Brain, Behavior, and Immunity xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Brain, Behavior, and Immunity

journal homepage: www.elsevier.com/locate/ybrbi

A role for inflammatory metabolites as modulators of the glutamate

N-methyl-D-aspartate receptor in depression and suicidality
Cecilie Bay-Richter a,⇑, Klas R. Linderholm b, Chai K. Lim c, Martin Samuelsson d, Lil Träskman-Bendz e,
Gilles J. Guillemin c, Sophie Erhardt b,1, Lena Brundin f,g,1
a
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark
b
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
c
Neuroinflammation Group, Australian School of Advanced Medicine, Macquarie University, NSW, Australia
d
Faculty of Health Sciences, Department of Clinical and Experimental Medicine, Division of Psychiatry, Linköping University, Linköping, Sweden
e
Department of Clinical Sciences, Section of Psychiatry, Lund University, Lund, Sweden
f
Division of Psychiatry and Behavioral Medicine, Michigan State University, Grand Rapids, MI, USA
g
Laboratory of Behavioral Medicine, Van Andel Research Institute, Grand Rapids, MI, USA

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

Article history: Background: Patients with depression and suicidality suffer from low-grade neuroinflammation. Pro-
Received 21 May 2014 inflammatory cytokines activate indoleamine 2,3-dioxygenase, an initial enzyme of the kynurenine path-
Received in revised form 16 July 2014 way. This pathway produces neuroactive metabolites, including quinolinic- and kynurenic acid, binding
Accepted 25 July 2014
to the glutamate N-methyl-D-aspartate-receptor, which is hypothesized to be part of the neural mecha-
Available online xxxx
nisms underlying symptoms of depression. We therefore hypothesized that symptoms of depression and
suicidality would fluctuate over time in patients prone to suicidal behavior, depending on the degree of
Keywords:
inflammation and kynurenine metabolite levels in the cerebrospinal fluid (CSF).
Suicide
Glutamate
Methods: We measured cytokines and kynurenine metabolites in CSF, collected from suicide attempters
Quinolinic acid at repeated occasions over 2 years (total patient samples n = 143, individuals n = 30) and healthy controls
Kynurenic acid (n = 36). The association between the markers and psychiatric symptoms was assessed using the Mont-
Interleukin-6 gomery Åsberg Depression Rating Scale and the Suicide Assessment Scale.
Cerebrospinal fluid Results: Quinolinic acid was increased and kynurenic acid decreased over time in suicidal patients versus
healthy controls. Furthermore, we found a significant association between low kynurenic acid and severe
depressive symptoms, as well as between high interleukin-6 levels and more severe suicidal symptoms.
Conclusions: We demonstrate a long-term dysregulation of the kynurenine pathway in the central ner-
vous system of suicide attempters. An increased load of inflammatory cytokines was coupled to more
severe symptoms. We therefore suggest that patients with a dysregulated kynurenine pathway are vul-
nerable to develop depressive symptoms upon inflammatory conditions, as a result the excess production
of the NMDA-receptor agonist quinolinic acid. This study provides a neurobiological framework support-
ing the use of NMDA-receptor antagonists in the treatment of suicidality and depression.
Ó 2014 Elsevier Inc. All rights reserved.

1. Introduction et al., 2014). Moreover, the biological changes associated with

Suicide accounts for 1.5% of all deaths and is the tenth leading
cause of death worldwide (Heron, 2012). Unfortunately, progress
in the prevention of suicide is limited by the large number, high
prevalence, and wide distribution of suicide risk factors (Olfson
⇑ Corresponding author. Address: Translational Neuropsychiatry Unit, Depart-
ment of Clinical Medicine, Aarhus University, Skovagervej 2, 8240 Risskov,
Denmark.
E-mail address: cbr@clin.au.dk (C. Bay-Richter).
1
Shared senior authorship.
symptoms of suicidality are incompletely known and a previous
suicide attempt is currently the best predictor of a future com-
pleted suicide (Harris and Barraclough, 1997).
Patients with depression and suicidality show signs of inflam-
mation in peripheral blood as well as within the brain (Dowlati
et al., 2010; Valkanova et al., 2013). For example, depressed
patients have elevated blood levels of interleukin (IL)-1b
(Thomas et al., 2005; Dahl et al., 2014), tumor necrosis factor
(TNF)-a (Hestad et al., 2003), IL-8 (Mikova et al., 2001) and IL-6
(Dahl et al., 2014; Berk et al., 1997). Interestingly, several reports
have described emerging depression and suicidality in previously

http://dx.doi.org/10.1016/j.bbi.2014.07.012
0889-1591/Ó 2014 Elsevier Inc. All rights reserved.

Please cite this article in press as: Bay-Richter, C., et al. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor
in depression and suicidality. Brain Behav. Immun. (2014), http://dx.doi.org/10.1016/j.bbi.2014.07.012
2 C. Bay-Richter et al. / Brain, Behavior, and Immunity xxx (2014) xxx–xxx
psychiatrically healthy individuals upon treatment with interfer-
ons (IFNs) (Fragoso et al., 2010; Dieperink et al., 2004). Cerebrospi-
nal fluid (CSF) IL-6 is significantly elevated in suicide attempters
(Lindqvist et al., 2009), and post-mortem analysis of brain tissue
from suicide victims show microgliosis (Steiner et al., 2008) and
increased mRNA for cytokines (Pandey et al., 2012; Tonelli et al.,
2008). Interestingly, the degree of inflammation seems to be more
pronounced in suicidal patients relative to non-suicidal, depressed
patients (Steiner et al., 2008; Janelidze et al., 2011).
Pro-inflammatory cytokines induce the kynurenine pathway of
tryptophan degradation, from which several neuroactive com-
pounds are produced (Schwarcz et al., 2012). IFNs are potent
inducers of indoleamine 2,3-dioxygenase (IDO-1), regulating the
initial step of the kynurenine pathway (Guillemin, 2012a). Kynure-
nic acid (KYNA] and quinolinic acid (QUIN] are two metabolites
produced by this pathway (Fig. 1), both with multiple effects on
neuroinflammation and neurotransmission. QUIN is an N-methyl-
D-aspartate (NMDA]-receptor agonist, activating receptors contain-
ing the NR1 + NR2A and the NR1 + NR2B subunits (de Carvalho
et al., 1996; Stone, 1993). QUIN is one-quarter as potent as NMDA,
and approximately similarly potent as glutamate and aspartate in
stimulating the receptor (Stone and Perkins, 1981) but with con-
siderable differences in sensitivity in different brain areas (Stone,
1993). Specifically, neurons within hippocampus, striatum and
neocortex are highly sensitive to QUIN, whereas cerebellar and
spinal cord neurons are less sensitive, most likely due to differ-
ences in NMDA-receptor configuration (Guillemin, 2012a). Apart
from the direct action on the NMDA-receptor, QUIN can also
increase glutamate release by neurons, inhibit its uptake by astro-
cytes and inhibit astroglial glutamine synthetase (see Guillemin,
2012a).
Fig. 1. A simplified diagram of the kynurenine pathway. TDO: tryptophan
2,3-dioxygenase, IDO: indoleamine 2,3-dioxygenase, KMO: kynurenine 3-monoox-
ygenase, KAT: kynurenine aminotransferase, KYNU: kynureninase, HAAO:
3-hydroxyanthranilinic acid dioxygenase, NAD: nicotinamide adenine dinucleotide,
QPRT: quinolinate phosphoribosyltransferase.
Please cite this article in press as: Bay-Richter, C., et al. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor
in depression and suicidality. Brain Behav. Immun. (2014), http://dx.doi.org/10.1016/j.bbi.2014.07.012
KYNA on the other hand blocks several receptors, i.e. the gly-
cine-site and the glutamate recognition-site of the NMDA receptor,
the cholinergic alpha7 nicotinic receptor and, at higher concentra-
tions, a-amino-3-hydroxy-5-metyl-4-isoxazolepropionic acid
(AMPA) and kainate receptors. Furthermore, KYNA is known to
stimulate the G protein-coupled receptor 35 (GPR35) Stone et al.,
2013.
Growing evidence indicates that enhanced NMDA-receptor
stimulation participates in the pathophysiology of major depres-
sion and suicidality (Serafini et al., 2013; Nowak et al., 1995;
Heresco-Levy and Javitt, 1998; Machado-Vieira et al., 2009). In
support of this, the NMDA-receptor antagonist ketamine shows
remarkable anti-suicidal properties (DiazGranados et al., 2010;
Larkin and Beautrais, 2011; Price et al., 2009; Zarate et al.,
2012). Connecting the findings of inflammation in suicidal and
depressive patients with NMDA-mediated neurotransmission,
we recently found increased CSF QUIN, concomitant with ele-
vated CSF levels of IL-6, in suicide attempters (Erhardt et al.,
2013). This indicates that the kynurenine pathway is induced in
suicidal patients, presumably by an ongoing inflammation in
the central nervous system, and that the degree of NMDA-recep-
tor agonism may be increased in these patients. Sublette and
coworkers have previously demonstrated that the kynurenine
pathway is activated in the peripheral blood of suicide attempters
to a higher degree than in non-suicidal depressive patients
(Sublette et al., 2011). Moreover, Steiner and colleagues provided
evidence of an increased expression of QUIN-reactive microglia
cells in the brains of depressed patients who died by suicide
(Steiner et al., 2011).
Even if experimental and clinical studies show that inflamma-
tory stimuli are associated with depressive and suicidal symptoms,
it is still not known if kynurenine metabolites are causal factors in
the underlying pathology. Thus, the aberrations in immune regula-
tion in suicidal patients may be causally related to symptoms, or
possibly generated by the suicide attempt per se, constituting an
epiphenomenon. Individuals vulnerable to develop suicidality
and depression might also have an on-going low-grade inflamma-
tion in blood and CSF over time, which could be associated with an
increased predisposition to develop symptoms (trait marker), or
only exhibit inflammation at specific time-points, related to acute
symptoms (state marker).
To further address these important issues, we assessed psychi-
atric patients for symptom severity over an extended period of
time, together with repeated lumbar punctures. The patients were
originally enrolled after a suicide attempt and followed for approx-
imately 2 years thereafter. We have previously reported the ele-
vated levels of CSF IL-6 and QUIN at the time-point of the suicide
attempt in these patients (Erhardt et al., 2013; Lindqvist et al.,
2009). In this study, we repeatedly evaluated depressive symptoms
and suicidality over 2 years, along with the analysis of the two key
kynurenine metabolites, QUIN and KYNA, in CSF. We hypothesized
that increased CSF QUIN and decreased CSF KYNA would be signif-
icantly associated with more severe psychiatric symptoms, specif-
ically an increased degree of suicidality and depression, over time
in the suicide attempters.
2. Materials and methods
2.1. Participants
The study was approved by the Regional Ethical Review Boards
in Lund, Linköping and Malmö and carried out in accordance with
‘The code of ethics of the world medical association (Declaration of
Helsinki)’. After complete description of the study to the partici-
pants, written informed consent was obtained.
 C. Bay-Richter et al. / Brain, Behavior, and Immunity xxx (2014) xxx–xxx
All patients were initially enrolled in the study on admission to
Lund University Hospital after a suicide attempt and subsequently
followed for a maximum of 56 months after the attempt (mean
16 months). Thirty patients (9 men and 21 women) with a mean
age of 40.0 ± 8.7 years (mean ± S.D.) were included. A total of 143
CSF samples were collected from these individuals between 1987
and 1992. Axis I diagnoses were set at an interview by a specialist
in psychiatry according to the DSM-III-R (American Psychiatric
Association, 1987). Table 1 summarizes diagnoses as well as the
psychotropic medication prescribed at the time of recruitment.
The control group consisted of 36 healthy individuals (29 males
and 7 females) with a mean age of 29.7 ± 7.3 years (mean ± S.D.)
recruited through the Psychiatric Clinics at the University Hospi-
tals in Lund and Linköping between 2003 and 2009. Data from
the controls have previously been published in Erhardt et al.
(2013), Atlas et al. (2013), Linderholm et al. (2012), Olsson et al.
(2010). The controls did not suffer from any previous or ongoing
psychiatric condition or substance abuse, and were somatically
healthy. They were thoroughly examined for psychiatric morbidity
using the Structured Clinical Interviews for DSM Disorders (SCID)
I and II and were free of medication.
2.1.1. Psychiatric assessment
The patients were assessed using the Montgomery Asberg
Depression Rating Scale (MADRS) (Montgomery and Asberg,
1979) and the Suicide Assessment Scale (SUAS) (Nimeus et al.,
2000; Stanley et al., 1986). The MADRS is a 10 item scale assessing
symptoms of depression. Each item is rated in steps 0–6, with a
maximum total score of 60. The scale is sensitive to changes in
symptom severity and further correlates positively with symptom
severity as measured with the Hamilton Rating Scale (Montgomery
and Asberg, 1979). Similarly, SUAS is a 20 item interview-based
scale assessing symptoms of suicidality over time, independent
of diagnosis. Each item is rated 0–4 and is grouped into five areas:
affect, bodily states, control and coping, emotional reactivity and
suicidal thoughts and behavior (Nimeus et al., 2000).
Table 1
Pharmacological treatment and diagnoses of patients at index.
Patient characteristics (n = 30)
Gender, males N (%)
Age at attempt, mean (min/max)
Main diagnosis N (%)
Major Depressive Disorder (DSM 296.3)
Depressive disorder not otherwise specified (DSM 311)
Dysthymia (DSM 300.4)
Adjustment disorder (DSM 309.0–309.2)
Schizoaffective disorder (DSM 295.7)
Panic disorder with agoraphobia (DSM 300.2)
Substance abuse (DSM 303.9, DSM 305
Bipolar disorder (DSM 296.5)
Co-morbid diagnoses
Personality disorder DSM Axis II disorder
Alcohol dependence
Panic disorder with agoraphobia (DSM 300.2)
Pain disorder with psychological factors (DSM 307.8)
Pharmacological treatment at index N (%)
None
Antidepressants
Neuroleptics
Benzodiazepines
Somatic diagnosis N (%)
Diabetes
Steatosis
Migraine
Peptic ulcer
No somatic diagnosis
Please cite this article in press as: Bay-Richter, C., et al. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor
in depression and suicidality. Brain Behav. Immun. (2014), http://dx.doi.org/10.1016/j.bbi.2014.07.012
3
2.2. Somatic comorbidity
All patients and controls went through a general physical exam-
ination at the time of the lumbar punctures. In order to identify
subjects with infections at the time of the CSF sampling, body tem-
perature was measured and blood samples were analyzed for
white blood cell count, erythrocyte sedimentation rate or C-reac-
tive protein. No evidence of ongoing clinical infection was found,
as defined by the normal reference intervals of these parameters.
2.3. Lumbar punctures
CSF was obtained from the L4–L5 interspace, using a standard-
ized protocol, between 8 and 11 AM after a night of fasting and bed
rest. After collection, samples were immediately frozen at –80 °C.
2.4. Analysis of QUIN
QUIN levels in CSF were examined using GC/MS with the spec-
trometer operating in electron capture negative ionization mode.
The method used is described in Smythe et al. (2002). The internal
standard, [2H3]QUIN (99%) was purchased from Le Research Inc.
(St Paul, MN, USA). Trifluoroacetic anhydride and 1,1,1,3,3,3-hexa-
fluoro-2-propanol of GC derivatization grade, QUIN and other
organic solvents of analytical grade were all obtained from
Sigma–Aldrich (St Louis, MO, USA). One ll of sample was injected
into an Agilent 6890 gas chromatograph, interfaced to an Agilent
5973 mass selective detector via an auto-sampler Agilent Technol-
ogies 7683, and controlled using Agilent ChemStation software
(Agilent, Santa Clara, CA, USA). Experiments were performed in
triplicates, and mean values were used for the further analysis.
2.5. Analysis of KYNA
CSF and serum KYNA was analyzed as previously described
(Olsson et al., 2010) utilizing an isocratic reversed-phase HPLC sys-
tem, including a dual piston, high liquid delivery pump (Bischoff,
Leonberg, Germany), a ReproSil-Pur C18 column (silica pore size,
3 lm (4  100 mm, Dr. Maisch GmbH, Ammerbuch, Germany)
and a fluorescence detector (Jasco Ltd., Hachioji City, Japan) with
an excitation wavelength of 344 nm and an emission wavelength
of 398 nm (18 nm bandwidth). A mobile phase of 50 mM sodium
9 (30%)
acetate (pH 6.2, adjusted with acetic acid) and 7.0% acetonitrile
40 (22/61)
was pumped through the reversed-phase column at a flow rate
of 0.5 ml/min. Fifty-microliter samples were manually injected
13 (43%)
2 (7%) (ECOM, Prague, Czech Republic). Zinc acetate (0.5 M, not pH
7 (23%) adjusted) was delivered post-column by a peristaltic pump (P-
2 (7%) 500, Pharmacia, Uppsala, Sweden) at a flow rate of 0.10 ml/min.
1 (3%) The signals from the fluorescence detector were transferred to a
1 (3%)
computer for analysis with Datalys Azur (Grenoble, France). Reten-
3 (10%)
1 (3%) tion time of KYNA was 7–8 min. Standard concentrations were
used to relate the height of the peaks in the chromatogram to
22 (73%) the correct concentration of KYNA in the samples. Initially, the sen-
2 (7%) sitivity of the system was verified by analysis of a standard mixture
1 (3%) of KYNA with concentrations of 0.5–30 nM, which resulted in a lin-
1 (3%)
ear standard plot. The sensitivity of the HPLC system is verified by
analysis of a standard set of KYNA samples with concentrations
3 (10%)
from 0.5 to 30 nM resulting in a linear standard plot. The precision
10 (33%)
4 (13%) of the HPLC method is routinely tested within (intra-assay) and
11 (37%) between days (inter-assay). For the determination of intra-assay
precision, aliquots (n = 10) of KYNA standards at concentrations
1 (3%) of 1 and 10 nM are analyzed. The precision of the assay is calcu-
1 (3%) lated from the percentage coefficient of variation (CV) of the mean,
4 (13%) according to the equation CV (%) = (standard deviation/
1 (3%)
mean) * 100. The CV values for 1 and 10 nM are below 5%. Inter-
23 (77%)
assay precision is calculated by analyzing aliquots of the same
4 C. Bay-Richter et al. / Brain, Behavior, and Immunity xxx (2014) xxx–xxx
KYNA standard (1 and 10 nM). The CV values for inter-assay preci-
sion are below 5% for both 1 and 10 nM. CSF samples were ana-
lyzed in singles. To verify the reliability of the method, some
samples were analyzed in duplicate, and the mean intra-individual
variation was below 5%.
2.6. Analysis of cytokines
IL-1b, IL-6, TNF-a and IL-8 in CSF were examined using high
sensitivity electrochemiluminescence-based multiplex immunoas-
say (Meso Scale Discovery, USA) following manufacturer’s instruc-
tions, with the exception of an overnight incubation step and
addition of 10% BSA to the blocking solution. All samples were ana-
lyzed in duplicates and mean values were used for further analysis.
2.7. Data analysis
Statistical analysis was performed using SPSS 21 for Macintosh.
Non-normally distributed samples were transformed by natural
logarithm before further statistical analysis. The relationship
between kynurenine metabolites, time and psychiatric ratings
was examined using mixed linear regression models. This analysis
was performed in collaboration with Lund University biostatisti-
cians. Separate models for cytokines, QUIN and KYNA were per-
formed comparing the cytokine/kynurenine metabolite and the
depression rating scale in question as fixed effects and time
(months after suicide attempt) as the repeated measure. Potential
confounders, including age, gender and time, were treated simi-
larly. All kynurenine metabolites and potential confounders with
p-values 60.3 were subsequently used to develop multivariate
mixed linear regression models that included the cytokine/kynu-
renine metabolite in question, potential confounders, months after
attempt as repeated variables and psychiatric rating as dependent
variables. Variables were omitted based on their p-values using
step-wise exclusion until all p-values were <0.1 or until the change
in b value from the original analysis exceeded 20%. The same strat-
egy was applied when examining the effect of time on psychiatric
symptom severity as well as in the analysis of patients versus con-
trol kynurenine pathway metabolite levels. In the analysis of
patients versus control levels, time-intervals using average values
over 6 months were used as the repeated measure in the model.
3. Results
3.1. Sample characteristics
QUIN and KYNA were associated with age and gender, and con-
sequently all statistical models were corrected for these two fac-
tors as described in Section 2.7. The samples from the patients
had been stored at 80 °C longer than the controls, but there were
no storage-time-dependent changes, or trends towards changes, of
the metabolite levels (NS for both). Symptom severity, as measured
with MADRS and SUAS, fluctuated slightly but remained elevated
in the patients over time (Fig. 2). MADRS scores increased some-
what [F(1,51.26) = 4.372, p < 0.05, b = 0.15], whereas SUAS scores
were not affected over time [F < 2].
3.2. Kynurenine pathway metabolites in the follow-up period
CSF QUIN was significantly elevated in the suicide attempters
compared to the healthy individuals, and the elevation remained
over time [F(1,71.067) = 4.237, p < 0.05] (Fig. 3a). In contrast, mean
CSF KYNA was significantly decreased in the suicide attempters
over time compared to the healthy controls [F(1,50.070) = 14.607,
p < 0.001] (Fig. 3b).
Please cite this article in press as: Bay-Richter, C., et al. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor
in depression and suicidality. Brain Behav. Immun. (2014), http://dx.doi.org/10.1016/j.bbi.2014.07.012
3.3. Kynurenine pathway metabolites relative to levels at the suicide
attempt
CSF QUIN remained significantly higher long-term in the
patients compared to the healthy controls as analyzed using aver-
age values from 6 month intervals, but the levels were lower than
at the initial suicide attempt [F(1,92.997) = 9.084, p < 0.001] (Index
point, Fig. 3a). There was a significant difference between the levels
at the suicide attempt and the first two follow-up time points spe-
cifically [1–6 months t(115.5) = 4.514, p < 0.001 and 7–12 months
t(119.7) = 4.090, p < 0.001] (Fig. 3). There was no significant change
in CSF KYNA compared to the initial measurement at the suicide
attempt [F(1,62.950) = 2.069, p = 0.11] (Index point, Fig. 3b).
3.4. QUIN, KYNA and psychiatric symptoms in the follow-up period
CSF KYNA was negatively associated with SUAS and MADRS
scores, obtained at all time-points throughout the follow-up per-
iod, [SUAS: F(1,82.79) = 5.38, p = 0.02, b = 6.01; MADRS:
F(1,69.12) = 6.028, p < 0.02, b = 2,73] (Table 2). Thus, the lower
CSF KYNA, the worse the degree of depression and suicidal symp-
toms. No significant correlations between symptoms and CSF QUIN
were found [all F’s < 4, NS].
3.5. CSF cytokines and symptom severity
We found a significant positive relationship between CSF IL-6
and SUAS over time (F(1,52.26) = 4.250, p < 0.05, b = 3.92) (Table 2).
No other cytokines correlated with SUAS nor with MADRS scores
[all F’s < 4].
4. Discussion
This is the first study to measure the kynurenine pathway
metabolites QUIN and KYNA in CSF together with depressive and
suicidal symptoms over time in psychiatric patients. We show that
CSF QUIN levels remain permanently elevated in patients com-
pared to healthy controls over 2 years after a suicide attempt.
CSF QUIN levels were highest at the time of the attempt, decreased
over the first year, but remained significantly elevated compared to
the healthy controls over time. We also provide evidence that CSF
KYNA in these patients is decreased compared to healthy individ-
uals, and negatively associated with suicidal ideation and symp-
toms of depression. In line with this, a previous study found
decreased plasma KYNA levels in depressive patients compared
to healthy controls (Myint et al., 2007). Our findings provide sup-
port to the hypothesis that kynurenine pathway metabolites are
playing a key role in depressive and suicidal states, and that they
could be causative in symptom generation.
Our results showing that QUIN is increased and KYNA
decreased, support a role for glutamate-based mechanisms in the
generation of depressive symptoms and suicidality, based on the
affinity of these metabolites to the NMDA-receptor. Interestingly,
new evidence has shown that ketamine has an effect in treat-
ment-resistant depression and suicidality (Machado-Vieira et al.,
2009; DiazGranados et al., 2010; Zarate et al., 2006). While keta-
mine has several biological effects, its primary pharmacological
classification is as an NMDA-receptor antagonist. Potentially, this
compound could thus exert its mechanism of action in suicidal
patients by antagonizing the effects of QUIN and/or reinstating
the effects of KYNA on NMDA-receptors. While in this study, we
opted to investigate the association between QUIN and KYNA on
depressive and suicidal symptoms, it should be acknowledged that
the patients might experience other symptoms of importance for
suicidality, such as aggression and impulsivity, not assessed here.
 C. Bay-Richter et al. / Brain, Behavior, and Immunity xxx (2014) xxx–xxx 5

20 25
a b
20
15

MADRS
15

SUAS
10
10
5
5

0 0

12

8
8
6

12

-1
-1

1-
1-

7-
7-

13
13
Months after suicide attempt Months after suicide attempt

Fig. 2. Raw (a) Montgomery–Asberg Depression Rating Scale (MADRS) and (b) Suicide Assessment Scale (SUAS) scores over time. Mean (±SEM).
CSF QUIN concentration (nM)

50 a direct causality in the patients. In order to test causality, interven-

Controls tional studies are required, which is highly warranted for the
40 Patients
future. Another aspect is that for ethical reasons, the majority of
30 *** patients in this follow-up were on psychotropic medications,
*** which could vary during the course of the study. We could not sta-
20 tistically control for this due to the individual regimens in the dif-
10
ferent patients. Thus, the observed differences in levels of
metabolites and inflammatory factors occurred irrespective of the
0 different medications used by the patients, and were still signifi-
x

12

cantly associated with psychiatric symptoms of depression and

de

1-

-1
7-

13
In

Months after suicide attempt suicidality. In the future, larger studies should evaluate whether
different medications affect the levels of kynurenine metabolites
and whether this could be an indication of treatment response.
CSF KYNA concentration (nM)

1.5 b Controls As another limitation, the gender and age of the controls and
Patients patients were not matched, however we controlled for these
1.0
potential confounders in the statistical analysis.
We here employed repeated lumbar punctures on suicide
attempters, which is a unique property of the study, although it
0.5 should be emphasized that control subjects only underwent one
such procedure, due to limitations in our ethical permit for con-
trols. We specifically used the MADRS and SUAS rating scales as
0.0
these scales are sensitive to change in symptom severity which is
8
x

12

-1
de

1-

particularly useful in this longitudinal study (Nimeus et al., 2000;

7-

13
In

Months after suicide attempt Montgomery and Asberg, 1979). MADRS scores typically correlate
with Hamilton Scale Scores, but we cannot rule out that using dif-
Fig. 3. (a) CSF quinolinic acid (QUIN) levels compared to CSF QUIN level at the
ferent psychiatric rating scales would uncover symptoms, which
suicide attempt and to CSF QUIN levels of healthy controls and index (at the suicide
attempt). (b) CSF KYNA levels compared to CSF kynurenic acid (KYNA) level at the we in the current analysis do not address.
suicide attempt and to CSF KYNA levels of healthy controls ⁄⁄⁄p < 0.001 compared to QUIN exerts several potential detrimental effects on the central
suicide attempt. #p < 0.05; ###p < 0.001 patients vs controls. All values represent nervous system (CNS). This compound induces neurotoxicity and
mean (±SEM). gliotoxicity as well as disrupts the integrity of the blood–brain bar-
rier, processes known to result from its NMDA-receptor stimula-
Table 2
tory effects (Stone, 1993; Guillemin, 2012b). Furthermore, QUIN
Regression coefficients [b (95% CIs)] and p-values for change in symptoms by a unit also induces neurotoxicity, which may be unrelated to its effects
increase in ln-transformed CSF KYNA, QUIN and IL-6 values. CI = confidence interval. on the NMDA receptor, e.g. by formation of a complex with Fe2+
or by causing microglial cells to induce inflammation in the brain
Variable Linear regression
(Schwarcz et al., 2012; Guillemin, 2012a). The synthesis of QUIN
Coefficient (95% CI) p-value
in the brain primarily takes place in infiltrating macrophages as
ln(CSF KYNA) vs SUAS 6.01 ( 11.16 0.86) 0.02 well as in resident and reactive microglia (Kita et al., 2002;
ln(CSF KYNA) vs MADRS 2.73 ( 4.94 0.51) 0.02
Lehrmann et al., 2001). Normal concentrations of QUIN in the
ln(CSF QUIN) vs SUAS 2.93 ( 6.12 0.27) NS
ln(CSF QUIN) vs MADRS 1.42 ( 2.83 0.01) NS human brain are found to be in the nanomolar range (controls span
ln(CSF IL-6) vs SUAS 3.92 (0.10 7.74) 0.04 a range of 20–40 nM (Raison et al., 2010; Chen et al., 2010), but
ln(CSF IL-6) vs MADRS 1.47 ( 0.11 3.04) NS methodological differences may impact the absolute levels). The
concentrations of QUIN, even the increased amount produced in
response to infections/inflammations might not be sufficient to
Future studies are warranted to establish the relation of these kyn- induce excitotoxicity (Obrenovitch and Urenjak, 2000, 2003;
urenine metabolites to such other aspects of suicidal behavior. Sapko et al., 2006; Schwarcz et al., 2010), unless enhanced levels
There are some limitations to our current study. First, even if of the compound are maintained for several weeks (Kerr et al.,
this study shows significant changes over time as well as associa- 1998; Khaspekov et al., 1989; Galarraga et al., 1990; Whetsell
tions between the kynurenine metabolites and psychiatric symp- and Schwarcz, 1989). Importantly, QUIN toxicity has been shown
toms, the study is still of a correlational nature and does not test to occur in the presence of a lowered concentration of the

Please cite this article in press as: Bay-Richter, C., et al. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor
in depression and suicidality. Brain Behav. Immun. (2014), http://dx.doi.org/10.1016/j.bbi.2014.07.012
6 C. Bay-Richter et al. / Brain, Behavior, and Immunity xxx (2014) xxx–xxx
neuroprotective KYNA (Sapko et al., 2006; Schwarcz et al., 2010).
Increased levels of QUIN as observed here, in combination with
reduced KYNA levels, might thus contribute to neuronal loss and
reduced hippocampal volume as observed in patients with major
depression (Bremner et al., 2000; McKinnon et al., 2009).
A condition of increased extracellular QUIN in combination
with reduced KYNA levels are likely to facilitate glutamate neuro-
transmission at concentrations lower than that required for neuro-
toxicity (Schwarcz et al., 2012). NMDA receptor alterations have
previously been found in the brains of suicide victims (Nowak
et al., 1995, 2003) and several studies have shown marked and
rapid antidepressant and anti-suicidal effects of NMDA-receptor
antagonists such as ketamine (DiazGranados et al., 2010; Zarate
et al., 2006). In addition to being a direct NMDA receptor agonist,
QUIN also increases neuronal glutamate release and decreases glu-
tamate uptake and recycling by astrocytes (Guillemin, 2012a).
Such effects on the glutamate system may contribute to the path-
ogenesis of major depressive disorders and suicidality (Schwarcz
et al., 2012; Hashimoto, 2009; Sanacora et al., 2008). We therefore
propose that the elevated levels of QUIN, in particular in combina-
tion with the reduced levels of KYNA, leads to an excess net-
stimulation of NMDA receptors, providing a neurobiological
rationale for the ketamine-induced alleviation of depression and
suicidality.
KYNA is known to have neuroprotective and anticonvulsant
properties (Foster et al., 1984; Schwarcz and Pellicciari, 2002). In
addition, recent evidence has emerged that KYNA is intricately
associated with dopamine neurotransmission (Schwarcz et al.,
2012). This is of interest as novel evidence pin-points a role of
the dopamine system in major depression (Chaudhury et al.,
2013; Savitz et al., 2013; Tye et al., 2013). In the present study,
low levels of CSF KYNA were associated with severe psychiatric
symptoms, including depression severity and suicidal thoughts.
In healthy controls and in patients with schizophrenia, CSF KYNA
is correlated with CSF homovanillic acid, a major dopamine metab-
olite (Nilsson et al., 2007; Nilsson-Todd et al., 2007). In view of this,
it is intriguing that experimental studies show a reduced number
of spontaneously firing midbrain dopamine neurons in the rat fol-
lowing decreased brain KYNA levels (Schwieler et al., 2006, 2008).
As the percentage of spontaneously firing dopamine neurons
determines the amplitude of the dopamine phasic burst response
(Lodge and Grace, 2006), a reduction in the number of this dopami-
nergic population would diminish the amplitude of the phasic
burst firing response (Lodge and Grace, 2006), attenuating the
positive affective response to a salient or rewarding stimulus
(Schultz, 1998). Indeed, reduced reward responsiveness is
observed in depression (Pizzagalli et al., 2008; Suslow et al.,
2001; Wang et al., 2006). Alterations of the two key kynurenine
pathway metabolites QUIN and KYNA may thus have a profound
impact on both the glutamate- and the dopamine systems in the
brain.
A low-grade inflammatory process is likely to account for the
increased CSF QUIN levels observed in the patients, as it is known
from previous studies that the kynurenine pathway is induced in
the brain following cerebral infections and inflammation (Atlas
et al., 2007; Heyes et al., 1992). In support of this, CSF IL-6 was ele-
vated in these patients at the time of the suicide attempt (Lindqvist
et al., 2009). That KYNA is decreased in CSF is intriguing, since
studies have shown that pro-inflammatory cytokines, such as
IFN-c, IL-1b and IL-6, should induce not only the production of
QUIN but also that of KYNA (Kim et al., 2012; King and Thomas,
2007). Why would the KYNA levels in these patients then be
decreased? A recent study suggests that a genetic variant encoding
for kynurenine aminotransferase (KAT) III, one enzyme catalyzing
the final step in the synthesis of KYNA, is responsible for the low
levels of KYNA observed in plasma of depressed patients (Claes
Please cite this article in press as: Bay-Richter, C., et al. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor
in depression and suicidality. Brain Behav. Immun. (2014), http://dx.doi.org/10.1016/j.bbi.2014.07.012
et al., 2011). Reduced expression or activity of the KAT III enzyme
might lead to diminished synthesis of KYNA. Alternatively, the
decrease in central levels of KYNA may be related to a prolonged
increase in brain QUIN, leading to astrocytic apoptosis, in line with
QUIN’s toxic properties. Indeed, administration of QUIN induces
apoptosis in cell cultures of astrocytes (Guillemin et al., 2005).
Thus, immune-stimulated microglial cells in the patients activate
the synthesis of QUIN, resulting in astrocyte death and dysfunction,
with consequently decreased KYNA production. This would be
more likely to occur in individuals with a genetic predisposition
(Claes et al., 2011).
In conclusion, we demonstrate increased CSF QUIN and
decreased CSF KYNA over time in individuals who had attempted
suicide. These findings are of importance for the development of
novel biomarkers of suicidality, and they provide a neurobiological
framework supporting the use of NMDA receptor antagonists in
the treatment of suicidality and depression. Moreover, they war-
rant the development of pharmacological tools modulating the
activity of the kynurenine pathway enzymes in suicidality and
depression.
Financial disclosures
The authors declare that there are no conflicts of interest.
Acknowledgments
This study was supported by Michigan State University and Van
Andel Research Institute (L.B.), the Swedish Research Council (V.R.)
Nos. 2009-4284 and 2011-4787 (L.B.), 2002-5297 and 2008-2922
(L.T-B.), 2009-7052 and 2013-2838 (SE), the Province of Scania
clinical state grants (ALF, for L.B. and L.T-B.), The Australian
Research Council and the National Health and Medical Research
Council, Australia (G.J.G.). The funding sources had no role in the
design and conduct of the study; collection, management, analysis,
and interpretation of the data; preparation, review, or approval of
the manuscript; and decision to submit the manuscript for
publication.
References
American Psychiatric Association, 1987. Diagnostic and Statistical Manual of Mental
Disorders. American Psychiatric Press, Washington, DC.
Atlas, A., Gisslen, M., Nordin, C., Lindstrom, L., Schwieler, L., 2007. Acute psychotic
symptoms in HIV-1 infected patients are associated with increased levels of
kynurenic acid in cerebrospinal fluid. Brain Behav. Immun. 21, 86–91.
Atlas, A., Franzen-Röhl, E., Söderlund, J., Jönsson, E.G., Samuelsson, M., Schwieler, L.,
Sköldenberg, B., Engberg, G., 2013. Sustained elevation of kynurenic acid in the
cerebrospinal fluid of patients with herpes simplex virus type 1 encephalitis.
Int. J. Tryptophan Res. 6, 89–96.
Berk, M., Wadee, A.A., Kuschke, R.H., O’Neill-Kerr, A., 1997. Acute phase proteins in
major depression. J. Psychosom. Res. 43, 529–534.
Bremner, J.D., Narayan, M., Anderson, E.R., Staib, L.H., Miller, H.L., Charney, D.S.,
2000. Hippocampal volume reduction in major depression. Am. J. Psychiatry
157, 115–118.
Chaudhury, D., Walsh, J.J., Friedman, A.K., Juarez, B., Ku, S.M., Koo, J.W., et al., 2013.
Rapid regulation of depression-related behaviours by control of midbrain
dopamine neurons. Nature 493, 532–536.
Chen, Y., Stankovic, R., Cullen, K.M., Meininger, V., Garner, B., Coggan, S., Grant, R.,
Brew, B.J., Guillemin, G.J., 2010. The kynurenine pathway and inflammation in
amyotrophic lateral sclerosis. Neurotox. Res. 18, 132–142.
Claes, S., Myint, A.M., Domschke, K., Del-Favero, J., Entrich, K., Engelborghs, S., De
Deyn, P., Mueller, N., Baune, B., Rothermundt, M., 2011. The kynurenine
pathway in major depression: haplotype analysis of three related functional
candidate genes. Psychiatry Res. 188, 355–360.
Dahl, J., Ormstad, H., Aass, H.C., Malt, U.F., Bendz, L.T., Sandvik, L., Brundin, L.,
Andreassen, O.A., 2014. The plasma levels of various cytokines are increased
during ongoing depression and are reduced to normal levels after recovery.
Psychoneuroendocrinology 45, 77–86.
de Carvalho, L.P., Bochet, P., Rossier, J., 1996. The endogenous agonist quinolinic acid
and the non endogenous homoquinolinic acid discriminate between NMDAR2
receptor subunits. Neurochem. Int. 28, 445–452.
 C. Bay-Richter et al. / Brain, Behavior, and Immunity xxx (2014) xxx–xxx
DiazGranados, N., Ibrahim, L.A., Brutsche, N.E., Ameli, R., Henter, I.D., Luckenbaugh,
D.A., Machado-Vieira, R., Zarate Jr., C.A., 2010. Rapid resolution of suicidal
ideation after a single infusion of an N-methyl-D-aspartate antagonist in
patients with treatment-resistant major depressive disorder. J. Clin. Psychiatry
71, 1605–1611.
Dieperink, E., Ho, S.B., Tetrick, L., Thuras, P., Dua, K., Willenbring, M.L., 2004. Suicidal
ideation during interferon-alpha2b and ribavirin treatment of patients with
chronic hepatitis C. Gen. Hosp. Psychiatry 26, 237–240.
Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E.K., Lanctôt, K.L.,
2010. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67,
446–457.
Erhardt, S., Lim, C.K., Linderholm, K.R., Janelidze, S., Lindqvist, D., Samuelsson, M.,
Lundberg, K., Postolache, T.T., Traskman-Bendz, L., Guillemin, G.J., Brundin, L.,
2013. Connecting inflammation with glutamate agonism in suicidality.
Neuropsychopharmacology 38, 743–752.
Foster, A.C., Vezzani, A., French, E.D., Schwarcz, R., 1984. Kynurenic acid blocks
neurotoxicity and seizures induced in rats by the related brain metabolite
quinolinic acid. Neurosci. Lett. 48, 273–278.
Fragoso, Y.D., Frota, E.R., Lopes, J.S., Noal, J.S., Giocomo, M.C., Gomes, S., Goncalves,
M.V., da Gama, P.D., Finkelsztejn, A., 2010. Severe depression, suicide attempts,
and ideation during the use of interferon beta by patients with multiple
sclerosis. Clin. Neuropharmacol. 33, 312–316.
Galarraga, E., Surmeier, D.J., Kitai, S.T., 1990. Quinolinate and kainate neurotoxicity
in neostriatal cultures is potentiated by co-culturing with neocortical neurons.
Brain Res. 512, 269–276.
Guillemin, G.J., 2012a. Quinolinic acid, the inescapable neurotoxin. FEBS J. 279,
1356–1365.
Guillemin, G.J., 2012b. Quinolinic acid: neurotoxicity. FEBS J. 279, 1355.
Guillemin, G.J., Wang, L., Brew, B.J., 2005. Quinolinic acid selectively induces
apoptosis of human astrocytes: potential role in AIDS dementia complex. J.
Neuroinflamm. 2, 16.
Harris, E.C., Barraclough, B., 1997. Suicide as an outcome for mental disorders. A
meta-analysis. Br J. Psychiatry 170, 205–228.
Hashimoto, K., 2009. Emerging role of glutamate in the pathophysiology of major
depressive disorder. Brain Res. Rev. 61, 105–123.
Heresco-Levy, U., Javitt, D.C., 1998. The role of N-methyl-D-aspartate (NMDA)
receptor-mediated neurotransmission in the pathophysiology and therapeutics
of psychiatric syndromes. Eur. Neuropsychopharmacol. 8, 141–152.
Heron, M., 2012. Deaths: leading causes for 2008. National vital statistics reports:
from the centers for disease control and prevention, national center for health
statistics. Natl. Vital Stat. Syst. 60, 1–94.
Hestad, K.A., Tonseth, S., Stoen, C.D., Ueland, T., Aukrust, P., 2003. Raised plasma
levels of tumor necrosis factor alpha in patients with depression: normalization
during electroconvulsive therapy. J ECT 19, 183–188.
Heyes, M.P., Saito, K., Crowley, J.S., Davis, L.E., Demitrack, M.A., Der, M., Dilling, L.A.,
Elia, J., Kruesi, M.J., Lackner, A., et al., 1992. Quinolinic acid and kynurenine
pathway metabolism in inflammatory and non-inflammatory neurological
disease. Brain 115, 1249–1273.
Janelidze, S., Mattei, D., Westrin, A., Traskman-Bendz, L., Brundin, L., 2011. Cytokine
levels in the blood may distinguish suicide attempters from depressed patients.
Brain Behav. Immun. 25, 335–339.
Kerr, S.J., Armati, P.J., Guillemin, G.J., Brew, B.J., 1998. Chronic exposure of human
neurons to quinolinic acid results in neuronal changes consistent with AIDS
dementia complex. AIDS 12, 355–363.
Khaspekov, L., Kida, E., Victorov, I., Mossakowski, M.J., 1989. Neurotoxic effect
induced by quinolinic acid in dissociated cell culture of mouse hippocampus. J.
Neurosci. Res. 22, 150–157.
Kim, H., Chen, L., Lim, G., Sung, B., Wang, S., McCabe, M.F., et al., 2012. Brain
indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and
depression. J. Clin. Investig. 122, 2940–2954.
King, N.J., Thomas, S.R., 2007. Molecules in focus: indoleamine 2,3-dioxygenase. Int.
J. Biochem. Cell Biol. 39, 2167–2172.
Kita, T., Morrison, P.F., Heyes, M.P., Markey, S.P., 2002. Effects of systemic and
central nervous system localized inflammation on the contributions of
metabolic precursors to the L-kynurenine and quinolinic acid pools in brain. J.
Neurochem. 82 (2), 258–268.
Larkin, G.L., Beautrais, A.L., 2011. A preliminary naturalistic study of low-dose
ketamine for depression and suicide ideation in the emergency department. Int.
J. Neuropsychopharmacol. 14, 1127–1131.
Lehrmann, E., Molinari, A., Speciale, C., Schwarcz, R., 2001. Immunohistochemical
visualization of newly formed quinolinate in the normal and excitotoxically
lesioned rat striatum. Exp. Brain Res. 141 (3), 389–397.
Linderholm, K.R., Skogh, E., Olsson, S.K., Dahl, M.L., Holtze, M., Engberg, G.,
Samuelsson, M., Erhardt, S., 2012. Increased levels of kynurenine and
kynurenic acid in the CSF of patients with schizophrenia. Schizophr. Bull. 38,
426–432.
Lindqvist, D., Janelidze, S., Hagell, P., Erhardt, S., Samuelsson, M., Minthon, L.,
Hansson, O., Bjorkqvist, M., Traskman-Bendz, L., Brundin, L., 2009. Interleukin-6
is elevated in the cerebrospinal fluid of suicide attempters and related to
symptom severity. Biol. Psychiatry 66, 287–292.
Lodge, D.J., Grace, A.A., 2006. The laterodorsal tegmentum is essential for burst
firing of ventral tegmental area dopamine neurons. Proc. Natl. Acad. Sci. U.S.A.
103, 5167–5172.
Machado-Vieira, R., Salvadore, G., Diazgranados, N., Zarate Jr, C.A., 2009. Ketamine
and the next generation of antidepressants with a rapid onset of action.
Pharmacol. Ther. 123, 143–150.
Please cite this article in press as: Bay-Richter, C., et al. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor
in depression and suicidality. Brain Behav. Immun. (2014), http://dx.doi.org/10.1016/j.bbi.2014.07.012
7
McKinnon, M.C., Yucel, K., Nazarov, A., MacQueen, G.M., 2009. A meta-analysis
examining clinical predictors of hippocampal volume in patients with major
depressive disorder. J. Psychiatry Neurosci. 34, 41–54.
Mikova, O., Yakimova, R., Bosmans, E., Kenis, G., Maes, M., 2001. Increased serum
tumor necrosis factor alpha concentrations in major depression and multiple
sclerosis. Eur. Neuropsychopharmacol. 11, 203–208.
Montgomery, S.A., Asberg, M., 1979. A new depression scale designed to be sensitive
to change. Br. J. Psychiatry 134, 382–389.
Myint, A.M., Kim, Y.K., Verkerk, R., Scharpe, S., Steinbusch, H., Leonard, B., 2007.
Kynurenine pathway in major depression: evidence of impaired
neuroprotection. J. Affect. Disord. 98, 143–151.
Nilsson, L.K., Nordin, C., Jonsson, E.G., Engberg, G., Linderholm, K.R., Erhardt, S.,
2007. Cerebrospinal fluid kynurenic acid in male and female controls –
correlation with monoamine metabolites and influences of confounding
factors. J. Psychiatr. Res. 41, 144–151.
Nilsson-Todd, L.K., Nordin, C., Jönsson, E.G., Skogh, E., Erhardt, S., 2007.
Cerebrospinal fluid kynurenic acid in male patients with schizophrenia –
correlation with monoamine metabolites. Acta Neuropsychiatrica 19, 45–52.
Nimeus, A., Alsen, M., Traskman-Bendz, L., 2000. The Suicide Assessment Scale: an
instrument assessing suicide risk of suicide attempters. Eur. Psychiatry 15, 416–
423.
Nowak, G., Ordway, G.A., Paul, I.A., 1995. Alterations in the N-methyl-D-aspartate
(NMDA) receptor complex in the frontal cortex of suicide victims. Brain Res.
675, 157–164.
Nowak, G., Szewczyk, B., Sadlik, K., Piekoszewski, W., Trela, F., Florek, E., Pilc, A.,
2003. Reduced potency of zinc to interact with NMDA receptors in hippocampal
tissue of suicide victims. Pol. J. Pharmacol. 55, 455–459.
Obrenovitch, T.P., Urenjak, J., 2000. In vivo assessment of kynurenate
neuroprotective potency and quinolinate excitotoxicity. Amino Acids 19, 299–
309.
Obrenovitch, T.P., Urenjak, J., 2003. Accumulation of quinolinic acid with
neuroinflammation: does it mean excitotoxicity? Adv. Exp. Med. Biol. 527,
147–154.
Olfson, M., Marcus, S.C., Bridge, J.A., 2014. Focusing suicide prevention on periods of
high risk. JAMA 311, 1107–1108.
Olsson, S.K., Samuelsson, M., Saetre, P., Lindström, L., Jönsson, E.G., Nordin, C.,
Engberg, G., Erhardt, S., Landén, M., 2010. Elevated levels of kynurenic acid in
the cerebrospinal fluid of patients with bipolar disorder. J. Psychiatry Neurosci.
35, 195–199.
Pandey, G.N., Rizavi, H.S., Ren, X., Fareed, J., Hoppensteadt, D.A., Roberts, R.C.,
Conley, R.R., Dwivedi, Y., 2012. Proinflammatory cytokines in the prefrontal
cortex of teenage suicide victims. J. Psychiatr. Res. 46, 57–63.
Pizzagalli, D.A., Iosifescu, D., Hallett, L.A., Ratner, K.G., Fava, M., 2008. Reduced
hedonic capacity in major depressive disorder: evidence from a probabilistic
reward task. J. Psychiatr. Res. 43, 76–87.
Price, R.B., Nock, M.K., Charney, D.S., Mathew, S.J., 2009. Effects of intravenous
ketamine on explicit and implicit measures of suicidality in treatment-resistant
depression. Biol. Psychiatry 66, 522–526.
Raison, C.L., Dantzer, R., Kelley, K.W., Lawson, M.A., Woolwine, B.J., Vogt, G., Spivey,
J.R., Saito, K., Miller, A.H., 2010. CSF concentrations of brain tryptophan and
kynurenines during immune stimulation with IFN-alpha: relationship to CNS
immune responses and depression. Mol. Psychiatry 15, 393–403.
Sanacora, G., Zarate, C.A., Krystal, J.H., Manji, H.K., 2008. Targeting the glutamatergic
system to develop novel, improved therapeutics for mood disorders. Nat. Rev.
Drug Discov. 7, 426–437.
Sapko, M.T., Guidetti, P., Yu, P., Tagle, D.A., Pellicciari, R., Schwarcz, R., 2006.
Endogenous kynurenate controls the vulnerability of striatal neurons to
quinolinate: implications for Huntington’s disease. Exp. Neurol. 197, 31–40.
Savitz, J., Hodgkinson, C.A., Martin-Soelch, C., Shen, P.H., Szczepanik, J., Nugent, A.,
et al., 2013. DRD2/ANKK1 Taq1A polymorphism (rs1800497) has opposing
effects on D2/3 receptor binding in healthy controls and patients with major
depressive disorder. Int. J. Neuropsychopharmacol. 16, 2095–2101.
Schultz, W., 1998. Predictive reward signal of dopamine neurons. J. Neurophysiol.
80, 1–27.
Schwarcz, R., Pellicciari, R., 2002. Manipulation of brain kynurenines: glial targets,
neuronal effects, and clinical opportunities. J. Pharmacol. Exp. Ther. 303, 1–10.
Schwarcz, R., Guidetti, P., Sathyasaikumar, K.V., Muchowski, P.J., 2010. Of mice, rats
and men: revisiting the quinolinic acid hypothesis of Huntington’s disease.
Prog. Neurobiol. 90, 230–245.
Schwarcz, R., Bruno, J.P., Muchowski, P.J., Wu, H.Q., 2012. Kynurenines in the
mammalian brain: when physiology meets pathology. Nat. Rev. Neurosci. 13,
465–477.
Schwieler, L., Erhardt, S., Nilsson, L., Linderholm, K., Engberg, G., 2006. Effects of
COX-1 and COX-2 inhibitors on the firing of rat midbrain dopaminergic
neurons – possible involvement of endogenous kynurenic acid. Synapse 59,
290–298.
Schwieler, L., Linderholm, K.R., Nilsson-Todd, L.K., Erhardt, S., Engberg, G., 2008.
Clozapine interacts with the glycine site of the NMDA receptor:
electrophysiological studies of dopamine neurons in the rat ventral tegmental
area. Life Sci. 83, 170–175.
Serafini, G., Pompili, M., Innamorati, M., Dwivedi, Y., Brahmachari, G., Girardi, P.,
2013. Pharmacological properties of glutamatergic drugs targeting NMDA
receptors and their application in major depression. Curr. Pharm. Des. 19, 1898–
1922.
Smythe, G.A., Braga, O., Brew, B.J., Grant, R.S., Guillemin, G.J., Kerr, S.J., Walker, D.W.,
2002. Concurrent quantification of quinolinic, picolinic, and nicotinic acids
8 C. Bay-Richter et al. / Brain, Behavior, and Immunity xxx (2014) xxx–xxx

using electron-capture negative-ion gas chromatography–mass spectrometry.
Anal. Biochem. 301, 21–26.
Stanley, B., Träskman-Bendz, L., Stanley, M., 1986. The Suicide Assessment Scale: a
scale evaluating change in suicidal behavior. Psychopharmacol. Bull. 22, 200–
205.
Steiner, J., Bielau, H., Brisch, R., Danos, P., Ullrich, O., Mawrin, C., Bernstein, H.G.,
Bogerts, B., 2008. Immunological aspects in the neurobiology of suicide:
elevated microglial density in schizophrenia and depression is associated
with suicide. J. Psychiatr. Res. 42, 151–157.
Steiner, J., Walter, M., Gos, T., Guillemin, G.J., Bernstein, H.G., Sarnyai, Z., Mawrin, C.,
Brisch, R., Bielau, H., Meyer, Z., Schwabedissen, L., Bogerts, B., Myint, A.M., 2011.
Severe depression is associated with increased microglial quinolinic acid in
subregions of the anterior cingulate gyrus: evidence for an immune-modulated
glutamatergic neurotransmission? J. Neuroinflamm. 8, 94.
Stone, T.W., 1993. Neuropharmacology of quinolinic and kynurenic acids.
Pharmacol. Rev. 45, 309–379.
Stone, T.W., Perkins, M.N., 1981. Quinolinic acid: a potent endogenous excitant at
amino acid receptors in CNS. Eur. J. Pharmacol. 72, 411–412.
Stone, T.W., Stoy, N., Darlington, L.G., 2013. An expanding range of targets for
kynurenine metabolites of tryptophan. Trends Pharmacol. Sci. 34, 136–143.
Sublette, M.E., Galfalvy, H.C., Fuchs, D., Lapidus, M., Grunebaum, M.F., Oquendo,
M.A., Mann, J.J., Postolache, T.T., 2011. Plasma kynurenine levels are elevated in
suicide attempters with major depressive disorder. Brain Behav. Immun. 25,
1272–1278.
Suslow, T., Junghanns, K., Arolt, V., 2001. Detection of facial expressions of emotions
in depression. Percept. Mot. Skills 92, 857–868.
Thomas, A.J., Davis, S., Morris, C., Jackson, E., Harrison, R., O’Brien, J.T., 2005. Increase
in interleukin-1beta in late-life depression. Am. J. Psychiatry 162, 175–177.
Tonelli, L.H., Stiller, J., Rujescu, D., Giegling, I., Schneider, B., Maurer, K., Schnabel, A.,
Moller, H.J., Chen, H.H., Postolache, T.T., 2008. Elevated cytokine expression in
the orbitofrontal cortex of victims of suicide. Acta Psychiatr. Scand. 117, 198–
206.
Tye, K.M., Mirzabekov, J.J., Warden, M.R., Ferenczi, E.A., Tsai, H.C., Finkelstein, J.,
et al., 2013. Dopamine neurons modulate neural encoding and expression of
depression-related behaviour. Nature 493, 537–541.
Valkanova, V., Ebmeier, K.P., Allan, C.L., 2013. CRP, IL-6 and depression: a systematic
review and meta-analysis of longitudinal studies. J. Affect. Disord. 150, 736–
744.
Wang, C.E., Brennen, T., Holte, A., 2006. Decreased approach motivation in
depression. Scand. J. Psychol. 47, 505–511.
Whetsell Jr., W.O., Schwarcz, R., 1989. Prolonged exposure to submicromolar
concentrations of quinolinic acid causes excitotoxic damage in organotypic
cultures of rat corticostriatal system. Neurosci. Lett. 97, 271–275.
Zarate Jr., C.A., Singh, J.B., Carlson, P.J., Brutsche, N.E., Ameli, R., Luckenbaugh, D.A.,
Charney, D.S., Manji, H.K., 2006. A randomized trial of an N-methyl-D-aspartate
antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63,
856–864.
Zarate Jr., C.A., Brutsche, N.E., Ibrahim, L., Franco-Chaves, J., Diazgranados, N.,
Cravchik, A., Selter, J., Marquardt, C.A., Liberty, V., Luckenbaugh, D.A., 2012.
Replication of ketamine’s antidepressant efficacy in bipolar depression: a
randomized controlled add-on trial. Biol. Psychiatry 71, 939–946.

Please cite this article in press as: Bay-Richter, C., et al. A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor
in depression and suicidality. Brain Behav. Immun. (2014), http://dx.doi.org/10.1016/j.bbi.2014.07.012