should be pursued or what the role of
reduced expression of a given gene signifies. In particular, does it
make a difference to brain function if the level of 5HT1A receptor is
1.2-fold lower in suicide brain compared to control brain? There
are multiple other avenues that could be informative in the study
of suicide neurobiology. For the remainder of this paper, we will
examine some of these avenues and the potential to be informative
in suicide research studies.
9.1. Whole genome association studies
Isolation of DNA from thousands of people with a specific
disease and matched control subjects, followed by SNP-chip DNA
hybridization and bioinformatics analysis, has led to many
significant and consistent findings for multiple complex traits
including diabetes (Saxena et al., 2007), restless leg syndrome
(Winkelmann et al., 2007) and others. These studies, which use a
chip-based technology, leave researchers with a small number of
SNPs that are more highly represented in a disease group
compared to a control group. These SNPs can be functionally
implicated in the etiology of the disease or of linkage disequili-
brium to the causative genetic variant.
While results from whole genome association studies in
psychiatry so far have been disappointing (Ferreira et al., 2008;
Sklar et al., 2008), psychiatric studies may benefit from WGA
analysis where the phenotype is clearly defined (e.g., schizo-
phrenic subjects with early onset that are responsive to
clopramazine). Some of these types of studies have emerged
recently (Potkin et al., 2009). This type of approach might decrease
the phenotypic heterogeneity and provide more meaningful
results. To date, no WGA study has been performed in suicidal
behavior but efforts are under way to conduct large-scale studies in
representative populations.
9.2. Individualized genetics
Recent genetic studies in complex disorders such as autism and
schizophrenia suggest that genetics does have a role to play in the
etiology of these diseases, but that the same clinical phenotype
 C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333
could be determined by multiple genotypes (Morrow et al., 2008;
Walsh et al., 2008). Increasingly, new strategies will need to be
employed to detect genetic variants at a microscale and this
technology will need to be both cost-effective and rapid. The
general hypothesis in these types of studies is to use genome
screening technology (SNP chips, copy-number variant analysis,
gene expression arrays), and to determine whether a higher
frequency of variation exists in the experimental compared to the
control group, irrespective of the loci of abnormality. In this way,
large samples can be used to examine the genetics of a disease,
with follow-up analysis involving different locations of interest for
different subjects.
9.3. Deep sequencing and large-scale methylation studies
Technology has evolved fast and it is now possible to sequence
large segments of the genome at relatively low cost. While deep
sequence studies of coding or regulatory sequences are currently
being conducted at many different labs, they still remain at their
early stages and pose important analytical and bioinformatic
challenges. Current barriers will soon be overcome and these
studies will become mainstream practice and replace genotyping
studies. This type of technology, which will eventually allow for
comparative sequencing of genomes, replacing GWAS studies as
costs decrease, will provide the ultimate opportunity to investigate
the role of genetic variation in suicide predisposition.
Similarly, as costs decrease, the large-scale sequencing studies
to assess methylation at the genomic level will become routine.
Added to the complexity, methylation effects are tissue and cell
specific, thus the investigation of methylation effects associated
with suicide will require major sequencing efforts in different
samples from the same individual and representative tissues.
Nevertheless, this type of effort is well justified in suicide research
given the important association between developmental stressors
and suicide.
9.4. MicroRNA analyses
MicroRNAs are small, single stranded 21 base RNA strands
that bind to mRNA and lead to the degradation of mRNA.
MicroRNA’s are encoded in the genome with approximately 400
known so far (Kosik, 2006). After transcription and subsequent
transport from the nucleus, microRNAs bind to any cytoplasmic
mRNA molecule with complementary bases. As double stranded
RNA in the cytoplasm is destroyed any mRNA with fully or
partially complimentary bases to a microRNA molecule is
degraded. This leads to less mRNA from a given gene, and
therefore, less protein product. MicroRNA’s could conceivably
bind to multiple different mRNAs, causing major changes in cell
function. The investigation of microRNA’s is a promising avenue
to better understand biological processes underlying the suicide
process.
9.5. RNA editing
Other areas of future study include transcriptomics (Garlow,
2002), the variation in different RNAs from the same gene, of which
a good example is RNA editing. RNA editing is the alterations of
particular nucleotides in an RNA molecule that alters the protein
code. One example of this, and one studied in psychiatry (Dracheva
et al., 2008; Schmauss, 2003), is the 5-HT2C receptor mRNA which
has five adenosine sites that can be edited to inosine which can
lead to alterations in the triplet codon sequence, affecting the
protein sequence. Other genes of interest to mood researchers have
also shown RNA editing (Paschen et al., 1994), yet have not been
explored in psychiatric studies.
327
9.6. Protein modifications
Studies of the post-translational modification of proteins
deviate conceptually from current research lines in that it is no
longer necessarily tied to ‘amount’ of a given gene product, but to
differences in form, structure, and stoichiometry that may
influence function. After translation in the cytoplasm, most
proteins undergo a series of different modifications. After protein
synthesis, proteins are targeted to the Golgi network where they
are packaged into vesicles and delivered to other sub-cellular
locations such as the cell membrane or the cytoskeleton. Within
the Golgi network, proteins may undergo different modifications
including ubiquitination (Bonifacino and Traub, 2003), phosphor-
ylation (Mostov et al., 1995), sulfation (Monigatti et al., 2006),
glycosylation (Helenius and Aebi, 2004) and fatty acylation (el-
Husseini Ael and Bredt, 2002; Resh, 1999). All of these modifica-
tions, and there are many types within each category, can affect
protein function, and this alteration in protein function could affect
mood and behavior.
9.7. Brain circuitry
Studies in depression and suicide have largely focused on
environmental (e.g., childhood abuse) and genetic factors (e.g.,
SNPs in 5-HTT). While the technology to study neuroanatomy has
been around for years (Llinas, 2003), the study of the actual
connections of cells and their micro-environment remain largely
unstudied in these disorders. Studying genetics alone, on the
assumption that gene variants will lead to a change in brain
circuitry, may miss out on important differences in brains from
psychiatric patients and control subjects. For example, even in
identical genetic environments, axon path-finding during devel-
opment never occurs identically across individuals. While axons
may terminate in the same general area based on chemo-attractant
and repellent cues, the environment-dependent competition that
ensues during synaptogenesis (and even throughout life) makes it
impossible that two individuals share the same synaptic connec-
tions. While accuracy may be maintained in brain organization,
absolute precision in synaptic connections is likely not. In this way,
diversity can be generated across individuals, without any genetic
differences. As imaging technologies progress towards increased
sensitivity, the ability to understand how neurons, astrocytes, and
other brain cells connect with each other in living or postmortem
human brains will be of tremendous interest. This concept is
recently being examined in the context of ‘connectomics’ (Licht-
man et al., 2008).
9.8. Conclusions
Moving forward, what should be the goals of biomedical
research of suicide? Until now, understanding the neurobiology of
suicide has tended to focus on uncovering markers, or biological
factors, associated with suicide risk. Because of the strong
influence of the environment – with both distal and proximal
effects – on suicidal behavior, uncovering markers of suicide risk
will be difficult as they will necessarily have low sensitivity and
low positive predictive value. This exercise may become more
precise when biological studies start integrating methodologically
robust environmental measures, including longitudinally assessed
distal effects, such as those affecting development.
To date, no formal neurobiological consensus has been put forth
associating the level or amount of a specific molecule with suicide.
Arguably, the association between indices of low serotonergic
neurotransmission and risk of suicidal behavior could be a
candidate for such a biological risk marker. However, after more
than three decades of intense investigation, this association
328 C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333
remains markedly unspecific, and in particular, is confounded with
the diathesis of the most important proxy of suicide risk: major
depression. Many groups, including our own, have published
genome-wide studies of brain expression levels of mRNA and
proteins. While many of these studies have, perhaps too quickly,
been dismissed as not conclusive and plagued by an excess of false
positive results, there has been some encouraging overlap in
independent findings of recent studies, such as dysfunction in the
GABAergic and glutamatergic sysyems in suicide (Choudary et al.,
2005; Sequeira et al., 2009). As such, given their exploratory
nature, these studies may provide some valuable insight into
neurobiological mechanisms underlying the suicide process
beyond prevailing current hypotheses. Below we discuss different
methodologies and theoretical assumptions that could help better
understand suicide neurobiology.
Etiological heterogeneity is a likely explanation for the
observed complexity of behavioral phenotypes such as suicide.
In human genetics, it has long been advocated that using
intermediate phenotypes, also referred to as endophenotypes,
particularly in the context of biochemical or similar laboratory
markers, could help decrease genetic heterogeneity and facilitate
the identification of risk loci. While the promise of endopheno-
types has not yet yielded concrete results in genetic studies, the
concept has been borrowed by other biological research fields in
psychiatry as a possibility of reducing other sources of hetero-
geneity. Caution should be paid to not introduce additional sources
of variability, as the candidate intermediate phenotype may
conceivably be etiologically more complex than the phenotype
itself. To help avoid such errors and pitfalls, some guidelines have
been proposed to define endophenotypes in psychiatry (Gottes-
man and Gould, 2003). Suicide research has a few promising
candidate intermediate phenotypes that meet these proposed
criteria; in particular, impulsive-aggressive behaviors (McGirr
et al., 2008b). Whereas we recognize that this type of approach will
require considerable effort to more extensively and systematically
characterize samples, investigators should attempt to routinely
measure and consider intermediate phenotypes when conducting
neurobiological research of suicide. As this approach may lead to
sacrificing (already small) sample sizes, one should be weary of
infinite possible post hoc analyses.
A few different, non-conventional analysis methods may also
provide some interesting research alternatives. For instance,
working with approaches that allow for etiological heterogeneity
may be a suitable avenue for studies with limited sample sizes,
which is frequently the case of postmortem brain studies. In
microarray expression studies, our group has used novel techni-
ques to identify sub-group instead of mean effects. We proposed a
systematic, non-hypothesis-driven method to reliably define sub-
group effects based on extreme values of brain gene expression
(Ernst et al., 2009). Another example of an individualized approach
is the investigation of cases with distinct features, such as a
particularly high familial loading of suicide, distinct comorbidity
patterns or course features. Using SNP chips, array-CGH, or gene
expression analysis may provide feasible and affordable avenues to
investigate specific risk factors at play in these cases. In summary,
carefully designed, individualized approaches should be explored
to circumvent the limitations posed by etiological heterogeneity in
suicide.
Until now, most studies investigating the neurobiology of
suicide have considered and analyzed the effect of single
biological variables. While experimentally this is the simplest
and operationally most feasible approach, it does not reflect the
underlying etiological complexity of suicide. It is time that studies
model and test more realistic hypotheses that incorporate the
multifactorial nature of the suicide phenotype. Our hope is that
future studies will examine and explore relationships between
different biological variables incorporating environmental
effects. Given that suicide and depression are ultimately disorders
that affect the brain, it is of extreme interest to identify patterns of
neural circuitry in the brains of suicide completers and, for
example, global patterns of DNA methylation or protein mod-
ification. Indeed it may even be that suicide and suicidal behavior
will need to be studied from multiple angles at once, including
genomic and epigenomic effects, imaging, clinical and develop-
mental histories, as well as social milieu. Perhaps only with this
complex, but more realistic, design will it be possible to identify
valid and robust factors explaining suicide risk and its underlying
neurobiological process. Because conducting comprehensive
studies will require large sample sizes, complementary expertises
and hefty budgets, they will only be possible if researchers
collaborate and share data.
There is no simple answer for how best to study suicide
neurobiology. While it is clear that much progress has been made
over the last 50 years since the first studies investigated levels of
cholinergic markers in the suicide brain, it is also clear that we are
still far away from understanding specific biological mechanisms
underlying suicide. Suicide is likely to result from the interaction of
several different factors, including a predisposing genetic back-
ground, brain microstructural organization and development, and
life trajectory. Future studies should model and test these different
dimensions in order to make substantial advances in the under-
standing of suicide neurobiology. The necessary technology to
conduct this type of studies is largely available, so the time is ripe
to conduct them.
Acknowledgements
This work was funded by an NSERC-CGS fellowship to C.E. and
grants from AFSP, CIHR, and FRSQ to G.T. The authors acknowledge
the contributions of Aleks Lalovic to this manuscript.
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