379

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Journal of Affective Disorders

journal homepage: www.else v i er.com/l o c a t e/jad

Research report

Serum Brain-derived neurotrophic factor levels in

post-stroke depression
Jie Li a, Yan-Dong Zhao b, Jun-Wei Zeng c, Xiao-Yan Chen a, Ruo-Dan Wang a, Sai-Yu Cheng a,n
a

Department of Neurology, Second Afliated Hospital and Xin Qiao Hospital, Third Military Medical University, Chongqing 400037, China
Department of Neurobiology, College of Basic Medical Sciences, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing
400038, China
c
Department of Physiology, Zunyi Medical College, Zunyi, Guizhou province 563000, China
b

a r t i c l e i n f o

ab s t ract

Article history:
Received 1 June 2014
Received in revised form
6 July 2014
Accepted 7 July 2014
Available online 18 July 2014

Background: Depression is a frequent mood disorder that affects around a third of stroke patients and
has been associated with poorer outcome. Our aim was to determine whether there is a relationship
between serum Brain-derived neurotrophic factor (BDNF) levels and post-stroke depression (PSD).
Methods: Two hundred and sixteen ischemic stroke patients admitted to the hospital within the rst
24 h after stroke onset were consecutively recruited and followed up for 3 months. Based on the
symptoms, diagnoses of depression were made in accordance with DSM-IV criteria for post-stroke
depression at day 90. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum levels of
BDNF at admission. Multivariate analyses were performed using logistic regression models.
Results: In our study, 59 patients (27.3%) were diagnosed as having major depression at 3 months.
Patients with major depression showed lower levels of serum BDNF [8.1 (5.69.4) vs. 13.7 (10.4
16.5)ng/ ml, P o 0.0001] at admission. In multivariate analyses, serum BDNF was an independent
predictor of PSD at 3 months [odds ratio (OR): 0.79(0.720.87), P 0.003]. Serum levels of BDNF r
10.2 ng/ml were independently associated with post-stroke (OR, 11.5; 95% CI, 5.623.4, P o 0.0001),
after adjustment for possible variables.
Conclusion: The present study demonstrates a strong relationship between serum BDNF levels at
admission and the development of PSD within 3 months. Further studies are necessary to conrm this
association, which may open the way to the proposal of new therapeutic options.
& 2014 Elsevier B.V. All rights reserved.

Keywords:
Brain-derived neurotrophic factor
Depression
Acute ischemic stroke
Chinese

1. Introduction
Depression
is
particularly prevalent
among
stroke
survivors, affecting approximately a third of individuals (Lindn
et al., 2007). Patients with depression experience worse strokerelated outcomes in the form of greater functional disability and
higher mortality (Ellis et al., 2010), and, nally, with worse
rehabilitation outcome. Early recognition of depression symptoms
and introduction of pharmacological treatment could lead to
better functional outcome (Zavoreo et al., 2009), making the
prevention and management of post-stroke depression an
important area of research.
Neurotrophins are an important class of signaling molecules in
the brain responsible for axon targeting, neuron growth, maturation of synapses during development, and synaptic plasticity
(Autry and Monteggia., 2012). Brain-derived neurotrophic factor
(BDNF) is a neurotrophin that has been linked to the viability of

Corresponding author. Tel.: 86 23 68755613.

E-mail address: cqpek1949@163.com (S.-Y. Cheng).

http://dx.doi.org/10.1016/j.jad.2014.07.011
0165-0327/& 2014 Elsevier B.V. All rights reserved.

neurons in brain circuits (Molendijk et al., 2011). In addition to its

importance in learning, studies have revealed BDNF's involvement
in cognition as well as mood-related behaviors (Autry and
Monteggia., 2012).
One study found that some BDNF gene polymorphisms may be
contributing factors in the pathogenesis of bipolar disorder (Sears
et al., 2011), and several studies reported that blood levels of
BDNF were reduced in patients with schizophrenia (Green et al.,
2011). Recent evidence supports the neurotrophin hypothesis of
depres- sion in its prediction that BDNF is involved in depression
(Taliaz et al., 2010). Several works have demonstrated decreased
levels in depressed patients and a recovery after antidepressants
treatment (Gazal et al., 2012; Zhou et al., 2011).
It was reported that BDNF could cross the bloodbrain barrier,
and that BDNF levels in the brain and serum underwent similar
changes during the maturation and aging processes in rats,
suggesting that serum BDNF levels may reect BDNF levels in the
brain (Hashimoto,
2010). Pikula et al. (2013) found that lower serum BDNF
were associated with increased risk of incident stroke/TIA, and
higher levels of BDNF were also associated with less white matter
hyperintensity

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J. Li et al. / Journal of Affective Disorders 168 (2014) 373

379

and better visual memory. Kim et al. (2008) reported that the
BDNF val66met polymorphism may modify the association
between stroke and depression. Thus, the role of BDNF in patients
with stroke and depression excited our interest. In a large cohort,
Kim et al. (2012) found evidence for serotonin and BDNF
polymorphisms as
suscept- ibility factors and genegene
interactions between these systems for depression at 2 weeks
post-stroke. Interestingly, there is rare study on serum BDNF levels
in Chinese patients with post-stroke depression (PSD). One study
reported that serum concentrations of
BDNF decrease in
Chinese PSD patients and BDNF may play an important role in
the pathogenesis of PSD. However, only
93 patients were
included (Zhou et al. 2011). Therefore, our aim
was to
determine whether there is a relationship between serum BDNF
and PSD in a large cohort.

examination. The presence of anhedonia and depressive mood

was essential for the diagnosis.

2. Methods

2.5. Statistical analyses

2.1. Study population

The results are expressed as percentages for categorical variables and as mean (standard deviation, S.D.) or median (interquartile range, IQR) for the continuous variables depending on
their normal distribution. ShapiroWilk tests were used for
normal distribution test. Proportions were compared using the
Chi-square test. Two-group comparison of not normally distributed data was performed using MannWhitney U test, and a twotailed Student's unpaired t-test was used for normally distributed
continuous variables. Spearman's Rank correlation was used
for bivariate correlations. Associations between the severity
of depression evaluated by HAM-D scale and the serum levels of
BDNF were also assessed by using ordered logistic regression
models with multivariate adjustment for possible confounders,
for instance, age, sex, body mass index, stroke syndrome, stroke
etiology, the NIHSS score, infarct volume, vascular risk factors and
a history of depression. The inuence of serum BDNF levels on PSD
was performed by binary logistic regression analysis, which allows
adjustment for above confounding factors. The results are
expressed as adjusted odds ratios (ORs) with the corresponding
95% condence intervals (CIs). Receiver operating characteristic
(ROC) curves were utilized to evaluate the accuracy of serum
BDNF to predict PSD. Area
under the curve (AUC) was
calculated as measurements of the accuracy of the test. All
statistical analysis was performed with SPSS for Windows, version
19.0 (SPSS Inc., Chicago, IL, USA). Statistical signicance was
dened as P o 0.05.

Two hundred and ninety-ve patients with a rst episode of

acute ischemic stroke admitted to our hospital within the rst 24
h of stroke onset were prospectively included in the study.
Patients with subarachnoid or intracranial hemorrhage, decreased
level of consciousness, severe aphasia or dysarthria, or psychiatric
illness, severe infectious or inammatory diseases, and life
expectancy o 3 month were excluded. One hundred and sixty out
of 295 patients (54.2%) were male, with a mean age of 68.9 7 11.3
years. Seventy- nine patients were not evaluated at 3 month (38
patients died and
12 refused to attend the follow-up, 10 patients had difculty in
being transported to hospital, and 19 patients were lost to followup); the remaining 216 patients were valid for analysis.
Informed consent was obtained after having provided verbal
and written information to participants or nearest relatives when
relevant. Ethics approval was granted by The Ethics Committee for
Medical Research at the Xin Qiao Hospital, Third Military Medical
University.
2.2. Clinical variables
At baseline, age, sex, body mass index and history of risk factors
were obtained. Stroke subtype was classied according to TOAST
(Trial of ORG 10172 in Acute Stroke Treatment) criteria (Adams
et al., 1993). Routine blood and biochemical tests, brain CT/MRI
scan were performed in all patients at admission. MRI with
diffusion- weighted imaging (DWI) was available in some
patients. The infarct volume was calculated by using the formula
0.5 a b c (Sims et al., 2009). Stroke severity was evaluated by
trained neurologists using the NIHSS at admission (Brott et al.,
1989). Functional outcome was evaluated by the modied
Rankin Scale (mRS) at 3 month (Bonita, 1988). A favorable
functional outcome was dened as an mRS score of 0 to 2 points,
while an unfavorable functional outcome was dened as an mRS
score of 3 to 6 points.
2.3. Psychological measurement
Depression assessments were conducted by a neurologist/
psychiatrist who was unaware of the type, size and location of
the index stroke at the time of 3 months after stroke onset.
Previous history of psychiatric disease and depression, educational
level and people living with the patient were recorded at admission. Patients should nish the Hamilton Rating Scale for Depression
(HAM-D) at 3 months follow-up (Hamilton., 1960). Clinical depression was diagnosed according to DSM-III-R criteria using algorithms based on psychiatric interview and neuropsychiatric

2.4. Laboratory tests

Fasting venous blood was collected from all participants in
vacutainer tubes and quickly centrifuged to avoid glycolysis.
Serum samples were kept at
80 1C until assay. Biomarker
concentrations were measured in a central laboratory by investigators blinded to the clinical outcome and neuroimaging ndings.
BDNF serum levels were measured with sandwich-ELISA, using a
commercial kit according to the manufacturer instructions
(DuoSet ELISA Development, R&D Systems, Inc., USA). The lower
detection limit was 1.6 ng/ml and the line range was 1.650
ng/ml. The intra-assay coefcient of variation [CV] and
inter-assay CV were 3.56.8% and 4.4%7.5%, respectively.

3. Results
3.1. Baseline characteristics of study samples
The study cohort consisted of 295 patients at baseline (stroke
admission). By the time of follow-up at 3 months, leaving 216
individuals were included in our study. However, these 216
patients were similar in terms of baseline characteristics [age
(P 0.632), gender
(P 0.803), NIHSS (P 0.654) and
weight (P 0.723)] compared to the overall cohort. In the study
popula- tion, 45.8% were females and the average age was
66.5 7 10.2 years. The median (quartiles) NIHSS score on
admission was 6 (3,
12), and the median time from symptom recognition to admission
to hospital was 4.8 h (IQR, 2.47.5). The number of tissue plasminogen activator-treated patients was 65 (30.1%).
3.2. Main ndings
Ninety-four patients (43.5%) showed depression (major and
minor) at 3 months after admission and in 59 patients (27.3%) this

J. Li et al. / Journal of Affective Disorders 168 (2014) 373379

depression was classied as major. The baseline characteristics of

216
stroke patients presented with depression or not are
described in Table 1. Patients with depression were older and
more fre- quently were female, living with offspring,
widowhood, higher admission stroke severity, higher serum
levels of Hs-CRP and lower BDNF. No association was found
between etiological subtype or infarct volume and the presence
of depression. Similarly, if the minor depression were included,
we got the equal conclusion.
The results indicated that the median serum BDNF level was
12.4 (IQR, 8.715.5) ng/ml. The serum BDNF levels were signicantly decreased in PSD patients at the time of admission as
compared with stroke patients without depression [8.1 (IQR, 5.6
9.4) ng/ml
and
13.7
(IQR,
10.416.5) ng/ml,
respectively;
P o 0.0001], Fig. 1a. Similarly, if the minor depression
were included, we also found that serum BDNF levels were
signicantly decreased in PSD patients [9.3 (IQR, 7.212.5) ng/ml
and 14.5 (IQR,
11.217.4) ng/ml, respectively; P o 0.0001], Fig. 1b. Serum
BDNF
levels decreased with increasing severity of stroke as dened by
the NIHSS score. There was a negative correlation between levels
of BDNF and the NIHSS (r 0.286, P o 0.0001; Fig. 2a.).
Similarly, the lower serum BDNF levels at
admission
corresponded to the higher HAM-D score at 3 months (r
0.361, P o 0.0001; Fig. 2b). BDNF
was
still
signicantly
associated with HAM-D score ( 0.304, P 0.009), after
controlling for age, gender, body mass index, stroke etiology,
the NIHSS score, infarct volume, vascular risk factors and a history
of depression. In addition, there was no correlation between level
of BDNF and sex (P 0.211), and age (P 0.326).
Based on ROC curves, the optimal cutoff value of serum BDNF
levels at admission which predicted the development of depression at 3 months was 10.2 ng/ml, which yielded the highest
sensitivity and specicity [80.3% and 81.8%, respectively; area
under the curve (AUC) 0.854, 95% CI: 0.7910.917; P o
0.0001]. See Fig. 3a. BDNF levels had a higher prognostic
accuracy as compared to Hs-CRP [AUC 0.58 (0.470.65), P
0.013], HCY [AUC
0.69 (0.510.82), P 0.008] and NIHSS score at admission
[AUC

375

0.66 (0.540.77), P 0.007]. In logistic regression analysis, BDNF

levels at admission were independently associated with depression (OR, 0.79; 95% CI, 0.720.87, P 0.003) after adjustment
for age, gender, widowhood, living with offspring, NIHSS on
admis- sion, serum levels of HS-CRP and HCY. See Table 2. Serum
levels of BDNF r 10.2 ng/ml were independently associated
with post- stroke (OR, 11.5; 95% CI, 5.623.4, P o 0.0001),
after adjustment for above variables.
Again, if the minor depression were included, we have produced similar results. Based on ROC curves, the optimal cutoff
value of 11.5 ng/ml, which yielded the highest sensitivity and
specicity [73.2% and 70.7%, respectively; area under the curve
(AUC) 0.780, 95% CI: 0.7170.843; P o 0.0001]. See Fig. 3b.
In logistic regression analysis, BDNF levels at admission were
inde- pendently associated with depression (OR, 0.85; 95% CI,
0.760.93, P 0.006) after adjustment for age,
gender,
widowhood, living with offspring, NIHSS on admission, serum
levels of HS-CRP and HCY. See Table 3. Serum levels of BDNF r
11.5 ng/ml were inde- pendently associated with post-stroke
(OR, 6.93; 95% CI, 3.89
12.31, P o 0.0001), after adjustment for
above
variables.

4. Discussion
Largely
in accord with previous ndings and with the
neurotrophin hypothesis of depression (Autry and Monteggia.,
2012; Molendijk et al., 2011; Hashimoto., 2010; Shimizu et al.,
2003), our data showed that serum BDNF levels were low in PSD
patients compared with stroke patients without depression. Our
results mainly suggested that serum BDNF level was a powerful
biological marker of risk of developing post-stroke major
depression at 3 month after adjustment by vari- ables, and serum
BDNF levelsr 10.2 ng/ml were associated with 11.5- fold increase
in risk of post-stroke depression. Similarly, Yang et al. (2011)
reported that serum BDNF on day 1 after admission may
predict the risk of subsequent PSD, and serum BDNF o 5.86
ng/ml was independently associated with incident PSD at the acute
stage of

Table 1
Basal characteristic of stroke patients with depression and no depression.
Depression patients (n 59)

Age (years), mean(SD)

Female sex, %
2
BMI(kg m , IQR)
Hypertension, %
Diabetes at baseline, %
Days of hospitalization, median (IQR)
Admission median NIHSS score (IQR)
mRS at follow-up, median (IQR)
Infarct volume (ml), mean(SD)
Widowhood (%)
Living with offspring (%)
Family history of depression, %
TOAST classication (%)
a. Large artery
b. Small artery
c. Cardioembolism
d. Other cause
e. Unknown
Laboratory ndings (Median, IQR)
White cell count,
109/L
Glucose level, mmol/L
Hs-CRP, mg/dL
HCY, umol/L
BDNF, ng/ml

72.8 (11.2)
59.3
26.5 (22.828.5)
49.2
32.2
14 (718)
8 (414)
3 (13)
12.5 (1.6)
40.7
32.2
13.6

63.6 (9.1)
40.8
27.2 (23.029.2)
51.6
29.3
13 (618)
5 (28)
2 (13)
12.2 (1.5)
19.7
12.1
5.7

0.024
0.015
0.214
0.762
0.624
0.627
0.011
0.221
0.424
0.002
0.001
0.085
0.126

15.3
16.9
33.9
18.6
15.3

19.1
22.3
38.2
10.8
9.6

7.8 (5.98.6)
5.45 (4.796.52)
0.80 (0.351.88)
18.2 (14,323.4)
8.1 (5.69.4)

7.6 (5.58.4)
5.39 (4.856.55)
0.55 (0.261.26)
14.9 (11.817.8)
13.7 (10.416.5)

0.512
0.242
0.013
0.008
o 0.0001

Results are expressed as percentages or as medians (IQR) and means (SD).

No depression (n 157)

Baseline characteristics

IQR: interquartile range; SD: standard deviation; Hs-CRP: high-sensitivity C-reactive protein; HCY: homocysteine; BMI: body mass index; BDNF: brain-derived neurotrophic
factor; TOAST: Trial of ORG 10172 in Acute Stroke Treatment; mRS: modied Rankin Scale; NIHSS: National Institutes of Health Stroke Scale.
a

MannWhitney U test, student's t test or chi-square test were used.

376

J. Li et al. / Journal of Affective Disorders 168 (2014) 373379

Fig. 1. Serum BDNF levels in stroke patients with depression and no-depression group. MannWhitney U-test. All data are medians and in-terquartile ranges (IQR).
(a) Depression patients were dened as major depression; (b) patients with minor depression were also included.

Fig. 2. Correlation between serum BDNF levels and other predictors. (a) Correlation between serum BDNF levels and the National Institutes of Health Stroke Scale (NIHSS)
score; (b) Correlation between serum BDNF levels and HAM-D score.

stroke (OR 28.992; 95% CI, 8.014104.891; p o 0.001 after

adjust- ment). Thus, it may open the way to the proposal of new
therapeutic options in patients with ischemic stroke. In addition,
our results also indicated a signicant negative correlation between
HAM-D score, the severity of depressive symptoms, and serum
BDNF levels. Several studies showed a negative correlation
between BDNF levels and severity of depressive symptoms
(Shimizu et al., 2003).
The prevalence of PSD varies over time with an apparent peak
36 months after stroke with a range of 934% during this timeframe and subsequently decline reaching about 50% of the initial
rates at one year (Whyte and Mulsant., 2002). In our study, we
found that 27.3% of stroke patients were classied as major
depression at 3 month, while the depression prevalence was
reported to be ranging from 17 to 62.2% among Chinese stroke
patients (Zhang et al., 2010; Tang et al., 2004; Cheng et al., 2014).
In addition, low
circulating BDNF concentrations have been
observed in patients with coronary artery disease, type
2 diabetes mellitus, metabolic syndrome, stroke and physical
inactivity (Autry and Monteggia., 2012; Pikula et al., 2013).
Consistent with those results, in our study, we found low serum
BDNF levels in
stroke patients and depression patients.
Depression had been widely docu- mented to reduce the
expression of BDNF in both animal and clinical studies (Gazal et
al., 2012).
One meta-analysis study demonstrated strong evidence that
BDNF levels were lower in depressed subjects than healthy

control

subjects (P o 6.8 10 8), and that BDNF levels were signicantly

(P 0.003) increased after antidepressant treatment (Sen et al.,
2008). The other meta-analysis similarly showed that BDNF levels
increased signicantly after antidepressant treatment (effect size:
0.62), and that there was a signicant (P 0.02) correlation
between changes in BDNF level and depression score changes
(Brunoni et al., 2008). Several lines of evidence suggest that the
expression of BDNF may be a downstream target of a variety of
antidepressant treatments; BDNF might therefore be an important
target for therapeutic recovery from depression, and it might
also provide protection against stress-induced neuronal damage
(Hashimoto., 2010).
The relationship between BDNF and stroke remains not completely understood. There is experimental evidence that neurons
and glial cells act as endogenous sources of BDNF after ischemic
and other brain injuries (Sandhofer et al., 2009). Dysfunction of
cerebral vascular BDNF signaling, therefore, may contribute to
disruption of the neurovascular unit, hence to an alteration of
tissue responses to vascular injury (Guo et al., 2008). A small
molecule BDNF mimetic (LM22A-4) when administered immediately after an ischemic stroke in adult mice lead to increased
neurogenesis and improved functional motor recovery (Han et al.,
2012). Therefore, BDNF could reduce stroke risk through its
neurotrophic or its vascular effect (Pikula et al., 2013).

J. Li et al. / Journal of Affective Disorders 168 (2014) 373379

377

Fig. 3. Receiver operating characteristic (ROC) curves were utilized to evaluate the accuracy of serum BDNF levels to predict PSD. (a) Depression patients were dened as
major depression; (b) patients with minor depression were also included.

Table 2
Adjusted OR of depression for BDNF levels in stroke patients.
a

Parameter
Age
Females
Widowhood
Living with offspring
NIHSS on admission
Hs-CRP
HCY
BDNF levels at admission
BDNF levels at admission( r 10.2 ng/ml)

OR
1.74
1.22
1.83
1.33
1.11
1.76
1.16
0.79
11.50

95% CI

1.102.79
1.041.55
1.183.09
1.091.78
1.041.18
1.252.89
1.031.29
0.720.87
5.6023.40

0.024
0.015
0.002
0.001
0.001
0.013
0.008
0.003
P o 0.0001

OR: odds ratio; CI: condence interval; NIHSS: National Institutes of Health Stroke
Scale; mRS: modied Rankin Scale; Hs-CRP: high-sensitivity C-reactive protein;
HCY: homocysteine; BDNF: Brain-derived neurotrophic factor.
a

The odds ratio corresponds to a unit increase in the explanatory variable.

Table 3
Adjusted OR of depression (minor depression were included) for BDNF levels in the
stroke patients.
Parameter

OR

Age
Females
Widowhood
Living with offspring
NIHSS on admission
Hs-CRP
HCY
BDNF levels at admission
BDNF levels at admission( r 11.5 ng/ml)

95% CI

1.77
1.22
1.87

1.082.81
1.051.56
1.153.14

0.019
0.016
0.002

1.37
1.13
1.79
1.18
0.85
6.93

1.111.82
1.031.22
1.232.95
1.041.33
0.760.93
3.8912.31

0.001
0.001
0.011
0.007
0.006
P o 0.0001

OR: odds ratio; CI: condence interval; NIHSS: National Institutes of Health Stroke
Scale; mRS: Modied Rankin Scale; Hs-CRP: high-sensitivity C-reactive protein;
HCY: homocysteine; BDNF: Brain-derived neurotrophic factor.
a

The odds ratio corresponds to a unit increase in the explanatory variable.

Many etiologies of PSD have been proposed but it is unlikely

that any single hypothesis can explain what appears to be heterogeneous. It is probable that complex interactions between

hormones, neurotransmitters, and environmental factors are

involved. In our study, one found that decreased BDNF levels may
be important in the pathophysiology of depression. One hypothesis
would be that
reduced BDNF might reect a genetic vulnerability in patients with
depression. Two studies using mice with a genetic deletion of
the
BDNF
gene have demonstrated that BDNF play a critical role
in
neuronal differentiation and survival (Ernfors et al., 1994; Jones
et
al., 1994). Monteggia et al. (2007) showed that conditional
knockout mice also display an increase in depression-like behavior
in the forced-swim and sucrose preference tests, suggesting that
low production of BDNF may precipitate depressive disorder.
Another possible explanation would be that stress-induced BDNF
reductions might cause neuronal damage, which would in turn
lead to acquired biological vulnerability. Stress, which can
precipitate and exacerbate depression, causes neuronal atrophy
and death, especially in the hippocampus (Shimizu et al., 2003)
proposed that stress-induced changes in the hippocampus may
be central to the development of depression in genetically
vulnerable individuals (Rajkowska, 2000). Levels in PSD may reect
the collapse of the stress-adaptation system and its failure to
protect the brain from stress-induced neuronal degeneration.
Third, BDNF has been shown to have antidepressant effects in
reported
that forced
swimming
decreased 2010).
BDNF mRNA
in
animal models
of depression
(Hashimoto.,
It has been
particular
regions
(CA1, CA3, and the dentate gyrus) of the hippocampus,
and a combination of physical activity and antidepressant
that
treatment the level of hippocampal BDNF mRNA to well above
increased
baseline value as well as enhanced swimming time in an animal
model (Russo-Neustadt et al., 2001). BDNF signaling appears to
be sufcient for antidepressant effects, as direct infusion of BDNF
into midbrain areas or the hippocampus induces behavioral
responses that are similar to those produced by antidepressants
(Rantamki et al., 2006).
This study has a number of limitations. The major limitation of
our study was that we were not able to examine the risk factors
for depressive episodes including lack
of social support,
poverty, family violence, and increased life stress. In addition,
the study subjects were few and not randomly selected. The
study was conducted in only one clinic. Therefore, our ndings
may not be generalizable to other Chinese stroke patients.
Further research is

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J. Li et al. / Journal of Affective Disorders 168 (2014) 373379

needed. Third, the serum levels of BDNF were only measured at

the acute stage of stroke in the patients and, hence, this study
yielded no data regarding when and how long biomarkers were
changed in these patients. Forth, depression assessment was
made only once, at the 3-month follow up, whereas the NIHSS
was used only at the acute stage. In addition, patients who had
more severe stroke died before the 3-month follow up were not
included. Some patients who died and had depression might be
excluded. Lastly, the depressive status might be inuenced by the
severity of stroke itself. Schbitz et al. (2007) found that BDNF
may have negative effects on the course and prognosis of
stroke. However, in this study, the stroke severity was not
evaluated at 3 months.
In spite of these limitations, the ndings of this study
remained important and showed that serum BDNF at admission
was sig- nicantly reduced
and
suggested that
these
alterations
might participate in
the
pathophysiology of
depression symptoms in stroke patients. Serum BDNF levels at
admission could be seen as one powerful biological marker of risk
for developing post-stroke major depression at 3 month.
Further studies are
necessary to conrm this association.
Brunoni et al. (2008) found that that BDNF levels increased
signicantly after antidepressant treatment, and suggested the
applicability of BDNF as an efcient and novel anti-depression
tool against depression in patients with ischemic stroke. Future
clinical trials with BDNF should be driven.

Role of funding source

The funding agencies played no role in the design and conduct of the study.

Conict of interest
We wish to conrm that there are no known conicts of interest associated
with this publication and there has been no signicant nancial support for this
work that could have inuenced its outcome.
We conrm that the manuscript has been read and approved by all named
authors and that there are no other persons who satised the criteria for authorship but are not listed. We further conrm that the order of authors listed in the
manuscript has been approved by all of us.
We conrm that we have given due consideration to the protection of
intellectual property associated with this work and that there are no impediments
to publication, including the timing of publication, with respect to intellectual
property. In so doing we conrm that we have followed the regulations of our
institutions concerning intellectual property.
We further conrm that any aspect of work covered in this manuscript that
has involved either experimental animals or human patients has been conducted
with the ethical approval of all relevant bodies and that such approvals are
acknowl- edged within the manuscript.
We understand that the corresponding author is the sole contact for the
editorial process (including Editorial Manager and direct communications with the
ofce). He/she is responsible for communicating with other authors about progress,
submissions of revisions and nal approval of proofs. We conrm that we have
provided a current, correct email address which is accessible by the corresponding
author and which has been congured to accept emails.

Acknowledgment
This research was supported by the fundamental and advanced research
projects of Chongqing (No: cstc2013jcyjA10147). We express our gratitude to
all the patients, the nurses and physicians who participated in this study, and
thereby made this work possible. Authors also acknowledge the contribution
of the reviewers who have helped us to improve the manuscript.

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