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Progress in Neurobiology 89 (2009) 315–333

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


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
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.


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: (G. Turecki).

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

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) 315–333 317

Walton, 1958). In one noteworthy case, researchers used the Subject Of Suicide. In this publication, Moore indicates that suicide
Minnesota Multiphasic Personality Inventory to classify person- has a propensity to affect successive generations of the same
ality types to determine who may commit suicide (Litman et al., family. A number of family and family history studies have shown
1961). The early 1950s studies largely concluded that personalities that suicidal behavior runs in families (reviewed in Baldessarini
did not differ between attempters and a non-attempter psychiatric and Hennen, 2004; Turecki, 2001). While most studies have shown
control group, but that there did appear to be personality trait that biological relatives of adolescent and adult suicide completers
differences between people who threatened suicide and those who or attempters have higher rates of suicidal behavior as compared
actually attempted it. These findings led scientists to suggest that with the relatives of control subjects (Brent et al., 1996; Cheng
suicidal behavior should be sub-grouped into suicidal ideation/ et al., 2000; Johnson et al., 1998; Malone et al., 1995; Murphy and
threats and suicide attempters, to reduce the heterogeneity in the Wetzel, 1982; Pfeffer et al., 1994; Roy, 2000; Tsuang, 1983), a
samples (Rosen et al., 1954). The results from these studies, where question that remained of critical importance is the potential
questionnaires were heavily influenced by the psychoanalytic overlap between the familial liability to suicidal behavior and that
model of psychiatry popular at the time, suggested that suicide conferring predisposition to psychiatric disorders. In other words,
was a result of poor masculine identification, narcissism, and poor as suicide is frequently associated with psychopathology, and
psychosexual development (Finn, 1955). primarily mood disorders, the question that researchers have been
In the mid-1960s, the concept of suicide as a neurobiological trying to address over the last decades is to what extent familial
entity emerged. To this point, it was unclear exactly what the aggregation of suicide is conditional on the familial aggregation of
relationship was between psychopathology and suicide. Debates psychopathology.
were ongoing about the causes of suicide, in particular whether most One of the first studies that was able to disentangle familial
people were reacting to a situation (e.g., break-up, lost job) or transmission of psychiatric disorders from familial aggregation of
whether there was an intrinsic, biological explanation why people suicide was the study carried out by Egeland and Sussex (1985) in
committed suicide. Studies investigating the biology of suicide the Old Order Amish, a conservative religious community in
specifically had to use a within group design, where a particular southeastern Pennsylvania. Although suicide is rare in the Amish,
variable was measured at different time points in the subject they have kept extensive genealogical and medical records,
manifesting suicide behavior, anticipating that these subjects would enabling the identification of all suicides that occurred during a
die by suicide. One of the first studies of this kind to be attempted was 100-year period (1880–1980). In all, there were 26 suicides. These
done using urine samples collected from individuals prior to suicide. suicides were clustered in only four families that also aggregated
Bunney and Fawcett observed that levels of 17-hydroxycorticoster- mood disorders, while no suicides occurred in many other families
oid, a breakdown product of cortisol, was elevated prior to suicide that also segregated mood disorders with the same density, illness
(Bunney and Fawcett, 1965). The ability to possess samples from severity and overall clinical characteristics. This finding was
patients who will commit suicide is an extremely difficult endeavor strongly suggestive that genetic factors increasing predisposition
because only a minority of patients will die by suicide (5% lifetime to suicide are different from those increasing predisposition to
risk in clinical populations) and that most people who die by suicide affective disorders. However, as families did not segregate suicide
are not followed by medical services. This difficulty is emphasized in in the absence of mood or other psychopathology, it seemed also
the Bunney and Fawcett study (1965) where it was only possible to clear that familial transmission of suicidal behavior was
recruit three subjects. Later studies used postmortem brain tissue to independent, but also conditional, on the liability for psycho-
analyze neurotransmitter and hormone metabolism where suicide pathology.
cases could be studied independently from psychopathology, The formal test of this hypothesis was first made in a study
provided a matched psychopathological control group was recruited carried out by Brent et al. (1996), which investigated familial
as well. This study design was employed with an investigation aggregation of suicide and measures of aggression in adolescent
measuring levels of the main metabolite 5-Hydroxyindoleacetic acid probands who had committed suicide, and compared these
(5-HIAA) of serotonin (5-HT), and noradrenaline (NA) in the measures with those of a sample of demographically similar
hindbrain of suicide and control subjects (Bourne et al., 1968). This controls who had never exhibited suicidal behaviors. A higher rate
study showed reduced levels of 5-HIAA in the brains of suicide of suicide attempts was found in the first-degree relatives of
completers compared to control subjects. Two subsequent studies of suicide probands compared with the relatives of controls. This
significance assessed levels of 5-HIAA and other electrolytes in the finding persisted even after controlling for increased rates of Axis I
brain of suicide completers (Shaw et al., 1967, 1969). During the late and II disorders in probands and families, supporting the notion
1960s, Pare and collaborators performed a comprehensive compara- that a genetic liability to suicide may be transmitted by a
tive analysis of 5-HT, NA and dopamine (DA) levels in three different mechanism separate from the familial transmission of psychiatric
brain regions of suicide and control subjects (Pare et al., 1969). These disorders. Of further interest is their finding that a higher familial
studies were limited, however, by having to have previously assessed loading of suicide attempts among suicide probands was
subjects for psychopathology and other clinical variables ante- associated with higher scores on aggression measures in the
mortem. Also, they investigated limited sample sizes as it was probands, even after controlling for family loading of aggression.
difficult to obtain pre-mortem information. This was changed by the This suggests that the genetic transmission of suicidal behavior
psychological autopsy method (Barraclough et al., 1974) which and aggressive traits are related. In a methodologically similar
allowed the assessment of suicide cases that were previously study in adult probands, our own group found that relatives of
unknown to researchers and elicit pre-mortem diagnoses based on suicide completers were over 10 times more likely than relatives of
proxy-based interviews. This permitted the expansion of postmor- comparison subjects to attempt or complete suicide after
tem studies in suicide, most of which will be discussed in this review. controlling for psychopathology (Kim et al., 2005). Similarly, other
studies corroborate the notion that factors accounting for familial
3. Genetics of suicide transmission of suicidal behavior act, at least in part, indepen-
dently from factors accounting for liability to psychopathology. In
3.1. Family studies two studies investigating high risk offspring of parents with
suicidal behavior, Brent and colleagues (Brent et al., 2002, 2003)
The notion that suicide aggregates in family is not new, as found that offspring of mood-disordered attempter parents were
indicated by Moore in 1790 in a book entitled A Full Enquiry Into The 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 among the biological and adoptive relatives. Particularly remark-
similar Axis I and II profiles. able was their finding that the frequency of suicide among the
biological relatives of the index adoptees was 15 times higher than
3.2. Twin studies that of the biological relatives of the control adoptees, with no
differential risk between the adoptive relatives of index and
Twin studies investigating suicide completion, given its control adoptees. Moreover, they noted an especially high
relatively infrequent nature, have been limited to case reports frequency of suicide among the biological relatives of a subset
on concordance between twin pairs, according to zygosity. Studies of index adoptees who were characterized as ‘‘affect reaction’’ type
focusing on suicide attempts, on the other hand, have investigated (i.e. more prone to make an impulsive suicide attempt in response
epidemiologically representative samples and are methodologi- to an emotional setback). In addition to providing further robust
cally more robust. Regardless of the design, however, twin studies evidence for a genetic predisposition to suicide that is transmitted
suggest that genes account for at least part of the familial independently of the genetic liability to psychopathology, this
aggregation of suicidal behavior, consistently indicating that study goes one more step forward to suggest that the genetic
concordance rates for MZ twins are higher than for DZ twins element in suicide may be related to impulse control.
(Roy et al., 1991, 1995; Glowinski et al., 2001; Statham et al., 1998). Family, twin and adoption studies provide consistent evidence
Roy et al. (1991) looked at concordance rates in a sample of 176 that there is an underlying genetic predisposition to suicidal
twin pairs in which at least one twin from each pair had committed behavior which is distinct from, although perhaps contingent on,
suicide. Seven of the 62 MZ twin pairs (11.3%) were found to be the genetic liability to psychiatric illness. Suicidal behavior, as a
concordant for suicide, while concordance was observed for only complex trait, is likely to be the result of a combination of
two of the 114 DZ twin pairs (1.8%). In a separate study, Roy et al. numerous environmental factors and the effect of multiple genes.
(1995) examined the frequency of attempted suicide in a sample of
living twins whose co-twins had committed suicide and found that 3.4. Genes for suicidal behavior? Conceptualizing genetic effects
38% of MZ co-twins had a history of attempted suicide, while none
of the DZ twins did. Thus, higher concordance rates are again As reviewed above, there is strong support for familial and
observed in MZ twins, particularly when a broader spectrum of genetic factors increasing vulnerability for suicidal behavior. It is
suicidal behavior is considered. unlikely, however, that genes have direct effects on suicide risk.
A large epidemiological and genetic study conducted in an More precisely, genetic effects are believed to act through
Australian community-based sample of MZ and DZ twin pairs intermediate phenotypes (Turecki, 2005), which are conceptua-
examined suicidal behavior and considered a number of important lized as the link between genes and suicidal behavior. In other
risk factors, including psychiatric history, personality traits, words, intermediate phenotypes, are factors that mediate the
traumatic life experiences and certain socio-demographic vari- relationship between genes and suicidal behaviors. There is
ables (Statham et al., 1998). It was found that even following considerable data suggesting that cluster B personality disorders
adjustment for these risk factors, history of suicidal behavior in one and impulsive-aggressive personality variants may act as inter-
MZ twin remained a powerful predictor of suicidal behavior in the mediate phenotypes of suicidal behavior (Brent et al., 1994;
other MZ co-twin, while failing to be consistently predictive in DZ Duberstein et al., 2000; Dumais et al., 2005a,b; Isometsa et al.,
twin pairs. Furthermore, this genetic liability was determined 1996). Accordingly, several studies suggest that suicide completers
using a genetic model-fitting approach to account for approxi- and attempters have higher levels of these behaviors (Brent et al.,
mately 55% of the variance in serious suicidal behavior. 1994; Brezo et al., 2007; Dumais et al., 2005a; McGirr et al., 2007a).
In a sample of male twins, Fu et al. found that a suicide attempt High levels of impulsive-aggressive behaviors appear to be related
in one MZ twin was predictive of suicide attempt or ideation in the to increased suicide risk among patients with the same psychiatric
co-twin, even after controlling for other risk factors, including diagnosis, such as major depression (Dumais et al., 2005a) and
psychiatric history, and concluded that the genetic liability to borderline personality disorder (McGirr et al., 2007a), as well as
suicidal behavior is likely independent of the genetic predisposi- when, in the course of the illness, suicide is more likely to occur
tion to psychiatric illness (Fu et al., 2002). Glowinski et al. (2001) (McGirr et al., 2008a). More importantly, high scores of impulsive-
reported similar findings in an adolescent female twin sample. aggressive behavior in probands predict increased familial loading
of suicidal behavior (Brent et al., 1996; Kim et al., 2005), history of
3.3. Adoption studies suicidal behavior is associated with increased levels of impulsive-
aggressive behaviors among psychiatric patients (Diaconu and
Adoption studies have produced data largely consistent with Turecki, 2008), and finally, familial aggregation of suicidal behavior
the findings from twin studies. The first adoption study on suicide co-segregates with (Brent et al., 1996; Kim et al., 2005), and seems
was carried out by Schulsinger et al. (1979) using the Danish case to be partly explained by (McGirr et al., 2007b), familial
registry of adoptions. There were 57 cases found of adoptees that transmission of impulsive-aggressive behaviors.
had committed suicide. These were matched to a control sample of
57 adoptees. Examination of the biological relatives of these 3.5. Association studies
adoptees revealed significantly more suicides among the biological
relatives of the suicide adoptees compared with the biological In light of the considerable support from genetic–epidemiolo-
relatives of the control adoptees. There were 12 suicides out of the gical studies for the role of genetic factors in suicidal behavior,
269 biological relatives of the suicide adoptees, while there were many case–control association studies have been conducted
only 2 cases of suicide among the 269 biological relatives of the exploring the effect of genetic variation on suicidal behavior.
control adoptees. There were no cases of suicide found among the We have generated a database, updated quarterly that catalogues
adoptive relatives of either the suicide or control adoptees. These all genetic association studies in suicide (available through
findings provide evidence that the tendency to suicide is To date, however, the
influenced by genetic factors. identification of putative susceptibility genes remains elusive.
Wender et al. (1986) selected 71 index adoptees with affective As with other psychiatric phenotypes, association-based searches
disorders and 71 control adoptees from the same Danish adoption for genes with small-to-moderate effects in complex diseases are
registry, and examined the frequency of psychiatric disorders plagued by insufficient power, population stratification, and
C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333 319

phenotype heterogeneity (Craddock and Forty, 2006) Additionally, rRNA (McGowan et al., 2008), GABAA (Poulter et al., 2008), the
the effects of some variants may only be obvious when considered glucocorticoid receptor (McGowan et al., 2009), and TrkB (Ernst
in the context of other genes and environments (Caspi et al., 2003; et al., 2009) have implicated a role of DNA methylation on reduced
De Luca et al., 2006). Along with methodological improvements, expression in suicide.
future research in the field should benefit from better character- While DNA methylation is cell specific, it is not clear how
ization of final and intermediate phenotypes, quantification of important DNA-region specificity is, in terms of dysfunction
both main and interactive genetic effects within and across possibly leading to suicide. Having an increased methylation
systems, and consideration of environmental and epigenetic pattern on certain genes in DNA extracted from hippocampal cells
factors. and no methylation change between cases and controls on, for
example, DNA extracted from cells from the frontal cortex may not
3.6. Epigenetics be as important as the actual molecules involved in methylation;
the expression of ‘methylation molecules’ may be region specific.
Epigenetic effects are non-heritable changes to the genome or The possible mechanism regulating these methylation molecules is
changes to those factors that regulate the genome. Some examples unknown, but it may be related to external stimuli. That is, that
of epigenetic changes include histone acetylation, phosphoryla- some environmental stimulation (e.g., divorce) leads to the up-
tion, and methylation, but by far the best studied example of regulation of a methylation molecule in a particular brain region,
epigenetics in suicide and psychiatry is DNA methylation. This is leading to altered DNA methylation of specific genes.
the addition of a methyl group to DNA and can alter DNA structure Epigenetic analyses in psychopathology offer a possible
or DNA binding protein accessibility. These changes can repress explanation for the difficulty geneticists have experienced trying
gene transcription affectively turning a gene on or off. DNA to link genetic polymorphisms to disease. Epigenetic effects alter
methylation has long been known to be important in cell specific gene expression without altering the genome and there is some
functioning (DNA is identical in every cell, yet neurons are evidence that environmental factors can influence methylation
different from hepatocytes) and X chromosome inactivation in status. More work is required in this area to clarify the role of
women. epigenetic modification to DNA or histones and the relationship to
DNA methylation is suggested to be involved in psychiatry as an psychopathology.
explanation for the apparent reductions in RNA or protein that may
be related to some mental disorders. For example, if a disease is 4. Neurotransmitters and their receptors
caused by reduced function of GABA-A receptor, than the
methylation of the GABA-A receptor gene may be the cause of 4.1. Serotonin (5-HT)
this reduction.
The first suggestion that a methylation-related mechanism was The 5-HT system has been the most widely investigated
involved in psychiatric illness was probably by Osmond and neuromodulatory system in studies of suicide attempters and
Smythies (1952), when they observed that some hallucinogens completers. The idea of a dysfunction in 5-HT transmission leading
(e.g., mescaline) are methylated versions of catecholamines— to depressed mood and possibly suicide emerged from the clinical
major neurotransmitters in the brain. They proposed that benefits of antidepressants acting on serotonergic neurotransmis-
psychosis was due to abnormal methylation (in this case of an sion, as well as to two studies where CSF-5HIAA was correlated
amine) of catechols in the brain. They termed this the ‘‘trans- with depression and suicide (Asberg et al., 1976a,b).
methylation hypothesis’’ (Osmond and Smythies, 1952). The dense 5-HT innervations pervading all brain regions
Methylation of DNA and its effects on gene transcription may originate exclusively from projection neurons located in the
have a role in psychiatric disorders. The epigenome (the pattern of brainstem’s raphe nuclei. Tryptophan hydroxylase (TPH), the
methylation throughout the genome) is programmed during enzyme of synthesis of 5-HT, has been widely used as a marker of
development, but recent data suggests that it could be responsive 5-HT activity. Quantitative immunocytochemical and immunoau-
to environmental cues during life. Signaling pathways activated by toradiographic studies in the dorsal raphe nucleus (DRN), which
neuronal and environmental stimuli could target DNA methylation projects mainly to the cerebral cortex and hippocampus, have
to specific loci, resulting in inter-individual epigenetic alterations shown significantly higher numbers and densities of TPH-
that would cause changes in gene expression. It is these inter- immunoreactive (TPH-IR) neurons in MDD subjects (Underwood
individual differences in methylation that may mediate the et al., 1999), depressed suicides (Boldrini et al., 2005) and alcohol-
interaction between the genome and the environment that may dependent depressed suicides (Bonkale et al., 2004) compared to
predispose people to the development or persistence of a mood controls. In accordance with these studies, Bach-Mizrachi and
disorder. Recent work has implicated altered methylation patterns colleagues (2006) reported a 33% increase in expression (mRNA) of
of a number of different genes in a psychiatric context. In an animal TPH2 in the raphe of suicide victims compared to controls. Given
model of early life environmental influences, a recent study has the multiple lines of evidence indicating an overall reduction in 5-
suggested that mice raised in environments with poor maternal HT transmission in both cortical and subcortical regions of MDD
care have increased methylation at a CpG nucleotide that forms a and suicide subjects (see below), increased TPH expression could
transcription factor binding site in the glucocorticoid receptor gene constitute a compensatory mechanism to alleviate central 5-HT
(Weaver et al., 2004). This data suggests that early life events can transmission, and/or a response to increased stress, which has also
alter methylation status and affect gene transcription of an been associated with alterations of TPH protein and mRNA levels
important gene in stress reactivity. This finding has recently been (Azmitia et al., 1993; Chamas et al., 2004). Alternatively, a
translated by our group to humans, by studying the epigenetic predisposing neurodevelopmental phenomenon may exist which
regulation of the glucocorticoid receptor in hippocampus tissue increases the number of 5-HT neurons in the DRN, as suggested by
from suicide completers with a history of severe childhood the observation of significantly higher numbers of TPH-IR neurons
adversity (McGowan et al., 2009). A number of different genes documented across the lifespan, even at a young age, in suicide
have also been investigated in humans in relation to psychiatric subjects (Underwood et al., 1999). A possible mechanisms
illness, mostly schizophrenia, including reelin (Grayson et al., accounting for such an increase would be an alteration in the
2005; Tochigi et al., 2008a), COMT (Abdolmaleky et al., 2006), programmed cell death normally occurring during brainstem
Sox10 (Iwamoto et al., 2005). In relation to suicide, such genes as development.
320 C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333

A large number of studies investigated 5HT receptor binding in Kim et al., 2007; Sequeira et al., 2006; Sibille et al., 2004; Tochigi
postmortem brain tissue from suicides or platelets from attemp- et al., 2008b).
ters and controls. Arango et al. (2001) examined [3H]-paroxetine Sibille et al. (2004) produced the first comprehensive micro-
binding to the 5-HT transporter (SERT) in the DRN of suicides and array study in the depressed suicide brain. In this study, 19
matched controls, and reported fewer SERT-expressing neurons depressed suicides were matched to controls and RNA extracted
accompanied by a greater expression of SERT per neuron. This from two frontal cortical regions was processed by microarray.
study also reported a decrease in 5-HT1A binding, thus suggesting After stringent microarray statistical processing, the authors found
a loss of receptors in the raphe, in contrast to earlier data from an no significant differences between groups. A follow-up analysis
independent group (Stockmeier et al., 1998). With regards to 5-HT examining only genes of the 5-HT system yielded no results of
innervations in terminal fields, Mann and colleagues reported a significance. Our own group using microarray data from 17
decrease of [3H]-paroxetine binding in prefrontal cortex (Mann different brain regions from 14 controls and 30 suicide completers,
et al., 1996) and ventro-lateral prefrontal cortex (Arango et al., most of whom had depression, also failed to detect any differences
1995) of suicide subjects. Although these data were not in expression of any genes in the serotonergic system (Ernst et al.,
consistently reproduced by others (Bligh-Glover et al., 2000; 2009; Klempan et al., 2007; Sequeira et al., 2006, 2007). In another
Hrdina et al., 1993; Lawrence et al., 1990) SERT-immunocyto- study (Kim et al., 2007), suicide completers were compared to
chemistry has supported the notion of a decrease in densities of 5- other subjects with the same Axis I diagnosis (either schizophrenia
HT innervations in prefrontal cortical areas (Austin et al., 2002). or bipolar disorder). Despite the large sample size used, not one
A few 5-HT receptor binding studies have compared terminal serotonergic-related gene was detected as significant between
fields between suicides and controls. Cheetham and collaborators groups. The negative evidence of 5-HT gene expression was further
reported no difference in 5-HT2 binding sites (Cheetham et al., solidified by the Tochigi study, where 99 differentially expressed
1988a) in cortex and amygdala, nor in 5-HT1A and 5-HT1B binding genes were identified, but none of which were serotonergic. The
(Cheetham et al., 1990) in frontal and temporal cortex of suicides Pritzker group (Atz et al., 2007) did not provide detailed analysis of
versus matched controls. They did, however, report a reduction in gene expression differences between groups, so it is impossible to
the number and affinity of 5-HT1 binding sites in the hippocampus say whether any serotonergic genes were detected as differentially
and amygdala, respectively (Cheetham et al., 1990). A subsequent expressed between suicide and non-suicide groups in that
study found a significant increase in [3H]-ketanserin (5-HT2 microarray study. It seems reasonable to suggest though, that
receptors) binding in both PFC and amygdala (67% and 96%, the lack of presentation of any serotonergic gene expression data
respectively) (Hrdina et al., 1993). However, using a very large likely signifies that there were no differences.
sample of 73 suicides and 70 controls, no difference between It is not clear exactly why protein studies of serotonergic
groups was observed in [3H]-ketanserin binding in any of six brain function have been mostly positive and RNA studies mostly
regions assessed (Lowther et al., 1994). In a similar sample, these negative (i.e. no differences in expression between groups). One
investigators found no difference in [3H]8-OH-DPAT (5-HT1A) possible explanation is that the dysfunction in serotonergic
binding either (Lowther et al., 1997). function occurs post-translationally. In that, RNA levels between
Neuroendocrine challenges have also been used to understand suicides and controls are similar, but some dysfunction after
the role of serotonin in suicide. Fenfluramine, the most commonly protein synthesis leads to altered levels of the serotonergic protein
used serotonin challenge agent, causes the release of serotonin product. It would be curious to see whether these protein findings
from pre-synaptic storage granules, inhibits its reuptake, and may would be substantiated if non-hypothesis-driven approaches were
also stimulate post-synaptic serotonin receptors (Rowland and used, as the RNA analyses were.
Carlton, 1984). The serotonergic activation leads to a dose- While some neuroanatomical studies have suggested a link
dependent increase in prolactin (Quattrone et al., 1983). Decreased between serotonergic receptor up- or down-regulation in depres-
prolactin responses are believed to reflect reduced serotonergic sion and suicide, this has not been supported by microarray
activity. Blunted prolactin responses to fenfluramine challenge studies. While microarray studies have been criticized for lack of
have been observed in patients with major depression and a accuracy (Geller et al., 2003; Pavlidis et al., 2003), these studies
history of suicidal behavior (Mann et al., 1995). have the initial benefit of being exploratory studies, which allow
Correa et al. (2000) found significantly lower prolactin experimenters to assess many possible leads without committing
responses to fenfluramine challenge in psychiatric patients with to any one in particular in the initial analysis. While involvement of
a history of attempted suicide compared with healthy controls and the serotonergic system cannot be ruled out, it has been suggested
patients without such a history, and propose that the blunted that more energy needs to be spent investigating other biological
serotonergic response may represent a marker for suicidality systems (Rujescu et al., 2007).
specifically, rather than depression. Furthermore, reduced prolac-
tin responses to fenfluramine challenge have also been seen in 4.2. Dopamine
psychiatric patients with diagnoses other than depression, such as
personality disorders (New et al., 1997; Soloff et al., 2003). The major dopaminergic innervations in the brain take their
Malone et al. (1996) found a significantly lower prolactin origin in the ventral tegmental area and substantia nigra in the
response to fenfluramine in patients with a history of a higher mesencephalon. To date, very little evidence has implicated
lethality suicide attempt, suggesting that high-lethality suicide dopaminergic transmission in suicide. Measurements of dopamine
attempters are more closely related to completed suicides not only concentrations in cortical and subcortical regions in suicide versus
behaviorally but also at a biochemical level. Keilp et al. (2008) matched control subjects did not reveal any significant difference
analyzed prolactin output after fenfluramine challenge and between groups (Allard and Norlen, 2001). However, it has been
followed subjects for a 2-year period. Suicide attempters and hypothesized that mesolimbic dopaminergic transmission is
psychiatric patients demonstrated a lower prolactin output. reduced in depression and suicide (Bowden et al., 1997), which
Microarray expression studies offer the possibility to assess could account for the dopaminergic-based antidepressant phar-
transcription levels of most known genes and 5-HT related genes macotherapies. In support for this, radioligand binding data have
can also be assessed in this way. A number of microarray studies in shown that there is a significant reduction in dopamine transport
human frontal cortex have been produced in recent years for both coupled with an increase in D2/D3 receptors in the amygdala of
the study of suicide and major depression (Choudary et al., 2005; major depressed subjects. It is thus conceivable that regional
C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333 321

changes in dopaminergic transmission may be involved in mood (Meana and Garcia-Sevilla, 1987). These data were supported by
disorders (e.g., by contributing to anhedonia) and lead to suicide. subsequent findings obtained with a similar sample set, where
increased a2-adrenergic receptor binding (Callado et al., 1998) and
4.3. Adrenaline and noradrenaline mRNA levels (Garcia-Sevilla et al., 1999) were described in frontal
cortex of depressed suicides compared to controls. Employing the
Adrenaline (epinephrine) is synthesized from tyrosine and a2-adrenergic agonist [3H]UK-14304, these authors further
phenylalanine in both the adrenal gland and the brain, and is reported a significant increase in [35S]GTPgs binding in hippo-
considered both a hormone and a neurotransmitter. Adrenaline is campal and frontal cortical tissues of suicides and depressed
an activator molecule well known to induce several physiological suicides compared to controls (Meana et al., 1992). More recent
effects (e.g., increased heart rate) and general cognitive enhance- studies by this group have provided further evidence that a2-
ment (e.g., increased awareness and attention). Although adre- adrenergic receptor expression is altered in the brains of depressed
nergic transmission has been hypothesized to play a role in mood suicides (Escriba et al., 2004; Gonzalez-Maeso et al., 2002).
and possibly suicide (Lipinski et al., 1987), no study has examined However, a number of negative studies by independent groups
in suicide the morphological features of the small adrenergic nuclei suggest that this may not be the case (Arango et al., 1993; De
located in the brainstem. Instead, most of the attention has been Paermentier et al., 1997; Gross-Isseroff et al., 2000). Other studies
devoted to central noradrenergic transmission, including the suggest that a2-adrenergic receptors may be involved in non-
adrenaline- and noradrenaline-binding adrenergic receptors; a frontal cortical regions (De Paermentier et al., 1997; Ordway et al.,
system also known to interact with the stress response through a 1994).
feed-forward mechanism. It is difficult to accurately assess a2-adrenergic receptor studies
Noradrenaline-synthesizing neurons are located in the locus because of the disparate nature of the studies from the
coeruleus (LC) of the brainstem and project to all brain regions independent groups. Different groups tend to use different brain
(Moore and Bloom, 1979). The LC has been reported to present areas for their studies and sometimes different technologies to
neurochemical alterations in MDD and suicide subjects (Merali assess the idea that a2-adrenergic receptors are increased in
et al., 2006), but there is no compelling evidence in the literature suicide brain, thereby supporting the monoaminergic reduction
suggesting that LC cells display morphological signs of altered theory of depression and suicide. If the number of current a2-
plasticity in these conditions. Thus, most studies have failed to find adrenergic studies is any indication though, it seems that most
differences between MDD suicides and control subjects in the groups see little evidence for a2-adrenergic receptor increases in
number of neuromelanin containing (NA-producing) cells in the LC suicide.
(Baumann et al., 1999; Syed et al., 2005). One report has indicated
significant reductions in the total number and average density of 4.4. Glutamate and GABA
pigmented LC neurons (left hemisphere only) in suicide com-
pleters (Arango et al., 1996), and another the inverse trend Glutamate and GABA are respectively the main excitatory and
(Ordway et al., 1994). In general, no differences have been reported inhibitory neurotransmitters in the mature brain. As a rule of
in the numbers of LC TH-immunoreactive neurons (TH-IR) thumb, glutamate is mainly synthesized by projection neurons,
between depressed suicides and control subjects. Interestingly, a whereas GABA is the fast-acting transmitter used mainly by
secondary analysis by Baumann and colleagues (1999) revealed interneurons. Glutamine is a core requirement for the synthesis of
that the patients with mood disorders not committing suicide had both glutamate and GABA. In nerve terminals, the enzyme
significantly fewer TH-IR neurons. Arguably, this observation glutaminase converts glutamine to glutamate, and the latter can
suggests that the LC undergoes similar increases in local be used for the synthesis of GABA via the enzymatic actions of GAD.
neurotransmitter synthesis than those in the DRN in subjects In glial cells, glutamine synthetase is the enzyme required to
with mood disorders which are prone to suicide. In line with this synthesize glutamine from the re-uptake of either glutamate or
argument, increased levels of TH protein have been observed in the GABA (Weiler et al., 1979).
LC of suicide subjects. Recently, it was reported that a highly significant increase in
In the CNS, the metabotropic adrenergic receptors are density of GABA neurons (GAD 65/67-immunoreactive (-IR))
subdivided into a- and b-subtypes (Hein, 2006). The a2- occurs in the hippocampus and in several neocortical areas in
adrenergic receptors have received the most attention with MDD suicide subjects versus controls (Bielau et al., 2007),
regards to suicide. At the time of these adrenergic studies, the suggesting GABA dysfunction as a widespread phenomenon in
reduced monoaminergic (serotonin and noradrenaline) function- the brain. However, these results need to be further investigated as
ing theory of depression was under intense investigation and studies using different methodologies have indicated a somewhat
epinephrine, or the catabolic products of epinephrine, reductions opposite trend. Recently, Rajkowska et al. (2007) focused on
had received little support from brain studies in depression and subpopulations of cortical GABA interneurons based on the co-
suicide to date (Moses and Robins, 1975; Riederer et al., 1980) The expression of GABAergic markers with calcium binding proteins
inhibitory presynaptic a2-adrenergic receptors then, represented and found significant reductions in both neuron somal size and
a different player in the adrenergic system to study with regard to density for BA9 calbindin (CB)-IR neurons in MDD (majority of
the monoaminergic theory of depression. Until 1992, a2- suicides) versus control subjects. In contrast, these authors found
adrenergic receptors had been investigated in depressed brain no differences in the density and somal size of parvalbumin-
in hippocampus, frontal cortex, and occipital lobes—with no immunoreactive (PV-IR) interneurons in the same sample (Raj-
significant differences between cases and controls (Crow et al., kowska et al., 2007).
1984; Ferrier et al., 1986). There are three major classes of glutamate receptors: AMPA,
Garcia-Sevilla and colleagues therefore performed a large study NMDA, and metabotropic glutamate receptors. AMPA receptors are
of multiple brain regions specifically in depressed suicides and composed of 4 subunits (GluR1–GluR4; Wisden and Seeburg,
controls assessing the level of a2-adrenergic receptors (Meana 1993), whereas NMDA receptors are composed of one NR1
et al., 1992) and reported increases in a2-adrenergic receptor receptor and one of NR2A, NR2B, NR2C, NR2D subunits (Wenthold
densities in the hypothalamus and frontal cortex of depressed et al., 2003). The family of metabotropic receptors comprises
suicides compared to matched controls, with no changes in mGluR1-mGluR8 (Conn and Pin, 1997). One study of NMDA
binding affinity, which supported some of their earlier work 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 transcripts identified by Choudary et al. (2005) as down-regulated
activation of NMDA receptors requires co-binding of glycine and are found in the samples we analyzed.
glutamate at distinct sites. To test the hypothesis that glycine While glutamate-associated findings show some consistency
displaceable sites may be altered in suicide brains, Nowak et al. across microarray studies, as well as other studies assessing MDD
(1995) assessed the proportion of high affinity glycine displaceable and suicide, future work will need to be performed cautiously as
[3H]CGP-39653 binding sites in the brain, and found that binding glutamate has a known role in brain cell death (Nicholls, 2008).
was reduced from 45  5% in controls to 27  6% in suicide victims. A Therefore, it will be important in future postmortem studies to
later study also suggested that the density of AMPA receptors may be control carefully for method of death and agonal state. For both
increased in the caudate nucleus of suicide subjects (Noga et al., glutamate and GABA associations with psychopathology, the lack
1997). of specificity to a particular mental illness is of some concern. For
Despite a slight difference observed in the hypothalamus, example, is glutamate/GABA dysfunction consistently present in
regional GABA levels in the brain do not seem to differ between schizophrenia, MDD, and bipolar disorder? Given the differing
suicide and control brains (Korpi et al., 1988). Similarly, assessing phenotypes, this would be surprising, although glutamate/GABA
binding to GABA transporter-1 (GAT-1) with the ligand [3H]- systems may be involved in different CNS systems or perhaps at
tiagabine in frontal cortex and anterior cingulate cortex of suicide the level of different receptor subunit stoichiometry for different
and control subjects led to no significant difference between diseases. In this perspective, subtle differences in the glutamate/
groups (Sundman-Eriksson and Allard, 2002). GABAA and GABAB GABA system, beyond analysis of up–down-regulation, will need to
receptors, the two GABA receptor subtypes (Macdonald and Olsen, be investigated.
1994), have received significant attention from suicide research-
ers, and studies have largely come up negative. Manchon et al. 4.5. Opioids
(1987) conducted one of the first GABA receptor binding studies in
suicide brains. These authors reported an increase in the number Opioids have long been known to have an effect on mood, but
of type I benzodiazepine binding sites in the hippocampus of not since the discovery of endogenous opioids and opioid receptors
suicides versus controls. This increase was accompanied by a (Cox et al., 1975; Goldstein, 1976; Hughes et al., 1975), and their
slightly greater binding affinity (Manchon et al., 1987). Using a effects (Belluzzi and Stein, 1977) have these molecules been
larger sample, the same group later reproduced these results examined as potential etiological factors in mood disorders (Ball,
(Rochet et al., 1992). However, an independent study using the 1987). The first study to examine the relationship between opioid
same radioligand with hippocampal and amygdalar tissues found receptors and suicide was performed with quantitative [3H]-DAGO
no difference between subject groups (Stocks et al., 1990). autoradiography to assess m-opioid receptors in the brain (Gross-
Similarly, investigating GABAA receptor binding with [3H]- Isseroff et al., 1990). This group reported that younger suicide
flunitrazepam at three anatomically defined levels of the locus completers had a higher density of m-opioid receptors in frontal
coreleus revealed no significant difference between depressed and temporal cortex than matched controls. These results were
suicides and controls (Zhu et al., 2006). A subsequent study of later independently replicated with the same technique on a
benzodiazepine receptors in BA10 using [3H]-RO15-1788 realized comparable sample (15 subjects per group) (Gabilondo et al.,
in schizophrenic suicides, non-schizophrenic suicides and con- 1995). In this study, a 40% increase in m-opioid receptors was
trols found a small increase in benzodiazepine receptors in the observed in frontal cortex and thalamus. Interestingly, a recent
suicide group, although this seemed mostly due to neuroleptic investigation employing the same approach found no difference in
treatment (Pandey et al., 1997). Similarly, Cheetham and m-opioid density or affinity in prefrontal cortex or pre-post central
colleagues (1988b) reported an increase in GABAA binding in gyrus of suicide completers compared to matched controls
the frontal (but not temporal) cortex of suicides versus controls. (Zalsman et al., 2005). This may be attributable to smaller sample
Two studies investigating metabotropic GABAB binding sites in size (n = 9/group). No study has yet addressed the distribution and
the brain found no difference between suicide and control affinity of other opioid receptor subtypes in the brain of suicide
subjects (Arranz et al., 1992; Cross et al., 1988). subjects.
GABA- and glutamate-associated dysregulations have been the
most consistent finding in microarray studies in psychiatry. 4.6. Acetylcholine
Choudary et al. (2005) used tissue from BA9 and anterior cingulate
cortex from 7 controls, 9 MDD subjects and 6 BPD to generate Acetylcholine (ACh) innervations in the brain originate from the
microarray data—these subjects appear to be identical to those basal forebrain, the pedunculopontine tegmentum, and from a
subjects used in the paper by Evans et al. (2004). In subjects with population of giant interneurons in the striatum. ACh has been
MDD, this group showed that SLC1A2, SLIC1A3, and glutamine implicated by several studies in cognitive states and functions,
synthase (GS) were all down-regulated in the sample of MDD such as attention and memory (Sarter et al., 2003). There are two
compared to controls in both regions, while GABAAa5 was main types of acetylcholine receptors: nicotinic (nAChRs) and
upregulated. The findings of SLC1A2, SLIC1A3, and GS down- muscarinc receptors (mAChRs) (Berg et al., 1989; Birdsall and
regulation are of interest as they are all glia specific genes, Hulme, 1976; McCarthy et al., 1986). Cholinergic dysfunction was
suggesting support for a glial hypothesis of mood abnormalities first considered in psychiatric disorders when sleep disturbances
(Coyle and Schwarcz, 2000). With regards to GABAAa5, Kim and in mood disorders were related to myasthenia gravis, an
colleagues also showed an upregulation of GABAAa5 in a large autoimmune disorder where antibodies attack nAChRs and
microarray sample (>50 microarray chips for both controls and generate weakened states (Gillin et al., 1979; Sitaram et al.,
suicides) in frontal cortex of suicide completers with mixed 1982). To our knowledge, no study has ever examined the
phenotype and controls subjects (Kim et al., 2007). This study also morphology of ACh neurons and their axonal projections in
found SLC1A3, and GLUL to be significantly down-regulated in suicide, and none have reported in this context on changes in
suicide brain. Our own group has conducted a series of studies nAChR binding in the brain. In contrast to Meyerson et al. (1982)
using microarray data generated from suicide completers and who reported that [3H]-quinuclidinyl benzilate binding to mAChRs
controls using brain tissues from the Quebec Suicide Brian Bank. increased by 47% in the cerebral cortex of suicide completers
Our data has implicated GABA and glutamate dysfunction compared to homicide victims (Meyerson et al., 1982), two
(Klempan et al., 2007; Sequeira et al., 2007), and the same gene subsequent studies using the same approach reported no
C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333 323

difference in mAChR binding affinity nor density between groups CNS. The TrkB gene has three main splice products, where full-
in the frontal cortex (Stanley, 1984) as well as in the pons and length TrkB and TrkB.T2 expression are mostly restricted to
hypothalamus (Kaufmann et al., 1984). An investigation using neurons and TrkB.T1 expression is restricted to astrocytes. A
[35S]-GTPgS binding to G-proteins largely supported the view that number of brain postmortem studies as well as serum BDNF level
mAChRs are generally unaltered in suicide brains (Gonzalez-Maeso studies have been performed both in suicide completers and
et al., 2002). More recently, however, using [3H]-pirenzepine, a subjects with major depression. Much of this work, that
ligand specific to M1 and M4 receptors, an effect of suicide on demonstrates a decrease in the BDNF/TrkB system, has been
binding was reported (Zavitsanou et al., 2004) in one patient supported by the animal literature.
population (SCZ) but not in others (bipolar and major depressive Antidepressants increase the expression of BDNF in human.
disorders). It remains to be seen if this result will be replicated in Early reports in rodent suggested that treatment with antide-
other samples. pressants or electro-convulsive therapy led to an increase in BDNF
expression (Nibuya et al., 1995), and it was these studies that
5. Cell signaling encouraged studies in human psychopathology to move forward.
While the conceptual model suggesting that individuals with
Extra- and intra-cellular signaling refers to the interaction and depression have chronic under expression of TrkB/BDNF is difficult
resulting effector cascade between proteins inside or outside the to test, testing the effect of antidepressants on TrkB/BDNF
cell. The processes can be seen as continuous in the sense that expression in human brain is more feasible. These studies followed
nuclear effects generate gene products which can be exported from a general procedure where postmortem brain sections were
the cell to stimulate receptors on other cells’ membranes which obtained from a particular brain region, usually hippocampus or
can then activate an intracellular signal cascade which stimulates frontal cortex, and assessed for gene expression level (Chen et al.,
nuclear effectors. In suicide research, the study of signaling 2001). These studies showed increased expression of BDNF mRNA
molecules is largely restricted to either measuring the quantity of after pharmacological treatment. Other studies addressing the
an RNA or protein molecule postmortem known from basic effects of antidepressants on BDNF collected serum from treated
neuroscience studies to be involved in cell signaling or, in some patients, largely with similar results to the postmortem studies
cases, from the attempt to measure activity of a protein extracted (Matrisciano et al., 2009). The idea that antidepressants can up-
from suicide brain (Shelton et al., 2009). regulate BDNF expression seems clear and a meta-analysis of this
Neurotrophic factors are extracellular signaling molecules and effect has been conducted (Sen et al., 2008); the role of
have emerged as candidate molecules in the neurobiology of antidepressants on TrkB expression is less clear, however (Linden
suicide. Neurotrophins are well known for their roles in neuronal et al., 2000).
survival and plasticity, and their altered expression could underlie, If antidepressants up-regulate BDNF mRNA, might a chronic
at least in part, changes in plasticity observed in the brains of decrease in BDNF/TRKB mRNA be an underlying cause of major
suicides. Neurotrophic receptors, meanwhile, are mostly found on depression? To assess this idea, a number of studies have been
the cell membrane and, after binding the ligand, can stimulate performed in both depressed people and suicide completers. Some
intracellular effects. While the major neurotrophic factors include studies have suggested that both BDNF and full-length TRKB are
NGF, NT3/4, FGF, and BDNF, only BDNF, FGF, or their respective down-regulated in different brain regions of suicide completers,
receptors have been associated with suicide or major depression most of who were diagnosed with major depression (Dwivedi et al.,
by multiple investigators. 2003; Pandey et al., 2008). A number of serum studies suggest,
FGF is an important molecule for cell and organ development controlling for medication effects, that BDNF is down-regulated in
throughout the body, including the brain (Turner et al., 2006; subjects with major depression (Brunoni et al., 2008).
Vaccarino et al., 1999). Two different studies have implicated the Microarray expression studies have not observed differences in
fibroblast growth factor (FGF) system in depression and suicide. BDNF mRNA in either depressed patients or suicide completers, but
Using brains collected as part of the Pritzker consortium, Evans have detected decreased expression of TrkB mRNA. As mentioned,
et al. (2004) used frontal cortical tissue from 14 controls, 6 bipolar, there are three main variants of TrkB and most microarray
and 13 MDD subjects, of which 6 were female. The most robust platforms are able to detect all three variants. To date, three
findings from their work were that two FGF receptors (FGFR2 and different microarray studies have implicated TrkB decrease in
FGFR3) are down-regulated in both DLPFC and anterior cingulated depressed mood (Aston et al., 2005; Ernst et al., 2009; Nakatani
cortex specifically in MDD subjects. The FGF system is of interest to et al., 2006), yet only one of these studies, performed by our group,
studies of suicide and depression and has received some support disclosed which variant was analyzed. Interestingly, in our own
from other research groups. For example, microarray data derived study it was the T1 variant that was down-regulated in suicide
from BA10 from Stanley subjects (15 bipolar, 15 depressed, 15 SCZ, brain with no alteration in either other TRKB variants. The T1
and 15 controls donated by Stanley Foundation) yielded alterations variant is mostly specific to astroglial cells and plays a role in
in the FGFR1, NCAM1, and CAMK2A (Tochigi et al., 2008b). The calcium signaling (Rose et al., 2003), suggesting a role for
FGFR3 gene was also shown to be reduced in frontal cortex in astrocytes and TRKB in depression and suicide. As astrocytes are
suicide brain in the Kim et al. microarray expression study (Kim the neural stem cell of the adult CNS (Doetsch et al., 1999), and it is
et al., 2007). Using our own microarray data, we confirmed that these cells that are implicated in the neurogenesis hypothesis of
FGFR3 and FGFR2 are down-regulated in multiple brain regions of depression (Duman et al., 1997; Kempermann and Kronenberg,
suicide completers (unpublished observations). In support of 2003), a decrease expression in TrkB.T1 could have an affect on
human gene expression studies, animal studies have also astroglial growth, signaling, and differentiation.
suggested that the FGF system may be involved in chronic defeat Intracellular signaling cascades often involve second messenger
stress. In these studies, chronic defeat stress decreased expression systems where an external signal is transduced in the cell by a
of multiple genes of the FGF system and this effect was sometimes series of enzymatic reaction that can significantly amplify a signal.
reversible by continuous antidepressant treatment (Bachis et al., This can come in the form, for example, of the addition of
2008; Mallei et al., 2002; Turner et al., 2008a,b). phosphate groups or from protein conformational changes. Other
TrkB is a trans-membrane receptor capable of high affinity signaling cascades involve the influx of ions in the cell, such as
binding to BDNF, a growth factor that acts to stimulate cell calcium, which can generate numerous downstream effects.
signaling cascades to affect cell growth and proliferation in the 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 behavior, providing consistent evidence in support of this
thorough reviews so we refer the reader to reviews that summarize relationship. Golier et al. (1995) found that male patients with
the relation of different signals to mood disorders and suicide low cholesterol were two times as likely to have ever made a
which have largely focused on the cAMP second messenger system serious suicide attempt than male patients with cholesterol levels
(Dwivedi and Pandey, 2008; Sulser, 2002). in the highest 25th percentile. In a large sample of psychiatric
inpatients, Modai et al. (1994) showed that the mean cholesterol
6. Lipid metabolism level of those who had attempted suicide at least once was
significantly lower than that of the non-suicidal psychiatric
The interest in cholesterol as a possible biological correlate of inpatients. Kunugi et al. (1997) found that the mean cholesterol
suicide and related behaviors goes as far back as 1979, when level of patients admitted to an emergency ward following a
Virkkunen demonstrated that male subjects with antisocial suicide attempt was significantly lower compared with both non-
personality disorder—a high risk group prone to violence and suicidal psychiatric and normal controls. Garland et al. (2000)
suicide—had lower levels of serum cholesterol than the control reported similar findings, and additionally, demonstrated that
group of male patients with other personality disorders (Virkku- higher impulsivity scores were associated with low cholesterol.
nen, 1979). Interest in cholesterol also relates to its relationship to Among suicide attempters, Alvarez et al. (1999) found that the
the stress system, where it is the building block of cortisol. It was mean cholesterol level of violent attempters was significantly
only after concerns were raised over the safety of using lower than that of the suicide attempters who used less violent
cholesterol-lowering medications that specific attention was paid means.
to the seeming relationship between cholesterol and violent How could serum cholesterol influence suicide risk? Studies in
behavior. In particular, two large randomized, double-blind lipid- humans (Ringo et al., 1994; Steegmans et al., 1996, 2000) and non-
lowering trials (Frick et al., 1987) revealed that although human primates (Kaplan et al., 1991, 1994; Muldoon et al., 1992)
decreasing serum cholesterol with lipid-lowering medications demonstrating a relationship between low or lowered cholesterol
was effective in reducing mortality from coronary heart disease, and low measures of serotonergic activity—which has been linked
the overall mortality rate was not significantly different. The to impulsive-aggressive and suicidal behaviors. Kaplan et al.
reduction in cardiac-related deaths appeared to be offset by an (1994) showed that juvenile cynomolgus monkeys fed diets low in
increase in violence-related deaths including suicide, accidents cholesterol displayed lower serotonergic activity (as determined
and homicide. Muldoon et al. (1990) combined the results of by lower CSF 5-HIAA measures), lower cholesterol levels, less
primary prevention trials using meta-analytic techniques and affiliative interaction and higher levels of aggression in comparison
concluded that there was a significant increase in non-illness- with monkeys fed high-cholesterol diets. These results are
related mortality (i.e. deaths from accidents, suicide or violence) in suggestive of an association among low cholesterol, low seroto-
groups receiving treatment to lower cholesterol concentrations nergic activity and impulsive-aggressive behaviors, but they do not
compared with controls. However, as many of the more recent reveal the mechanisms behind this apparent association.
primary prevention trials have not had similar outcomes as the A hypothesis involving a more direct role for cholesterol in the
first ones (Muldoon et al., 2001), the issue of whether or not there is brain as a factor influencing suicide risk requires an under-
a relationship between the lowering of cholesterol and violent standing of how serum cholesterol levels relate to brain
behaviors, including suicide, remains controversial. In part, lack of cholesterol levels. This is certainly worth examining more closely,
observation of significant increases in violent-related deaths in particularly given the growing evidence demonstrating essential
more recent statin trials can be explained by a modification of roles for cholesterol in the brain. Cholesterol is crucial for normal
inclusion and exclusion criteria of these trails, which began development of the central nervous system, and is a major
excluding individuals at risk of suicidal behavior. component of brain cell membranes and of the myelin sheath that
Support for a relationship between peripheral cholesterol and surrounds the axons of nerve cells (Dietschy and Turley, 2004).
violent deaths also come from other lines of evidence. A few Glia-derived cholesterol has been shown to be necessary for the
epidemiological studies, some of which conducted in large formation of new synapses in the adult brain (Mauch et al., 2001).
samples, reported significant associations between low, or This presents the possibility that a deficient supply of cholesterol
lowered, serum cholesterol and violence or suicide (Ellison and in the brain could limit synaptic plasticity, and hence, have
Morrison, 2001; Lindberg et al., 1992; Neaton et al., 1992; Partonen important neurobehavioral consequences (Pfrieger, 2003). A key
et al., 1999; Zureik et al., 1996). For instance, mortality and step that must be taken in further studies is to determine whether
cholesterol data from over 350,000 men screened for the Multiple the low serum cholesterol levels reported to be associated with
Risk Factor Intervention Trial (MRFIT) and followed up for an suicidal behavior actually reflect reduced cholesterol in the brain.
average of 12 years revealed that the risk of death by suicide was Data from our lab is relevant in this regard. Our findings suggest
significantly greater in the men with serum cholesterol levels less that the relationship between peripheral cholesterol and suicidal
than 4.14 mmol/L compared with those in each of the upper three behavior also holds true at central levels, as we observed inverse
cholesterol level strata (Neaton et al., 1992). Similar results were correlations between frontal cortex cholesterol levels and violent
observed in epidemiological cohorts from other populations, such suicide. Similarly, we have shown that the association with
as those from Canada (Ellison and Morrison, 2001) and Finland suicidal behavior may have developmental origins, as we found
(Partonen et al., 1999). The association between low cholesterol that carriers of a mutation involved in Smith–Lemli–Opitz (SLO)
and high relative risk of suicide has not been replicated in every syndrome, all of whom are phenotypically normal but have levels
cohort study (Iribarren et al., 1995), adding to the controversy. One of cholesterol in the low percentiles, are more likely than normal
possible reason for the inconsistency is that suicide is relatively carriers of mutations involved in other inborn errors of
rare in the general population and may represent an event rate too metabolism not related to cholesterol metabolism to manifest
small to be detected in these studies. suicidal behaviors (Lalovic et al., 2004). SLO is an autosomal
This relationship has also been investigated in clinical popula- recessive syndrome comprising multiple malformations and
tions at risk of suicide. Although not demonstrated by every study characterized by abnormally low cholesterol levels resulting
(Apter et al., 1999; Tanskanen et al., 2000), the majority of studies from mutations in the gene coding for the enzyme 7-dehydro-
have frequently demonstrated an association between low cholesterol reductase (DHCR7), which is involved in cholesterol
cholesterol level and violent, impulsive-aggressive or suicidal biosynthesis (Lalovic et al., 2004).
C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333 325

In summary, considerable amount of evidence suggests that an intermediary and play a role in cell stress system response
low serum cholesterol is associated with suicidal behavior, (Moinard et al., 2005). Inhibition of the most widely studied
however more thorough investigation is required. While sub- polyamines, which include spermidine, putrescine, and spermine,
stantial amount of data has been produced suggesting a relation- leads to cell death (Gilad and Gilad, 2003). A number of these
ship between peripheral cholesterol levels and violent/suicidal compounds or the rate-limiting enzymes in the metabolic path-
behaviors, it remains unclear if this is a primary or secondary ways, have been related to psychiatric illness, particularly
association, and more importantly, what are the mechanisms schizophrenia, anxiety, and major depression (Gilad et al., 1995).
mediating this association. Both human and animal studies have associated polyamine
dysfunction with psychopathology. In animal models of depres-
7. Stress systems sion, levels of putrescine, spermine and spermidine have been
shown to be down-regulated (Genedani et al., 2001) and
7.1. Hypothalamic–pituitary–adrenal axis antidepressant effects of different medications have been shown
to alter the polyamine system, particularly the interaction of
The hypothalamic–pituitary–adrenal (HPA) axis is the major agmantine or putrescine on NMDA receptors (Aricioglu and
biological infrastructure of the human stress system with Altunbas, 2003; Li et al., 2003; Zeidan et al., 2007; Zomkowski
interconnections between the structures by the hormones CRH, et al., 2006). Stress has also been shown to have an effect on the
ACTH, and cortisol. It is the over- or under-activity of these polyamine system in rodents, including stress-increased putres-
hormones that is often tested in suicidal behavior and depression cine levels in frontal cortex (Gilad and Gilad, 2002; Lee et al., 2006;
studies and how their long-term effects can alter brain structures. Sohn et al., 2002), as well as non-human primate models of
In particular, the stress-related theory of depression postulates depression (Karssen et al., 2007b). In human, most studies involve
that long-term chronic activation of the HPA axis leads to only assessments of the rate-limiting enzymes in polyamine
detrimental effects on hippocampal neurons (Duman et al., metabolic pathways; these include spermidine/spermine N1-
1997; McKinnon et al., 2009). acetyltransferase (SSAT), ornithine decarboxylase (ODC), and
The dexamethasone suppression test is used to assess HPA axis polyamine oxidase (PAO). Dahel et al. (2001) found an increase
functioning. Dexamethasone is an exogenous synthetic glucocor- in PAO in serum of depressed patients which returned to more
ticoid hormone that provides negative feedback on the HPA axis, normal levels after electro-convulsive therapy. Our own group has
thereby suppressing the release of ACTH from the hypothalamus demonstrated in multiple brain regions of suicide completers that
and consequent release of cortisol from the adrenal gland. Cortisol SSAT expression is down-regulated in frontal cortex of suicide
can be easily measured. completers with or without major depression (Sequeira et al.,
While there is very strong data suggesting that cortisol non- 2006). Other reports have also emerged indicating a possible role
suppression to the dexamethasone challenge is a strong predictor of SSAT in animal models of depression (Karssen et al., 2007a), and
to suicide completion (Coryell and Schlesser, 2001), there is a lack in independent human samples (Guipponi et al., 2008; Klempan
of consensus in studies assessing suicide attempters compared to et al., 2009b).
controls. This has been reviewed in detail elsewhere (Currier and
Mann, 2008; Westrin, 2000). Hypoactivity of cortisol in suicide 8. Astrocytes and oligodendrocytes
attempters after dexamethasone has been interpreted as a ‘burnt-
out’ HPA axis; that is, that chronic stress has over-exerted the Glia includes primarily astrocytes, oligodendrocytes, and
system and cortisol can no longer be released properly. Alter- microglia and the understanding of their role and importance in
natively, hyperactivity of cortisol in suicide attempters after the central nervous system continues to expand (Barres, 2008).
dexamethasone challenge has been interpreted as an HPA axis that Microglial progenitor cells are derived from mesodermal origins,
releases too much cortisol leading to detrimental brain effects and unlike oligodendrocytes and astrocytes which are derived from
feelings of chronic stress. How can these divergent findings and ectodermal origins (Chan et al., 2007). Microglia are mononuclear
explanations be interpreted? Most likely, these discrepancies phagocytes in the CNS, and one of their key roles is to clear cell
result from phenotypic and etiological heterogeneity in the suicide debris and to support cell survival (Gonzalez-Scarano and Baltuch,
attempt group, differences in sampling procedure, analysis 1999). They are the housekeepers of the resting nervous system,
methodology, and time of the suicide attempt in relation to the continuously surveying the brain with small mobile processes
dexamethasone challenge. Also, recent data from our group (Nimmerjahn et al., 2005). Oligodendrocytes are the myelin
suggest that the expression regulation of the hippocampal GR generating cells of the CNS and myelination of axonal membranes
receptor, a key component of the HPA axis, is decreased primarily allows for action potential functioning in neurons (McTigue and
among suicides with history of childhood adversity (McGowan Tripathi, 2008; Peters, 1960). More recent work also expands the
et al., 2009). Therefore, given the frequent history of childhood role of oligodendrocyes to receptor clustering on the neuronal
abuse among individuals displaying suicidal behavior, it is possible membrane and neuron survival (Wilkins et al., 2003). Astrocytes
that suicidal behavior acts as a proxy variable of childhood are a heterogeneous group of cells with many functions (Wang and
adversity in its relationship to HPA dysregulation. An alternative Bordey, 2008) and this category of cells is likely the most diverse of
explanation is that there is genuinely some dysfunction the HPA glial cells. Astrocytes release and take-up neurotransmitters,
system in suicide completers at a base infrastructure level, but that propagate calcium waves, play a role in synapse development
the manifestation could come in different forms (e.g., hypo- or and maintenance, and are involved in the immune response
hyper-activity) of this dysfunction is not necessarily in specific (Kettenman and Ransom, 2005), among many other roles not least
changes of particular markers. of which is acting as the neural progenitors cells in the adult brain
(Bonfanti and Peretto, 2007; Doetsch, 2003). Glial cells, particularly
7.2. Polyamines astrocytes and oligodendrocytes have been implicated in major
depression and suicide.
Polyamines are ubiquitously expressed, highly regulated Astrocytes were first implicated in depression and suicide
compounds found in all organisms and contain two or more through neuro-anatomical and hypothesis-driven gene expression
amine (NH2) groups (Tabor and Tabor, 1984). While their function studies. Using postmortem brain sections, initial anatomical
in cells in not entirely clear, they are known to bind DNA through 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; matter scarring in people with late-life depression (Herrmann
Rajkowska, 2003; Rajkowska et al., 1999). Due to the type of et al., 2008).
staining techniques used it was impossible to distinguish which A number of gene expression studies have implicated
type of glial cell that was reduced, but still independent reports oligodendroglial genes in depression and suicide. One exploratory
suggested that the frequency of non-neuronal cells in the brain was gene expression study found a large number of oligo-specific genes
less in depressed subjects than in controls. These findings suggest a to be down-regulated in postmortem brain of depressed subjects
general decrease in astrocytes, oligodendrocytes, and microglia in (Aston et al., 2005). Research from our group also suggests down-
brains from depressed subjects but the lack of cell-type specificity regulation of multiple oligodendroglial genes, particularly the RNA
as well as the difficulty in accurately counting cells in postmortem binding protein QKI (Klempan et al., 2009a). In a mouse study of
brain (Gundersen et al., 1988) left a requirement for more evidence depression using unpredictable chronic stress, a gene set enriched
to demonstrate global glial reduction in depression. Investigating with oligodendroglial genes was observed to be significantly
expression levels of astrocyte-specific genes is a different way to down-regulated. Because of the wide variety of confounding
assess a reduction in astrocytes. The glial fibrillary acidic protein factors that can affect gene expression studies done using human
(GFAP), an astrocyte-specific marker, has been used in studies brain such as postmortem interval or pH (Vawter et al., 2006), an
using frontal or anterior cingulate tissue from depressed subjects. animal study such as this supports oligodendrocyte involvement in
These studies have suggested that astrocyte levels are normal or chronic stress/depression and suggests that oligodendroglial
increased in the depressed brain, with the exception possibly in reduction is not due to postmortem artifacts.
younger suicides where a slight reduction in astrocytes has been
observed (Davis et al., 2002; Miguel-Hidalgo et al., 2000; Si et al., 9. Future outlook
2004; Webster et al., 2005).
Astrocyte dysfunction, without reduction in cell number, may Early on, studies of the neurobiology of suicide explored levels
be a factor in major depression and suicide. Microarray studies of a particular gene or protein in specific brain areas, blood, or CSF
have implicated a number of genes that are specific to astrocytes of suicide completers and control subjects. While more technically
and a number of these genes have been replicated by independent advanced, studies of this nature continue to be performed in the
groups. Astrocyte expressed genes that are detected across form of proteomics and transcriptomics. While valence studies
multiple microarray studies using frontal cortical tissue from (more or less of a certain product in affected subjects compared to
depressed subjects or suicide completers include FGFR2/3, SLC1A3, controls) may turn-out to be informative, it is not clear whether
SLC1A2, and GLUL. We note the distinct glutamate involvement of this is the only approach that should be pursued or what the role of
some of these astrocyte-specific genes (Choudary et al., 2005; Ernst reduced expression of a given gene signifies. In particular, does it
et al., 2009; Evans et al., 2004; Kim et al., 2007). Given the role of make a difference to brain function if the level of 5HT1A receptor is
glutamate in mood disorders and the role of astrocytes in 1.2-fold lower in suicide brain compared to control brain? There
glutamate metabolism, astrocytes may be mediators of glutamate are multiple other avenues that could be informative in the study
dysfunction detected in major depression and suicide. Astrocytes of suicide neurobiology. For the remainder of this paper, we will
have a number of roles in the brain and slight alterations in examine some of these avenues and the potential to be informative
functioning could affect mood. Two roles of distinct curiosity are in suicide research studies.
astrocyte glutamate release at the synapse and the long-range
propagation of calcium waves throughout the brain. 9.1. Whole genome association studies
Oligodendrocytes and myelin-related disturbances have been
noted in multiple psychiatric disorders, particularly schizophrenia, Isolation of DNA from thousands of people with a specific
but also in major depression. A number of histochemical studies of disease and matched control subjects, followed by SNP-chip DNA
oligodendroglia in depression, (Regenold et al., 2007) used a hybridization and bioinformatics analysis, has led to many
detection technique that stains all cells, requiring experimenters to significant and consistent findings for multiple complex traits
make challenging cell-type decisions based on cell morphology. including diabetes (Saxena et al., 2007), restless leg syndrome
These studies found a consistent decrease in oligodendrocytes in (Winkelmann et al., 2007) and others. These studies, which use a
brain areas of depressed subjects; however, the interpretation is chip-based technology, leave researchers with a small number of
difficult due to the staining technique used (Uranova et al., 2004; SNPs that are more highly represented in a disease group
Vostrikov et al., 2007). One study done in amygdala that suggests compared to a control group. These SNPs can be functionally
reduction in cell number is due to oligodendrocytes used implicated in the etiology of the disease or of linkage disequili-
immunochemical stains for astrocytes and microglia and a general brium to the causative genetic variant.
stain for all cells. By detecting an overall cell number deficit in While results from whole genome association studies in
depressed subjects, with non-significant differences in cell number psychiatry so far have been disappointing (Ferreira et al., 2008;
of astrocytes or microglia this data points to the idea that cell Sklar et al., 2008), psychiatric studies may benefit from WGA
number reduction is due to oligodendrocytes (Hamidi et al., 2004). analysis where the phenotype is clearly defined (e.g., schizo-
Other studies using specific chemical stains for myelin observed phrenic subjects with early onset that are responsive to
decreased myelin in the depressed brain (Regenold et al., 2007). clopramazine). Some of these types of studies have emerged
The suggestion that oligodendrocyte dysfunction plays a role in recently (Potkin et al., 2009). This type of approach might decrease
depression and suicide have been recently supported by a study of the phenotypic heterogeneity and provide more meaningful
a molecular signature of depression in amygdala (Sibille et al., results. To date, no WGA study has been performed in suicidal
2009), where some oligodendroglial genes were down-regulated, behavior but efforts are under way to conduct large-scale studies in
and in rodent models of depression and the effects of antide- representative populations.
pressant treatment (Surget et al., 2009).
White matter (myelin) scarring, as detected by hyper- 9.2. Individualized genetics
intensities using magnetic resonance imaging, is suggested to
be increased in people with depression (Dupont et al., 1995). Recent genetic studies in complex disorders such as autism and
While this appears to be due to cerebrovascular disease risk schizophrenia suggest that genetics does have a role to play in the
(Lenze et al., 1999), there does appear to be an increase in white etiology of these diseases, but that the same clinical phenotype
C. Ernst et al. / Progress in Neurobiology 89 (2009) 315–333 327

could be determined by multiple genotypes (Morrow et al., 2008; 9.6. Protein modifications
Walsh et al., 2008). Increasingly, new strategies will need to be
employed to detect genetic variants at a microscale and this Studies of the post-translational modification of proteins
technology will need to be both cost-effective and rapid. The deviate conceptually from current research lines in that it is no
general hypothesis in these types of studies is to use genome longer necessarily tied to ‘amount’ of a given gene product, but to
screening technology (SNP chips, copy-number variant analysis, differences in form, structure, and stoichiometry that may
gene expression arrays), and to determine whether a higher influence function. After translation in the cytoplasm, most
frequency of variation exists in the experimental compared to the proteins undergo a series of different modifications. After protein
control group, irrespective of the loci of abnormality. In this way, synthesis, proteins are targeted to the Golgi network where they
large samples can be used to examine the genetics of a disease, are packaged into vesicles and delivered to other sub-cellular
with follow-up analysis involving different locations of interest for locations such as the cell membrane or the cytoskeleton. Within
different subjects. the Golgi network, proteins may undergo different modifications
including ubiquitination (Bonifacino and Traub, 2003), phosphor-
9.3. Deep sequencing and large-scale methylation studies ylation (Mostov et al., 1995), sulfation (Monigatti et al., 2006),
glycosylation (Helenius and Aebi, 2004) and fatty acylation (el-
Technology has evolved fast and it is now possible to sequence Husseini Ael and Bredt, 2002; Resh, 1999). All of these modifica-
large segments of the genome at relatively low cost. While deep tions, and there are many types within each category, can affect
sequence studies of coding or regulatory sequences are currently protein function, and this alteration in protein function could affect
being conducted at many different labs, they still remain at their mood and behavior.
early stages and pose important analytical and bioinformatic
challenges. Current barriers will soon be overcome and these 9.7. Brain circuitry
studies will become mainstream practice and replace genotyping
studies. This type of technology, which will eventually allow for Studies in depression and suicide have largely focused on
comparative sequencing of genomes, replacing GWAS studies as environmental (e.g., childhood abuse) and genetic factors (e.g.,
costs decrease, will provide the ultimate opportunity to investigate SNPs in 5-HTT). While the technology to study neuroanatomy has
the role of genetic variation in suicide predisposition. been around for years (Llinas, 2003), the study of the actual
Similarly, as costs decrease, the large-scale sequencing studies connections of cells and their micro-environment remain largely
to assess methylation at the genomic level will become routine. unstudied in these disorders. Studying genetics alone, on the
Added to the complexity, methylation effects are tissue and cell assumption that gene variants will lead to a change in brain
specific, thus the investigation of methylation effects associated circuitry, may miss out on important differences in brains from
with suicide will require major sequencing efforts in different psychiatric patients and control subjects. For example, even in
samples from the same individual and representative tissues. identical genetic environments, axon path-finding during devel-
Nevertheless, this type of effort is well justified in suicide research opment never occurs identically across individuals. While axons
given the important association between developmental stressors may terminate in the same general area based on chemo-attractant
and suicide. and repellent cues, the environment-dependent competition that
ensues during synaptogenesis (and even throughout life) makes it
9.4. MicroRNA analyses impossible that two individuals share the same synaptic connec-
tions. While accuracy may be maintained in brain organization,
MicroRNAs are small, single stranded 21 base RNA strands absolute precision in synaptic connections is likely not. In this way,
that bind to mRNA and lead to the degradation of mRNA. diversity can be generated across individuals, without any genetic
MicroRNA’s are encoded in the genome with approximately 400 differences. As imaging technologies progress towards increased
known so far (Kosik, 2006). After transcription and subsequent sensitivity, the ability to understand how neurons, astrocytes, and
transport from the nucleus, microRNAs bind to any cytoplasmic other brain cells connect with each other in living or postmortem
mRNA molecule with complementary bases. As double stranded human brains will be of tremendous interest. This concept is
RNA in the cytoplasm is destroyed any mRNA with fully or recently being examined in the context of ‘connectomics’ (Licht-
partially complimentary bases to a microRNA molecule is man et al., 2008).
degraded. This leads to less mRNA from a given gene, and
therefore, less protein product. MicroRNA’s could conceivably 9.8. Conclusions
bind to multiple different mRNAs, causing major changes in cell
function. The investigation of microRNA’s is a promising avenue Moving forward, what should be the goals of biomedical
to better understand biological processes underlying the suicide research of suicide? Until now, understanding the neurobiology of
process. suicide has tended to focus on uncovering markers, or biological
factors, associated with suicide risk. Because of the strong
9.5. RNA editing influence of the environment – with both distal and proximal
effects – on suicidal behavior, uncovering markers of suicide risk
Other areas of future study include transcriptomics (Garlow, will be difficult as they will necessarily have low sensitivity and
2002), the variation in different RNAs from the same gene, of which low positive predictive value. This exercise may become more
a good example is RNA editing. RNA editing is the alterations of precise when biological studies start integrating methodologically
particular nucleotides in an RNA molecule that alters the protein robust environmental measures, including longitudinally assessed
code. One example of this, and one studied in psychiatry (Dracheva distal effects, such as those affecting development.
et al., 2008; Schmauss, 2003), is the 5-HT2C receptor mRNA which To date, no formal neurobiological consensus has been put forth
has five adenosine sites that can be edited to inosine which can associating the level or amount of a specific molecule with suicide.
lead to alterations in the triplet codon sequence, affecting the Arguably, the association between indices of low serotonergic
protein sequence. Other genes of interest to mood researchers have neurotransmission and risk of suicidal behavior could be a
also shown RNA editing (Paschen et al., 1994), yet have not been candidate for such a biological risk marker. However, after more
explored in psychiatric studies. 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 different biological variables incorporating environmental
the diathesis of the most important proxy of suicide risk: major effects. Given that suicide and depression are ultimately disorders
depression. Many groups, including our own, have published that affect the brain, it is of extreme interest to identify patterns of
genome-wide studies of brain expression levels of mRNA and neural circuitry in the brains of suicide completers and, for
proteins. While many of these studies have, perhaps too quickly, example, global patterns of DNA methylation or protein mod-
been dismissed as not conclusive and plagued by an excess of false ification. Indeed it may even be that suicide and suicidal behavior
positive results, there has been some encouraging overlap in will need to be studied from multiple angles at once, including
independent findings of recent studies, such as dysfunction in the genomic and epigenomic effects, imaging, clinical and develop-
GABAergic and glutamatergic sysyems in suicide (Choudary et al., mental histories, as well as social milieu. Perhaps only with this
2005; Sequeira et al., 2009). As such, given their exploratory complex, but more realistic, design will it be possible to identify
nature, these studies may provide some valuable insight into valid and robust factors explaining suicide risk and its underlying
neurobiological mechanisms underlying the suicide process neurobiological process. Because conducting comprehensive
beyond prevailing current hypotheses. Below we discuss different studies will require large sample sizes, complementary expertises
methodologies and theoretical assumptions that could help better and hefty budgets, they will only be possible if researchers
understand suicide neurobiology. collaborate and share data.
Etiological heterogeneity is a likely explanation for the There is no simple answer for how best to study suicide
observed complexity of behavioral phenotypes such as suicide. neurobiology. While it is clear that much progress has been made
In human genetics, it has long been advocated that using over the last 50 years since the first studies investigated levels of
intermediate phenotypes, also referred to as endophenotypes, cholinergic markers in the suicide brain, it is also clear that we are
particularly in the context of biochemical or similar laboratory still far away from understanding specific biological mechanisms
markers, could help decrease genetic heterogeneity and facilitate underlying suicide. Suicide is likely to result from the interaction of
the identification of risk loci. While the promise of endopheno- several different factors, including a predisposing genetic back-
types has not yet yielded concrete results in genetic studies, the ground, brain microstructural organization and development, and
concept has been borrowed by other biological research fields in life trajectory. Future studies should model and test these different
psychiatry as a possibility of reducing other sources of hetero- dimensions in order to make substantial advances in the under-
geneity. Caution should be paid to not introduce additional sources standing of suicide neurobiology. The necessary technology to
of variability, as the candidate intermediate phenotype may conduct this type of studies is largely available, so the time is ripe
conceivably be etiologically more complex than the phenotype to conduct them.
itself. To help avoid such errors and pitfalls, some guidelines have
been proposed to define endophenotypes in psychiatry (Gottes- Acknowledgements
man and Gould, 2003). Suicide research has a few promising
candidate intermediate phenotypes that meet these proposed This work was funded by an NSERC-CGS fellowship to C.E. and
criteria; in particular, impulsive-aggressive behaviors (McGirr grants from AFSP, CIHR, and FRSQ to G.T. The authors acknowledge
et al., 2008b). Whereas we recognize that this type of approach will the contributions of Aleks Lalovic to this manuscript.
require considerable effort to more extensively and systematically
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