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Psychoneuroendocrinology 63 (2016) 296310

Contents lists available at ScienceDirect

Psychoneuroendocrinology
journal homepage: www.elsevier.com/locate/psyneuen

Review

The role of cytokines in the pathophysiology of suicidal behavior


Licnia Gananca a,b,d , Maria A. Oquendo a,b , Audrey R. Tyrka e ,
Sebastian Cisneros-Trujillo a,b , J. John Mann a,b,c , M. Elizabeth Sublette a,b,
a
Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, 10032 NY, USA
b
Department of Psychiatry, Columbia University, New York, 10032 NY, USA
c
Department of Radiology, Columbia University, New York, 10032 NY, USA
d
Department of Psychiatry, School of Medicine, University of Lisbon, 1649-035 Lisbon, Portugal
e
Laboratory for Clinical and Translational Neuroscience, Butler Hospital and Department of Psychiatry and Human Behavior, Alpert Medical School of
Brown University, Providence, 02912 RI, USA

a r t i c l e i n f o a b s t r a c t

Article history: Objective: Immune dysregulation has been implicated in depression and other psychiatric disorders.
Received 30 June 2015 What is less clear is how immune dysregulation can affect risk of suicidal behavior. We reviewed the
Received in revised form scientic literature concerning cytokines related to suicidal ideation, suicidal behavior and suicide, and
18 September 2015
surveyed clinical and neurobiological factors associated with cytokine levels that may modulate effects
Accepted 13 October 2015
of inammation on suicide risk.
Methods: We searched PubMed, Embase, Scopus and PsycINFO for relevant studies published from 1980
Keywords:
through February, 2015. Papers were included if they were written in English and focused on cytokine
Cytokines
Suicide measurements in patients with suicidal behaviors.
Depression Results: The literature search yielded 22 studies concerning cytokines and suicidal ideation, suicide
Inammation attempts or suicide completion. The most consistent nding was elevated interleukin (IL)-6, found in
Stress 8 out of 14 studies, in CSF, blood, and postmortem brain. In one study, IL-6 in CSF was also found to be
higher in violent than nonviolent attempters and to correlate with future suicide completion. Low plasma
IL-2 was observed in 2 studies of suicide attempters, while divergent results were seen for tumor necrosis
factor (TNF)-, interferon (IFN)-, transforming growth factor (TGF)-, IL-4, and soluble Il-2 receptors.
Conclusions: Given the complexity suggested by the heterogenous cytokine ndings, putative mediators
and moderators of inammation on suicidal behavior merit further study. Elevated IL-6 was the most
robust cytokine nding, associated with suicidal ideation and both nonfatal suicide attempts and suicides.
Future studies should evaluate the predictive value of high IL-6, consider how this may alter brain function
to impact suicidal behavior, and explore the potential benecial effects of reducing IL-6 on suicide risk.
2015 Published by Elsevier Ltd.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
3.1. Literature search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
3.2. Results for individual cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
3.2.1. Interleukin-6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
3.2.2. Tumor necrosis factor- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
3.2.3. Interleukin-2 and interleukin-2 soluble receptor (sIL-2R) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
3.2.4. Interleukin-1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .300
3.2.5. Interferon- and transforming growth factor- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300

Corresponding author at: New York State Psychiatric Institute, 1051 Riverside Drive, Unit 42, NY, NY 10032, USA. Fax: +1 646 774 7589.
E-mail address: es2316@cumc.columbia.edu (M.E. Sublette).

http://dx.doi.org/10.1016/j.psyneuen.2015.10.008
0306-4530/ 2015 Published by Elsevier Ltd.
L. Gananca et al. / Psychoneuroendocrinology 63 (2016) 296310 297

3.2.6. Interleukin-4, interleukin-13 and interleukin-8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300


3.2.7. Interleukin-5 and interleukin-10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
3.3. Meta-analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
4.1. Factors affecting stress response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
4.1.1. Genetics and heritability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
4.1.2. Acute psychosocial stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
4.1.3. Early life adversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
4.1.4. Chronic social stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
4.1.5. Clinical depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
4.2. Symptom domains and inammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
4.2.1. Illness severity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
4.2.2. Anhedonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
4.2.3. Trait aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
4.2.4. Impulsivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
4.2.5. Hopelessness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
4.3. Mechanistic considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
4.3.1. Peripheral vs central cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
4.3.2. Polyunsaturated fatty acids (PUFAs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
4.3.3. Neurocircuitry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
4.3.4. Monoaminergic neurotransmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
4.3.5. Immune dysregulation mechanisms governing resilience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
4.4. Causality or epiphenomenon? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
4.5. Effects of suicidality independent from depression? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
4.6. Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
Conicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

1. Introduction physiology of suicidal behavior (Oquendo et al., 2014). As the


stress response is intrinsically linked with the immune system,
Suicide is a major public health concern. The World Health Orga- the involvement of inammatory responses must be considered
nization (WHO) estimated that in the year 2000, approximately one in suicide-related pathophysiology.
million people died from suicide, and 1020 times more attempted Within the immune system, cytokines such as interleukins (IL),
suicide, worldwide (WHO, 2002). Suicide and suicidal behaviors are interferons (IFN), and tumor necrosis factor (TNF) play pivotal
cross-diagnostic, multifactorial phenomena. Several clinical, psy- roles as signaling proteins mediating innate and adaptive immune
chosocial and demographic factors have been shown to increase responses (Commins et al., 2010). T-cell derived cytokines from the
the risk for suicidal behaviors (Hawton et al., 2013). However, Th1 lineage are involved in cellular mediated immune processes
predictive value of known risk factors for accurate assessment (IL-1, IL-1, IL-2, IFN-, TNF-) whereas those derived from the
of who will ultimately make suicide attempts remains low (May Th2 lineage promote humoral immune response (IL-4, IL-6, IL-10)
et al., 2012). Therefore, identication of relevant biomarkers has and are implicated in allergic reactions (Chaplin, 2010). Certain
assumed increasing importance in suicide research, as objective cytokines can be functionally categorized as pro-inammatory (IL-
markers of risk could signicantly improve the chances of effec- 1, IL-6, TNF-) or anti-inammatory (IL-4, IL-10, IL-13) (Commins
tive clinical intervention. Moreover, greater understanding of the et al., 2010).
biological processes impacting neural pathways involved of suicide The role of cytokines in the pathophysiology of psychiatric
risk could suggest new treatment approaches. disorders was postulated after observations that patients with
Even though 90% of suicides have a psychiatric diagnosis inammatory diseases had a higher prevalence of depression, and
(Beautrais et al., 1996), only 5% of psychiatric patients die by sui- that symptoms similar to those observed in major depression could
cide. A Stress-Diathesis Model of suicidal behavior was proposed be provoked by administration of therapeutic cytokines, such as
by Mann et al. (1999), in which suicidal behavior was conceptual- IFN- (reviewed in (Raison et al., 2005)). Depression has been asso-
ized as the result of the interplay between stressors such as acute ciated with increased inammatory markers, including cytokines
episodes of psychiatric illness or psychosocial stressors, and the such as IL-6 and TNF- (Liu et al., 2012), although inammation
individuals constitutional vulnerability to respond with suicidal may be implicated in only a subset of depressed patients (Raison
behavior. This model thus implicates the stress-response system and Miller, 2013).
as a potential contributor to the pathophysiology of suicidal behav- In recent years, inammation has emerged as potentially rel-
ior. In humans, the hypothalamic-pituitary-adrenal (HPA) axis and evant in the pathophysiology of suicidal behavior. The earliest
the sympathetic nervous system play key roles in adaptation to suggestions came from reports of suicidal ideation induced after
physical or psychological stress, acting on numerous systems to medical treatment with therapeutic cytokines (Dieperink et al.,
maintain homeostasis through the release of corticosteroids and 2004). A parallel set of discoveries stems from well-replicated
catecholamines (McEwen, 2008). However, chronic stress states in ndings that the incidence of suicide peaks during the spring, an
vulnerable individuals can produce alterations of basal and reac- initially bafing phenomenon later noted to covary with peak sea-
tive cortisol which, in turn, can have deleterious effects on health. son for allergens (Postolache et al., 2008). Additional studies have
Maladaptive stress responses have been implicated in the patho- directly linked allergic conditions to suicide completion (Qin et al.,
298 L. Gananca et al. / Psychoneuroendocrinology 63 (2016) 296310

2011; Timonen et al., 2004). Corroborative evidence is provided ideation, 188 patients with no suicidal ideation, and 176 normal
from an ecological study showing associations between intranasal controls. See Tables 13 for a description of the included stud-
corticosteroid anti-inammatory therapy and lower suicide rates ies. Additionally, two recently published meta-analyses concerning
(Woo et al., 2011). In this review, we will focus on the contribu- cytokines related to suicidal ideation, suicidal behavior and suicide
tion of later studies measuring inammatory cytokines associated were identied (Black and Miller, 2015; Ducasse et al., 2015). We
with suicidal behaviors in vivo or, in the case of completed sui- have summarized ndings for individual cytokines in Section 3.2.
cide, on postmortem ndings. We provide a critical overview of and in Table 4.
the literature and offer a contextualized interpretation of ndings
on how cytokine changes may alter brain function to favor suicidal 3.2. Results for individual cytokines
behavior.
Identifying specic inammatory markers and important con- 3.2.1. Interleukin-6.
textual factors could inform suicide risk prediction. Treatments The cytokine most frequently associated with suicidality was
targeting constituents of the inammatory pathway are currently IL-6, elevated in eight (Hoyo-Becerra et al., 2013; Janelidze et al.,
undergoing testing for a variety of psychiatric conditions, and this 2011; Karlovic et al., 2012; Lindqvist et al., 2011, 2009; Martinez
approach could be developed as a novel therapeutic tool for the et al., 2012; ODonovan et al., 2013; Pandey et al., 2012) of the four-
prevention of suicide. teen studies. One study only (Kim et al., 2008) reported lower IL-6
in suicide attempters; we note that in this study, blood was col-
lected from depressed suicide attempters at the time of arriving
2. Methods
in the emergency room, whereas in the comparator groupsand
in all the other studies in which this cytokine was measured
Articles eligible for this review were identied by two inves-
in blood or CSFspecimens were collected in the morning in a
tigators (L.G. and S.C.-T.) who independently performed database
fasted state. This might have created a confound, since a bipha-
searches of PubMed from 1980 through February 2015, and
sic diurnal variation has been described for IL-6 with morning and
Embase, Scopus and PsycINFO from 1980 until 2015 for articles
evening peaks (Vgontzas et al., 2005). Another potential expla-
in English (see Fig. 1). The nal search strategy comprised the
nation is that as samples were collected in the emergency room
following (with slight differences for individual database logic
directly following suicide attempts, resulting acutely high cortisol
rules): (suicid* AND (inammat* OR cytokines OR chemokines OR
levels could account for lower IL-6 levels (Coutinho and Chapman,
receptors, cytokines OR tumor necrosis factor OR interferon OR
2011). Finally, unlike any other studies reviewed, Kim et al. utilized
interleukin OR neuroglia) NOT (apoptosis OR suicide gene OR
mitogen-stimulated whole blood, which may yield different results
genet* OR cancer OR hepatitis OR multiple sclerosis)). The ref-
than plasma levels. The remaining studies found no differences in
erence lists of the retrieved publications were examined for other
IL-6 CSF or blood levels in adult suicide attempters compared with
eligible articles. Publications were included if they met the follow-
controls (Isung et al., 2012a; Martinez et al., 2012; Vargas et al.,
ing criteria: (a) evaluated suicidal ideation, completed suicide or
2013), in adolescents with active suicidal intent and a high lethality
suicide attempts, and (b) focused on the relationship of suicidal
plan compared with depressed, non-suicidal peers (Gabbay et al.,
behaviors to cytokines, and publications were excluded if (a) the
2009), or with regard to mRNA expression in prefrontal cortex
inammatory markers measured in relation to suicidal ideation,
(Tonelli et al., 2008) or plasma (Isung et al., 2012b) of suicides
complete suicide or suicide attempts did not include cytokines,
compared with controls. It may be relevant to interpretation of the
or (b) if the publications presented sample overlap with other
postmortem studies that differences in mRNA expression for Il-6
included studies. Manual bibliography search did not reveal any
were found in hippocampus (Hoyo-Becerra et al., 2013), while a
additional articles. Four articles were excluded due to overlapping
lack of group differences was seen in a study of adult prefrontal
samples (Grudet et al., 2014; Isung et al., 2014; Janelidze et al., 2015;
cortex (Tonelli et al., 2008).
Lee and Kim, 2010).
3.2.2. Tumor necrosis factor-
3. Results Only three of fteen studies found higher TNF- associated
with suicidal behavior (Janelidze et al., 2011), suicidal ideation
3.1. Literature search (Martinez et al., 2012), or suicide (Pandey et al., 2012). Lower lev-
els were found in only one small study of depressed adolescents
We found 22 articles that directly examined relationships with high suicidal ideation (a group that included recent suicide
between cytokines and suicidal ideation, suicidal behavior or sui- attempters), compared with depressed non-ideators (Gabbay et al.,
cide, that fullled the inclusion criteria, involving 1813 research 2009). In another study (Li et al., 2013), TNF- levels were higher
participants. Ten articles concerned cytokines in suicide attempts in MDD than in controls but did not distinguish suicidal MDD
(Huang and Lee, 2007; Isung et al., 2012a; Janelidze et al., 2011; Kim from non-suicidal MDD non-attempers, in which suicidality com-
et al., 2008; Li et al., 2013; Lindqvist et al., 2011, 2009; Nssberger prised persistent thoughts of suicide or death, specic suicide plan,
and Trskman-Bendz, 1993; Rothenhusler et al., 2006; Vargas and suicide attempt or completion. The remainder of the studies
et al., 2013), with a total of 1077 research participants: 423 sui- (Hoyo-Becerra et al., 2013; Huang and Lee, 2007; Isung et al., 2012b;
cide attempters, 353 non-attempters, and 301 normal controls. Karlovic et al., 2012; Lindqvist et al., 2009; ODonovan et al., 2013;
Four articles concerned postmortem studies (Hoyo-Becerra et al., Tonelli et al., 2008; Torres-Platas et al., 2014; Vargas et al., 2013)
2013; Pandey et al., 2012; Tonelli et al., 2008; Torres-Platas et al., found no group differences with respect to TNF-.
2014) of cytokines in 85 suicides and 61 comparison participants.
Two prospective studies (Isung et al., 2012b; Lindqvist et al., 2011) 3.2.3. Interleukin-2 and interleukin-2 soluble receptor (sIL-2R)
concerned the ability of baseline cytokine levels, among 182 indi- IL-2 levels were lower in depressed suicide attempters than
viduals with a history of suicide attempt, to predict 16 subsequent depressed non-attempters and healthy controls in both studies
suicides. Seven articles concerned suicidal ideation (Gabbay et al., where this cytokine was measured (Janelidze et al., 2011; Kim
2009; Juengst et al., 2014; Karlovic et al., 2012; Martinez et al., et al., 2008). No differences were found between groups in studies
2012; Mendlovic et al., 1999; Monfrim et al., 2014; ODonovan measuring suicidal ideation (Mendlovic et al., 1999). In a prospec-
et al., 2013) in 499 research participants: 156 patients with suicidal tive study of 58 suicide attempters, IL-2 levels were lower in
L. Gananca et al. / Psychoneuroendocrinology 63 (2016) 296310 299

Fig. 1. Algorithm employed to perform literature search and article selection process.
This owchart describes the databases used for article search, the number of retrieved articles and the process and criteria used to achieve the nal article selection.

those who suicided at follow-up (N = 7); this reduced to a trend cellular internalization of the sIL-2R/IL-2 complex could account for
when covariates were included in the model (Isung et al., 2012b). the decreased IL-2 levels found in the above-mentioned studies.
Among the two studies which measured sIL-2R, Nssberger and However, Rothenhusler et al. (2006) found no difference in sIL-2R
Trskman-Bendz (1993) found higher levels in suicide attempters levels between formerly depressed patients with previous suicide
with mood disorders or other psychiatric diagnoses, when com- attempts and healthy controls.
pared to healthy controls. Increased sIL-2R binding and consequent
300 L. Gananca et al. / Psychoneuroendocrinology 63 (2016) 296310

Table 1
Studies of cytokines and suicidal ideation.

Study Sample Source Results

Mendlovic et al., 1999 N = 6 depressed with suicidal ideation; PHA-stimulated INF- in suicidal depressed patients than healthy
N = 3 depressed without suicidal ideation; lymphocytes controls
N = 9 controls INF- in non-suicidal depressed than in healthy controls
= IL-2, IL-4,IL-5, IL-10 in the 3 groups
Gabbay et al., 2009 N = 12 suicidal depressed adolescents; Plasma TNF- in suicidal depressed adolescents vs non-suicidal
N = 18 depressed non-suicidal adolescents; depressed patients
N = 15 healthy controls = TNF- in suicidal depressed vs controls
IFN- in depressed suicidal and non-suicidal adolescents
vs controls
=IL-6, IL-1, IL-4 in the 3 groups
Martinez et al., 2012 N = 18 depressed patients undergoing 8 week treatment CSF + correlation between IL-6, TNF- and SSI scores after
protocol treatment;
N = 8 had IL-6 no correlation at baseline
N = 9 had TNF-
ODonovan et al., 2013 N = 29 depressed with high suicidal ideation; Plasma IL-6 and CRP depressed high suicidal ideation vs
N = 45 depressed with low suicidal ideation; depressed low suicidal ideation and controls
N = 48 healthy controls = TNF-, TGF-, IL-10 in the 3 groups
= individual inammatory markers for low suicidal
ideation depressed vs controls
Monfrim et al., 2014 N = 40 bipolar with suicidal ideationa ; Serum IL-1 in bipolar patients with suicidal risk vs both other
N = 40 bipolar without suicidal ideationa ; groups
N = 40 control patients
Juengst et al., 2014 N = 37 participants with TBI and CSF levels at baseline CSF + TNF- levels at baseline predicted suicidal ideationb at
N = 32 at 6-month follow-up 12-month but not 6-month follow-up
N = 33 at 12-month follow-up
Li et al., 2013 N = 33 depressed with suicidal ideation; Plasma TNF- in depressed patients vs healthy controls on
N = 12 depressed suicide attempters; admission
N = 19 depressed without suicidal ideation; N = 64 healthy TNF- in depressed patients post treatment
controls TNF- greater for responders vs non-responders to
venlafaxine treatment
= TNF- levels between depressed patients with suicidal
ideation vs depressed suicide attempters vs non-suicidal
depressed patients
Karlovic et al., 2012 N = 23 melancholic depressed with suicidal ideationc ; Serum IL-6 in depressed melancholic with suicidal ideationc vs
N = 20 melancholic depressed without suicidal ideationc ; depressed melancholic without ideationc
N = 7 atypical depressed melancholic depressed with
suicidal ideationc ;
N = 16 atypical depressed melancholic depressed without
suicidal ideationc

Abbreviations: CRPC-reactive protein; CSFcerebrospinal uid; ILinterleukin; IFNinterferon; PHAphytohemagglutinin; SSIScale for Suicidal Ideation; TBItraumatic
brain injury; TGFtransforming growth factor; TNFtumor necrosis factor.
Symbols: increased; decreased; = no change; + positive.
a
Reported as suicide risk; dened as any positive answer(s) in the suicidality module of the Mini International Neuropsychiatric Interview (M. Kaster, personal commu-
nication).
b
Reported as suicidal endorsement.
c
Reported as suicidal behavior.

3.2.4. Interleukin-1 in death by cardiac events (Tonelli et al., 2008). Three other stud-
Three out of nine studies found higher levels of IL-1 in samples ies found no differences for IL-4 in patients with suicidal ideation
of CSF (Martinez et al., 2012) and serum (Monfrim et al., 2014), or (Gabbay et al., 2009; Mendlovic et al., 1999) or suicide (Isung et al.,
with suicide, in postmortem tissue (Pandey et al., 2012) but six 2012b) compared to the control groups. Low IL-8 was seen in one
found no association with suicidal ideation or behavior (Gabbay (Isung et al., 2012a) of two studies (Isung et al., 2012a; Lindqvist
et al., 2009; Huang and Lee, 2009; Isung et al., 2011b; Lindqvist et al., 2009) of suicide attempters; however, in another study by
et al., 2009; Tonelli et al., 2008; Torres-Platas et al., 2014). the same group, IL-8 did not differentiate those who went on to
complete suicide from individuals who did not (Isung et al., 2012b).
3.2.5. Interferon- and transforming growth factor-
Higher levels of IFN- were found in depressed patients with 3.2.7. Interleukin-5 and interleukin-10
suicidal ideation compared to depressed non-suicidal and healthy None of the studies measuring IL-5 (Mendlovic et al., 1999;
controls in one (Mendlovic et al., 1999) of two studies (Gabbay et al., Tonelli et al., 2008) or IL-10 (Huang and Lee, 2007; Isung et al.,
2009; Mendlovic et al., 1999). For both IFN- (Gabbay et al., 2009; 2012b; Mendlovic et al., 1999; ODonovan et al., 2013; Torres-Platas
Kim et al., 2008) and TGF- (Kim et al., 2008; Lee and Kim, 2010; et al., 2014) found any associations with suicidal ideation, attempts,
ODonovan et al., 2013), there was no difference in blood levels or suicide for these cytokines.
between depressed attempters and non-attempters, but cytokine
levels did distinguish depressed patients from healthy controls 3.3. Meta-analyses
(Gabbay et al., 2009; Kim et al., 2008; Lee and Kim, 2010), indicating
more of a role as biomarkers for depression than suicide. Two meta-analyses (Black and Miller, 2015; Ducasse et al.,
2015) were found and utilized for bibliographic searching. Black
3.2.6. Interleukin-4, interleukin-13 and interleukin-8 and Miller (2015) included 18 studies, 2 of which concerned
In the only postmortem study that looked at IL-4 and IL-13 in the chemokines exclusively, and the remainder covered cytokines;
prefrontal cortex of suicides, both IL-4 and IL-13 were higher than with respect to cytokines, their observations comprised in vivo (IL-
L. Gananca et al. / Psychoneuroendocrinology 63 (2016) 296310 301

Table 2
Studies of cytokines and suicide attempts.

Study Sample Source Results

Nssberger and N = 30 suicide attempters (various psychiatric disorders); Plasma sIL-2R in suicide attempters
Trskman-Bendz, 1993 N = 25 healthy controls
Rothenhusler et al., N = 25 formerly depressed suicide attempters; Plasma = sIL-2R in suicide attempters
2006 N = 25 healthy controls
Huang and Lee, 2007 N = 11 depressed suicide attempters; Serum = IL-1, TNF-, IL-10 between depressed suicide
N = 31 depressed non-attempters; attempters and depressed non-attempters
N = 40 healthy controls
Kim et al., 2008 N = 36 depressed suicide attempters; Mitogen stimulated IL-6 in depressed non-attempters vs depressed
N = 33 depressed non-attempters; whole blood attempters and controls
N = 40 healthy controls IL-6 in depressed attempters vs controls when correcting
for sampling time
IL-2 in suicide attempters vs non-attempters and controls
IFN- and IL-4 total depressed patients vs controls
TGF-1 total depressed patients vs controls
Lindqvist et al., 2009 N = 63 suicide attempters (various psychiatric disorders); CSF IL-6 in suicide attempters
N = 47 healthy controls = IL-1, IL-8 and TNF- in both groups
Janelidze et al., 2011 N = 47 depressed suicide attempters; Plasma IL-6, TNF- and IL-2 in depressed suicide attempters vs
N = 33 depressed non-attempters; depressed non-attempters and controls
N = 40 healthy controls
Lindqvist et al., 2011 N = 124 suicide attempters at baseline CSF Factor consisting of IL-6, 5-HIAA, HVA and orexin
Of these, at follow-up (mean 15 4 years), associated with violent suicide attempts
N = 31 were violent suicide attempters
Isung et al., 2012a N = 43 suicide attempters (various psychiatric disorders); CSF IL-8, VEGF in suicide attempters
N = 20 healthy controls = IL-6 in both groups
Martinez et al., 2012 N = 18 depressed CSF + correlation between IL-1 and history of suicide attempts
N = 15 depressed with IL-1;
Li et al., 2013 N = 33 depressed with suicidal ideation; Plasma TNF- in depressed patients vs healthy controls on
N = 12 depressed suicide attempters; admission
N = 19 depressed without suicidal ideation; TNF- in depressed patients post treatment
N = 64 healthy controls TNF- greater for responders vs non-responders to
venlafaxine treatment
= TNF- levels between depressed patients with suicidal
ideation vs depressed suicide attempters vs non-suicidal
depressed patients;
Vargas et al., 2013 N = 141 suicide attempters; Serum = IL-6, TNF- in both groups
N = 201 non-attempters
(all outpatients at a smoking treatment clinic)

Abbreviations: CS cerebrospinal uid; 5-HIAA5-hydroxyindoleacetic acid; HVAhomovanillic acid; ILinterleukin; IFNinterferon; PHAphytohemagglutinin; sIL-
2Rsoluble interleukin receptor; TGFtransforming growth factor; TNFtumor necrosis factor; VEGFvascular endothelial growth factor.
Symbols: increased; decreased; = no change.

Table 3
Studies of cytokines and suicides.

Study Sample Source Results

Tonelli et al., 2008 N = 34 suicide completers (various psychiatric diagnosis); Postmortem IL-4 in female suicides
N = 17 controls orbitofrontal cortex IL-13 in male suicides
brain tissue (RT-PCR = IL-1, TNF-, IL-6, IL-5
for mRNA)
Pandey et al., 2012 N = 24 adolescent suicides (various psychiatric disorders); Postmortem prefrontal IL-6, IL-1, TNF- in suicides
N = 24 controls cortex brain tissue
Hoyo-Becerra et al., N = 20 suicides (N = 8 depressed, N = 12 undisclosed Postmortem IL-6 in suicides hippocampus
2013 diagnoses); hippocampus, = TNF-
N = 13 controls amygdala and gyrus
cinguli tissue
Torres-Platas et al., N = 7 depressed suicides; Postmortem dorsal = IL-1, IL-1Ra, TNF-, IL-10 in both groups
2014 N = 7 controls anterior cingulate
white matter
Lindqvist et al., 2011 N = 124 suicide attempters at baseline CSF Factor consisting of IL-6, 5-HIAA, HVA and orexin
Of these, at follow-up associated with suicide
N = 9 suicides
Isung et al., 2012b N = 58 suicide attempters at baseline (various psychiatric Plasma IL-2 in suicides
diagnosis); = IL-1, IL-1, IL-4, IL-6, IL-8, IL-10, IFN-, TNF-, MCP-1,
Of these, at follow-up, EGF in both groups
N = 51 survivors
N = 7 suicides

Abbreviations: CSFcerebrospinal uid; 5-HIAA5-hydroxyindoleacetic acid; HVAhomovanillic acid; ILinterleukin; IFNinterferon; PHAphytohemagglutinin; RT-
PCRreverse transcription polymerase chain reaction; TGFtransforming growth factor; TNFtumor necrosis factor.
Symbols: increased; decreased; =no change; RT-PCRreverse transcription polymerase chain reaction.

1, IL-6, IL-10, CRP, and TNF-) and in vitro (IL-2, IL-4, IFN-, TGF-) suicidality compared to healthy controls. Ducasse et al. (2015) ana-
determinations. They reported high IL-6 and IL-1, and low IL-2, in lyzed 11 articles, limiting their meta-analysis a priori to 6 cytokines
patients with suicidality compared to patients without suicidality (IL-2, IL-6, TNF-, IFN-, IL-4, TGF-). They likewise found low
and healthy controls; and low CSF levels of IL-8 in patients with plasma IL-2 levels in patients with suicidal behaviors compared to
Table 4
Results according to individual cytokines and outcome measures studied.

302
Cytokine Suicidal ideation Suicide attempt Suicide

= = =
IL-6 (3) (1) (3) (1) (2) (3) (2)
Martinez et al., Gabbay et al., 2009 (P) Janelidze et al., Kim et al., 2008 Vargas et al., 2013 (S); Hoyo-Becerra Tonelli et al.,
2012 (CSF); 2011 (P); (MSB) Isung et al., 2012a (CSF) et al., 2013 2008 (PMB);
ODonovan Lindqvist et al., (PMB); Isung et al.,
et al., 2013 (P) 2011 (CSF); Pandey et al., 2012b
Karlovic et al., Lindqvist et al., 2012 (PMB); (P)
2012a (S) 2009 (CSF) Lindqvist et al.,
2011 (CSF)
TNF- (1) (1) (2) (1) (3) (1) (4)
Martinez et al., Gabbay et al., 2009 ODonovan et al., 2013 Janelidze et al., Huang and Lee, 2007; Pandey et al., Hoyo-Becerra
2012 (CSF) (P) (P); 2011 Vargas et al., 2013 (S); 2012 (PMB) et al., 2013
Juengst et al., 2014 (CSF) (P) Lindqvist et al., 2009 (CSF) (PMB);
Tonelli et al.,
2008 (PMB);
Torres-Platas
et al., 2014)

L. Gananca et al. / Psychoneuroendocrinology 63 (2016) 296310


(PMB);
Isung et al.,
2012b (P)
IL-2 (1) (2) (1)
Mendlovic et al., 1999 (PSL) Kim et al., 2008 Isung et al.,
(MSB); 2012b (P)
Janelidze et al.,
2011 (P)
IL-1 (1) (1) (1) (2) (1) (3)
Monfrim et al., Gabbay et al., 2009 (P) Martinez et al., Huang and Lee, 2007(S); Pandey et al., Tonelli et al.,
2014 (S) 2012 (CSF) Lindqvist et al., 2009 (CSF) 2012 (PMB) 2008 (PMB);
Torres-Platas
et al., 2014
(PMB);
Isung et al.,
2012b (P)
INF- (1) (1) (1) (1)
Mendlovic Gabbay et al., 2009 (P) Kim et al., 2008 (MSB) Isung et al.,
et al., 1999 2012b (P)
(PSL)
IL-4 (2) (1) (1)
Mendlovic et al., 1999 Tonelli et al., Isung et al.,
(PSL); 2008 (PMB) 2012b (P)
Gabbay et al., 2009 (P)
IL-13 (1)
Tonelli et al.,
2008 (PMB)
IL-8 (1) (1) (1)
Isung et al., Lindqvist et al., 2009 (CSF) Isung et al.,
2012a (CSF) 2012b (P)
IL-10 (2) (1) (2)
Mendlovic et al., 1999 Huang and Lee, 2007 Torres-Platas
(PSL); (S) et al., 2014
ODonovan et al., 2013 (P) (PMB);
Isung et al.,
2012b (P)
TGF- (1) (1)
ODonovan et al., 2013 (P) Kim et al., 2008 (MSB)

Abbreviations: CSFcerebrospinal uid; MSBmitogen stimulated blood; Pplasma; PMBpostmortem brain; PSLphytohemagglutinin-stimulated lymphocytes; Sserum.
Symbols: (#)number of studies; increased; decreased; =no change.
a
Reported as suicidal behavior.
L. Gananca et al. / Psychoneuroendocrinology 63 (2016) 296310 303

the other two groups, and as well, reported lower IL-4 and higher tional polymorphisms found no differences in either codon 10 or
TGF- plasma levels in both suicidal and non-suicidal patients than codon 20 polymorphisms in depressed suicide attempters (n = 124)
in healthy controls. The studies included in the two meta-analyses compared with depressed non-attempters (n = 61) or healthy con-
mostly overlap, but Black and Miller (2015) included additional trols (n = 125), whereas another study (Omrani et al., 2012) found
studies in which positive ndings for IL-1 (Monfrim et al., 2014) the TGF-1-10 polymorphism to be more prevalent in suicide com-
and IL-6 (Monfrim et al., 2014; Pandey et al., 2012) were found, pos- pleters (n = 145) compared to non-psychiatric controls (n = 200).
sibly explaining the divergent results. We include in our review six Single reports found the IL-10 -1082 genotype higher in suicides
additional studies that were not included in either meta-analysis than non-psychiatric controls and the IFN- +874 genotype more
(Hoyo-Becerra et al., 2013; Juengst et al., 2014; Lindqvist et al., prevalent in male suicides (Omrani et al., 2009), and no differences
2009; Rothenhusler et al., 2006; Torres-Platas et al., 2014). in polymorphisms of the IL-1 gene complex [IL-1 -889C/T, IL-1
+3953C/T, IL-1RA (86 bp)n ] between a mixed diagnostic group of sui-
cide attempters (n = 193) and healthy controls (n = 420) (Siz et al.,
4. Discussion
2008).

Taken together, the current literature suggests that inamma-


4.1.2. Acute psychosocial stress
tion plays a role in suicidal behavior, but the heterogeneity of
Recently, Frank et al. (2013) proposed that after an acute stress-
specic ndings, even among the two available meta-analyses, is
ful event, glucocorticoids prime microglia into an enhanced state of
considerable. Possible explanations for discrepancies among stud-
inammatory sensitivity, promoting enhanced immune responses,
ies include the following: (1) different phenotypes of suicidal
such as microglial cytokine production, to subsequent challenges.
behavior may be associated with distinct biological inammatory
Stress-induced effects on neuronal activation are reversed by
patterns, exemplied by ndings of Karlovic et al. (2012), in which
administering the microglial activation inhibitor minocycline, sug-
IL-6 levels differed among suicidal compared with non-suicidal
gesting that microglial activation may mediate the effects of stress
patients and correlated with depression severity, but only in the
on resulting depressive symptoms (Hinwood et al., 2012). Microglia
presence of melancholic as opposed to atypical features. (2) Com-
also have been implicated more directly in suicide risk, as Steiner
parability of different cytokine indices may be questionable, e.g.
et al. (2008) found higher microgliosis in suicides, with no effect
in one study (Isung et al., 2014), plasma and CSF IL-6 levels were
of diagnostic group (schizophrenia, depression or healthy). Thus
found not to be associated. (3) Control of confounders is extremely
we might speculate that microglial activation moderates effects
challenging, since blood cytokine and soluble cytokine receptor
of life events such as major depressive episodes and psychosocial
levels are affected by a large number of factors such as age, sex,
stressors on suicide risk.
socioeconomic status, acute exercise, excessive caffeine use, BMI,
smoking, sleep quality and habits, alcohol use, psychotropic med-
4.1.3. Early life adversity
ications, and medical comorbidities (OConnor et al., 2009b). (4)
This subset of psychosocial stress is a major contributor to
Different immunoassay techniques may yield different results (de
enhanced vulnerability to suicidal behaviors later in life (Brodsky
Koning et al., 2012). (5) Genetic and epigenetic effects may strongly
and Stanley, 2008) and is predictive of multiple suicide attempts
inuence individual reactivity to inammatory stimuli (Kim et al.,
(Brodsky et al., 2001). Biologically, early life adversity is asso-
2013).
ciated with abnormal cortisol stress response, persistent high
This level of heterogeneity can be considered an indicator of
levels of pro-inammatory cytokines including TNF- and IL-6,
inherent complexity. Thus additional approaches are needed to
low-grade elevations in other pro-inammatory markers such as
parse out relevant factors that may act as mediators and moder-
C-reactive protein (CRP), and greater inammatory responses to
ators of the relationship between inammation and suicide risk,
later psychosocial stress (reviewed in (Fagundes et al., 2013)).
some of which may have potential as intervention points. For exam-
An explanatory model has been proposed by Miller et al. (2011),
ple, pivotal to the vulnerability for suicidal behaviors is a disturbed
which posits that early life stress modulates inammatory cells
stress response (reviewed by Oquendo et al. (2014)), which has
(monocytes/macrophages) so they exhibit hyper-responsivity to
been described with the Stress-Diathesis Model (Mann et al., 1999).
challenges and muted responsiveness to inhibitory feedback, and
Two of the most powerful inuences on stress response, including
are further affected by hormonal signals and behaviors that
inammatory responses, are genetics and early life experiences,
heighten inammation later in life.
considered in Section 4.1.
4.1.4. Chronic social stress
4.1. Factors affecting stress response Extensively studied with regard to both suicide risk and inam-
matory changes, chronic psychosocial stress is associated with
4.1.1. Genetics and heritability glucocorticoid receptor resistance. Furthermore, pro-inammatory
These factors appear to contribute as much as 30-50% to the cytokines can induce glucocorticoid receptor resistance, thus cre-
broad suicidality phenotype (Mann et al., 2009). Genes that regulate ating a perpetuating cycle of enhanced inammatory states. For
activity in the serotonergic, dopaminergic and GABAergic systems, example, individuals in a chronically stressful adult care-giving role
HPA axis, and BDNF have been the most extensively studied in exhibit elevated IL-6 (Kiecolt-Glaser et al., 2003). A recent study
suicide (Mann et al., 2009). Studies of relationships between func- reported increased suicidal ideation in dementia family care-givers
tional polymorphisms in cytokine genes and suicide attempts are (ODwyer et al., 2013).
few and do not provide a consensus. Investigations of the func-
tional polymorphism TNF- -308 (A/G) variously have found no 4.1.5. Clinical depression
differences in suicide attempters with various psychiatric diagnosis Depressed patients exhibit changes in multiple inammatory
(n = 193) vs. healthy controls (n = 420) (Siz et al., 2008); a posi- indices, such as elevated CRP (Scrandis et al., 2008), loss of brain
tive association between the GG genotype and depressed suicide astroglia and activation of microglia (McNally et al., 2008), and
attempters (n = 204) vs. depressed non-attempters (n = 97); and (in altered circulating levels of inammatory cytokines and their sol-
a sample with both sexes) greater prevalence in male suicides uble receptors, including soluble IL-2-receptor (sIL-2R), IL-6 and
(n = 28) than in non-psychiatric controls (n = 46) (Omrani et al., TNF- (Liu et al., 2012). Severity of depressive symptoms also has
2009). Similarly, one study (Lee and Kim, 2010) of TGF-1 func- been shown to correlate positively with levels of pro-inammatory
304 L. Gananca et al. / Psychoneuroendocrinology 63 (2016) 296310

cytokines and chemokines (Suarez, 2003). Among patients receiv- evaluated trait aggression in participants, suggesting an important
ing pro-inammatory agents such as chronic IFN- therapy for direction for future investigation.
the treatment of infectious diseases or cancer, 20%50% develop
clinically signicant depression (Capuron et al., 2002). Conversely,
anti-inammatory therapy has been shown to have antidepressant 4.2.4. Impulsivity
activity (Muller et al., 2006). Frequently, impulsivity is characteristic of individuals who
However, not all depressed patients show changes in inamma- engage in suicidal behaviors (Gvion and Apter, 2011) and has
tory markers (Miller et al., 2013). It may be instructive to identify been recently associated with increased inammatory markers as
additional phenotypes associated with depression, inammation, well. Isung et al. (2014) found increased plasma IL-6 in suicide
and suicidality. For example, increased inammatory markers are attempters with high impulsivity and sensation-seeking person-
more prominent in depressed patients with a history of childhood ality traits. Whether these characteristics constitute a behavioral
adversity (Fagundes et al., 2013), treatment resistance (Lanquillon link between inammation and suicidal behavior requires further
et al., 2000) and obesity (Shelton and Miller, 2010), all factors that study.
have been linked to suicidal behavior (Brodsky and Stanley, 2008;
Klinitzke et al., 2013; Olin et al., 2012).
4.2.5. Hopelessness
Another emotional state that may increase vulnerability to suici-
4.2. Symptom domains and inammation dal behavior, hopelessness was also positively related to IL-6 levels
(Sjgren et al., 2006). Studies with a longitudinal design could clar-
4.2.1. Illness severity ify the relationship between inammation, suicidal behavior and
Depression severity could potentially be a major confound, hopelessness.
as inammatory changes could represent a function of sever-
ity rather than suicidal behavior per se (Lindqvist et al., 2009;
4.3. Mechanistic considerations
Martinez et al., 2012). However, results of several studies indi-
cate that severity cannot account for the ndings. In one study
4.3.1. Peripheral vs central cytokines
where depressed patients with suicidal ideation also reported
As cytokines are rather large molecules that do not easily cross
higher symptom severity (even when omitting the HDRS suicide
the blood brain barrier (BBB) (Haroon et al., 2012), the relationship
evaluation item), this did not signicantly account for variations
between blood and CSF cytokine levels may not be a simple one,
in inammatory index between groups (ODonovan et al., 2013).
complicating the interpretation of studies of peripheral cytokines
Moreover, in another study in which depressed suicide attempters
and suicidal behaviors. Increased circulating cytokines may affect
had elevated inammatory markers compared with depressed
brain and behavior through several mechanisms, including entry
non-attempters (Janelidze et al., 2011), a trend was seen toward
through leaky regions or by active transport (reviewed in (Haroon
higher severity MADRS scores in depressed non-attempters com-
et al., 2012)). Alternatively, within-brain cytokine production could
pared to attempters. Five additional studies found no effect of
be increased by external factors such as stress-induced microglial
depression symptom severity (Gabbay et al., 2009; Isung et al.,
activation (Frank et al., 2007). Although CSF measures of cytokines
2012a,b; Kim et al., 2008; Li et al., 2013). Thus depression severity
and chemokines would seem to be a better index of brain inamma-
does not seem to explain the relationship between inammation
tion, nevertheless procedural feasibility, lower invasiveness burden
and suicidal behavior.
for research participants, and ability to perform repeated measures
make blood sampling more attractive. Surprisingly, none of the
4.2.2. Anhedonia studies reported herein measured both CSF and peripheral cytokine
Anhedonia has been shown to predict suicide (Winer et al., levels; such studies are essential to clarify this issue.
2014). Moreover, on magnetic resonance imaging (MRI), structural
and functional correlates of anhedonia are seen in stress-sensitive
4.3.2. Polyunsaturated fatty acids (PUFAs)
brain regions such as the nucleus accumbens and anterior cingulate
These essential dietary nutrients play a key role in the regulation
gyrus, in both healthy (Wacker et al., 2009) and depressed sub-
of inammation, largely through the actions of their metabolites,
jects (Keedwell et al., 2005). In a rat model, microglial activation
and have been implicated in depression and suicide risk. Omega-
has been demonstrated in analogous brain regions, in the context
6 (n-6) PUFA metabolites include the primarily pro-inammatory
of restraint stress that induces anhedonia, as modeled by reduced
eicosanoids, while omega-3 (n-3)-PUFA-derived metabolites are
sucrose intake (Tynan et al., 2010). Whether anhedonia is linked
the generally anti-inammatory docosanoids (Calder, 2015). In
to microglial activation in these brain areas in humans has not yet
humans, plasma omega-3 PUFA levels correlate negatively with
been studied.
levels of pro-inammatory cytokines and positively with levels of
anti-inammatory cytokines (Ferrucci et al., 2006). Among in vitro
4.2.3. Trait aggression studies, pre-incubation with long-chain omega-3 PUFA results in
This characteristic has been associated with suicide (Dumais reduction of TNF- and IL-6 expression and enhanced secretion of
et al., 2005), suicide attempts (Dumais et al., 2005; Oquendo et al., anti-inammatory IL-10 (Oliver et al., 2012). Omega-3 PUFAs are
2004) and future suicidal behavior (Oquendo et al., 2004), and also lower in suicides (Lewis et al., 2011) and in suicide attempters in
with inammatory changes. Aggression, anger, and hostility were a concentration-dependent manner (Huan et al., 2004). Low lev-
positively associated with monocyte-associated TNF- expression els of the omega-3 species docosahexaenoic acid (DHA) and an
following lipopolysaccharide (LPS) stimulation (Suarez et al., 2002) increased omega-6/omega-3 ratio also have been shown to predict
in healthy men. Hostility also has been associated with higher IL- suicide attempts in depression (Sublette et al., 2006). In studies of
6 in men (Suarez, 2003) and greater LPS-stimulated expression of self-harming individuals, omega-3 fatty acid supplementation has
IL-1, IL-8 and IL-1 in women (Suarez et al., 2004), with highest been shown to reduce suicidal ideation (Hallahan et al., 2007). Spe-
inammation levels among depressed individuals. Although one cic effects of omega-3 PUFA supplementation on cytokines include
study found an association between IL-6 and violent suicide meth- reduction of IL-6 responses to test-taking stressors (Kiecolt-Glaser
ods (Lindqvist et al., 2009), none of the reviewed studies above et al., 2011).
L. Gananca et al. / Psychoneuroendocrinology 63 (2016) 296310 305

4.3.3. Neurocircuitry cides, depressed non-suicides, and controls (Pandey et al., 2014).
Increased cytokine levels could enhance suicidal behaviors by TLRs are innate immune receptors that recognize pathogen- or
affecting specic areas in the brain or specic neurochemical pro- damage-associated molecular patterns and stimulate microglia to
cesses associated with suicidality. For example, using positron release pro-inammatory cytokines. Elevated TLR3 and TLR4 mRNA
emission tomography with [18 F]uorodeoxyglucose (FDG-PET) in expression was seen in all depressed patients, irrespective of cause
an MDD population, we found (1) lower regional cerebral metabolic of death, compared with controls, while elevated TLR3 and TLR4
rates of glucose (rCMRglu) in right dorsolateral prefrontal regions protein levels were seen in both suicide groups compared with
in suicide attempters, and higher rates in ventromedial regions in non-suicides irrespective of diagnosis (Pandey et al., 2014).
non-attempters (Sublette et al., 2013); and (2) lower rCMRglu in
high-lethality suicide attempters than in low-lethality attempters 4.3.4. Monoaminergic neurotransmission
in ventral, medial, and lateral prefrontal cortex (Oquendo et al., One of the mechanisms by which cytokines may inuence
2003). In a recent meta-analysis of twelve MRI studies (van suicidal behavior is through effects on monoaminergic neurotrans-
Heeringen et al., 2014), structural changes in the left superior mission, extensively associated with both depression and suicidal
temporal gyrus, rectal gyrus and caudate nucleus, and functional behaviors (reviewed in (Mann, 2003)). For example, increased sero-
changes in the anterior and posterior cingulate were associated tonin transporter (SERT) mRNA is seen after IFN- administration
with suicidal behavior. This distribution partially overlaps with in mice (Morikawa et al., 1998). Additionally, there is evidence
brain regions reportedly targeted by cytokines in the brain: basal suggesting that genetic SERT variants may be more susceptible
ganglia (especially ventral striatum) and anterior cingulate cor- to the actions of pro-inammatory cytokines: hepatitis C patients
tex (Miller et al., 2013). In patients with hepatitis C treated with with the SLC6A4(SERT) genetic variant are more likely to develop
IFN- compared with untreated patients, left-sided activation was a depressive episode during INF- treatment (Lotrich et al., 2009;
seen on fMRI during a visuospatial attention task in the inferior Pierucci-Lagha et al., 2010).
frontal gyrus and dorsal anterior cingulate (Capuron et al., 2005); Another critical link between inammatory and serotonin sys-
and extensive bilateral rCMRglu increases were seen on FDG- tems is provided by cytokine-activated enzyme indoleamine-2,3-
PET in subcortical regions including basal ganglia and cerebellum dioxygenase (IDO), which catalyzes the production of kynurenine
(Capuron et al., 2007) studies. from tryptophan. Activation of this pathway could reduce gen-
Decreased brain volumes in the prefrontal cortex of suicidal eration of serotonin, the other downstream tryptophan product
patients also have been described (Ding et al., 2015), possibly (Maes et al., 1993). Many of the cytokines studied in relation to sui-
reecting neuroplasticity impairment. Pro-inammatory cytokines cide (Janelidze et al., 2011; Kim et al., 2008; Lindqvist et al., 2009;
are associated with decreased neurogenesis and induce reduc- Tonelli et al., 2008) are known stimulators of IDO, and knockout
tions in BDNF expression, mRNA and protein levels (Calabrese mice for the IDO gene fail to express depressive-like symptoms
et al., 2014). BDNF, the most relevant neuroplasticity mediator, despite immune activation (OConnor et al., 2009a). However,
affecting neuronal survival, growth and neurogenesis (Bramham high levels of kynurenine also have been associated with suicide
and Messaoudi, 2005), also has been linked to suicidal behav- attempts without evidence of tryptophan depletion (Sublette et al.,
iors. Reduced prefrontal cortex BDNF mRNA and protein levels, 2011), suggesting an alternative mechanism whereby elevations of
regardless of psychiatric diagnosis (Dwivedi et al., 2003) and kynurenine or its metabolites, quinolinic acid and kynurenic acid,
increased BDNF gene DNA methylation (Keller et al., 2010) have may inuence mood and suicide risk through direct effects on brain.
been reported in suicides, and lower peripheral BDNF levels This is supported by a study showing that treatment with IFN-
have been noted in suicidal patients. Volumetric changes also increased CSF kynurenine, quinolinic acid and kynurenic acid with-
may be mediated through cytokine effects on corticoid secretion out any decrease of CSF tryptophan (Raison et al., 2010). Moreover,
(Goshen et al., 2008), as increased cortisol levels are associated quinolinic acid is an N-methyl-D-aspartate (NMDA) receptor ago-
with decreased volumes in the prefrontal cortex and other brain nist; and ketamine, a known NMDA receptor antagonist, reduced
areas. suicidality in some recent studies (DiazGranados et al., 2010; Larkin
Unlike neuroimaging methodologies, postmortem techniques and Beautrais, 2011). This hypothetical pathway is illustrated in
necessitate a priori choice of single or few brain regions for study Fig. 2.
and thus cannot provide larger-scale information about regional
interconnectedness. The small number of studies focused on brain 4.3.5. Immune dysregulation mechanisms governing resilience
inammatory components related to completed suicide all found In addition to higher production of pro-inammatory cytokines
evidence of increased inammation, instantiated by measurements as a risk factor for suicidal behaviors, decreases in anti-
of cytokine activity in the prefrontal cortex (Pandey et al., 2012; inammatory processes should also be considered. For example,
Tonelli et al., 2008), microglial priming and macrophage recruit- low omega-3 PUFA intake may contribute to a perpetuation of
ment (Torres-Platas et al., 2014) and hypertrophy of astrocytes immune dysregulation through lower production of the docosanoid
in the dorsal anterior cingulate (Torres-Platas et al., 2011), and metabolites, resolvins, protectins, and maresins, so named because
toll-like receptor (TLR) expression in the dorsolateral prefrontal of their role facilitating resolution of inammation (Calder, 2015).
cortex (Pandey et al., 2014). Elevated mRNA expression of IL-4 Other changes in resiliency systems may also confer vulnerabil-
and IL-13 (Tonelli et al., 2008), and mRNA and protein expres- ity to disease. Following mild stress, BDNF+/ mice did not increase
sion of IL-1, IL-6 and TNF- (Pandey et al., 2012) were seen production of the anti-inammatory cytokine IL-10 or of the neuro-
among suicides with a variety of diagnoses compared with nor- protective branch of the kynurenine pathway, contrary to wild-type
mal controls dying of other causes. Elevated microglial priming, mice (Dugan et al., 2015). More studies are needed to clarify these
macrophage recruitment (Torres-Platas et al., 2014), and hyper- less investigated pathways.
trophic astrocytes (Torres-Platas et al., 2011) were seen in the
dorsal anterior cingulate of depressed suicides compared to psy- 4.4. Causality or epiphenomenon?
chiatrically healthy controls; however, since all case subjects were
depressed suicides, no conclusions could be drawn regarding speci- These observations support a connection between alterations
city for suicidal behavior as opposed to depression. In contrast, in cytokine levels, vulnerability factors, and suicidal behavior.
a study of TLRs compared depressed suicides, non-depressed sui- What remains to be elucidated is the nature of this relation-
ship. Thus, these ndings could represent an epiphenomenon,
306 L. Gananca et al. / Psychoneuroendocrinology 63 (2016) 296310

Fig. 2. Hypothetical pathways through which pro-inammatory cytokines may inuence suicide risk.
Stressors and constitutional factors associated with suicidal behaviors reciprocally interact with the immune system resulting in increased levels of pro-inammatory
cytokine in vulnerable individuals. Pro-inammatory cytokines strongly induce IDO enzyme favoring the kynurenine pathway, which results in decreased serotonin and
increased quinolinic acid, both associated with depression and suicidal behaviors.
Abbreviations: 5-HT5-hydroxytryptamine (serotonin); IDOIndoleamine 2,3-dioxygenase; NMDA N-Methyl-D-aspartate.

in which increased cytokine concentrations observed in suicide report equal levels of TNF-a among suicidal and non-suicidal MDD;
attempters are the result of the stress response activation. For and Boehm et al. (2010) is not a study of depressed patients.
example, physical tissue damage, as may be seen in more violent These ndings are in direct contrast with Black and Miller (2015),
suicidal attempts, could partly explain increased levels of circu- who, using quantitative meta-analytic methods, found a marked
lating cytokines. Indeed, in one of the reviewed studies (Lindqvist lack of effect with respect to TNF- but did nd signicant differ-
et al., 2009), increased levels of IL-6 were greatest in violent sui- ences in suicidal compared with non-suicidal patients in IL-1 and
cide attempts. However elevated inammatory markers are also in IL-6 after removing one study through sensitivity analysis for
seen in connection with high suicidal ideation independent of pre- heterogeneity. Thus IL-1 and IL-6 seem to be the most likely can-
vious suicide attempts (ODonovan et al., 2013). Therefore cytokine didates for continued research. Once again, we note that control
increases cannot be attributed solely to the physiologic conse- of confounders is of paramount importance in continuing studies
quences of a recent suicidal attempt, although they could arise to distinguish the interrelationships between cytokines, suicidal
from the stress and emotional pain that triggered the suicidal behavior, and depression. For instance, not only cytokines (Raison
urge. For instance, increases in IL-1 gene expression, plasma IL-6 and Miller, 2013) but many of the factors associated with suicidal
(Brydon et al., 2005) and IL-2 (Wieck et al., 2014) occur follow- behaviorsuch as acute and chronic stress, anhedonia, hopeless-
ing a purely psychologically challenging task. On the other hand, ness, and differences in PUFAs, brain functioning and circuits, or
favoring a causal relationship in at least a subset of patients are monoaminergic transmission (Gelenberg, 2010) are also linked to
reports describing suicidal behaviors in patients receiving treat- depression.
ment for medical conditions with therapeutic cytokines (Dieperink
et al., 2004). 4.6. Limitations

4.5. Effects of suicidality independent from depression? The number of studies focusing on the relationship between
cytokines and suicidal behaviors is still small, with modest sample
One of the most relevant remaining questions is whether sizes, and the methodologies employed are diverse. Accordingly,
specic changes in cytokines associate with suicidal ideation or this review was non-quantitative in nature and cannot yield con-
behaviors independently from effects of psychiatric diagnosis. clusions about effect sizes. Additionally, we did not address possible
We found nine studies that directly compared depressed suici- effects of publication bias. Recruitment bias is also a general issue
dal patients to depressed non-suicidal patients (see Table 5). On in suicidal behavior studies, as differences may exist between par-
qualitative review, there is no clear suggestion that any particu- ticipants who do or do not agree to participate. Caution is needed
lar cytokine abnormality distinguishes suicidal from non-suicidal in interpreting combined results from suicide attempters and sui-
depressed patients. Serani et al. (2013) also reviewed the liter- cides since, although suicide attempt is a risk factor for completion,
ature and tabulated cytokines more frequently associated with and suicides are obviously a subset of suicide attempters, it is
MDD compared to those related to suicidality. Each cytokine unclear whether suicide completion is simply suicidal behavior
abnormality was reported in one or two studies, with the most on the extreme end of a severity continuum, or whether suicides
prominent nding in suicidal MDD of higher TNF- in 4 studies represent a distinct neurobiological subtype. Different methods for
(Boehm et al., 2010; Janelidze et al., 2011; Li et al., 2013; Pandey suicide attempt or completion may also reect differences in lethal-
et al., 2012); however, this is confusing as Pandey (Pandey et al., ity and intent, and may be associated with distinct inammatory
2012) did not utilize a depressed control group; Li et al., (2013) patterns. In most studies presented in our review, suicide meth-
L. Gananca et al. / Psychoneuroendocrinology 63 (2016) 296310 307

Table 5
Cytokine ndings with respect to group comparisons among studies that compared suicidal major depressive disorder (MDD) to non-suicidal MDD or healthy controls.

Study Source Suicidal MDD vs. Suicidal MDD vs. Non-Suicidal MDD vs.
Non-Suicidal MDD/BD Controls Controls

Suicide attempts
Huang and Lee, 2007 Plasma = IL-1
= TNF-
= IL-10
Janelidze et al., 2011 Plasma IL-6 IL-6
TNF- TNF-
IL-2 IL-2
Kim et al., 2008 Mitogen-stimulated IL-6 IL-2 IL-6
whole blood IL-2 IL-4 IL-4
IFN- IFN-
TGF-1 TGF-1
Li et al., 2013 Plasma = TNF- TNF- TNF-

Suicidal ideation
Gabbay et al., 2009 Plasma TNF- IFN- IFN-
= IL-1 = IL-1 = IL-1
= IL-4 = IL-4 = IL-4
= IL-6 = IL-6 = IL-6
Karlovic et al., 2012 Serum IL-6
Martinez et al., 2012 CSF IL-1 IL-6
TNF-
Mendlovic et al., 1999 PHA-stimulated IFN- IFN- IFN-
lymphocytes () IL-4 = IL-2 = IL-2
() IL-5 = IL-4 = IL-4
= IL-2 = IL-5 = IL-5
= IL-10 = IL-10 = IL-10
ODonovan et al., 2013 Plasma IL-6 IL-6 = IL-6
= IL-10 = IL-10 = IL-10
=TNF- =TNF- =TNF-
=TGF- =TGF- =TGF-

Postmortem studies were not included because they did not utilize non-depressed control groups.
Abbreviations: CSFcerebrospinal uid; IL interleukin; IFNinterferon; PHAphytohemagglutinin; TGFtransforming growth factor; TNFtumor necrosis factor.
Symbols: increased; decreased; = no change.

ods were not controlled. Also, interactions with other biological as it could potentially decrease the devastating impact of suicidal
markers associated with suicidal behaviors, such as monoamines behaviors on at-risk individuals, their families, and society.
or HPA axis mediators, might create potential confounds that were
not evaluated in the majority of the included studies. Moreover, it Conicts of interest
may be methodologically problematic to compare in vivo and post-
mortem results, since agonal processes may inuence cytokines, Drs. Mann and Oquendo receive royalties from the commer-
and clinical information obtained through psychological autop- cial use of the Columbia Suicide Severity Rating Scale (C-SSRS)
sies are not directly comparable to psychiatric assessments of live from the Research Foundation for Mental Hygiene. Dr. Oquendos
patients. Other limitations to postmortem studies of suicide include family owns stock in Bristol Myers Squibb. Drs. Gananca, Sublette,
prolonged postmortem intervals and effects of psychoactive med- Cisneros-Trujillo and Tyrka have no conicts to report.
ications (Pandey and Dwivedi, 2010). Finally, a priori hypotheses
concerning specic cytokines were not comparable across all stud-
ies. Contributors

Drs. Gananca, Oquendo, Tyrka, Mann and Sublette participated


5. Conclusions in the conceptualization of the manuscript and interpretation of
ndings. Dr. Gananca wrote the rst draft of the manuscript. Drs.
Suicide risk has been associated with chronic stress, HPA Gananca and Cisneros-Trujillo performed the literature review and
hyperactivity, serotonergic abnormalities, and in some studies, selection of articles for inclusion. All authors participated in draft-
persistently elevated inammatory markers, especially elevation ing and/or critically revising the article for important intellectual
of IL-6. Larger, methodologically rigorous studies are needed to content and have approved the submitted version.
draw denitive conclusions regarding the association of inam-
matory proteins and suicide. Such studies would contribute to an
integrated understanding of the interplay among these different Funding
elements, and allow the identication of proximate suicide risk
factors that are potentially modiable. For example, if immune Funding sources made no contribution to study design, collec-
responses such as IL-6 activation mediate the effects of chronic tion, analysis or interpretation of data, writing of the report, or the
stress on suicide risk, then treatments that reduce IL-6 could have decision to submit the article for publication.
promise. Future studies using prospective designs could focus on
whether IL-6 predicts risk of suicidal behavior. Associated clinical Acknowledgements
characteristics that could modulate the effects of IL-6 also should
be taken into account. A better understanding of suicide risk factors Sources of Support: MH P50 MH090964 Conte Center: Neuro-
that could be amenable to intervention, such as reducing inam- biological and Developmental Antecedents to Suicidal Behavior
mation or altering dietary intake of PUFAs, is of crucial importance (Mann and Oquendo); R01 MH101107, R01 MH083704 (Tyrka);
308 L. Gananca et al. / Psychoneuroendocrinology 63 (2016) 296310

American Foundation for Suicide Prevention (Sublette); The Asso- Ferrucci, L., Cherubini, A., Bandinelli, S., Bartali, B., Corsi, A., Lauretani, F., Martin, A.,
ciation for Research and Development of the School of Medicine, Andres-Lacueva, C., Senin, U., Guralnik, J.M., 2006. Relationship of plasma
polyunsaturated fatty acids to circulating inammatory markers. J. Clin.
University of Lisbon (Gananca) Endocrinol. Metab. 91, 439446.
Frank, M.G., Baratta, M.V., Sprunger, D.B., Watkins, L.R., Maier, S.F., 2007. Microglia
serve as a neuroimmune substrate for stress-induced potentiation of CNS
pro-inammatory cytokine responses. Brain Behav. Immun. 21, 4759.
References Frank, M.G., Watkins, L.R., Maier, S.F., 2013. Stress-induced glucocorticoids as a
neuroendocrine alarm signal of danger. Brain Behav. Immun. 33, 16.
Beautrais, A.L., Joyce, P.R., Mulder, R.T., Fergusson, D.M., Deavoll, B.J., Nightingale, Gabbay, V., Klein, R.G., Guttman, L.E., Babb, J.S., Alonso, C.M., Nishawala, M., Katz,
S.K., 1996. Prevalence and comorbidity of mental disorders in persons making Y., Gaite, M.R., Gonzalez, C.J., 2009. A preliminary study of cytokines in suicidal
serious suicide attempts: a case-control study. Am. J. Psychiatry 153, and nonsuicidal adolescents with major depression. J. Child Adolesc.
10091014. Psychopharmacol. 19, 423430.
Black, C., Miller, B.J., 2015. Meta-analysis of cytokines and chemokines in Gelenberg, A.J., 2010. Depression symptomatology and neurobiology. J. Clin.
suicidality: distinguishing suicidal versus nonsuicidal patients. Biol. Psychiatry Psychiatry 71, e02.
78, 2837. Goshen, I., Kreisel, T., Ben-Menachem-Zidon, O., Licht, T., Weidenfeld, J., Ben-Hur,
Boehm, J., Fischer, K., Bohnert, M., 2010. Putative role of TNF-alpha, interleukin-8 T., Yirmiya, R., 2008. Brain interleukin-1 mediates chronic stress-induced
and ICAM-1 as indicators of an early inammatory reaction after burn: a depression in mice via adrenocortical activation and hippocampal
morphological and immunohistochemical study of lung tissue of re victims. J. neurogenesis suppression. Mol. Psychiatry 13, 717728.
Clin. Pathol. 63, 967971. Grudet, C., Malm, J., Westrin, A., Brundin, L., 2014. Suicidal patients are decient in
Bramham, C.R., Messaoudi, E., 2005. BDNF function in adult synaptic plasticity: the vitamin D, associated with a pro-inammatory status in the blood.
synaptic consolidation hypothesis. Prog. Neurobiol. 76, 99125. Psychoneuroendocrinology 50, 210219.
Brodsky, B.S., Oquendo, M., Ellis, S.P., Haas, G.L., Malone, K.M., Mann, J.J., 2001. The Gvion, Y., Apter, A., 2011. Aggression, impulsivity, and suicide behavior: a review
relationship of childhood abuse to impulsivity and suicidal behavior in adults of the literature. Arch. Suicide Res. 15, 93112.
with major depression. Am. J. Psychiatry 158, 18711877. Hallahan, B., Hibbeln, J.R., Davis, J.M., Garland, M.R., 2007. Omega-3 fatty acid
Brodsky, B.S., Stanley, B., 2008. Adverse childhood experiences and suicidal supplementation in patients with recurrent self-harm. Single-centre
behavior. Psychiatry Clin. North Am. 31, 223235. double-blind randomised controlled trial. Br. J. Psychiatry 190, 118122.
Brydon, L., Edwards, S., Jia, H., Mohamed-Ali, V., Zachary, I., Martin, J.F., Steptoe, A., Haroon, E., Raison, C.L., Miller, A.H., 2012. Psychoneuroimmunology meets
2005. Psychological stress activates interleukin-1beta gene expression in neuropsychopharmacology: translational implications of the impact of
human mononuclear cells. Brain Behav. Immun. 19, 540546. inammation on behavior. Neuropsychopharmacology 37, 137162.
Calabrese, F., Rossetti, A.C., Racagni, G., Gass, P., Riva, M.A., Molteni, R., 2014. Hawton, K., Casanas, I.C.C., Haw, C., Saunders, K., 2013. Risk factors for suicide in
Brain-derived neurotrophic factor: a bridge between inammation and individuals with depression: a systematic review. J. Affect. Disord. 147, 1728.
neuroplasticity. Front. Cell. Neurosci. 8, 430. Hinwood, M., Morandini, J., Day, T.A., Walker, F.R., 2012. Evidence that microglia
Calder, P.C., 2015. Marine omega-3 fatty acids and inammatory processes: effects, mediate the neurobiological effects of chronic psychological stress on the
mechanisms and clinical relevance. Biochim. Biophys. Acta 1851, 469484. medial prefrontal cortex. Cereb. Cortex 22, 14421454.
Capuron, L., Gumnick, J.F., Musselman, D.L., Lawson, D.H., Reemsnyder, A., Hoyo-Becerra, C., Huebener, A., Trippler, M., Lutterbeck, M., Liu, Z.J., Truebner, K.,
Nemeroff, C.B., Miller, A.H., 2002. Neurobehavioral effects of interferon-alpha Bajanowski, T., Gerken, G., Hermann, D.M., Schlaak, J.F., 2013. Concomitant
in cancer patients: phenomenology and paroxetine responsiveness of interferon alpha stimulation and TLR3 activation induces neuronal expression
symptom dimensions. Neuropsychopharmacology 26, 643652. of depression-related genes that are elevated in the brain of suicidal persons.
Capuron, L., Pagnoni, G., Demetrashvili, M., Woolwine, B.J., Nemeroff, C.B., Berns, PLoS One 8, e83149.
G.S., Miller, A.H., 2005. Anterior cingulate activation and error processing Huan, M., Hamazaki, K., Sun, Y., Itomura, M., Liu, H., Kang, W., Watanabe, S.,
during interferon-alpha treatment. Biol. Psychiatry 58, 190196. Terasawa, K., Hamazaki, T., 2004. Suicide attempt and n-3 fatty acid levels in
Capuron, L., Pagnoni, G., Demetrashvili, M.F., Lawson, D.H., Fornwalt, F.B., red blood cells: a case control study in China. Biol. Psychiatry 56, 490496.
Woolwine, B., Berns, G.S., Nemeroff, C.B., Miller, A.H., 2007. Basal ganglia Huang, T.L., Lee, C.T., 2007. T-helper 1/T-helper 2 cytokine imbalance and clinical
hypermetabolism and symptoms of fatigue during interferon-alpha therapy. phenotypes of acute-phase major depression. Psychiatry Clin. Neurosci. 61,
Neuropsychopharmacology 32, 23842392. 415420.
Chaplin, D.D., 2010. Overview of the immune response. J. Allergy Clin. Immunol. Isung, J., Aeinehband, S., Mobarrez, F., Mrtensson, B., Nordstrm, P., Asberg, M.,
125, S323. Piehl, F., Jokinen, J., 2012a. Low vascular endothelial growth factor and
Commins, S.P., Borish, L., Steinke, J.W., 2010. Immunologic messenger molecules: interleukin-8 in cerebrospinal uid of suicide attempters. Transl. Psychiatry 2,
cytokines, interferons, and chemokines. J. Allergy Clin. Immunol. 125, S53S72. e196.
Coutinho, A.E., Chapman, K.E., 2011. The anti-inammatory and Isung, J., Mobarrez, F., Nordstrm, P., Asberg, M., Jokinen, J., 2012b. Low plasma
immunosuppressive effects of glucocorticoids, recent developments and vascular endothelial growth factor (VEGF) associated with completed suicide.
mechanistic insights. Mol. Cell. Endocrinol. 335, 213. World J. Biol. Psychiatry 13, 468473.
de Koning, L., Liptak, C., Shkreta, A., Bradwin, G., Hu, F.B., Pradhan, A.D., Rifai, N., Isung, J., Aeinehband, S., Mobarrez, F., Nordstrom, P., Runeson, B., Asberg, M., Piehl,
Kellogg, M.D., 2012. A multiplex immunoassay gives different results than F., Jokinen, J., 2014. High interleukin-6 and impulsivity: determining the role of
singleplex immunoassays which may bias epidemiologic associations. Clin. endophenotypes in attempted suicide. Transl. Psychiatry 4, e470.
Biochem. 45, 848851. Janelidze, S., Mattei, D., Westrin, ., Trskman-Bendz, L., Brundin, L., 2011.
DiazGranados, N., Ibrahim, L.A., Brutsche, N.E., Ameli, R., Henter, I.D., Luckenbaugh, Cytokine levels in the blood may distinguish suicide attempters from
D.A., Machado-Vieira, R., Zarate, C.A., 2010. Rapid resolution of suicidal depressed patients. Brain Behav. Immun. 25, 335339.
ideation after a single infusion of an N-methyl-D-aspartate antagonist in Janelidze, S., Suchankova, P., Ekman, A., Erhardt, S., Sellgren, C., Samuelsson, M.,
patients with treatment-resistant major depressive disorder. J. Clin. Psychiatry Westrin, A., Minthon, L., Hansson, O., Trskman-Bendz, L., Brundin, L., 2015.
71, 16051611. Low IL-8 is associated with anxiety in suicidal patients: genetic variation and
Dieperink, E., Ho, S.B., Tetrick, L., Thuras, P., Dua, K., Willenbring, M.L., 2004. decreased protein levels. Acta Psychiatr. Scand. 131, 269278.
Suicidal ideation during interferon-alpha2b and ribavirin treatment of patients Juengst, S.B., Kumar, R.G., Arenth, P.M., Wagner, A.K., 2014. Exploratory
with chronic hepatitis C. Gen. Hosp. Psychiatry 26, 237240. associations with tumor necrosis factor-alpha, disinhibition and suicidal
Ding, Y., Lawrence, N., Oli, E., Cyprien, F., le Bars, E., Bonaf, A., Phillips, M.L., endorsement after traumatic brain injury. Brain Behav. Immun. 41, 134143.
Courtet, P., Jollant, F., 2015. Prefrontal cortex markers of suicidal vulnerability Karlovic, D., Serretti, A., Vrkic,
N., Martinac, M., Marcinko, D., 2012. Serum
in mood disorders: a model-based structural neuroimaging study with a concentrations of CRP, IL-6, TNF- and cortisol in major depressive disorder
translational perspective. Transl. Psychiatry 5, e516. with melancholic or atypical features. Psychiatry Res. 198, 7480.
Ducasse, D., Olie, E., Guillaume, S., Artero, S., Courtet, P., 2015. A meta-analysis of Keedwell, P.A., Andrew, C., Williams, S.C., Brammer, M.J., Phillips, M.L., 2005. The
cytokines in suicidal behavior. Brain Behav. Immun. 46, 203211. neural correlates of anhedonia in major depressive disorder. Biol. Psychiatry
Dugan, A.M., Parrott, J.M., Redus, L., Hensler, J.G., OConnor, J.C., 2015. Low-level 58, 843853.
stress induces production of neuroprotective factors in wild-type but mot Keller, S., Sarchiapone, M., Zarrilli, F., Videtic, A., Ferraro, A., Carli, V., Sacchetti, S.,
BDNF+/ Mice: interleukin-10 and kynurenic acid. Int. J. Lembo, F., Angiolillo, A., Jovanovic, N., Pisanti, F., Tomaiuolo, R., Monticelli, A.,
Neuropsychopharmacol., http://dx.doi.org/10.1093/ijnp/pyv089. Balazic, J., Roy, A., Marusic, A., Cocozza, S., Fusco, A., Bruni, C.B., Castaldo, G.,
Dumais, A., Lesage, A.D., Alda, M., Rouleau, G., Dumont, M., Chawky, N., Roy, M., Chiariotti, L., 2010. Increased BDNF promoter methylation in the Wernicke
Mann, J.J., Benkelfat, C., Turecki, G., 2005. Risk factors for suicide completion in area of suicide subjects. Arch. Gen. Psychiatry 67, 258267.
major depression: a case-control study of impulsive and aggressive behaviors Kiecolt-Glaser, J.K., Belury, M.A., Andridge, R., Malarkey, W.B., Glaser, R., 2011.
in men. Am. J. Psychiatry 162, 21162124. Omega-3 supplementation lowers inammation and anxiety in medical
Dwivedi, Y., Rizavi, H.S., Conley, R.R., Roberts, R.C., Tamminga, C.A., Pandey, G.N., students: a randomized controlled trial. Brain Behav. Immun. 25, 17251734.
2003. Altered gene expression of brain-derived neurotrophic factor and Kiecolt-Glaser, J.K., Preacher, K.J., MacCallum, R.C., Atkinson, C., Malarkey, W.B.,
receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch. Gen. Glaser, R., 2003. Chronic stress and age-related increases in the
Psychiatry 60, 804815. proinammatory cytokine IL-6. Proc. Natl. Acad. Sci. U. S. A. 100, 90909095.
Fagundes, C.P., Glaser, R., Kiecolt-Glaser, J.K., 2013. Stressful early life experiences Kim, Y.K., Hong, J.P., Hwang, J.A., Lee, H.J., Yoon, H.K., Lee, B.H., Jung, H.Y., Hahn,
and immune dysregulation across the lifespan. Brain Behav. Immun. 27, S.W., Na, K.S., 2013. TNF-alpha -308G>A polymorphism is associated with
812. suicide attempts in major depressive disorder. J. Affect. Disord. 150, 668672.
L. Gananca et al. / Psychoneuroendocrinology 63 (2016) 296310 309

Kim, Y.K., Lee, S.W., Kim, S.H., Shim, S.H., Han, S.W., Choi, S.H., Lee, B.H., 2008. assess, to control, to exclude: effects of biobehavioral factors on circulating
Differences in cytokines between non-suicidal patients and suicidal patients in inammatory markers. Brain Behav. Immun. 23, 887897.
major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 356361. ODonovan, A., Rush, G., Hoatam, G., Hughes, B.M., McCrohan, A., Kelleher, C.,
Klinitzke, G., Steinig, J., Blher, M., Kersting, A., Wagner, B., 2013. Obesity and OFarrelly, C., Malone, K.M., 2013. Suicidal ideation is associated with elevated
suicide risk in adultsa systematic review. J. Affect. Disord. 145, 277284. inammation in patients with major depressive disorder. Depress. Anxiety 30,
Lanquillon, S., Krieg, J.C., Bening-Abu-Shach, U., Vedder, H., 2000. Cytokine 307314.
production and treatment response in major depressive disorder. ODwyer, S.T., Moyle, W., Zimmer-Gembeck, M., De Leo, D., 2013. Suicidal ideation
Neuropsychopharmacology 22, 370379. in family carers of people with dementia: a pilot study. Int. J. Geriatr.
Larkin, G.L., Beautrais, A.L., 2011. A preliminary naturalistic study of low-dose Psychiatry 28, 11821188.
ketamine for depression and suicide ideation in the emergency department. Olin, B., Jayewardene, A.K., Bunker, M., Moreno, F., 2012. Mortality and suicide risk
Int. J. Neuropsychopharmacol. 14, 11271131. in treatment-resistant depression: an observational study of the long-term
Lee, H.Y., Kim, Y.K., 2010. Transforming growth factor-beta1 and major depressive impact of intervention. PLoS One 7, e48002.
disorder with and without attempted suicide: preliminary study. Psychiatry Oliver, E., McGillicuddy, F.C., Harford, K.A., Reynolds, C.M., Phillips, C.M., Ferguson,
Res. 178, 9296. J.F., Roche, H.M., 2012. Docosahexaenoic acid attenuates macrophage-induced
Lewis, M.D., Hibbeln, J.R., Johnson, J.E., Lin, Y.H., Hyun, D.Y., Loewke, J.D., 2011. inammation and improves insulin sensitivity in adipocytes-specic
Suicide deaths of active-duty US military and omega-3 fatty-acid status: a differential effects between LC n-3 PUFA. J. Nutr. Biochem. 23, 11921200.
case-control comparison. J. Clin. Psychiatry 72, 15851590. Omrani, M.D., Bagheri, M., Bushehri, B., Azizi, F., Anoshae, M.R., 2012. The
Li, Z., Qi, D., Chen, J., Zhang, C., Yi, Z., Yuan, C., Wang, Z., Hong, W., Yu, S., Cui, D., association of TGF-1 codon 10 polymorphism with suicide behavior. Am. J.
Fang, Y., 2013. Venlafaxine inhibits the upregulation of plasma tumor necrosis Med. Genet. B Neuropsychiatr. Genet. 159B, 772775.
factor-alpha (TNF-) in the Chinese patients with major depressive disorder: a Omrani, M.D., Bushehri, B., Bagheri, M., Salari-Lak, S., Alipour, A., Anoshae, M.R.,
prospective longitudinal study. Psychoneuroendocrinology 38, 107114. Massomi, R., 2009. Role of IL-10-1082, IFN-gamma +874, and TNF-alpha
Lindqvist, D., Janelidze, S., Erhardt, S., Trskman-Bendz, L., Engstrm, G., Brundin, -308 genes polymorphisms in suicidal behavior. Arch. Suicide Res. 13,
L., 2011. CSF biomarkers in suicide attemptersa principal component analysis. 330339.
Acta Psychiatr. Scand. 124, 5261. Oquendo, M.A., Galfalvy, H., Russo, S., Ellis, S.P., Grunebaum, M.F., Burke, A., Mann,
Lindqvist, D., Janelidze, S., Hagell, P., Erhardt, S., Samuelsson, M., Minthon, L., J.J., 2004. Prospective study of clinical predictors of suicidal acts after a major
Hansson, O., Bjrkqvist, M., Trskman-Bendz, L., Brundin, L., 2009. depressive episode in patients with major depressive disorder or bipolar
Interleukin-6 is elevated in the cerebrospinal uid of suicide attempters and disorder. Am. J. Psychiatry 161, 14331441.
related to symptom severity. Biol. Psychiatry 66, 287292. Oquendo, M.A., Placidi, G.P., Malone, K.M., Campbell, C., Keilp, J., Brodsky, B.,
Liu, Y., Ho, R.C., Mak, A., 2012. Interleukin (IL)-6, tumour necrosis factor alpha Kegeles, L.S., Cooper, T.B., Parsey, R.V., van Heertum, R.L., Mann, J.J., 2003.
(TNF-) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients Positron emission tomography of regional brain metabolic responses to a
with major depressive disorder: a meta-analysis and meta-regression. J. Affect. serotonergic challenge and lethality of suicide attempts in major depression.
Disord. 139, 230239. Arch. Gen. Psychiatry 60, 1422.
Lotrich, F.E., Ferrell, R.E., Rabinovitz, M., Pollock, B.G., 2009. Risk for depression Oquendo, M.A., Sullivan, G.M., Sudol, K., Baca-Garcia, E., Stanley, B.H., Sublette,
during interferon-alpha treatment is affected by the serotonin transporter M.E., Mann, J.J., 2014. Toward a biosignature for suicide. Am. J. Psychiatry 171,
polymorphism. Biol. Psychiatry 65, 344348. 12591277.
Maes, M., Meltzer, H.Y., Scharp, S., Bosmans, E., Suy, E., De Meester, I., Calabrese, J., Pandey, G.N., Dwivedi, Y., 2010. What can post-mortem studies tell us about the
Cosyns, P., 1993. Relationships between lower plasma l-tryptophan levels and pathoetiology of suicide? Future Neurol. 5, 701720.
immune-inammatory variables in depression. Psychiatry Res. 49, 151165. Pandey, G.N., Rizavi, H.S., Ren, X., Bhaumik, R., Dwivedi, Y., 2014. Toll-like receptors
Mann, J.J., 2003. Neurobiology of suicidal behaviour. Nat. Rev. Neurosci. 4, 819828. in the depressed and suicide brain. J. Psychiatr. Res. 53, 6268.
Mann, J.J., Arango, V.A., Avenevoli, S., Brent, D.A., Champagne, F.A., Clayton, P., Pandey, G.N., Rizavi, H.S., Ren, X., Fareed, J., Hoppensteadt, D.A., Roberts, R.C.,
Currier, D., Dougherty, D.M., Haghighi, F., Hodge, S.E., Kleinman, J., Lehner, T., Conley, R.R., Dwivedi, Y., 2012. Proinammatory cytokines in the prefrontal
McMahon, F., Moscicki, E.K., Oquendo, M.A., Pandey, G.N., Pearson, J., Stanley, cortex of teenage suicide victims. J. Psychiatr. Res. 46, 5763.
B., Terwilliger, J., Wenzel, A., 2009. Candidate endophenotypes for genetic Pierucci-Lagha, A., Covault, J., Bonkovsky, H.L., Feinn, R., Abreu, C., Sterling, R.K.,
studies of suicidal behavior. Biol. Psychiatry 65, 556563. Fontana, R.J., Kranzler, H.R., Group, H.-C.T., 2010. A functional serotonin
Mann, J.J., Waternaux, C., Haas, G.L., Malone, K.M., 1999. Toward a clinical model of transporter gene polymorphism and depressive effects associated with
suicidal behavior in psychiatric patients. Am. J. Psychiatry 156, 181189. interferon-alpha treatment. Psychosomatics 51, 137148.
Martinez, J.M., Garakani, A., Yehuda, R., Gorman, J.M., 2012. Proinammatory and Postolache, T.T., Komarow, H., Tonelli, L.H., 2008. Allergy: a risk factor for suicide?
resiliency proteins in the CSF of patients with major depression. Depress. Curr. Treat. Options Neurol. 10, 363376.
Anxiety 29, 3238. Qin, P., Mortensen, P.B., Waltoft, B.L., Postolache, T.T., 2011. Allergy is associated
May, A.M., Klonsky, E.D., Klein, D.N., 2012. Predicting future suicide attempts with suicide completion with a possible mediating role of mood disordera
among depressed suicide ideators: a 10-year longitudinal study. J. Psychiatr. population-based study. Allergy 66, 658664.
Res. 46, 946952. Raison, C.L., Dantzer, R., Kelley, K.W., Lawson, M.A., Woolwine, B.J., Vogt, G., Spivey,
McEwen, B.S., 2008. Central effects of stress hormones in health and disease: J.R., Saito, K., Miller, A.H., 2010. CSF concentrations of brain tryptophan and
understanding the protective and damaging effects of stress and stress kynurenines during immune stimulation with IFN-alpha: relationship to CNS
mediators. Eur. J. Pharmacol. 583, 174185. immune responses and depression. Mol. Psychiatry 15, 393403.
McNally, L., Bhagwagar, Z., Hannestad, J., 2008. Inammation, glutamate, and glia Raison, C.L., Demetrashvili, M., Capuron, L., Miller, A.H., 2005. Neuropsychiatric
in depression: a literature review. CNS Spectr. 13, 501510. adverse effects of interferon-alpha: recognition and management. CNS Drugs
Mendlovic, S., Mozes, E., Eilat, E., Doron, A., Lereya, J., Zakuth, V., Spirer, Z., 1999. 19, 105123.
Immune activation in non-treated suicidal major depression. Immunol. Lett. Raison, C.L., Miller, A.H., 2013. Do cytokines really sing the blues? Cerebrum 2013,
67, 105108. 10.
Miller, A.H., Haroon, E., Raison, C.L., Felger, J.C., 2013. Cytokine targets in the brain: Rothenhusler, H.B., Stepan, A., Kapfhammer, H.P., 2006. Soluble interleukin 2
impact on neurotransmitters and neurocircuits. Depress. Anxiety 30, 297306. receptor levels, temperament and character in formerly depressed suicide
Miller, G.E., Chen, E., Parker, K.J., 2011. Psychological stress in childhood and attempters compared with normal controls. Suicide Life Threat. Behav. 36,
susceptibility to the chronic diseases of aging: moving toward a model of 455466.
behavioral and biological mechanisms. Psychol. Bull. 137, 959997. Siz, P.A., Garca-Portilla, P., Paredes, B., Arango, C., Morales, B., Alvarez, V., Coto, E.,
Monfrim, X., Gazal, M., De Leon, P.B., Quevedo, L., Souza, L.D., Jansen, K., Oses, J.P., Bascarn, M.T., Bousono, M., Bobes, J., 2008. Association study of the
Pinheiro, R.T., Silva, R.A., Lara, D.R., Ghisleni, G., Spessato, B., Kaster, M.P., 2014. interleukin-1 gene complex and tumor necrosis factor alpha gene with suicide
Immune dysfunction in bipolar disorder and suicide risk: is there an attempts. Psychiatr. Genet. 18, 147150.
association between peripheral corticotropin-releasing hormone and Scrandis, D.A., Langenberg, P., Tonelli, L.H., Sheikh, T.M., Manogura, A.C., Alberico,
interleukin-1? Bipolar Disord. 16, 741747. L.A., Hermanstyne, T., Fuchs, D., Mighty, H., Hasday, J.D., Boteva, K., Postolache,
Morikawa, O., Sakai, N., Obara, H., Saito, N., 1998. Effects of interferon-alpha, T.T., 2008. Prepartum depressive symptoms correlate positively with
interferon-gamma and cAMP on the transcriptional regulation of the serotonin C-reactive protein levels and negatively with tryptophan levels: a preliminary
transporter. Eur. J. Pharmacol. 349, 317324. report. Int. J. Child Health Hum. Dev. 1, 167174.
Muller, N., Schwarz, M.J., Dehning, S., Douhe, A., Cerovecki, A., Goldstein-Muller, B., Serani, G., Pompili, M., Elena Seretti, M., Stefani, H., Palermo, M., Coryell, W.,
Spellmann, I., Hetzel, G., Maino, K., Kleindienst, N., Moller, H.J., Arolt, V., Riedel, Girardi, P., 2013. The role of inammatory cytokines in suicidal behavior: a
M., 2006. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in systematic review. Eur. Neuropsychopharmacol. 23, 16721686.
major depression: results of a double-blind, randomized, placebo controlled, Shelton, R.C., Miller, A.H., 2010. Eating ourselves to death (and despair): the
add-on pilot study to reboxetine. Mol. Psychiatry 11, 680684. contribution of adiposity and inammation to depression. Prog. Neurobiol. 91,
Nssberger, L., Trskman-Bendz, L., 1993. Increased soluble interleukin-2 receptor 275299.
concentrations in suicide attempters. Acta Psychiatr. Scand. 88, 4852. Sjgren, E., Leanderson, P., Kristenson, M., Ernerudh, J., 2006. Interleukin-6 levels
OConnor, J.C., Lawson, M.A., Andre, C., Briley, E.M., Szegedi, S.S., Lestage, J., in relation to psychosocial factors: studies on serum, saliva, and in vitro
Castanon, N., Herkenham, M., Dantzer, R., Kelley, K.W., 2009a. Induction of IDO production by blood mononuclear cells. Brain Behav. Immun. 20, 270278.
by bacille Calmette-Guerin is responsible for development of murine Steiner, J., Bielau, H., Brisch, R., Danos, P., Ullrich, O., Mawrin, C., Bernstein, H.G.,
depressive-like behavior. J. Immunol. 182, 32023212. Bogerts, B., 2008. Immunological aspects in the neurobiology of suicide:
OConnor, M.F., Bower, J.E., Cho, H.J., Creswell, J.D., Dimitrov, S., Hamby, M.E., Hoyt, elevated microglial density in schizophrenia and depression is associated with
M.A., Martin, J.L., Robles, T.F., Sloan, E.K., Thomas, K.S., Irwin, M.R., 2009b. To suicide. J. Psychiatr. Res. 42, 151157.
310 L. Gananca et al. / Psychoneuroendocrinology 63 (2016) 296310

Suarez, E.C., 2003. Joint effect of hostility and severity of depressive symptoms on Tynan, R.J., Naicker, S., Hinwood, M., Nalivaiko, E., Buller, K.M., Pow, D.V., Day, T.A.,
plasma interleukin-6 concentration. Psychosom. Med. 65, 523527. Walker, F.R., 2010. Chronic stress alters the density and morphology of
Suarez, E.C., Lewis, J.G., Krishnan, R.R., Young, K.H., 2004. Enhanced expression of microglia in a subset of stress-responsive brain regions. Brain Behav. Immun.
cytokines and chemokines by blood monocytes to in vitro lipopolysaccharide 24, 10581068.
stimulation are associated with hostility and severity of depressive symptoms van Heeringen, K., Bijttebier, S., Desmyter, S., Vervaet, M., Baeken, C., 2014. Is there
in healthy women. Psychoneuroendocrinology 29, 11191128. a neuroanatomical basis of the vulnerability to suicidal behavior? A
Suarez, E.C., Lewis, J.G., Kuhn, C., 2002. The relation of aggression, hostility, and coordinate-based meta-analysis of structural and functional MRI studies.
anger to lipopolysaccharide-stimulated tumor necrosis factor (TNF)-alpha by Front. Hum. Neurosci. 8 (824).
blood monocytes from normal men. Brain Behav. Immun. 16, 675684. Vargas, H.O., Nunes, S.O., Pizzo de Castro, M., Bortolasci, C.C., Sabbatini Barbosa, D.,
Sublette, M.E., Galfalvy, H.C., Fuchs, D., Lapidus, M., Grunebaum, M.F., Oquendo, Kaminami Morimoto, H., Venugopal, K., Dodd, S., Maes, M., Berk, M., 2013.
M.A., Mann, J.J., Postolache, T.T., 2011. Plasma kynurenine levels are elevated in Oxidative stress and lowered total antioxidant status are associated with a
suicide attempters with major depressive disorder. Brain Behav. Immun. 25, history of suicide attempts. J. Affect. Disord. 150, 923930.
12721278. Vgontzas, A.N., Bixler, E.O., Lin, H.M., Prolo, P., Trakada, G., Chrousos, G.P., 2005. IL-6
Sublette, M.E., Hibbeln, J.R., Galfalvy, H., Oquendo, M.A., Mann, J.J., 2006. Omega-3 and its circadian secretion in humans. Neuroimmunomodulation 12, 131140.
polyunsaturated essential fatty acid status as a predictor of future suicide risk. Wacker, J., Dillon, D.G., Pizzagalli, D.A., 2009. The role of the nucleus accumbens
Am. J. Psychiatry 163, 11001102. and rostral anterior cingulate cortex in anhedonia: integration of resting EEG,
Sublette, M.E., Milak, M.S., Galfalvy, H.C., Oquendo, M.A., Malone, K.M., Mann, J.J., fMRI, and volumetric techniques. Neuroimage 46, 327337.
2013. Regional brain glucose uptake distinguishes suicide attempters from WHO, 2002. World report on violence and health. N. S. W. Public Health Bull. 13,
non-attempters in major depression. Arch. Suicide Res. 17, 434447. 190.
Timonen, M., Viilo, K., Hakko, H., Srkioja, T., Meyer-Rochow, V.B., Visnen, E., Wieck, A., Grassi-Oliveira, R., do Prado, C.H., Rizzo, L.B., de Oliveira, A.S.,
Rsnen, P., 2004. Is seasonality of suicides stronger in victims with Kommers-Molina, J., Viola, T.W., Marciano Vieira, E.L., Teixeira, A.L., Bauer,
hospital-treated atopic disorders? Psychiatry Res. 126, 167175. M.E., 2014. Pro-inammatory cytokines and soluble receptors in response to
Tonelli, L.H., Stiller, J., Rujescu, D., Giegling, I., Schneider, B., Maurer, K., Schnabel, acute psychosocial stress: differential reactivity in bipolar disorder. Neurosci.
A., Mller, H.J., Chen, H.H., Postolache, T.T., 2008. Elevated cytokine expression Lett. 580, 1721.
in the orbitofrontal cortex of victims of suicide. Acta Psychiatr. Scand. 117, Winer, E.S., Nadorff, M.R., Ellis, T.E., Allen, J.G., Herrera, S., Salem, T., 2014.
198206. Anhedonia predicts suicidal ideation in a large psychiatric inpatient sample.
Torres-Platas, S.G., Cruceanu, C., Chen, G.G., Turecki, G., Mechawar, N., 2014. Psychiatry Res. 218, 124128.
Evidence for increased microglial priming and macrophage recruitment in the Woo, J.M., Gibbons, R.D., Qin, P., Komarow, H., Kim, J.B., Rogers, C.A., Mann, J.J.,
dorsal anterior cingulate white matter of depressed suicides. Brain Behav. Postolache, T.T., 2011. Suicide and prescription rates of intranasal
Immun. 42, 5059. corticosteroids and nonsedating antihistamines for allergic rhinitis: an
Torres-Platas, S.G., Hercher, C., Davoli, M.A., Maussion, G., Labont, B., Turecki, G., ecological study. J. Clin. Psychiatry 72, 14231428.
Mechawar, N., 2011. Astrocytic hypertrophy in anterior cingulate white matter
of depressed suicides. Neuropsychopharmacology 36, 26502658.