Journal of Affective Disorders 259 (2019) 1–6

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Journal of Affective Disorders

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

Research paper

Repeated intravenous infusions of ketamine: Neurocognition in patients T

with anxious and nonanxious treatment-resistant depression
Liu Weijiana,b, Zhou Yanlinga,b, Zheng Weia,b, Wang Chengyua,b, Zhan Yannia,b, Lan Xiaofenga,b,
Zhang Bina,b, Li Hanqiua,b, Chen Lijiana,b, Ning Yupinga,b,⁎
a
The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
b
Guangdong Engineering Technology Research Center for Translational Medicine of Metal Disorders, Guangzhou, China

ARTICLE INFO ABSTRACT

Keywords: Background: Recent studies have suggested that neurocognition is changed after repeated infusions of ketamine
Ketamine in patients with treatment-resistant depression (TRD). The objective of this study was to investigate whether
Repeated infusions differences existed in the neurocognitive effect of six ketamine infusions in patients with anxious and nonanxious
Anxious treatment-resistant depression TRD and to determine the association between baseline neurocognition and changes in symptoms after the
Neurocognition
infusions.
Method: Patients with anxious (n = 30) and nonanxious TRD (n = 20) received six intravenous infusions of
ketamine (0.5 mg/kg over 40 min) over 12 days. Speed of processing (SOP), working memory (WM), verbal
learning and memory (VBM), visual learning and memory (VSM) and the severity of depressive and anxious
symptoms were assessed at baseline, one day after the last infusion (day 13) and two weeks after the completion
of the serial infusions (day 26). A linear mixed model was used to determine whether the neurocognitive changes
differed between the two groups. Pearson correlation analysis was used to determine the relationship between
baseline neurocognition and the changes in the symptomatic scores.
Results: Patients with anxious TRD had significant increases in SOP on day 13 and day 26 (both p < 0.001), and
in VBM on day 13 (p = 0.028). However, no significant increase in any neurocognitive domain was found in
patients with nonanxious TRD. Faster SOP at baseline was associated with greater improvement of anxious
symptoms in patients with anxious TRD, and better VSM at baseline was associated with greater improvement of
depressive symptoms in patients with nonanxious TRD.
Limitation: The major limitation of this study is the open-label design.
Conclusion: After six ketamine infusions, neurocognitive improvement was observed in patients with anxious
TRD but not in patients with nonanxious TRD.

1. Introduction
Anxious depression, which is defined as a major depressive disorder
(MDD) with a high degree of anxiety symptoms, is a noteworthy type of
MDD. As its prevalence is high (approximately 45.1−81.0%), an in-
creasing number of researchers have turned their attention to anxious
depression (Lin et al., 2014; Fava et al., 2006; Wu et al., 2013). Com-
pared with patients with nonanxious depression, patients with anxious
depression had more severe symptoms, poorer quality of life, more
severe functional impairments, and poorer treatment outcomes, and
they had a greater likelihood of reporting melancholic features and
family pathology (Fava et al., 2008; Goldberg et al., 2014; Lin et al.,
2014). In addition, Wetherell et al. found that poorer visual learning,
visuospatial, and general knowledge performance were associated with
an increased degree of anxiety (Wetherell et al., 2002). Camacho et al.
found that patients with anxious depression had neurocognitive dys-
function (Camacho et al., 2018).
Recently, the importance of the glutamatergic system in anti-
depressant treatment has drawn much attention (Zanos et al., 2016).
Ketamine, a glutamatergic N-methyl-D-aspartate (NMDA) receptor an-
tagonist, has been proven to have a rapid and robust antidepressant
effect in patients with treatment-resistant depression (TRD)
(DiazGranados et al., 2010; Murrough et al., 2013; Zarate and Niciu,
2015). A previous study with a small sample size (n = 26) indicated

⁎
Corresponding author at: The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou Huiai Hospital, Mingxin Road #36, Liwan District,
Guangzhou, 510370, China.
E-mail address: ningjeny@126.com (Y. Ning).

https://doi.org/10.1016/j.jad.2019.08.012
Received 5 May 2019; Received in revised form 3 August 2019; Accepted 12 August 2019
Available online 12 August 2019
0165-0327/ © 2019 Elsevier B.V. All rights reserved.
W. Liu, et al.
that patients with anxious depression (n = 15) responded better than
those with nonanxious depression (n = 11) to a single infusion of ke-
tamine (0.5 mg/kg over 40 min) (Ionescu et al., 2014). Nevertheless,
another study revealed that no differences were found in response to a
single infusion of ketamine in anxious and nonanxious TRD patients
(Salloum et al., 2019).
However, studies have shown that frequent ketamine users had
neurocognitive impairment (Morgan et al., 2009, 2010). Thus, whether
neurocognitive deficits existed in patients subject to antidepressant
treatment with repeated infusions of ketamine at subanesthetic dosages
was of concern to scientists and clinicians. A study showed that neu-
rocognitive adverse events were not found after a single intravenous
infusion of ketamine, and patients with decreased baseline scores for
processing speed achieved increased improvement in depressive
symptoms (Murrough et al., 2015). Another study found no neurocog-
nitive deficit was found after six infusions of ketamine in TRD patients,
and that increased response likelihood was related to decreased base-
line neurocognition (Shiroma et al., 2014).
Although the studies mentioned above have investigated the re-
lationship between antidepressant treatment via ketamine infusion and
neurocognition, it is not clear whether neurocognitive differences will
be found between patients with anxious and nonanxious TRD after re-
peated infusions of ketamine. Thus, the aim of this study was to in-
vestigate the neurocognitive changes in patients with anxious and
nonanxious TRD, and to clarify whether baseline neurocognition was
associated with an improvement of symptoms. According to previous
studies, we hypothesized that neurocognitive deficits would not be
found in anxious or nonanxious TRD subjects after six infusions of ke-
tamine, and that lower baseline neurocognition would be associated
with greater symptomatic improvement in the current study.
2. Method
This study is part of a large clinical trial focusing on mood disorders
(Zhou et al., 2018). The selection of patients and the procedure used for
the ketamine infusions have been described in a previous study (Zheng
et al., 2018a; Zheng et al., 2018b). Thus, we describe these briefly here.
2.1. Patient selection
This study was conducted at the Affiliated Brain Hospital of
Guangzhou Medical University (Guangzhou Huiai Hospital) from
November 2016 to December 2017 and was registered at http://www.
chictr.org.cn/ (registration no. ChicCTR-OOC-17012239). All patients
participated in our study after signing the informed consent form. In
addition, the Ethics Committee of the Affiliated Brain Hospital of
Guangzhou Medical University approved the trial.
The inclusion criteria were as follows: (1) men and women aged
from 18 to 65 years; (2) patients fulfilling the diagnostic criteria listed
in the Diagnostic and Statistical Manual of Mental Disorders, 5th edi-
tion (DSM-5), for MDD without psychotic symptoms
(Association, 2013); (3) patients with a baseline score ≥17 on the 17-
item Hamilton Depression Rating Scale (HAMD-17) (Hamiltom, 1960);
(4) patients with TRD, which meant that the patients were had been
treated ineffectively with at least two classes of antidepressants at
sufficient dosages for a full course of treatment (Diamond et al., 2014).
Participants were excluded if they met one of the following criteria:
(1) had other serious mental disorders, including schizophrenia, bipolar
disorder, substance use disorder, or organic mental disorders; (2) had
current, serious and unstable somatic diseases; (3) had a history of
neurological diseases; (4) were pregnant or breast feeding; (5) had a
positive urine toxicology screen; (6) were unable to understand and
sign an informed consent form.
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Journal of Affective Disorders 259 (2019) 1–6
2.2. Study process and sample size
Six subanesthetic doses of open-label ketamine (0.5 mg/kg over
40 min) were administered in subjects via intravenous infusions with a
finely controlled infusion pump over 12 days (days 1, 3, 5, 8, 10, and
12). The therapeutic schedule was based on that used for a previous
trial (Monday–Wednesday–Friday) (Shiroma et al., 2014). Moreover,
all subjects received the infusions after fasting overnight. In con-
sideration of safety, blood pressure, pulse frequency, and respiratory
rate were recorded by trained clinicians every 10 min during every
infusion. The patients stayed in the treatment room for at least half an
hour after every infusion.
In our study, 60 TRD patients were included at baseline, among
which 34 had anxious TRD and 26 had nonanxious TRD. In addition,
among those with anxious TRD, 3 patients withdrew their consent
during the infusions, and one patient did not finish the neurocognitive
measurements after the infusions. In the following two weeks, 2 pa-
tients were lost to follow-up. In those with nonanxious TRD, 2 patients
discontinued because of inefficacy, one patient withdrew the consent,
and one patient discontinued because of suicidal behavior during the
infusion process. Two patients did not finish the neurocognitive mea-
surements at the end of the infusions. In the following two weeks, 2
patients were lost to follow-up. Patients who finished six ketamine in-
fusions and the neurocognitive measurements after the infusion process
were included in the statistical analysis (anxious TRD: n = 30; non-
anxious TRD: n = 20).
2.3. Definition of anxious treatment-resistant depression
Anxious TRD was defined by a HAMD-17 anxiety/somatization (A/
S) factor score ≥7 in the presence of TRD at baseline, which was
consistent with that used in previous studies (Fava et al., 2008; Salloum
et al., 2019). This score was useful for discovering the differences be-
tween anxious and nonanxious patients in terms of clinical features,
sociodemographic characteristics, and treatment outcomes (Fava et al.,
2004, 2008, 2006).
2.4. Outcome measures
Patients were assessed at baseline, one day after the last infusion
and two weeks after the completion of the serial infusions (baseline, day
13 and 26) by professional clinicians. The primary outcome measures
for efficacy included (1) the Montgomery–Asberg Depression Rating
Scale (MADRS) for depressive symptoms (Montgomery and
Asberg, 1979); (2) the 14-item Hamilton Anxiety Rating Scale (HAMA)
for anxious symptoms (Hamiltom, 1959); (3) response was defined as
≥50% decrease in the MADRS scores at day 13; (4) four domains of the
MATRICS Consensus Cognitive Battery (MCCB), including speed of
processing (SOP), working memory (WM), verbal learning and memory
(VBM), and visual learning and memory (VSM) for neurocognition
(Green et al., 2004).
2.5. Statistical analyses
Data analyses were conducted using SPSS 23.0 statistical software
(SPSS Inc., Chicago, United States). The means ± standard deviations
(SD) or percentages (%) were used to describe data. The independent
samples t-test, the Mann–Whitney U test, and the chi-square test were
used to compare the differences between patients with anxious and
nonanxious TRD. The linear mixed models were used to detect changes
in depressed symptoms, anxious symptoms, and neurocognition in the
two groups. The effect of demographic characteristics was tested by
adding these variables to the linear mixed models as covariates.
Moreover, a compound symmetry covariance structure with restricted
maximum likelihood estimation was used in the linear mixed model.
Multiple comparisons were corrected with Bonferroni correction. In
W. Liu, et al. Journal of Affective Disorders 259 (2019) 1–6

Table 1
Comparison of demographic and clinical characteristics between anxious and nonanxious TRD patients at baseline.
Total (n = 50) Anxious TRD (n = 30) Nonanxious TRD (n = 20) Statistics
n % n % n % χ2 p

Gender (female) 28 56.00 17 56.67 11 55.00 0.01 0.907

Unmarried 25 50.00 15 50.00 10 50.00 0.00 1.000
Unemployed 27 54.00 15 50.00 12 60.00 0.48 0.487
Family history of mental disorder 16 32.00 13 43.33 3 15.00 4.43 0.035
On antidepressants 44 88.00 26 86.67 18 90.00 0.13 0.722
On antipsychotics 29 58.00 20 66.67 9 45.00 2.31 0.128
On mood stabilizers 12 24.00 9 30.00 4 20.00 1.48 0.224
On benzodiazepines 21 42.00 11 36.67 10 50.00 0.88 0.349
Mean SD Mean SD Mean SD t/Z p
Age (years) 34.00 11.34 33.80 10.63 34.30 12.62 0.15 0.880
Education (years) 12.32 3.44 12.37 3.49 12.25 3.45 −0.12 0.908
BMI (kg/m2) 22.46 3.53 22.94 2.95 21.75 4.24 −1.17 0.249
Duration of illness (months) 84.02 75.20 85.53 76.46 77.25 74.70 −0.66 a 0.507
A/S 7.56 2.67 9.23 2.05 5.05 0.95 −8.54 < 0.001
HAMD-17 23.16 5.00 25.00 5.26 20.40 3.00 −3.54 0.001
MADRS 31.22 6.68 32.57 7.06 29.20 5.63 −1.78 0.081
HAMA 18.96 6.71 22.30 5.78 13.95 4.59 −5.42 < 0.001
SOP 35.38 12.04 34.97 10.87 36.00 13.89 0.29 0.770
WM 36.38 10.14 37.17 10.67 35.20 9.45 −0.67 0.507
VBM 36.47 12.86 37.37 11.61 35.80 14.81 −0.42 0.677
VSM 38.50 10.80 38.17 10.90 39.00 10.91 0.27 0.792
FLUeq (mg/day) 30.60 23.79 33.83 26.41 25.75 18.80 −0.95a 0.340
CPZeq (mg/day) 105.08 119.74 120.69 125.95 81.67 108.64 −1.31a 0.190

Values are marked in bold if p < 0.05.

Abbreviations: A/S: anxiety/somatization factor; BMI: body mass index; HAMA: the Hamilton Anxiety Scale; HAMD-17: the 17-item Hamilton Depression Rating
Scale; MADRS: the Montgomery–Asberg Depression Rating Scale; TRD: treatment-resistant depression; FLUeq: fluoxetine equivalent milligrams (total doses of
antidepressants); CPZeq: chlorpromazine equivalent milligrams (total doses of antipsychotics); SOP: speed of processing; WM: working memory; VBM: verbal
learning and memory; VSM: visual learning and memory.
a
Mann–Whitney U test.

Table 2
Changes of neurocognition and symptomatic scores in patients with anxious and nonanxious TRD.
Baseline Day 13 Day 26 Baseline vs. Day 13 Baseline vs. Day 26
Mean SD Mean SD Mean SD p Cohen's d p Cohen's d

Anxious group SOP 34.97 10.87 44.40 8.86 46.81 13.39 <0.001 0.950 <0.001 0.970
WM 37.17 10.67 39.17 14.06 37.67 12.18 0.928 0.160 1.000 0.040
VBM 37.37 11.61 43.17 10.58 34.76 13.67 0.028 0.520 0.902 −0.210
VSM 38.17 10.90 38.33 8.68 39.67 13.55 1.000 0.020 1.000 0.120
MADRS 32.57 7.07 15.27 10.57 14.19 13.14 <0.001 −1.924 <0.001 −1.742
HAMA 22.30 5.78 10.07 6.65 10.26 8.28 <0.001 −1.963 <0.001 −1.696
Nonanxious group SOP 36.00 13.89 38.45 18.02 38.83 15.00 0.855 0.150 0.190 0.200
WM 35.20 9.45 39.85 12.33 37.17 13.33 0.167 0.420 1.000 0.170
VBM 35.80 14.81 41.45 14.13 37.83 13.50 0.112 0.390 1.000 0.140
VSM 39.00 10.91 35.40 10.63 40.25 12.64 0.325 −0.330 1.000 0.110
MADRS 29.20 5.63 15.20 10.57 15.94 13.61 <0.001 −1.653 <0.001 −1.273
HAMA 13.95 4.59 10.15 8.12 9.61 10.31 0.074 −0.576 0.045 −0.544

Data was controlled for age, gender, and family history of mental disorder.
Bonferroni correction was used in multiple comparison.
Values are marked in bold if p < 0.05.
Abbreviations: BMI: body mass index; HAMA: the Hamilton Anxiety Scale; MADRS: the Montgomery–Asberg Depression Rating Scale; TRD: treatment-resistant
depression; SOP: speed of processing; WM: working memory; VBM: verbal learning and memory; VSM: visual learning and memory.

addition, Pearson correlation analyses were performed to determine the
relationship between baseline neurocognition and change of sympto-
matic scores in the anxious and nonanxious groups. Significant p values
were set at 0.05 (two-tailed).
differences in the MADRS scores and the neurocognitive scores between
the two groups were not statistically significant.
3.2. Efficacy of ketamine infusions

3. Results
3.1. Demographic and clinical features
The demographic and clinical characteristics are shown in Table 1.
Patients with anxious TRD were more likely to show a family history of
mental disorder and had higher A/S, HAMD-17, and HAMA scores than
patients in the nonanxious TRD group (all p < 0.05). However, the
After controlling for age, gender, and family history of mental dis-
order, the MADRS scores decreased significantly in patients with both
anxious and nonanxious TRD on days 13 and 26 compared to the
baseline (all p < 0.001). In the anxious group, patients had significantly
decreased HAMA scores on days 13 and 26 (both p < 0.001). However,
in the nonanxious group, the HAMA scores did not decrease sig-
nificantly on day 13 (p = 0.074) but did decrease significantly on day
26 (p = 0.045). There was no difference in the response rates on day 13

3
W. Liu, et al.
between the two groups (anxious group vs nonanxious group: 56.67%
vs. 45.00%, χ2 = 0.65, p = 0.419).
3.3. Differences in changes in neurocognition
In the present study, compared with the baseline, patients with
anxious depression had a significant improvement in SOP on days 13
and 26 (both p < 0.001), and large differences were found at these two
time points (d ≥ 0.95). Moreover, there was a significant improvement
in VBM on day 13 (p = 0.028) along with a large difference (d = 0.52),
but there was no significant improvement on day 26 (p = 0.902).
However, patients with nonanxious TRD showed no significant im-
provement in any neurocognitive domain at any time point (Table 2).
Further Pearson correlation analyses showed that no significant
associations were found between changes in neurocognitive function on
day 13 and changes in symptoms on day 13 (SOP and the MADRS
scores: r = −0.10, p = 0.602; SOP and the HAMA scores: r = −0.17,
p = 0.376; VBM and the MADRS scores: r = −0.15, p = 0.440; VBM
and the HAMA scores: r = −0.23, p = 0.227).
3.4. Association between baseline neurocognition and change in
symptomatic scores
In the anxious group, the baseline SOP was significantly positively
associated with the changes in HAMA scores on day 13 (r = 0.36,
p = 0.045). In the nonanxious group, the baseline VSM was sig-
nificantly positively associated with the changes in MADRS scores
(r = 0.48, p = 0.025) on day 13 (Fig. 1).
4. Discussion
To the best of our knowledge, this is the first study to explore the
differences in neurocognitive changes in Chinese patients with anxious
and nonanxious TRD treated with six infusions of ketamine. The major
findings of our study were as follows: (1) Patients with anxious TRD
showed significant improvements in SOP and VBM. However, those
with nonanxious TRD showed no significant changes in neurocognition.
(2) Faster baseline SOP was associated with greater improvement in
anxious symptoms in patients with anxious TRD, and better baseline
VSM was associated with greater improvements in depressive symp-
toms in patients with nonanxious TRD.
Previous studies have demonstrated that patients with anxious de-
pression were more likely to be female, to be older, to have severe
Fig. 1. Correlation between baseline neurocognition and changes in symptomatic scores on day 13.
In the anxious group, baseline SOP was significantly associated with the change of HAMA scores on day 13 (r = 0.36, p = 0.045).
In the nonanxious group, baseline VSM was significantly associated with the change of MADRS scores on day 13 (r = 0.48, p = 0.025).
Abbreviations: HAMA: the Hamilton Anxiety Rating Scale; MADRS: the Montgomery–Asberg Depression Rating Scale; SOP: speed of processing; VSM: visual learning
and memory.
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Journal of Affective Disorders 259 (2019) 1–6
depression, or to have a family history of drug abuse and depression
(Clayton et al., 1991; Fava et al., 2008; Lin et al., 2014; Wu et al.,
2013). In our study, patients with anxious TRD were more likely to
show a family history of mental disorder, and to have more severe
depressive and anxious symptoms than those with nonanxious TRD,
which was not completely consistent with the findings of previous
studies. The reason for this result may be due to the different enrolment
criteria.
Depressive symptoms decreased significantly after treatment in
patients with both anxious TRD and nonanxious TRD in the present
study, but the response rates were not different between the groups.
This result was similar to that found in a previous study conducted by
Salloum et al. (2019). In the anxious group, the anxiety scores de-
creased significantly on days 13 and 26, while in the nonanxious group,
they decreased significantly only on day 26. This might be accounted
for by differences in the baseline anxious symptom scores. In patients
with nonanxious TRD, there was less opportunity for the anxiety scores
to decrease. This might have led to the nonsignificant change on day
13. However, on day 26, the anxiety scores decreased significantly in
the nonanxious group, which might account for the efficacy of another
medicines.
Ketamine was shown to be harmful to neurocognition in chronic
users, and decreased performance on pattern recognition memory tasks
and spatial working memory tasks was associated with increasing use of
ketamine (Morgan et al., 2010). Furthermore, deficits in verbal
learning, visual learning, selective attention, and verbal fluency were
also found in chronic ketamine users (Chan et al., 2013). However, a
recent open-label study showed that six infusions of ketamine at sub-
anesthestic dosages did not cause memory impairment in patients with
unipolar or bipolar TRD (Diamond et al., 2014). Moreover, Shiroma
et al. found that patients with TRD achieved significant improvement in
complex working memory, simple working memory, and visual
memory after six infusions of ketamine (Shiroma et al., 2014). Mur-
rough et al. did not find neurocognitive deficits after a single infusion of
ketamine in a double-blind randomized controlled trial that enrolled 62
TRD patients (Murrough et al., 2015). Nevertheless, an open-label study
that enrolled 25 patients with TRD showed that memory recall deficits
were associated with a single subanesthetic ketamine infusion
(Murrough et al., 2014). In the present study, neurocognitive deficits
were not found in patients with anxious TRD or nonanxious TRD. In-
terestingly, significant improvements in SOP and VBM were found in
patients with anxious TRD, but none of the neurocognitive domains
improved significantly in patients with nonanxious TRD. It is
W. Liu, et al.
reasonable to consider that patients with anxious TRD may experience
superior neurocognitive gains form repeated intravenous infusions of
ketamine. Moreover, there were no significant associations between
changes in neurocognitive function and changes in symptoms in our
study. To some extent, it indicates that the improvement in neurocog-
nitive function observed in patients with anxious TRD is a direct effect
of ketamine but is not due to an effect of ketamine on depressive and
anxious symptoms.
In a previous study, Krystal et al. found that brain-derived neuro-
trophic factor (BDNF) synaptogenesis increased after ketamine anti-
depressant treatment (Krystal et al., 2013). Moreover, studies have
demonstrated that the rapid production of BDNF and an increase hip-
pocampus volume were observed after subanesthetic ketamine infusion
(Abdallah et al., 2017; Autry et al., 2011). As BDNF and the hippo-
campus are associated with neurocognition (Köbe et al., 2016;
Vinogradov et al., 2009), we hypothesized that increases in BDNF levels
and hippocampus volume were potential causes of neurocognitive im-
provement after subanesthetic ketamine antidepressant treatment.
However, the mechanism involved in the improvement of neuro-
cognition in patients with anxious TRD but not in patients with non-
anxious TRD after six infusions of ketamine is unclear so far. The evi-
dence has suggested that metabotropic glutamate (mGlu) receptors,
especially the mGlu2 and mGlu3 receptors in the prefrontal cortex
(PFC) and hippocampal nuclei, play a primary role in the anti-
depressant mechanism of ketamine (Autry et al., 2011; Muguruza et al.,
2014), and some animal models have shown that mGlu2/3 receptor
antagonists have antianxiety effects (Fukumoto et al., 2014; Stachowicz
et al., 2011). We hypothesized that the antidepressant and antianxiety
effects of ketamine made it uniquely effective for the treatment of an-
xious TRD. Furthermore, previous studies found increased monocyte
counts, increased innate cytokine production capacity, and subdued
adrenocorticotropic hormone responses in patients with anxious de-
pression (Gaspersz et al., 2017; Ionescu et al., 2013; Meller et al., 1995;
Shim et al., 2016). In addition, cortical thinning and dysfunction in the
anterior cingulate cortex (ACC), the insula, and other brain regions,
which have been proven to be associated with neurocognition
(Dalmases et al., 2015; Hadjikhani et al., 2006; López Zunini et al.,
2013; Spence et al., 2005), have been found to be related to higher
levels of anxiety (Gaspersz et al., 2018; Potvin et al., 2015). In sum-
mary, the differences in the neurocognitive efficacy of ketamine in
anxious and nonanxious TRD patients may be due to differences in
certain biomarkers, as mentioned above.
Several studies have demonstrated that baseline neurocognition is
related to the ketamine response. Slower processing speed and lower
attention at baseline were proven to be related to a higher likelihood of
response (Murrough et al., 2014; Shiroma et al., 2014). Furthermore,
Murrough et al. found that greater improvement of depressive symp-
toms was predicted by slower processing speed at baseline
(Murrough et al., 2015). However, in our study, faster SOP at baseline
was associated with greater improvement of anxious symptoms in pa-
tients with anxious TRD, and better VSM at baseline was associated
with greater improvement of depressive symptoms in patients with
nonanxious TRD. The reason for the inconsistent results has been un-
clear thus far. Previous studies showed that higher serum BDNF and
larger hippocampus volume predicted better antidepressant response
(Colle et al., 2018; Wolkowitz et al., 2011), which are the potential
reasons for the present result.
There were some limitations in the present study. First, this was an
open-label study and lacked a placebo-controlled group. Hence, re-
peated verification is needed in future randomized double-blind stu-
dies. Second, this was a real-world clinical study, and drugs other than
ketamine might affect neurocognition, although the type and dosage of
medication were unchanged during the infusion treatment. It is un-
known whether similar results will be found in drug-free patients.
Therefore, drug-free patient studies are needed to verify the present
conclusions. Third, 10 patients did not finish the whole infusion process
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Journal of Affective Disorders 259 (2019) 1–6
or did not finish the MCCB at the end of the infusions, data from these
patients were not included in the statistical analysis, which created
some degree of bias. Fourth, due to the limited sample size, a larger
sample size study is needed in the future to verify the current findings.
Finally, further exploration of certain meaningful biological indicators,
such as serum BDNF and hippocampus volume, is necessary to in-
vestigate the essential cause of the current findings.
In conclusion, no neurocognitive impairment was found in patients
with anxious or nonanxious TRD in the current study. Neurocognitive
improvement after six infusions of subanesthetic ketamine was found in
patients with anxious TRD, but not in patients with nonanxious TRD.
Furthermore, faster baseline SOP was associated with greater im-
provement of anxious symptoms in TRD patients with anxious features,
and better baseline VSM was associated with greater improvement of
depressive symptoms in TRD patients with nonanxious features. These
conclusions should be verified by future studies.
Role of funding source
This work was supported by the National Key Research and
Development Program of China (grant number 2016YFC0906300), the
National Natural Science Foundation of China (grant number
81801343, 81801345), Science and Technology Department of
Guangdong Province major science and technology (grant number
2016B010108003), Grant of Guangzhou Municipal Science and
Technology Bureau (201904010354), the International Communication
Foundation Science and Technology Commission of Shanghai
Municipality (grant number: 16410722500) and Guangzhou Municipal
Psychiatric Disease Clinical Transformation Laboratory (grant number
201805010009), Key Laboratory for Innovation platform Plan, Science
and Technology Program of Guangzhou, China. The funding source had
no role in the study design, analysis or interpretation of data or in the
preparation of the report or decision to publish.
CRediT authorship contribution statement
Liu Weijian: Data curation, Formal analysis. Zhou Yanling:
Conceptualization, Writing - original draft, Data curation. Zheng Wei:
Data curation. Wang Chengyu: Data curation. Zhan Yanni: Data
curation. Lan Xiaofeng: Data curation. Zhang Bin: Data curation. Li
Hanqiu: Data curation. Chen Lijian: Data curation. Ning Yuping:
Conceptualization, Writing - original draft, Data curation, Supervision.
Declaration of Competing Interest
All authors declare no actual or potential conflicts of interest.
Acknowledgments
We thank for all the participants in this study.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.jad.2019.08.012.
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