ORIGINAL ARTICLE
Effect of Cognitive Behavioral Therapy on Improving the
Cognitive Function in Major and Minor Depression
Hui-Li He, PhD,* Ming Zhang, MD,† Chuan-Zheng Gu, MD,* Ran-Ran Xue, MD,* Hong-Xia Liu, MD,‡
Cai-Feng Gao, MD,‡ and Hui-Feng Duan, MD, PhD§
Abstract: The aim of this study was to investigate the effectiveness of cognitive
behavioral therapy (CBT) on improving the cognitive function in minor depres-
sion (MiD) and major depression (MaD). The study will constitute a placebo-
controlled single-blind parallel-group randomized controlled trial. The selected
participants will be randomly allocated into one of two parallel groups with a
1:1 ratio: the CBT-based group and the general health education group. CBT sig-
nificantly alleviated depressive symptoms of MiD and MaD at 12 weeks
(p < 0.001), and the treatment effect was maintained for at least 12 months
(p < 0.001). Interestingly, CBT significantly promotes more cognitive function
of MiD and partial cognitive function of MaD at 12 weeks in the intervention
group than in the control group (p < 0.01). CBT can alleviate depressive symp-
toms of both minor and MaDs. The effectiveness of CBT is different on improv-
ing the cognitive function in MiD and MaD.
Key Words: minor depression, major depression, cognitive behavioral therapy,
cognitive function
(J Nerv Ment Dis 2019;207: 232–238)
M ajor depressive disorder (MDD) is considered to be among the
most commonly diagnosed and treated of all psychiatric disor-
ders (American Psychiatric Association, 1994). It is well-established
that MDD patients are associated with multidomain cognitive dysfunc-
tions, including attention, executive function, memory function, mental
rotation, and information processing speed (Chen et al., 2013, 2014,
2015; Papakostas, 2014; Snyder, 2013; Taylor Tavares et al., 2007). Re-
cently, a large number of randomized controlled trial (RCT) studies
have been performed to elucidate therapeutic options for MDD. How-
ever, it remains difficult to treat for MDD due to its wide range of fluc-
tuating symptoms (i.e., course and severity almost always differ from
patient to patient). Therefore, according to the heterogeneous nature
of MDD (Stahl, 2013), it is very important to understand the specific
therapeutic options, especially the effectiveness on improving the cog-
nitive functions in minor depression (MiD) and major depression
(MaD), as a continuum of depression.
Converging evidence has consistently reported that cognitive
behavioral therapy (CBT) is considered as efficacious treatment with
antidepressant medication alone and adding CBT to antidepressant
medication can enhance treatment efficacy (Cuijpers et al., 2009,
2014; de Jonghe et al., 2001; Karyotaki et al., 2016; Schwartz and
*The Third Psychiatric Department, †The Fifth Psychiatric Department, and ‡Depart-
ment of Psychiatry Rehabilitation, Jining Psychiatric Hospital, Jining, Shandong
Province; and §Department of Psychiatry, Mental Diseases Prevention and Treat-
ment Institute of Chinese PLA, PLA 91st Central Hospital, Jiaozuo, Henan Prov-
ince, People's Republic of China.
Send reprint requests to Hui-Li He, PhD, and Chuan-Zheng Gu, MD, The Third
Psychiatric Department, Jining Psychiatric Hospital, Jining, Shandong Province,
272051, People's Republic of China. E‐mail: gcz666@126.com;
guchuanzheng120@163.com; and Hui-Feng Duan, MD, PhD, Department of
Psychiatry, Mental Diseases Prevention and Treatment Institute of Chinese PLA,
PLA 91st Central Hospital, Jiaozuo 454000, Henan Province, People's Republic
of China. E‐mail: lixiang1110@163.com.
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0022-3018/19/20704–0232
DOI: 10.1097/NMD.0000000000000954
232 www.jonmd.com The Journal of Nervous and Mental Disease • Volume 207, Number 4, April 2019
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Santarsieri, 2016; Thase et al., 2007). However, the treatment efficacy
of CBT in different subtypes of depression, that is, MiD and MaD, is
still unkown. Recently, numerous studies have demonstrated that MiD
and MaD may exist on a spectrum or continuum of severity (Cuijpers
et al., 2004; Kessler et al., 1997; Rapaport et al., 2002; Wu et al.,
2016), which displayed different behavioral performance and neurophys-
iological deficits (Wu et al., 2016). MiD is considered to be at a signifi-
cant risk for subsequent developing MaD (Cuijpers et al., 2005; Judd
and Akiskal, 2002), and a seven-fold risk for development of MaD
compared with healthy controls (Lyness et al., 2009). Furthermore, some
studies have indicated that antidepressants are broadly thought to be gener-
ally more effective in treating those with severe MDD and placebo effects
are often considered to be greater in those with milder MDD (Schwartz and
Santarsieri, 2016). Therefore, it is reasonable to speculate that MiD and
MaD treated by CBT will present different treatment efficacy, especially
the effectiveness on improving the cognitive functions.
The objective of the present study was thus to perform an RCT to
investigate the effectiveness of CBT on improving the cognitive function in
MiD and MaD. We hypothesized that CBT combination with antidepres-
sant medication in MiD and MaD would show better treatment efficacy
on improving the cognitive functions than antidepressant medication alone.
Furthermore, we hypothesized that these curative effects would remain up
to 12 months after treatment. We further hypothesized that MiD and MaD
would appear to have different treatment efficacy of CBT on improving the
cognitive function during different treatment courses.
METHODS
Trial Design
The proposed study is a placebo-controlled single-blind parallel-
group RCT with a 12-month follow-up (Fig. 1). These studies were ap-
proved by the Human Participants Ethics Committee of Jining Psychiatric
Hospital. The patients and controls provided their written informed consent
after having received instructions concerning the experimental procedure.
Choice of Comparator
To help measure the effects of CBT, a placebo control interven-
tion, that is, general health education (GHE), will be performed for the
control group. To rule out potential placebo effects such as attention
from therapists and knowledge of treatment conditions, the GHE pro-
gram will only provide information related to general health issues such
as healthy food choices and foot care.
Null Hypothesis
The null hypothesis will be that the efficacy of CBT does not dif-
fer significantly from that of GHE in alleviating depressive symptoms,
and improving the cognitive functions in MiD and MaD.
Participants
The subjects were selected among outpatients and inpatients at
Third and Fifth Psychiatric Department, Jining Psychiatric Hospital,
The Journal of Nervous and Mental Disease • Volume 207, Number 4, April 2019
FIGURE 1. Consort diagram of participant flow through the study.
Jining. Fifty-seven MiD and 74 MaD participated (Table 1). Psychiatric
diagnoses were made using a structured clinical interview (SCID) for
the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition
(DSM-4) criteria for MaD, including completion of a DSM-4 Research
Diagnostic Criteria (RDC) checklist for miD (American Psychiatric
Association, 1994). Exclusion criteria for all patients was serious sui-
cide risk, bipolar disorder, comorbid Axis I diagnosis, history of
substantial head injury, seizures, neurological diseases, dementia,
impaired thyroid function, corticoid use or alcohol or substance
abuse or dependence, and history of electroconvulsive therapy treat-
ment (Wu et al., 2016).
Information about depressive episodes in the MiD and MaD
groups was acquired from patients and caregivers. Although all MiD
participants met the DSM-4 RDC criteria, including loss of interest in
activities and/or low mood and at least one additional depressive symp-
tom from the DSM-4 checklist, the duration criterion was increased
from 2 weeks to 1 month to enhance the likelihood that patients were
not merely experiencing a transient dysphoria (Mesholam-Gately
et al., 2012). All MiD participants were asked to report the index epi-
sode as their first episode of a mood disturbance, and their scores on
the Hamilton Depression Rating Scale (HDRS; Zheng et al., 1988) were
required to be within the 7 to 17 range. Most MiD participants were drug
naive, and all were free of psychotropic medications for at least 2 weeks
before study participation. Other MiD participants received the same an-
tidepressant medication (serotoninergic antidepressant).
In addition to meeting the standard DSM-4 diagnostic criteria for
MaD, MaD participants obtained an HDRS score that was 17 or greater.
About MaD participants received the same antidepressant medication (se-
rotoninergic antidepressant) and were clinically stable at the time of testing.
Neuropsychological Assessment
All participants underwent a standardized comprehensive neuro-
psychological assessments performed by these neuropsychologists. Gen-
eral cognitive function was assessed by Mini-Mental State Examination
(MMSE). Moreover, a neuropsychological battery covering episodic
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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
CBT on Cognitive Function
memory, information processing speed, and executive function domains
was used, comprising auditory verbal learning test with 20-minute delay
recall (AVLT-20 min DR), digit symbol substitution test (DSST), and trail
making test-B (TMT-B; Chen et al., 2015, 2016).
Randomization and Masking
According to previous studies (Nakagawa et al., 2017), all eligi-
ble participants were randomly allocated (in a ratio of 1:1) to receive ei-
ther CBT + GHE or GHE alone. Allocation was concealed with the use
of a Web-based random allocation system set up and managed indepen-
dently of the study. Randomization was stratified by study site with the
minimization method to balance the age of the participants at study en-
try (<20 years, ≥20 years). Psychiatrists and clinical psychologists
assessed the assessor-rated outcome measures. Because of the nature
of the interventions, neither the participants nor the treating psychia-
trists or therapists could be masked to randomization status, but the out-
come assessors were masked as much as possible. The assessors were
not involved with the treatment delivery or study coordination and were
prohibited from accessing any information that could confer participant
allocation. Participants were instructed not to disclose their allocated
treatment in the assessment interviews. The success of the assessor
masking was investigated by randomly evaluating one third of the pri-
mary outcome interviews by asking the assessors to guess the treatment
allocations after the assessment interviews, and the percentage of agree-
ment and κ coefficients between the actual and guessed allocations
were calculated. The percentage of agreement and κ coefficients were
59.0% and 0.01 (95% confidence interval [CI], −0.39 to 0.39), respec-
tively, based on the available primary outcome interviews, indicating
that masking was successful (Nakagawa et al., 2017).
Treatment Procedures
CBT Setting
According to previous studies (Zhang et al., 2016), patients were
randomly allocated to a therapist and received a 12-week individual
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He et al. The Journal of Nervous and Mental Disease • Volume 207, Number 4, April 2019

TABLE 1. Participant Characteristics at Baseline

MiD MaD
CBT + GHE GHE CBT + GHE GHE
Characteristic (n = 28) (n = 29) (n = 38) (n = 36)
Age, mean (SD), y 29.8 (7.7) 30.7 (8.2) 30.3 (8.7) 31.1 (10.1)
Sex, male/female 15/13 14/15 19/19 19/17
Education, mean (SD), y 12.1 (1.4) 12.6 (1.6) 13.2 (1.1) 13.3 (1.8)
Unemployed, n (%) 10 (35.7) 8 (27.6) 14 (36.8) 13 (36.1)
Marital status, n (%)
Married 20 (71.4) 23 (79.3) 24 (62.2) 23 (63.9)
Separated, divorced, widowed 1 (3.6) 1 (3.4) 3 (7.9) 2 (5.6)
Single 7 (25.0) 5 (17.3) 11 (28.9) 11 (30.6)
Total no. depressive episodes, mean (SD) 1.3 (0.4) 1.5 (1.1) 3.1 (1.8) 3.2 (1.4)
Previous hospitalization, n (%) 7 (25.0) 8 (27.6) 18 (47.4)a 17 (47.2)a
Previous suicide attempts, n (%) 2 (7.1) 2 (6.9) 3 (7.9) 3 (8.3)
Illness duration, mean (SD), mo 21.0 (11.2) 22.5 (9.5) 36.0 (21.0)a 35.1 (23.1)a
Comorbid DSM-4 Axis I diagnoses, n (%) any anxiety disorder 4 (14.3) 3 (10.3) 6 (15.8) 6 (16.7)
No. antidepressant medications prescribed at baseline, mean (SD) 1.6 (0.7) 1.5 (0.7) 1.6 (0.7) 1.5 (0.7)
0 medication, n (%) 12 (42.9) 13 (44.8) 12 (31.6) 13 (36.1)
1 medication, n (%) 11 (39.3) 12 (41.4) 14 (36.8) 13 (36.1)
≥2 medications, n (%) 5 (17.8) 4 (13.8) 12 (31.6) 10 (27.8)
Clinical measures, mean (SD)
HDRS17 score 12.8 (3.4) 13.8 (4.4) 24.8 (6.4)a 26.1 (7.4)a
MMSE score 26.2 (1.4) 26.5 (2.1) 25.5 (2.4) 25.3 (2.1)
Cognitive measures, mean (SD)
AVLT-20 min DR 6.1 (1.8) 5.9 (1.4) 2.8 (1.1)a 2.9 (1.0)a
SSDT 38.8 (11.8) 38.6 (11.5) 22.7 (12.8)a 22.2 (13.6)a
TMT-B 180.2 (90.2) 181.3 (104.5) 189.2 (112.4) 186.6 (108.2)
a
p < 0.05, MiD group vs. MaD group.

CBT program that consisted of 12 sessions (each session lasting
2 hours). All patients were taking psychoactive medications (typical an-
tidepressant medications) during the treatment period. Both groups re-
ceived normal outpatient follow-up for depression (i.e., biweekly clinic
visits for drug monitoring) during the 12-week treatment period and the
48-week follow-up period provided by two senior psychiatrists. None
of the patients received any form of professional psychotherapy during
the 48-week follow-up period. The patients were taking standard doses
of the antidepressants (typical antidepressant medications) commonly
used at our clinic: paroxetine (20 mg/d), sertraline (50 mg/d),
citalopram (20 mg/d), and venlafaxine (75–150 mg/d). All patients in
both groups stayed on the same antidepressant medication throughout
the initial 12 weeks of treatment and the subsequent 48-week follow-
up; dosages remained unchanged during the initial 12 weeks, but were
altered for some patients during the 48-week follow-up. Two attending
psychiatrists who were blind to the group allocation of participants used
the various measures (described below) to evaluate depressive symp-
toms and psychosocial factors at entry, after 12 weeks of treatment,
and after 48 weeks of follow-up.
The groups were led by two experienced psychotherapists who
based their treatment on the three-part model described in “A Group
Cognitive Behavior Therapy Manual for Depression” written by Tian
Po Oei (Oei, 2012). The details of the CBT sessions are summarized
in Table 2.
GHE Sessions
The control group will attend 16 health talks (two sessions per
week for 45 minutes per session) delivered as an inactive attention
placebo by a research assistant in groups of three to five. The materials
used in the GHE sessions will include audiovisual presentations, dem-
onstrations, video clips, mini-games, oral quizzes, and posters and pam-
phlets on various health topics. The GHE sessions will be designed to
raise awareness of general health issues and increase general health
knowledge among an elderly population. The details of the GHE ses-
sions are summarized in Table 3.
Therapists
CBT was undertaken by four experienced therapists at postgrad-
uate level, who had completed 400 hours of CBT training. They all had
relevant work experience for at least 5 years. Before the study, all ther-
apists underwent one month of training by qualified CBT trainers. The
therapists undertook the treatment through the guidance of the treat-
ment manual of CBT on MiD and MaD, and accepted 1 hour of super-
vision each week from a senior therapist during the study period.
Outcome Measures
Primary Outcome Measure
The Chinese Hamilton Depression Rating Scale 17 (HDRS17),
the Hamilton Anxiety Rating Scale (HAMA), and the Clinical Global
Impressions Scale were used to evaluate the severity of clinical symp-
toms at baseline, at the end of the initial 12 weeks of treatment, at the
end of the 3-month follow-up, at the end of the 6-month follow-up,
and at the end of the 12-month follow-up.

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The Journal of Nervous and Mental Disease • Volume 207, Number 4, April 2019 CBT on Cognitive Function

TABLE 2. Details of the CBT Sessions in MiD and MaD

Sessions 1 to 4 1. The psychotherapist developed group cohesion and introducing CBT.

2. Group members and the psychotherapist agreed upon communal group rules and treatment goals.
3. Patients assisted one another in understanding their own unique cognitive and behavioral characteristics and how
these characteristics were related to their depressive emotions.
Sessions 5 to 10 1. The psychotherapist helped group members examine their moods, encouraged them to listen to one another's problems
and challenges, and helped them identify the causes of their own anxious and depressive emotions.
2. The therapist clarified specific things group members could do and taught them how to detect their own negative
automatic cognitions.
3. Group activities included assigning and practicing homework, doing relaxation exercises, completing a mood log, learning
how to become aware of and record automatic negative cognitions, and reassessing their current perceptions of self-worth.
Sessions 11 and 12 1. Group members learned how to self-regulate anxious and depressive emotions and make new plans for their lives. They
also discussed their feelings about concluding the group.
2. Group members shared their emotions and thoughts relating to self-growth, gains, regrets, worries, concerns, and so forth.

Secondary Outcome Measures
All subjects underwent a standardized clinical interview and com-
prehensive neuropsychological assessments that were performed by neu-
ropsychologists (Drs Zhang, Gu, and Xue). MMSE, AVLT-20 min DR,
DSST, and TMT-B were used to evaluate general cognitive function, ep-
isodic memory, information processing speed, and executive function at
baseline, at the end of the initial 12 weeks of treatment, at the end of
the 3-month follow-up, at the end of the 6-month follow-up, and at the
end of the 12-month follow-up, respectively.
Statistical Analysis
The statistical analyses were conducted with SPSS 22.0 software
(SPSS Inc, Chicago, IL). The analysis of variance (ANOVA), t-tests,
and chi-square test were used to compare the demographic data and
neuropsychological performances between MiD (CBT + GHE and
GHE group) and MaD (CBT + GHE and GHE group).
Thus the main analysis was based on the 28 individuals in the
CBT + GHE group for MiD and the 29 individuals in the GHE group
for MiD, and the 38 individuals in the CBT + GHE group for MaD
and the 36 individuals in the GHE group for MaD who completed the
first 12 weeks of treatment. Continuous variables were assessed using
t-tests and a 2  5 repeated measures ANOVA with group (MiD and
MaD) as one between-subjects factor and time (baseline, 12 weeks of
treatment, 3-month follow-up, 6-month follow-up, and 12-month fol-
low-up) as within-subject factors. Comparisons between the CBT + GHE
group and the GHE-only control group at baseline, at the end of the initial
12 weeks of treatment, at the end of the 3-month follow-up, at the end of
the 6-month follow-up, and at the end of the 12-month follow-up were
adjusted for sex, age, duration of current episode, total score on the
HDRS, total score on the HAMA, and baseline values of the measures

TABLE 3. Weekly Topics of GHE Sessions

Week Topic Content Materials

1 Home safety
2 Choice of healthy foods
3 Diet
4 Brain health
5 Hand care
6 Foot care
7 Flu prevention
8 Handicrafts
Strategies for removing potential home hazards • Audiovisual presentation
to prevent residential accidents, such • Pamphlets
as the proper placement of sharp objects, the • Video clips
safe use of electric appliances, and fire safety.
Information on food labels and allergies will be • Audiovisual presentation
provided to facilitate the choice of healthy foods. • Poster
• Pamphlets
• Mini-games
• Oral quiz
Tips on healthy diet, such as a food pyramid and • Audiovisual presentation
healthy recipes, will be introduced to • Pamphlets
establish a healthy eating style. • Oral quiz
Concepts of the mind and memory will be • Audiovisual presentation
introduced and mini-games relating to brain • Mini-games
health will be played to raise awareness of • Video clips
the importance of maintaining brain health.
The importance of hand and wrist care will be • Audiovisual presentation
emphasized and the appropriate choice • Demonstration
and use of hand-care products introduced.
The importance of foot and ankle care will be • Audiovisual presentation
introduced, followed by information on • Video clips
maintaining foot and ankle care.
Health information, including the symptoms, prevention, • Audiovisual presentation
and treatment of flu, will be • Pamphlets
provided and ways to prevent flu discussed.
The importance of developing hobbies and leisure activities • Audiovisual presentation
will be discussed, followed • Demonstration
by a demonstration of some common handicrafts. • Mini-games

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He et al. The Journal of Nervous and Mental Disease • Volume 207, Number 4, April 2019

FIGURE 2. Effects of treatment on alleviation of depressive symptoms for MiD and MaD over time. B indicates baseline; 12 weeks, the initial 12 weeks of
treatment; 24 weeks, 3-month follow-up; 36 weeks, 6-month follow-up; 60 weeks, 12-month follow-up.

using analysis of covariance. Post hoc comparisons were analyzed by Furthermore, at the end of the 12-month follow-up, HDRS17 score in
Bonferroni test. The statistical significance threshold was set at p < 0.05. GHE group still showed more than 7.

RESULTS General Cognitive Function for MiD and MaD

Demographic and Neuropsychological Characteristics
Demographic and neuropsychological characteristics are pro-
vided in Table 1. No significant differences were found in age, sex, or
years of education between all groups (p > 0.05). No significant differ-
ences were found in HDRS, MMSE, AVLT-20 min DR, SSDT, or
TMT-B scores between CBT + GHE versus GHE for MiD group and
MaD group (p > 0.05). Compared with MiD group, MaD showed the sig-
nificant declines in multidomains of cognitive function to include attention
switching (i.e., TMT-B) and perceptual speed (i.e., SSDT) while MiD only
showed significant declines in HDRS scores (p < 0.05; Table 1).
Depressive Symptoms for MiD and MaD Over Time
HDRS17 scores showed that alleviation of depressive symptoms
at 12 weeks was greater in the CBT group than in the GHE group for
MiD and MaD (−5.5 vs. −1.6 for MiD, −11.5 vs. −6.9 for MaD, re-
spectively), and the between-group mean difference was significant
(difference = −3.9, 95% CI −6.2 to −2.2, p < 0.0001 for MiD; differ-
ence = −5.7, 95% CI −8.7 to −3.1, p < 0.005 for MaD; Fig. 2). The ben-
eficial effects of CBT were maintained over the 12-month follow-up
and were confirmed at 24 weeks (3 months; −1.1 vs. −1.1; difference,
0; 95% CI, −1.3 to 0.6; p > 0.05 for MiD; −6.1 vs. −1.1; difference,
−5.0; 95% CI, −6.3 to −3.6; p < 0.0001 for MaD), at 36 weeks
(6 months; −0.4 vs. −0.7; difference, 0.3; 95% CI, −0.2 to 1.1;
p > 0.05 for MiD; −1.4 vs. −1.7; difference, 0.3; 95% CI, −0.3 to 0.5;
p > 0.05 for MaD), and at 60 weeks (12 months; −1.2 vs. −3.1; differ-
ence, 1.9; 95% CI, 0.2 to 2.2; p < 0.01 for MiD; −2.2 vs. −6.1; differ-
ence, 3.9; 95% CI, 1.7–4.1; p < 0.005 for MaD). Compared with
CBT, GHE in MiD and MaD showed significantly higher HDRS17
score at the end of the initial 12 weeks of treatment, 3-month follow-
up, 6-month follow-up, and 12-month follow-up (p < 0.005).
Over Time
Our study showed that MMSE scores at the end of the initial
12 weeks of treatment and 12-month follow-up were greater in the
CBT and GHE groups than those scores at baseline for MiD and MaD
(Fig. 3). The beneficial effects of CBT were maintained over the
12-month follow-up and were confirmed at 24 weeks (3 months),
at 36 weeks (6 months), and at 60 weeks (12 months). Compared
with CBT, GHE in MaD showed significantly lower MMSE score
at 12-month follow-up (p < 0.005).
Multidomains of Cognitive Function for MiD and MaD
Over Time
As shown in Figure 4, for episodic memory, AVLT-20 min DR
scores in CBT group for MiD and MaD were significantly higher at
the end of the initial 12 weeks of treatment, 3-month follow-up,
6-month follow-up, and 12-month follow-up than those scores at baseline
(p < 0.005). Furthermore, compared with CBT group, AVLT-20 min DR
scores in GHE group for MiD and MaD were significantly lower at 3-month
follow-up, 6-month follow-up, and 12-month follow-up (p < 0.005).
As shown in Figure 4, for information processing speed, DSST
scores in CBT group for MiD and MaD were significantly higher at
the end of the initial 12 weeks of treatment, 3-month follow-up, 6-month
follow-up, and 12-month follow-up than those scores at baseline (except
at the end of the initial 12 weeks of treatment for MiD, p < 0.005). Fur-
thermore, compared with CBT group, DSST scores in GHE group
for MiD were significantly lower at 3-month follow-up, 6-month fol-
low-up, and 12-month follow-up, and for MaD at the end of the initial
12 weeks of treatment, 3-month follow-up, 6-month follow-up, and
12-month follow-up (p < 0.005).
As shown in Figure 4, for executive function, TMT-B scores in
CBT group for MiD and MaD were significantly higher at the end of

FIGURE 3. Effects of treatment on MMSE scores for MiD and MaD over time. B indicates baseline; 12 weeks, the initial 12 weeks of treatment; 24 weeks,
3-month follow-up; 36 weeks, 6-month follow-up; 60 weeks, 12-month follow-up.

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The Journal of Nervous and Mental Disease • Volume 207, Number 4, April 2019 CBT on Cognitive Function

FIGURE 4. Effects of treatment on cognitive function for MiD and MaD over time. B indicates baseline; 12 weeks, the initial 12 weeks of treatment;
24 weeks, 3-month follow-up; 36 weeks, 6-month follow-up; 60 weeks, 12-month follow-up.

the initial 12 weeks of treatment, 3-month follow-up, 6-month follow-up,
and 12-month follow-up than those scores at baseline (except at the end
of the initial 12 weeks of treatment for MaD, p < 0.005). Furthermore,
compared with CBT group, TMT-B scores in GHE group for MiD and
MaD were significantly higher at 12-month follow-up (p < 0.005).
DISCUSSION
To our best knowledge, the present study is the first to explore
the effectiveness of CBT on improving the cognitive function in MiD
and MaD, as a continuum of depression. The most compelling findings
of the study should be as follows. First, both MiD and MaD treated by
CBT exhibited alleviation of depressive symptoms at 12 weeks, as evi-
denced by the decrease of HDRS17 scores. Second, both MiD and
MaD also presented more treatment efficacy on improving the cogni-
tive functions in adding CBT to antidepressant medication than treat-
ment with antidepressant medication alone. Finally, MiD and MaD
appeared to have different treatment efficacy of CBT on improving
the cognitive function during different treatment courses. Therefore,
our results suggest that MiD and MaD may seem to own different
neurocognitive mechanisms and depressive syndromes may exist on a
spectrum of severity.
This study showed that CBT could relieve depressive symptoms
in both MiD and MaD, and the mean difference between CBT and GHE
groups was significant. Our findings are in line with previous studies,
which suggests that adding CBT to antidepressant medication can be
more effective than treatment with antidepressant medication alone
(Cuijpers et al., 2009, 2014; de Jonghe et al., 2001; Karyotaki et al.,
2016; Schwartz and Santarsieri, 2016; Thase et al., 2007). Particularly,
we found clear evidence that the superior effects of combined treatment
remained significant at 1-year follow-up. Furthermore, a trend indi-
cated possible superior effects in MiD patients. However, the relation-
ships between the effects CBT and antidepressant medication were
not established well. We speculate that the relationships may be as fol-
lows: complementation, independent independence, or interaction (de
Jonghe et al., 2004; Karyotaki et al., 2016). Our finding suggests that
the relationships may be largely independent from each other and addi-
tive, not interfering with each other, and both contribute about equally
to the effects of combined treatment.
Another principal novel finding is that both MiD and MaD also
present more treatment efficacy on improving the cognitive functions
by adding CBT to antidepressant medication than treatment with antide-
pressant medication alone. These findings showed close correspondence,
with a similar trajectory to the recovery of clinical symptoms. Indeed,
cognitive impairments and depressive symptoms have consistently been
considered as core characteristics of symptoms in MDD. Convincing ev-
idence sheds light on that cognitive impairments and depressive symp-
toms may be in a coexistence relationship.
Interestingly, MiD and MaD appeared to have different treatment
efficacy of CBT on improving the cognitive function during different
treatment courses. This suggests that MiD and MaD may exist different
neurocognitive mechanisms and depressive syndromes may also exist
on a spectrum of severity. Recently, numerous studies have demon-
strated that MiD and MaD may exist on a spectrum or continuum of se-
verity (Cuijpers et al., 2004; Kessler et al., 1997; Rapaport et al., 2002;
Wu et al., 2016), which displayed different behavioral performance and
neurophysiological deficits (Wu et al., 2016). Patients with MiD is con-
sidered to be at a significant risk for subsequent developing MaD

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

He et al. The Journal of Nervous and Mental Disease • Volume 207, Number 4, April 2019
(Cuijpers et al., 2005; Judd and Akiskal, 2002), and a seven-fold risk
for development of MaD compared with healthy controls (Lyness
et al., 2009). Therefore, it is reasonable to speculate that severity of de-
pression may have prognostic implications, which is of increasing clin-
ical importance in the enrichment of clinical trials of disease-modifying
therapies. From a clinical point of view, our findings suggest that com-
bined treatment should be used in more patients than is currently done
in clinical practice according to different severity of depression.
Limitations and Strengths
Some limitations of this study deserve comment. First, this study
was limited in relatively small sample size, which might influence the
explanation of the results. In addition, MaD and MiD participants
may be receiving different doses antidepressant medication, which
leads to differences between MiD and MaD. Finally, this study selected
GHE as a placebo. GHE and CBT may exist interaction. Future study
should be used to clarify this relationship between GHE and CBT.
CONCLUSIONS
The present study provides novel evidence about the effective-
ness of CBT combination with antidepressant medication on improving
the cognitive function in MiD and MaD. Our findings also suggest that
depressive syndromes exist on a spectrum or continuum of severity
with a potential for establishing novel disease treatments. Therefore,
the spectrum or continuum of severity can be for use in precisely
selecting individuals for a clinical trial.
ACKNOWLEDGMENT
We sincerely thank all psychiatric nurses for their help.
DISCLOSURE
The authors declare no conflict of interest.
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