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Molecular Psychiatry
https://doi.org/10.1038/s41380-019-0589-8
ARTICLE
The kynurenine pathway and bipolar disorder: intersection of the
monoaminergic and glutamatergic systems and immune response
Bashkim Kadriu1●Cristan A. Farmer1●Peixiong Yuan1●Lawrence T. Park 1●Zhi-De Deng1●Ruin Moaddel2●
Ioline D. Henter1●Bridget Shovestul1●Elizabeth D. Ballard1●Cristoph Kraus1●Philip W. Gold3●
Rodrigo Machado-Vieira1,4 ●Carlos A. Zarate Jr.1
Received: 6 June 2019 / Revised: 21 October 2019 / Accepted: 30 October 2019
This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019
Abstract
Dysfunction in a wide array of systems—including the immune, monoaminergic, and glutamatergic systems—is implicated in
the pathophysiology of depression. One potential intersection point for these three systems is the kynurenine (KYN) pathway.
This study explored the impact of the prototypic glutamatergic modulator ketamine on the endogenous KYN pathway in
individuals with bipolar depression (BD), as well as the relationship between response to ketamine and depression-related
behavioral and peripheral inflammatory markers. Thirty-nine participants with treatment-resistant BD (23 F, ages 18–65)
received a single ketamine infusion (0.5 mg/kg) over 40min. KYN pathway analytes—including plasma concentrations of
indoleamine 2,3-dioxygenase (IDO), KYN, kynurenic acid (KynA), and quinolinic acid (QA)—were assessed at baseline (pre-
infusion), 230 min, day 1, and day 3 post-ketamine. General linear models with restricted maximum likelihood estimation and
robust sandwich variance estimators were implemented. A repeated effect of time was used to model the covariance of the
residuals with an unstructured matrix. After controlling for age, sex, and body mass index (BMI), post-ketamine IDO levels were
significantly lower than baseline at all three time points. Conversely, ketamine treatment significantly increased KYN and KynA
levels at days 1 and 3 versus baseline. No change in QA levels was observed post-ketamine. A lower post-ketamine ratio of QA/
KYN was observed at day 1. In addition, baseline levels of proinflammatory cytokines and behavioral measures predicted KYN
pathway changes post ketamine. The results suggest that, in addition to having rapid and sustained antidepressant effects in BD
participants, ketamine also impacts key components of the KYN pathway.
Introduction
The etiology of bipolar depression (BD) remains unknown,
in part due to both the heterogeneous nature of the disease
and its complex underlying neuropathology [1]. In addition,
the lack of reliable biomarkers substantially complicates
treatment of the disorder, worsens prognosis, and increases
treatment refractoriness. Recent studies have implicated
both altered glutamatergic neurotransmission and excessive
immune activation in the neurobiology of BD as well as
treatment resistance [2,3]. In particular, evidence from
preclinical and clinical studies suggests that the abnormal
activation of the kynurenine (KYN) pathway may underlie
BD [3,4]. Neuroactive byproducts of the KYN pathway are
involved in the interface between inflammatory/immune
response [5,6] and serotoninergic neurotransmission via
catabolism of tryptophan to KYN [7], ultimately altering
downstream synaptic glutamatergic neurotransmission
[8]. The KYN pathway also facilitates inter-organ
*Bashkim Kadriu
bashkim.kadriu@nih.gov
1Section on the Neurobiology and Treatment of Mood Disorders,
National Institute of Mental Health, National Institutes of Health,
Bethesda, MD, USA
2National Institute on Aging, National Institutes of Health,
Baltimore, Maryland, USA
3Clinical Neuroendocrinology Branch, National Institute of Mental
Health, National Institutes of Health, Bethesda, MD, USA
4Department of Psychiatry and Behavioral Sciences, McGovern
Medical School, University of Texas Science Center,
Houston, TX, USA
Supplementary information The online version of this article (https://
doi.org/10.1038/s41380-019-0589-8) contains supplementary
material, which is available to authorized users.
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communication between the brain and the immune system
by affecting neural afferents and circulating immune med-
iators that activate brain endothelial and innate immune
cells (microglia) [9,10]. This communication is primarily
achieved via two rate-limiting enzymes: tryptophan 2,3-
dioxygenase (TDO) and indoleamine 2,3-dioxygenase
(IDO) [11,12] (see Fig. 1), both of which are implicated in
the catabolism of tryptophan into KYN. Of the two
enzymes, TDO is mostly intra-hepatic and regulated by
glucocorticoid induction [13], whereas IDO is extra-hepatic,
highly expressed in the brain, and tightly upregulated in
response to proinflammatory mediators, glucocorticoids,
and psychosocial stress [14].
In the brain, KYN can be differentially processed by
either astrocytes or microglia to produce distinct neuroac-
tive compounds. During homeostasis, KYN aminotransfer-
ase converts KYN to kynurenic acid (KynA), a metabolite
of the astrocytic process [15], which clears accumulated
KYN in the central nervous system (CNS). KynA binds at
the glycine co-agonist site of the NR2B N-methyl-D-
aspartate receptor (NMDAR) and also has antagonist
properties at the α7-nicotinic acetylcholine receptor; both of
these receptors are neuroprotective when activated
physiologically [16,17] and are closely linked to synaptic
plasticity and cognitive processes [18], partly via their anti-
inflammatory properties [19] and ability to clear glutamate
spillover in the brain [2,17].
Conversely, the microglial processing of KYN results in
the formation of quinolinic acid (QA), a byproduct that
exerts powerful excitotoxic effects and promotes neuronal
apoptosis [3,19,20] (Fig. 1). Evidence suggests that during
depressive episodes, proinflammatory components of the
KYN system in the brain are either directly or indirectly
activated, altering the neuroprotective/neurotoxic balance of
the KYN pathway and leading to the overproduction of
neurotoxic microglial byproducts (such as QA) that
potentiate NMDA activation [3,5,21–23]. This increased
activation of inflammatory circuitry within the brain, in
turn, contributes to the pathological activation of the glu-
tamatergic system [5,24], which leads to decreased neu-
rotrophic support, synaptic dysregulation, oxidative stress,
excitotoxicity, and loss of glial tissue in multiple sites in the
CNS [17,25].
The KYN pathway is best known for regulating the
interaction between the immune and stress pathways (see
Fig. 1)[26]. Psychosocial stress stimulates inflammatory
Fig. 1 The impact of depression on the kynurenine (KYN) pathway in
brain and periphery. The figure depicts KYN metabolites and their
related effects on neuronal cells (inside boxes) and the enzymes that
metabolize them (arrows). The impact of inflammation or stress-related
conditions on key rate-limiting enzymes such as indoleamine 2,3-
dioxygenase (IDO) shifts KYN metabolism towards microglial
byproducts such as 3-hydroxykynurenine (3-HK) and quinolinic acid
(QA). This metabolic change is associated with elevated oxidative
stress (3-HK and QA) and glutamate excitotoxicity that could
contribute to depressive symptoms (right panel). Conversely, during
homeostasis, substantial amounts of KYN are converted to kynurenic
acid (KynA), a process mediated by kynurenine aminotransferase II
(KAT II) in astrocytes (left panel). At physiologic levels, KynA is an
N-methyl-D-aspartate receptor (NMDAR) antagonist and contributes
to the clearance of glutamate spillover in the brain. TNF-αtumor
necrosis factor alpha, IFN-gamma interferon gamma, IL-6 interleukin-
6, α7nAChR alpha-7-nicotinic acetylcholine receptor
B. Kadriu et al.
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mediators in the periphery and brain via multiple mechan-
isms; for example, peripheral immune cells, including T-
cells, can gain access to the brain [27], resulting in increased
IDO production. This, in turn, triggers the activation of
resident microglial cells that secrete the proinflammatory
cytokine tumor necrosis factor alpha (TNF-α), with neuro-
nal injury as the net result (see Fig. 1). Postmortem human
data support this result, with studies showing that proin-
flammatory cytokines (such as interleukin-6 (IL-6) and
TNF-α) and other byproducts of microglial activation
(mainly QA) were significantly upregulated in the frontal
cortex of individuals with BD [28]. Positive correlations
have also been found between QA and specific proin-
flammatory immunologic variables, such as IL-6, in the
CSF of individuals with previous suicide attempts [29]. In
contrast, KynA levels in the CSF were found to be inversely
correlated with the severity of depressive symptoms [30], as
well as significantly downregulated in suicidal individuals
[29]. Another study found that the QA/KynA ratio was
significantly elevated in the CSF of suicide attempters
compared with healthy participants [31], suggesting that net
positive QA levels in the brain might result in detrimental
structural and functional deficits, likely due to enhanced
activation of microglial cells and a corresponding upsurge
in NMDAR agonism [32,33].
Previous studies found that a single infusion of
subanesthetic-dose ketamine leads to rapid (within hours),
robust, and sustained antidepressant effects in individuals
with BD [34,35]. Preclinical evidence also suggests that,
within this time frame, ketamine reverses deficits in neu-
roplasticity and neurogenesis [36,37]. Ketamine has also
been found to reduce levels of key proinflammatory med-
iators [38] as well as bone biomarkers and adipokines
[39,40] within hours to days following acute treatment. In
addition, ketamine abolished lipopolysaccharide (LPS)-
induced depressive-like behaviors in preclinical mouse
models [41]. Previous work from our laboratory also found
that ketamine’s antidepressant effects may depend on its
ability to affect KYN pathway metabolites [42].
This study explores the complex interactions between
ketamine and relevant behavioral and biological immune/
inflammatory markers that affect the KYN pathway in
depression. The study had four main goals: (1) to explore
the impact of a single dose of ketamine on specific proin-
flammatory KYN pathway metabolites in participants with
treatment-resistant BD; (2) to assess whether baseline
values of specific KYN pathway analytes predicted change
in depressive symptom ratings post-ketamine; (3) to
investigate whether baseline levels of inflammatory markers
predicted change in KYN pathway analytes post-ketamine
infusion; and (4) to determine whether inflammatory mar-
kers were longitudinally associated with KYN pathway
analytes post-ketamine infusion.
Materials and methods
Study design and participants
The current data were drawn from the ketamine condition of
a randomized, placebo (saline)-controlled, crossover study
designed to assess the antidepressant efficacy of adjunctive
ketamine administered intravenously at 0.5 mg/kg over 40
min in participants with BD; all participants were receiving
adjunctive treatment with a mood stabilizer (either lithium
or valproic acid). Details regarding study design have been
previously published [34,35]. Clinical and demographic
data are presented in Table 1, and additional information
about the participant sample can be found in the Supple-
mentary Materials.
Psychiatric rating scales included the Beck Depression
Inventory [43], the Hamilton Depression Rating Scale [44],
the Montgomery–Asberg Depression Rating Scale [45], and
the Snaith–Hamilton Pleasure Scale [46]. For the purposes
of this analysis, empirically derived unidimensional scores
comprising items from all four scales were used [47]. The
three largest subscales—Depressed Mood,Negative Cog-
nition, and Anhedonia—were selected for use, though
results for all subscales are available upon request.
Table 1 Participant demographics
N(%) Mean ± SD
Age 39 (100) 45.92 ± 10.52
Sex
Male 16 (41)
Female 23 (59)
Race
Caucasian 32 (82)
African-American 4 (10)
Other 2 (5)
Not reported 1 (3)
BMI 29.84 ± 5.83
Age of illness onset 17.51 ± 6.88
MADRS Total 33.00 ± 4.39
Substance use disorder 18 (46%)
Alcohol dependence 14 (36%)
Generalized anxiety disorder 6 (15%)
Mood stabilizer
Lithium 26 (67)
Valproic acid 13 (33)
BMI data were missing for one participant; age of onset was missing
for two participants; substance/alcohol abuse data were missing for
one participant; and comorbid psychiatric diagnosis data were missing
for five participants
BMI body mass index, MADRS Montgomery–Asberg Depression
Rating Scale
The kynurenine pathway and bipolar disorder: intersection of the monoaminergic and glutamatergic. . .
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ELISA and multiplex immunoassay
Plasma samples were collected 60 min prior to ketamine
infusion (baseline) and at 230 min, day 1, and day 3 post-
ketamine infusion. Levels of human KYN, KynA, QA, and
IDO were measured using specific ELISA kits. Circulating
levels of several inflammatory cytokines (TNF-α, soluble
tumor necrosis factor receptor 1 (sTNFR1), interferon
gamma (IFN-γ), IL-2, IL-5, IL-6, IL-8, and IL-10) were
measured in plasma using a high-sensitivity multiplex
Luminex immunoassay. For additional details, see the Sup-
plementary Materials.
Statistical analysis
General linear models with restricted maximum likelihood
estimation and robust sandwich variance estimators were
implemented using PROC MIXED in SAS/STAT Version
9.3. The syntax for all models is provided in the Supple-
mentary Materials. A repeated effect of time was used to
model the covariance of the residuals with an unstructured
matrix. Mood stabilizer (lithium or valproic acid), age, and
body mass index (BMI) were entered as covariates in all
analyses. The first research question—which sought to
assess changes to the KYN pathway in response to ketamine
—was investigated via prespecified contrasts between
baseline and follow-up points (230 min, day 1, day 3). The
second research question—whether baseline KYN pathway
values predicted change in depressive symptom ratings post-
ketamine—was assessed by estimating the simple slopes for
KYN pathway member-by-time interactions. The third
research question—whether baseline levels of inflammatory
markers predicted KYN pathway changes post-ketamine—
was similarly assessed by estimating the simple slope for
each baseline-to-follow-up contrast (i.e., simple slopes for
the inflammatory marker-by-time interactions in predicting
KYN pathway changes post-ketamine). Finally, the fourth
research question—whether inflammatory markers were
longitudinally associated with KYN pathway analytes post-
ketamine infusion—was evaluated by determining whether
the inflammatory markers changed over time (a mixed
model predicting inflammatory marker from time and cov-
ariates); if so, whether that change correlated with changes
in the KYN pathway was then assessed (Spearman corre-
lations). Prior to the analyses, plasma data (for the KYN
pathway and for inflammatory cytokines) were natural-log
transformed after adding 1 to all values. Ratios (e.g., KYN/
KynA) are the ratios of the transformed variables.
It should be noted that with regard to the third research
question, high intercorrelations were observed among the
pro- and anti-inflammatory circulating markers (i.e., TNF-α,
sTNFR1, IFN-γ, IL-2, IL-5, IL-6, IL-8, and IL-10), and a
principal components analysis was therefore implemented.
Two components with eigenvalues greater than 1.0
explained 55% of the variance in the inflammatory markers
(see Supplementary Table S1); the first component included
mainly proinflammatory markers and represented TNF-α,
sTNFR1, IFN-γ, IL-5, IL-6, and IL-8. The second compo-
nent, which included mainly anti-inflammatory markers,
represented IL-2, IL-8 (reverse loading), and IL-10. These
pro- and anti-inflammatory component scores were used in
the analysis rather than the values of the individual circu-
lating inflammatory cytokines.
In addition, because this was a secondary analysis of
participants from a clinical trial, an aprioripower analysis
was not performed. Given the exploratory nature of this
study, we also did not adjust alpha or p-values for multi-
plicity. All parameter estimates with standard errors, as well
as exact p-values, are shown in Supplementary Tables S1–S8.
Results
Changes in KYN pathway metabolites post-
ketamine infusion
After controlling for type of mood stabilizer, age, and BMI,
post-ketamine levels of IDO were significantly lower than
baseline at all time points (Table 2, Fig. 2). Both KYN and
KynA levels were significantly higher at days 1 and 3, as
was their ratio (KYN/KynA). No changes in QA levels were
observed post-ketamine administration, though the ratio of
QA to KYN was significantly lower from baseline to day 1.
No post-ketamine difference was observed for KynA/QA
ratio, a measure of NMDA agonist/antagonist balance.
Model results appear in Table 2and Supplementary
Table S2.
Members of the KYN pathway as predictors of
change in depressive symptoms post-ketamine
infusion
Baseline concentrations of IDO, KYN, QA, and the KynA/
QA ratio were evaluated as predictors of Depressed Mood,
Negative Cognition, and Anhedonia subscale scores. Higher
baseline IDO levels (t(33) =−3.84, p=0.0005) and lower
baseline QA levels (t(33) =2.35, p=0.02) were associated
with less severe baseline Depressed Mood scores, and lower
QA/KYN ratio was associated with less severe baseline
Negative Cognition scores (t(33) =2.58, p=0.01) (see
Supplementary Table S3 for slopes).
Baseline IDO levels were unrelated to antidepressant
response to ketamine on any subscale, and lower baseline
KYN levels were nominally related to improved Anhedonia
scores at day 3 (t(33) =2.09, p=0.04) (Fig. 3b, Supple-
mentary Table S4). Higher baseline QA levels predicted
B. Kadriu et al.
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improvement in Depressed Mood scores at 230 min (t(33)
=−2.34, p=0.03) and at day 3 (t(33) =−3.21, p=0.003)
and improvement in Negative Cognition scores at day 3 (t
(33) =−2.79, p=0.009) (Supplementary Table S4). A
lower baseline ratio of KynA/QA (a measure of NMDA
antagonist/agonist balance) predicted improvement in
Depressed Mood score at 230 min (t(33) =2.53, p=0.02)
and in Anhedonia score at day 3 (t(33) =2.29, p=0.02)
(Supplementary Table S4).
Baseline inflammatory markers as predictors of
change in the KYN pathway post-ketamine infusion
Ten participants who were missing inflammatory marker
concentrations were excluded from this analysis. The base-
line values of the two inflammatory cytokine principal
component scores (the proinflammatory cytokine component
score, representing TNF-α, sTNFR1, IFN-γ, IL-5, IL-6, and
IL-8, and the anti-inflammatory cytokine component score,
representing IL-2, reverse loading IL-8, and IL-10) were
entered as predictors of IDO, KYN, and KynA levels, as
well as KYN/KynA and QA/KYN ratios. Baseline proin-
flammatory component score was not related to baseline
KYN pathway values (Supplementary Table S5). Nominal
trends were observed for higher baseline proinflammatory
cytokine component levels to predict larger increases in
KYN levels and in the KYN/KynA ratio. These were
strongest at the 230-min time point (t(24) =2.46, p=0.02
and t(24) =2.42, p=0.02, respectively) (Fig. 3a,
Supplementary Table S6), when neither KYN levels nor the
KYN/KynA ratio had yet changed significantly from
baseline.
In addition, higher baseline anti-inflammatory cytokine
component scores were associated with higher baseline
KYN levels (t(24) =2.94, p=0.007) and higher baseline
KYN/KynA ratio (t(24) =3.47, p=0.002), but not with
KynA levels or the QA/KynA ratio (Supplementary
Table S5). Baseline anti-inflammatory component values
predicted change in IDO levels at 230 min post-ketamine,
such that higher anti-inflammatory levels were associated
with less of a decrease in IDO levels (t(24) =2.74, p=
0.01) (Fig. 3a, Supplementary Table S6). Higher baseline
anti-inflammatory levels were also associated with less of
an increase in KYN levels (t(24) =−2.85, p=0.009) and
in the KYN/KynA ratio (t(24) =−2.40, p=0.02) at day 1
(Fig. 3a, Supplementary Table S6).
The proinflammatory component did not change over
time (Supplementary Table S7), but the anti-inflammatory
component was increased at day 3 (t(24) =2.87, p=0.008).
Change in the anti-inflammatory component was moderately
and positively correlated with change in KynA levels at day
3(r=0.39, p=0.45) (see Supplementary Table S8).
Discussion
This study is the first to explore the impact of ketamine on
KYN pathway metabolites in individuals with treatment-
Table 2 Results of mixed models predicting post-ketamine change from baseline in the KYN pathway
Dependent variable 230 min Day 1 Day 3
IDO (ln) Change from baseline (95% CI) −0.16 (−0.27 to −0.06) −0.24 (−0.35 to −0.12) −0.2 (−0.31 to −0.1)
Statistical test t(34) =−3.05, p=0.004 t(34) =−4.12, p=0.0002 t(34) =−3.91, p=0.0004
KYN (ln) Change from baseline (95% CI) 0.07 (−0.11–0.26) 0.5 (0.23–0.76) 0.39 (0.08–0.7)
Statistical test t(34) =0.77, p=0.45 t(34) =3.69, p=0.0008 t(34) =2.44, p=0.02
KynA (ln) Change from baseline (95% CI) 0.03 (−0.04–0.1) 0.12 (0.04–0.2) 0.15 (0.06–0.23)
Statistical test t(34) =0.82, p=0.42 t(34) =2.85, p=0.007 t(34) =3.36, p=0.002
QA (ln) Change from baseline (95% CI) 0.01 (−0.01–0.04) 0.01 (−0.01–0.04) 0.03 (−0.02–0.08)
Statistical test t(34) =1.28, p=0.21 t(34) =0.94, p=0.35 t(34) =1.26, p=0.22
KYN/KynA Change from baseline (95% CI) 0.01 (−0.03–0.06) 0.09 (0.03–0.15) 0.07 (−0.01–0.14)
Statistical test t(34) =0.59, p=0.56 t(34) =2.91, p=0.006 t(34) =1.76, p=0.087
QA/KYN Change from baseline (95% CI) 0 (−0.01 to 0.01) −0.02 (−0.03 to −0.01) −0.01 (−0.02 to 0.01)
Statistical test t(34) =0.24, p=0.81 t(34) =−3.31, p=0.002 t(34) =−0.91, p=0.37
KynA/QA Change from baseline (95% CI) −0.09 (−0.32–0.13) 0.03 (−0.18–0.25) −0.12 (−0.42–0.19)
Statistical test t(34) =−0.82, p=0.42 t(34) =0.29, p=0.78 t(34) =−0.75, p=0.46
Results of a mixed model with empirical sandwich variance estimator and repeated effect of time. Type 3 tests are shown in Supplementary
Table S2. Table shows specific contrast between estimated values at baseline and follow-up (illustrated in Fig. 2). Age, body mass index (BMI),
and type of mood stabilizer were included as covariates in all analyses
Bold values indicate statistical significance p< 0.05
IDO indoleamine 2,3-dioxygenase, KYN kynurenine, KynA kynurenic acid, QA quinolinic acid, ln natural logarithm
The kynurenine pathway and bipolar disorder: intersection of the monoaminergic and glutamatergic. . .
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resistant BD. A number of salient findings emerged. First,
ketamine significantly lowered IDO levels at 230 min, day
1, and day 3 post-ketamine infusion. Surprisingly,
participants who had higher baseline levels of anti-
inflammatory cytokines experienced less of an immediate
(230 min post-infusion) decrease in IDO levels. Second, and
Fig. 2 Results of mixed models: post-ketamine change in the kynur-
enine (KYN) pathway. Least square mean estimated scores (with
standard error) are plotted by time point. Significance refers to change
from baseline (−60 min). IDO indoleamine 2,3-dioxygenase, KYN
kynurenine, KynA kynurenic acid, QA quinolinic acid. Results of the
full analysis can be found in Supplementary Table S2
B. Kadriu et al.
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in contrast, plasma levels of KYN and KynA were sig-
nificantly increased on days 1 and 3 relative to baseline.
Third, the relatively neuroprotective index ratio KYN/
KynA was upregulated in response to ketamine at day 1.
Interestingly, increased baseline levels of anti-inflammatory
cytokines were associated with less change at day 1 for
KYN and the KYN/KynA ratio, but not for KynA itself.
Finally, a significantly lower QA/KYN index ratio was
observed, but only at day 1 post-ketamine infusion, which
coincides with ketamine’s peak antidepressant effects [34];
given that this ratio is broadly accepted as an index of high
inflammation and excitotoxicity, any decrease reflects a
desirable outcome.
IDO is an intracellular enzyme mainly produced by
immune cells and the brain and appears to be critical to
some forms of immunologically mediated depression
[11,21,23,29,48]. Preclinical studies also found that IDO
is induced in both brain and periphery after a systemic
inflammatory challenge [14,48,49]. During depressive
episodes, stress and immune activation enhance the con-
version of tryptophan to KYN, mostly via IDO induction. In
addition, numerous studies have shown that proin-
flammatory cytokines such as IFN-γ, IFN-α, IL-6, and TNF-
αrobustly induce IDO production via immune cells [50–
52], which subsequently shifts tryptophan metabolism away
from the liver [53]. Furthermore, IDO levels are also
affected by oxidative stress and LPS injection [5]. During
LPS-induced brain inflammation, most KYN and QA pro-
duction is mediated via IDO induction [54]. In humans,
vulnerability to cytokine-induced depression was found to
be enhanced by a polymorphism in the IDO gene, providing
a possible explanation for the clinical heterogeneity sur-
rounding the occurrence of depressive symptoms following
immune system activation [55]. In this context, genetic
manipulation or pharmacological inhibition of IDO was
found to abolish the LPS-induced depressive phenotype in
mouse models independently of cytokine induction, sug-
gesting that IDO itself is sufficient to trigger depressive-like
behaviors in mice [56]. Studies assessing indirect IDO
activity (measured via the KYN/tryptophan ratio) found that
increased plasma IDO levels mediated the link between
inflammation and depressive symptomatology [57]. The
present data support the evidence that IDO is critical for
shunting KYN towards the microglial pathway, but also
suggest that ketamine’s robust ability to significantly lower
IDO levels at 230 min, day 1, and day 3 may protect against
this eventuality. Interestingly, we found that higher baseline
IDO levels were associated with less severe depressive
symptoms at baseline but were unrelated to degree of
antidepressant response to ketamine.
In addition, our finding that KYN and KynA levels were
significantly upregulated in individuals with BD compared
Fig. 3 Baseline inflammatory cytokine component scores as mod-
erators of change in the kynurenine (KYN) pathway (a), and baseline
KYN levels as moderators of change in depressive symptom ratings
(b). (a) Results of a mixed model with the component scores of
proinflammatory (top) or anti-inflammatory (bottom) cytokines entered
as moderators of change in KYN pathway analytes (Y-axis) at three
time points post-ketamine infusion (X-axis). T-values (all df =24) for
the simple slope of the moderator for change at each time point are
plotted; positive values indicate that higher cytokine component scores
were associated with increases in respective KYN pathway analytes,
and negative values indicate that higher cytokine component scores
were associated with decreases in respective KYN pathway analytes.
(b) Results of a mixed model with baseline KYN pathway member
entered as a moderator of change in depressive symptom ratings
(Y-axis) post-ketamine infusion. T-values (all df =33) for the simple
slope of the moderator for change at each time point are plotted;
positive values indicate that higher baseline KYN pathway con-
centrations were associated with less improvement in depressive
symptoms, and negative values indicate that higher baseline KYN
pathway concentrations were associated with more improvement in
depressive symptoms. In both models, age, body mass index (BMI),
and type of mood stabilizer were included as covariates. Results of the
full analysis can be found in Supplementary Table S5 and Supple-
mentary Table S6. IDO indoleamine 2,3-dioxygenase, KYN kynur-
enine, KynA kynurenic acid, QA quinolinic acid
The kynurenine pathway and bipolar disorder: intersection of the monoaminergic and glutamatergic. . .
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with baseline in response to a single ketamine infusion at
both days 1 and 3 (Fig. 2) broadly supports a number of
recent results linking the KYN pathway and depression. For
instance, a large, recent meta-analysis demonstrated that,
compared with healthy volunteers, individuals with
depression had lower overall plasma levels of KYN and
KynA and higher levels of QA [58]. Other studies found
lower levels of KYN metabolites in depressed individuals
[22] as well as in adolescents with melancholic depression
[59]. The severity of depressive symptoms in suicidal
individuals has also been linked to increased plasma levels
of QA and decreased plasma levels of KynA [20,31].
Another study found lower KYN levels and a higher QA/
KYN ratio in participants with major depressive disorder
(MDD) compared with healthy controls; notably, in that
study, higher baseline KYN levels predicted remission in
response to adjunctive treatment with celecoxib, suggesting
that these metabolites were associated with better anti-
inflammatory outcomes [60].
In this context, the present study found that higher baseline
levels of KynA were associated with greater improvement in
Depressed Mood score at 230 min and day 3 and with
Negative Cognition score at day 3. In contrast, lower baseline
KYN levels were linked to improved Anhedonia score at day
3. Interestingly, higher baseline QA levels were associated
with greater improvement in Depressed Mood score post-
ketamine infusion at 230 min and day 3, and with greater
improvement in Negative Cognition score at day 3.
With regard to QA in particular, selective serotonin
reuptake inhibitor treatment was found to reduce QA levels
in the rodent brain [61]; in contrast, this study found that
ketamine had no direct impact on QA levels in humans,
though—as noted above—it did significantly affect other
KYN byproduct metabolites, including IDO, KYN, and
KynA. Interestingly, previous postmortem studies found
elevated QA levels in the brains of severely depressed or
suicidal individuals [33], suggesting an excess of QA’s
precursor, KYN, which would thus be available for con-
version to QA. There are two potential reasons why, under
pathological conditions, the QA pathway appears to pre-
dominate over the neuroprotective KynA pathway [62].
First, while microglia produce QA, astrocytes produce
KynA; studies have shown that, in response to increased
microglial activity, MDD participants typically have sig-
nificant astrocytic dysfunction in critical areas such as the
subgenual prefrontal cortex [63,64]. Second, QA binds
with tenfold greater affinity to NR2B NMDA glutamate
receptor subunits, which are preferentially localized in the
prefrontal cortex, amygdala, hippocampus, and ventral
striatum [65]. These regions thus bear a greater excitotoxic
burden, which often reflects activation of the KYN pathway
in the brain. KynA has no such preferential localization,
though it should be noted that KynA inhibition can lead to
inflammation and excitotoxicity. Previous studies found that
a higher plasma KynA/QA ratio—a putative neuroprotec-
tive marker—was positively correlated with hippocampal
and amygdalar volumes [66].
KYN readily crosses the blood-brain barrier. Overall,
40% of KYN in the CNS is produced in the brain, and 60%
is supplied by TDO, which is present only in the liver [67].
For this reason, it is almost certain that the increased plasma
levels of KYN and KynA observed in the present study after
ketamine administration derive from the liver. Interestingly,
peripheral KYN possesses pronounced anti-inflammatory
properties; it is known to block T-cell proliferation, induce
T-cell death, and suppress the activity of natural killer cells
and antigen-presenting cells (e.g., dendritic cells, mono-
cytes, and macrophages) [29,68]. Thus, ketamine-induced
increases in hepatic KYN production would be expected to
counter the substantial peripheral proinflammatory state
associated with depression. However, increased hepatic
KYN production would also present a greater KYN load to
the brain. While this might ordinarily increase production of
toxic metabolites, the ketamine-induced suppression of IDO
could protect against this potential eventuality.
Given the chronicity and long-lasting changes underlying
BD, considerable evidence suggests that epigenetic mod-
ifications are involved in the pathophysiology of both
depression [69] and glutamatergic dysregulation [70]. Epi-
genetic mechanisms also help regulate KYN 3-
monooxygenase (KMO), a critical enzyme in the KYN
pathway that influences bioactive KYN pathway metabo-
lites [71]. Recent genetic, epigenetic, and pharmacological
studies are targeting KMO as a way of impacting the
bioactive byproducts of the KYN pathway, including KynA
[72,73]. Interestingly, preclinical studies found that keta-
mine’s rapid-acting antidepressant actions are in part
mediated epigenetically [74,75]. In this context, it is highly
likely that ketamine’s effects on the KYN pathway may be
mediated by epigenetic mechanisms.
One key strength of this study is that our participants
were well-characterized and hospitalized for several weeks
before and after ketamine administration. The study was
also associated with several limitations, including the
absence of a control group. In addition, ten participants
were missing inflammatory cytokine data. Because CSF
measures were lacking, another potential limitation is that
only peripheral measures of KYN pathway mediators were
assessed. Finally, the lack of ethnic diversity in the cohort
may limit the generalizability of the results.
Despite these limitations, this study is the first to
demonstrate that ketamine, in addition to exerting rapid and
sustained antidepressant effects, also impacts key compo-
nents of the KYN pathway. These rate-limiting enzymes and
analytes are highly impacted by inflammation and stress,
underscoring ketamine’s acute anti-inflammatory effects.
B. Kadriu et al.
Content courtesy of Springer Nature, terms of use apply. Rights reserved
Acknowledgements Funding for this work was supported by the
Intramural Research Program at the National Institute of Mental
Health, National Institutes of Health (IRP-NIMH-NIH) (ZIA-
MH002857; NCT00088699; 04-M-0222); by a NARSAD Independent
Investigator to CAZ; by a Brain & Behavior Mood Disorders Research
Award to CAZ; and by the Intramural Research Program at the
National Institute of Aging (RM). The authors thank the 7SE research
unit and staff for their support.
Compliance with ethical standards
Conflict of interest CAZ is listed as a co-inventor on a patent for the
use of ketamine in major depression and suicidal ideation. CAZ and
RM are listed as co-inventors on a patent for the use of (2R,6R)-
hydroxynorketamine, (S)-dehydronorketamine, and other stereo-
isomeric dehydro and hydroxylated metabolites of (R,S)-ketamine
metabolites in the treatment of depression and neuropathic pain; and as
co-inventors on a patent application for the use of (2R,6R)-hydro-
xynorketamine and (2S,6S)-hydroxynorketamine in the treatment of
depression, anxiety, anhedonia, suicidal ideation, and posttraumatic
stress disorders. They have assigned their patent rights to the US
government but will share a percentage of any royalties that may be
received by the government. The remaining authors declare that they
have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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