Impaired visual, working, and verbal memory in first-episode, drug-naive patients with major depressive disorder in a Chinese population
Impaired visual, working, and verbal memory in first-episode, drug-naive patients with major depressive disorder in a Chinese population
Ce Chen 0 1
Wen-hui Jiang 0 1
Wei Wang 0 1
Xian-cang Ma 0 1
Ye Li 0 1
Jin Wu 1
Kenji Hashimoto 1
Cheng-ge Gao 0 1
0 Department of Psychiatry, First Affiliated Hospital of Medical College of Xi'an Jiaotong University , Xi'an, Shaanxi , China , 2 Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health , Chiba , Japan
1 Editor: Hidenori Yamasue, Hamamatsu University School of Medicine , JAPAN
Cognitive impairment has been observed in patients with major depressive disorder (MDD). However, it remains unclear whether the deficits in specific cognitive domains are present in first-episode, drug-naïve patients or medicated patients. In the present study, using the CogState battery (CSB) Chinese language version, we evaluated the visual, working, and verbal memory in first-episode drug-naive patients and medicated patients with MDD in a Chinese population. We measured the cognitive function in first-episode drug-naïve patients (n = 36), medicated MDD patients (n = 71), and age- and sex-matched healthy control subjects (n = 59) in a Chinese population. The CSB composite scores in both first-episode drugnaive patients and medicated patients were significantly poorer than those in the healthy control subjects. The CSB sub-scores, including visual, working, and verbal memory were also significantly poorer in both patient groups than those in the healthy control subjects. In contrast, processing speed, attention/vigilance, executive function, spatial working memory, and social cognition were no different from healthy controls, whereas the executive function was significantly better in the medicated patients than in the healthy control subjects and first-episode drug-naïve patients. These findings suggest an impairment in the visual, working, and verbal memory in first-episode, drug-naive MDD patients in a Chinese population.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
Major depressive disorder (MDD) is a leading cause of functional disability worldwide [
MDD patients usually have cognitive impairments, and these cognitive impairments may
contribute to functional impairment [2±5]. There is also some evidence of impairment across
most domains of cognitive function, including processing speed [
], attention [
learning and memory [
], and executive function [
]. Interestingly, research has
suggested that the cognitive impairment persists even after the remission of depressive symptoms
[13±15]. A large meta-analysis showed that treatment most commonly affects the domains of
verbal memory, working memory, processing speed, and executive function . In contrast,
a recent randomized longitudinal study demonstrated no relative improvement with acute
treatment (controlled for time or repeated testing), irrespective of the antidepressant treatment
group, even in patients whose depression acutely improved according to clinical measures
]; this finding reinforced the fact that cognitive impairment is an unmet need in MDD
]. Thus, it remains unclear whether deficits in specific cognitive domains are
present in first-episode, drug-naive patients or in medicated patients.
The CogState battery (CSB) is a sensitive, computer-based cognitive assessment instrument
and is suitable for assessing cognitive impairment in patients with schizophrenia [19±23],
], and substance abuse [
]. In addition, the CSB has been widely used in clinical
trials for a number of new drugs [26±30]. A recent study suggested that the CSB may be more
suitable than the Food Drug Administration (FDA)-accepted MATRICS consensus cognitive
battery (MCCB) to measure changes in the absence of repeated baselines [
In the present study, using the Chinese language version of the CSB [
measured cognitive function in first-episode, drug-naive patients; medicated patients with MDD;
and age- and sex-matched healthy control subjects in a Chinese population. Furthermore, we
examined the correlations between cognitive domains and clinical variables in these patients.
Materials and methods
Hundred-seven hospitalized patients with major depression including 36 first-episode
drugnaive and 71 medicated patients were recruited from the First Hospital of Xi'an Jiaotong
University, Xi'an, Shaanxi, China (Table 1). All patients satisfied the diagnostic and statistical
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manual of mental disorders criteria (DSM-IV) for depression according to the structured
clinical interview for DSM-IV [
]. The inclusion criteria for the study were (1) written, informed
consent; (2) >9 years of education; (3) aged 18±50 years; and (4) normal or
corrected-to-normal vision and hearing. The exclusion criteria for the study were (1) current or previous
episodes of a psychiatric disorder, including alcohol or drug dependence; (2) traumatic brain
injury, cerebrovascular disease, epilepsy, spasms, or intellectual disability; (3) inability to
follow the study protocol due to severe aggressive behavior or suicidal tendencies and/or
behavior; (4) treatment with cognitive-enhancing drugs (such as donepezil) within 6 months prior
to study entry; and (5) the presence of cataract or other ophthalmic diseases or hearing
impairment, which would compromise completion of the CSB. All medicated patients were
treated by using oral administration of antidepressant drugs, selective serotonin reuptake
inhibitors (SSRIs: paroxetine, fluoxetine, escitalopram, fluvoxamine) or serotonin
norepinephrine reuptake inhibitors (SNRIs: venlafaxine, duloxetine), and no performed psychotherapy
or behavior therapy. Healthy normal controls were matched by sex, age and years of education
of both MDD patient groups were recruited from the community of Xi'an city, China
(Table 1). Healthy controls without pre-existing any DSM-IV Axis I disorders and affective
disorder or schizophrenia in their first degree family histories were included. The inclusion
and exclusion criteria for the healthy controls were the same as those for the patients. This
study was approved by the Institutional Review Board of the First Hospital of Xi'an Jiaotong
University. All subjects were given a full explanation of the study, which included potential
risks and benefits of study participation. Then we received the written, informed consent from
them. Our study was performed in keeping with the Declaration of Helsinki II.
The Hamilton depression rating scale [
] is the most common application scale for assessing
clinical depression. This scale has 17 items and was tested by two trained clinicians through
conversation and observation. The Hamilton anxiety scale [
] was used to assess anxiety; this
scale includes 14 items and the patient is evaluated by a physician. Montgomery±Åsberg
depression rating scale (MADRS) [
] is a 14-item scale for the assessment of clinical
depression. The social adaptation self-evaluation scale (SASS) is a 21-item, self-reporting scale to
evaluate broad areas of social functioning (such as spare time, work, family, life-coping skills).
The response scores (0 to 3), with higher scores represent better social adjustment [
Chinese version of the SASS [
] was used.
The World Health Organization (WHO)±Quality of Life (QOL) instrument
(WHOQOLBREF) is a 26-item, self-administered questionnaire. This is also a shortened version of the
WHOQOL-100 scale, which measures the four domains of physical health and wellbeing,
psychological health and wellbeing, social relationships, and the environment. A previous study
showed that higher scores represent a better QOL [
]. Therefore, the Chinese version of the
] was used in this study.
The Chinese language version of the CSB contains the following eight tasks: the detection task
(DET, speed of processing), identification task (IDN, attention/vigilance), one card learning
task (OCL, visual learning and memory), two back task (TWOB, working memory),
international shopping list task (ISL, verbal learning and memory), the Groton maze learning task
(GML, problem solving/error monitoring), social emotional cognition task (SEC, social
cognition), and continuous paired association learning task (CPAL, spatial working memory)
]. The CSB includes all seven cognitive domains of the MCCB [19±21, 40]. These tasks
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were presented on a green screen along with standardized instructions that were provided
by trained researchers before the commencement of each task to ensure that the subjects
completely understood and followed the rules. The results were uploaded to a secure account
on the CogState server site (http://www.Cogstate.com), where the data were calculated and
normalized (logarithmic transformation for reaction time, arcsine transformation for
accuracy). The results of each domain on the CSB were calculated as Z-scores, where the healthy
control mean was set to 0 and the standard deviation was set to 1; this followed the
methodology used by Keefe et al . A composite score was calculated by averaging all Z-scores of the
eight primary measures from the CSB.
The subjects were enrolled from January 2014 to December 2017. We collected demographic
data and performed semi-structured interviews to obtain clinical histories. Each subject
performed the CSB in a quiet room. The subjects were allowed to have a short break of
approximately 5 min to prevent fatigue and withdrawal symptoms. All subjects performed the tests in
their entirety, but some subjects could not complete the tests. The clinicians examined the
HAMD, HAMA, and MADRS tests and the Chinese word reading test (CWRT).
SPSS 13.0 was used to describe and analyze the data (S1 Table). Differences between the groups
were examined using multivariate analysis of variance (MANOVA), followed by the post-hoc
Fisher's least significant difference testing. One-way ANOVA (ANOVA) was used to evaluate
the effects of the following independent variables on cognitive performance: age, years of
education, the CWRT, SASS, and QOL. In addition, using only patient data, student's t-test was
used to examine the following variables: HAMD, HAMA, and MADRS. Factor analysis was
determined by adopting the Principal Component extraction methods, with Quartimax
rotation. The correlation matrix of the inter-subsets for the patients (first-episode, drug-naïve
patients and medicated patients) was tested using the Pearson rank correlation test. Statistical
significance was determined as a P-value of <0.05.
Demographic and clinical characteristics of the sample
The demographic and clinical variables of all subjects are presented in Table 1. Demographic
variables, such as age, sex, and education, as well as CWRT scores did not differ between the
groups. The SASS and QOL scores were significantly different between the two groups
(controls vs. first-episode, drug-naive group, controls vs. medicated group). The HAMD, HAMA,
and MADRS scores in the first-episode, drug-naïve group were significantly higher than those
of medicated group (Table 1).
Cognitive impairment in first-episode, drug-naive patients and medicated
Fig 1 shows the cognitive performance of the first-episode, drug-naive patients and medicated
patients compared with that of the healthy controls. The analysis revealed significant effects
(F = 8.369, P < 0.001). Compared with the healthy controls, significant differences in the OCL,
TWOB, GML, ISL, and composite were observed for first-episode, drug-naïve patients (Fig 1).
The scores for the OCL, TWOB, ISL, and composite of the medicated patients were
significantly poorer than those of the healthy controls (Fig 1). Interestingly, the MANOVA analysis
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Fig 1. Magnitude of cognitive impairment in first-episode drug naive MDD patients and medicated MDD patients relative to healthy controls.
DET: Detection task (processing speed), IDN: Identification task (attention/vigilance), OCL: One card learning task (visual memory), TWOB: Two
back task (working memory), GML: Groton maze learning task (executive function), ISL: International shopping list task (verbal memory), SEC: Social
emotional cognition task (social emotional cognition) and CPAL: Continuous paired association learning task (visual spatial working memory). The
data are the mean +/- SD. p < 0.05, p < 0.01, p < 0.001 compared with respective healthy controls. #p < 0.05 compared with the medicated
revealed a significant effect of antidepressant treatment in the improvement of the GML scores
in medicated patients (medicated group vs. controls: P < 0.001; medicated group vs.
first-episode, drug-naive group: P = 0.008) (Fig 1). However, there was no difference of GML scores
between SSRIs and SNRIs in the medicated patients.
Correlation between cognition and clinical variables
The correlation matrix of the inter-subsets between the CSB composite score and clinical
variables for patients is shown in Tables 2±4 and Fig 2. First, we examined the inter-correlations
for all patients (n = 107). We found that the OCL were negatively correlated with the HAMD
(r = −0.339, P = 0.006), HAMA (r = −0.385, P = 0.002), and MADRS scores (r = −0.267,
P = 0.032); the TWOB scores were negatively correlated with the HAMD (r = −0.391,
P = 0.001), HAMA (r = −0.392, P = 0.001), and MADRS scores (r = −0.362, P = 0.003); and the
composite scores were negatively correlated with the HAMD (r = −0.391, P = 0.001), HAMA
(r = −0.434, P = 0.000), and MADRS scores (r = −0.394, P = 0.001) in all patients (Fig 2A). We
also found that the DET scores negatively correlated with QOL (r = −2.297, P = 0.020). The
ISL scores positively correlated (r = 0.306, P = 0.012) with the CWRT scores.
Next, we examined the inter-correlations between different scores in the first-episode,
drug-naive patients (n = 36)(Table 3). We found that the DET scores negatively correlated
with the QOL scores (r = −0.388, P = 0.050) in first-episode, drug-naive patients (n = 33), the
OCL scores negatively correlated with the HAMD (r = −0.415, P = 0.028), and HAMA scores
(r = −0.376, P = 0.049) in first-episode, drug-naive patients (n = 35). In addition, the CPAL
scores positively correlated with the MADRS scores (r = 0.397, P = 0.041) and negatively
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correlated with the CWRT scores (r = −0.425, P = 0.027) in first-episode, drug-naive patients
(n = 34).
We examined the inter-correlations between different scores for medicated patients
(n = 71)(Table 4). The TWOB scores negatively correlated with the HAMD (r = −0.570,
P = 0.000), HAMA (r = −0.545, P = 0.000), and MADRS scores (r = −0.494, P = 0.002) in
medicated patients (n = 71). The composite scores negatively correlated with the HAMD (r =
−0.447, P = 0.006), HAMA (r = −0.529, P = 0.001), and MADRS scores (r = −0.413, P = 0.011)
in medicated patients (n = 71)(Fig 2B). There were no other significant correlations between
the subtests of the CSB and clinical variables.
(n = 29)
(n = 29)
(n = 29)
(n = 29)
(n = 29)
(n = 29)
Factor analysis of the CSB
In the factor analysis of the CSB for all patients, the eigenvalue-greater-than-one rule and scree
plot converged on a three-factor solution that accounted for 63.48% of the total variance. The
factor loadings were presented in Table 5. The OCL and TWOB were loaded on Factor 2, and
the GML, ISL, SEC, and CPAL were loaded on Factor 1. Subtests that needed speed loaded on
Factor 3, including the DET and IDN.
We further examined the factor analysis of the CSB for the first-episode patients and
medicated patients. For the first group, the eigenvalue-greater-than-one rule and scree plot
converged on a three-factor solution that accounted for 70.15% of the total variance. The GML,
ISL, SEC, and CPAL were loaded on Factor 1. The OCL and TWOB were loaded on Factor 2.
Subtests that needed speed loaded on factor 3, including DET and IDN. For the second group,
the eigenvalue-greater-than-one rule and scree plot converged on a three-factor solution that
accounted for 62.14% of the total variance. The GML, ISL, SEC, and CPAL were also loaded
on Factor 1. The OCL and TWOB were loaded on Factor 2. Subtests that needed speed loaded
on Factor 3, including DET and IDN was not loaded on which one of three-factor. The DET
and IDN were also loaded on Factor 3.
The major findings of this study were that cognitive function in first-episode, drug-naive
patients with MDD was significantly poorer than that in healthy control subjects. Across all
cognitive domains on the CBS, the visual, working, and verbal memory were significantly
poorer in first-episode, drug-naive patients than those in healthy control subjects.
Furthermore, working and verbal memory were also significantly poorer in medicated patients than
in healthy control subjects. In contrast, cognitive domains, including processing of speed,
attention/vigilance, executive function (reasoning and problem solving), spatial working
memory, and social cognition, were intact in MDD patients in a Chinese population.
Cognitive performances, reflected in some scores of the CSB subset, were significantly
poorer in the first-episode, drug-naive patients and medicated patients compared with their
respective age-, sex-, and education-matched healthy controls; this indicated that both
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Fig 2. Correlations between the scores of CogState battery (composite and TWOB score) and clinical variables (HAMD, HAMA and MADRS
score) in all MDD patients (A), and in the medicated MDD patients (B). TWOB: Two back task (working memory). HAMD: The Hamilton
depression rating scale. HAMA: The Hamilton anxiety scale. MADRS: Montgomery±Åsberg depression rating scale.
Extraction Method: Principal Component Analysis.
Rotation Method: Quartimax with Kaiser Normalization.
First-episode drug naive group
Factor 1 Factor 2 Factor 3
-0.045 0.058 0.883
0.025 0.151 0.842
-0.057 0.905 0.107
0.172 0.813 0.153
-0.613 0.022 -0.073
0.861 -0.219 -0.033
0.658 0.370 -0.119
-0.790 -0.409 0.025
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groups of patients exhibited cognitive impairment on neuropsychological tasks.
Interestingly, we found that the GML (executive function) subtest in medicated patients was
significantly better than that in first-episode, drug-naïve patients. These findings suggested that an
antidepressant medication may improve executive function in MDD patients as
antidepressants have neurotrophic actions. The reasons underlying the better scores in medicated
patients compared with control subjects are currently unknown. In contrast, a recent
metaanalysis showed that antidepressants had a positive effect on psychomotor speed and delayed
recall, but not executive function [
]. Furthermore, a recent randomized longitudinal study
showed that cognitive impairments (attention, response inhibition, verbal memory, decision
speed, information processing) in depressed patients showed no relative improvement with
acute treatment [
]. A recent follow-up study showed that depressive symptoms at baseline
were predicted by verbal memory, while 12-month changes were predicted by executive
function and language [
], suggesting that cognitive performance might predict depressive
symptoms at baseline and at follow-up. To further examine the effects of medication on
GML, follow-up longitudinal studies on cognitive performance in first-episode, drug-naïve
patients will be necessary.
For the cognitive domains, impairment has been reported for executive function in MDD
]. A recent meta-analysis showed significant executive dysfunction in MDD
patients compared with healthy controls and an improvement in the Stroop performance
during the course of treatment . However, in this study, we did not find any difference in the
GML (executive function) in first-episode, drug-naive MDD patients. Furthermore, we also
found that several domains, including processing of speed, attention/vigilance, spatial working
memory, and social cognition were not impaired in any MDD patient including the
first-episode, drug-naive patients. In contrast, drug-free MDD patients (n = 44) were significantly
impaired in a range of cognitive domains, including attention, executive function, and
visuospatial learning and memory, compared with healthy controls (n = 44) [
]. The reasons
underlying this discrepancy are currently unknown. Interestingly, there are some papers showing
racial and ethnic differences in cognitive function in adults [
]. One possibility is an ethnic
difference (Chinese vs. Caucasian). Another possibility is a difference in the specific battery
used (CSB vs. CANTAB). Nonetheless, further study using a large sample size with different
ethnic populations will be needed.
The composite scores of the CSB subdomains [OCL (visual memory) and TWOB (working
memory)] showed significant negative correlations with the HAMD, HAMA, and MADRS
scores in all patients, suggesting a negative correlation between visual and working memory
and the severity of depression and anxiety symptoms in MDD patients. Therefore, cognitive
impairment is a substantial unmet need in patients with MDD [
] because most MDD
patients complain about cognitive problems even after other symptoms of depression have
]. In addition, the localization of cognitive impairments in MDD patients
remains poorly understood [
]. Further detailed studies using neuroimaging will be needed
to ascertain anatomical localization of cognitive impairments in MDD.
This study has some limitations such as small sample size, age, education, work
information. Further study on the role of blood biomarkers (e.g., brain-derived neurotrophic factor,
inflammatory cytokines, metabolites)[48±52] in the cognitive function in MDD is needed.
This study suggests significant impairment in the visual, working, and verbal memory in
firstepisode, drug-naive MDD patients in a Chinese population. Furthermore, there are negative
correlations between visual memory (or working memory) and the severity of depression and
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anxiety scores in MDD patients. A follow-up longitudinal study of the effects of
antidepressants on cognitive performance in first-episode, drug-naive patients will be necessary.
S1 Table. Raw data.
We would like to thank to all subjects who participated in this study.
Conceptualization: Ce Chen, Wen-hui Jiang, Wei Wang, Xian-cang Ma, Ye Li, Cheng-ge
Data curation: Ce Chen, Wen-hui Jiang, Wei Wang, Xian-cang Ma, Ye Li, Cheng-ge Gao.
Formal analysis: Ce Chen, Wen-hui Jiang, Xian-cang Ma, Jin Wu.
Funding acquisition: Cheng-ge Gao.
Investigation: Ce Chen, Wen-hui Jiang, Wei Wang, Xian-cang Ma, Ye Li.
Methodology: Ce Chen, Wen-hui Jiang, Xian-cang Ma, Ye Li.
Project administration: Xian-cang Ma, Jin Wu, Cheng-ge Gao.
Supervision: Kenji Hashimoto, Cheng-ge Gao.
Writing ± original draft: Ce Chen, Wen-hui Jiang, Jin Wu, Kenji Hashimoto, Cheng-ge Gao.
Writing ± review & editing: Kenji Hashimoto.
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