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Serum Interleukin-6 Is a Predictive Biomarker for Ketamine’s Antidepressant

Effect in Treatment-Resistant Patients With Major Depression

Article  in  Biological Psychiatry · December 2014

DOI: 10.1016/j.biopsych.2014.06.021

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CORRESPONDENCE
Serum Interleukin-6 Is a Predictive Biomarker for
Ketamine’s Antidepressant Effect in Treatment-
Resistant Patients With Major Depression
To the Editor:
This study was approved by the Ethics Committee of the People’s
Liberation of Army (PLA) 102nd Hospital, Changzhou, China. A total
of 16 inpatients who fulfilled the DSM-IV criteria were recruited to
the study. Recruits were antidepressant-free for at least 2 weeks
before study start, ensuring that there were no residual effects of

T
he N-methyl-D-aspartate receptor antagonist ketamine is
the most attractive antidepressant therapy for treatment-
resistant patients with major depressive disorder (MDD) and
bipolar disorder (1,2). A single subanesthetic dose (.5 mg/kg) of
ketamine produces a rapid antidepressant effect in two thirds of
these patients, which can last for over a week (3,4). However,
biomarkers able to differentiate between responding and non-
responding patients have yet to be identified (3,5).
Depression and suicidal ideation in patients with MDD are
associated with increased levels of pro-inflammatory cytokines,
such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α
(6–9). Inhibition of these cytokines improves depressive symp-
toms and increases the response to antidepressant medication
(7–9). An obvious conclusion of these data is that inflammatory
processes are integral to the pathophysiology of MDD; therefore,
these pro-inflammatory cytokines could act as potential biomar-
kers, capable of predicting a treatment response to antidepres-
sants. A recent review proposed two primary mechanisms
underlying ketamine’s antidepressant activity, namely its direct
effect on inflammatory cytokines and involvement of the trypto-
phan (TRY)-kynurenine (KYN) pathway (10). In this study, we
evaluated the relationship between pro-inflammatory cytokines
and antidepressant responses to ketamine in treatment-resistant
patients with MDD. We also examined whether baseline levels of
pro-inflammatory mediators could be used as potential predictors
for ketamine’s antidepressant efficacy.
previous antidepressant treatment on our biomarkers of interest.
Participants were administered an intravenous infusion of .5 mg/kg
ketamine over 40 minutes. Twenty-four matched, healthy volunteers
were enrolled as control subjects and were required to have no
present or past history of any DSM-IV Axis I or Axis II diagnosis.
Depressive symptoms were evaluated at 60 minutes (baseline)
before the ketamine infusion and then at 110 minutes and 230
minutes, continuing at time points 1, 3, and 7 days postinfusion,
using the 17-item Hamilton Depression Rating Scale and Montgom-
ery–Åsberg Depression Rating Scale. Patients exhibiting a 50% or
greater reduction in Montgomery–Åsberg Depression Rating Scale
scores were classified as ketamine responders (n ¼ 12), while
nonresponders (n ¼ 4) were defined as having a less than 50%
improvement. Venous blood samples were collected to determine
the levels of serum IL-1β, IL-6, and TNF-α by radioimmunoassay and
KYN and tryptophan by high-performance liquid chromatography at
the aforementioned time points. The control subjects were not
re-evaluated after their initial baseline visit.
At baseline, serum levels of IL-1β and TNF-α in both responder
and nonresponder groups were significantly higher than those of
the control group (Figure 1). Also at baseline, serum levels of IL-1β
and IL-6 in the responder group were significantly higher than
those of the control and nonresponder groups. Levels of IL-6 did
not differ between control and nonresponder groups. Serum
levels of IL-1β showed a significant decrease at 230 minutes and
1 day postinfusion, as did IL-6 at 230 minutes to 3 days

Figure 1. Serum levels of interleukin (IL)-1β (A), IL-6 (B), tumor necrosis factor (TNF)-α (C), and the ratio (D) of tryptophan (TRY)/kynurenine (KYN) in
responder (n ¼ 12), nonresponder (n ¼ 4), and control (n ¼ 24) groups. The data are shown as the mean ⫾ SEM. ̂p ⬍ .05, ̂ ̂ ̂p ⬍ .001 compared with
healthy control subjects at baseline; #p ⬍ .05, ##p ⬍ .01 compared with nonresponders at baseline (one-way analysis of variance, followed post hoc
Bonferroni test); *p ⬍ .05 and **p ⬍ .01 compared with intragroup baseline levels (repeated analysis of variance, followed post hoc Bonferroni test).

0006-3223/$36.00 BIOL PSYCHIATRY 2014;]:]]]–]]]

& 2014 Society of Biological Psychiatry
e2 BIOL PSYCHIATRY 2014;]:]]]–]]]
postinfusion in the responder group (F ¼ 4.495, df ¼ 2.602, p ¼
.013 for IL-1β; F ¼ 9.450, df ¼ 2.914, p ⬍ .001 for IL-6) but not in
the nonresponder group (all p ⬎ .05). In contrast, serum levels of
TNF-α and the serum KYN/TRY ratio remained the same after
ketamine infusion.
Ketamine has the potential to elicit psychotomimetic and
dissociative side effects and abuse liability, factors which could limit
its use in the clinical setting. Identifying novel biomarkers capable of
predicting the response to ketamine will be invaluable for selecting
suitable patients for this therapy. In this study, we found that baseline
serum levels of IL-6 in the responder group were significantly higher
than those in the nonresponder group. This is the first study to
demonstrate that serum IL-6 is a useful predictor of response to
ketamine’s rapid antidepressant action in treatment-resistant patients
with MDD. In conclusion, serum IL-6 levels at baseline could be a
useful predictive biomarker to select treatment-resistant patients with
MDD and bipolar disorder who would best benefit from ketamine’s
rapid antidepressant action. However, further studies using larger
sample sizes are needed to confirm this hypothesis.
Jian-jun Yanga
Nan Wanga
Chun Yangc
Jin-yun Shia,b
Hai-ying Yub
Kenji Hashimotoc,n
a
Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing
University, Nanjing, China; bDepartment of Psychiatry, PLA 102nd Hospital and
Mental Health Center of Military, Changzhou, China; and cDivision of Clinical
Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
n
Corresponding author E-mail: hashimoto@faculty.chiba-u.jp.
This work was supported by grants from the National Natural Science Foundation
of China (Number 81271216 to J-JY) and by a Grant-in-Aid for Scientific Research on
Innovative Areas of the Ministry of Education, Culture, Sports, Science and Technology,
Japan (Number 24116007 to KH).
www.sobp.org/journal
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Correspondence
Dr. Hashimoto is an inventor on a filed patent application on “The use of
R-ketamine in the treatment of psychiatric diseases” by Chiba University. Dr. Hashimoto
has served as a scientific consultant to Astellas and Taisho, and he also received
research support from Abbvie, Dainippon Sumitomo, Otsuka, and Taisho. The other
authors report no biomedical financial interests or potential conflicts of interest.
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http://dx.doi.org/10.1016/j.biopsych.2014.06.021