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Comprehensive Psychiatry 65 (2015) 9 – 14
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The effect of cigarette smoking on vitamin D level and depression in male

patients with acute ischemic stroke
Wenwei Ren, Yingying Gu, Lin Zhu, Liping Wang, Yaling Chang, Mengjiao Yan,
Bin Han, Jincai He⁎
Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

Abstract

Objective: The association between low vitamin D levels and depression has been well documented in nonstroke subjects. Accumulating
evidence shows that low vitamin D levels may be also associated with depression post stroke. Cigarette smoking was associated with lower
vitamin D levels. The purposes of this study were to compare vitamin D levels in smokers to nonsmokers and examine the association
between vitamin D levels and depression symptoms in patients with acute ischemic stroke.
Materials and methods: Serum levels of 25-hydroxyvitamin D [25(OH)D] were measured in 194 males within 24 h after admission: 116
smokers and 78 nonsmokers. Depression symptoms were assessed with the 17-item Hamilton Depression Scale (HAMD-17). Patients with
the HAMD-17 score N7 were identified to have depression symptoms.
Results: The chi-square test showed that the frequency of depression in the smoker group was 23.3% (27/116), which was significantly
higher than that in the nonsmoker group (11.5% = 9/78), with an odds ratios (OR) of 2.33 (95% CI: 1.03–5.27; χ 2 = 4.25, df = 1,
p = 0.039, φ = 0.15). Vitamin D levels were significantly lower in smokers than in nonsmokers (52.4 ± 20.8 vs 61.7 ± 19.2; F = 9.88,
p = 0.002), with an effect size of 0.05 (ηp 2). Patients with depression symptoms showed lower vitamin D levels than those with no
depression symptoms (49.2 ± 19.6 vs 57.7 ± 20.6; F = 5.03, p = 0.03), with an effect size of 0.03 (ηp 2).
Conclusion: Higher rates of depression in smokers with acute ischemic stroke may be associated with lower vitamin D levels induced by smoking.
© 2015 Elsevier Inc. All rights reserved.

1. Introduction individuals with a life-time history of depression were past

Depression is a quite prevalent issue among stroke survivors,
affecting approximately one-third of individuals [1]. Patients
with depression experience worse stroke-related outcomes in the
form of greater functional disability and higher mortality [2].
Therefore, it will be beneficial to learn more about the risk
factors for depression, which may help us to develop a better
intervention to improve the outcomes of stroke survivors.
Cigarette smoking has been well established to be a risk
factor for stroke [3,4]. Besides, smoking is also tightly
associated with mental illness. Previous studies have
demonstrated that smoking is associated with an increased
risk of depression, suicide, and other mental illnesses [5–11].
In the National Comorbidity Survey, about 59% of
⁎ Corresponding author at: Department of Neurology, The First
Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000,
Zhejiang Province, China. Tel./fax: +86 577 555 79363.
E-mail address: hjc@wmu.edu.cn (J. He).
http://dx.doi.org/10.1016/j.comppsych.2015.09.006
0010-440X/© 2015 Elsevier Inc. All rights reserved.
or current smokers, compared to less than 39% of those
without a life-time history of depression [9,12]. Considering
the link between smoking and depression, it will be
interesting to see whether smoking was associated with the
mental health of patients with acute ischemic stroke (AIS),
which has not been studied yet. Moreover, we would also
like to explore an underlying mechanism which may explain
for this relationship.
Vitamin D is a neurosteroid, with the vitamin D receptors
widely expressed in the cerebrum, in glial and neuronal cells.
Vitamin D may play a part in neuroprotection through
different mechanisms such as antioxidation/anti-inflamma-
tory mechanisms, inhibition of inducible nitric oxide
synthase, neuronal calcium regulation, detoxification path-
ways, or enhanced nerve conduction [13]. Besides, vitamin
D is also associated with depression. Previous studies have
demonstrated a strong relationship between vitamin D and
depression [14,15]. A study by Przybelski et al. found that
patients suffering from mood disorders showed lower
10 W. Ren et al. / Comprehensive Psychiatry 65 (2015) 9–14
vitamin D concentrations [16]. Moreover, recent researches
have demonstrated a strong relationship between low
vitamin D level and depression in acute ischemic stroke
patients [17,18].
Vitamin D deficiency is associated with various factors such
as bad dietary habit and reduced sun exposure. Meanwhile,
more and more studies have observed a strong association
between smoking and vitamin D deficiency [19–21]. A study
by Jaaskelainen et al. including 5714 subjects (47% men) aged
30–79 years found that smokers had lower vitamin D
concentrations than nonsmokers [21]. Moreover, Thuesen
et al. in a recent study including 6146 subjects demonstrated
that the odds ratios of vitamin D severe deficiency (25(OH)D
b10 ng/ml)/vitamin D deficiency (25(OH)D b20 ng/ml)
associated with smoking were 1.47 and 1.36, respectively [22].
Based on the close relationship between smoking and
vitamin D insufficiency, as well as the link between depression
and vitamin D deficiency, we hypothesize that smoking may
play a role in the altered vitamin D levels of stroke patients,
which was associated with the depression. Because smoking is
substantially more common among Chinese men than in
women, we included only male subjects. The purposes of this
study were to determine (1) differences in vitamin D levels
between smokers and nonsmokers and (2) any associations
between vitamin D levels and depression symptoms in
smokers and nonsmokers with acute ischemic stroke.
2. Materials and methods
2.1. Participants
One hundred and ninety four patients with first-ever or
recurrent acute ischaemic stroke were recruited from the Stroke
Unit of The First Affiliated Hospital of Wenzhou Medical
University between October 2013 and May 2014. The inclusion
criteria were (1) Chinese; (2) age 18–80 years; (3) acute stroke
occurring within 7 days before admission; (4) confirmed by
computerized tomography (CT) or magnetic resonance imag-
ing (MRI). The exclusion criteria were (1) transient ischemic
attack; (2) patients with a history of central nervous system
diseases such as Parkinson’s disease, dementia, trauma, tumor
or hydrocephalus; (3) patients who had a history of mental
illness and had recently accepted antidepressant, antipsychotics
and participated in any psychological treatment; (4) patients
who were unconscious and showed serious cognitive impair-
ment; (5) patients with severe visual or auditory impairments;
(6) active alcohol or drug abuse; and (7) patients with
osteoporosis or taking vitamin D supplementation.
All the patients in the research had signed an informed
consent and the study was approved by the ethics committee of
The First Affiliated Hospital of Wenzhou Medical University.
2.2. Measures
Demographic data was obtained through the patients’
self-reports. Clinical data was abstracted from the medical
records as well as the self-reports. All the scales were measured
at admission. Depression symptoms were measured using the
17-item Hamilton Depression Scale (HAMD-17) at admission
[23]. Subjects with the HAMD-17 score N7 were identified to
have depression symptoms. Stroke severity was assessed by
experienced neurologists using the National Institutes of
Health Stroke Scale (NIHSS) at admission. Sleep quality of the
patients was evaluated by the Pittsburgh Sleep Quality Index
(PSQI) questionnaire [24]. Cognition function was assessed by
the Mini-Mental State Examination.
In addition, we adopted a cigarette smoking questionnaire
to record the smoking behavior, smoking history, as well as
family history of smoking. Smokers were defined as
individuals who smoked more than one cigarette per day
and had smoked for more than one year. Nonsmokers were
defined as those who had smoked less than 100 cigarettes
during their lifetime. If the subject identified themselves as a
smoker, then further questions were asked: (1) the average
number of cigarettes per day in the week before admission
and (2) the total years of smoking. If the subject currently
was a nonsmoker, further questions were asked including
whether or not they had quit smoking, regarding previous
smoking behavior. Quitters were excluded from our study.
According to the questionnaire responses, 116 (59.8%) were
identified as “smokers”, whereas 78 (40.2%) were identified
as “nonsmokers”. The baseline characteristics of the two
groups are displayed in Table 1.
The cranial computerized tomography was performed on
patients within 24 h after admission. The cranial magnetic
resonance imaging was performed on patients within 72 h
after admission. The lesion locations of acute stroke were
also recorded.
Blood samples were collected within 24 h after admis-
sion. Serum 25-hydroxyvitamin D [25(OH)D] was selected
as the measure of vitamin D status for its widespread clinical
application, testing protocol and standardized ranges. Serum
25(OH)D level was measured by a competitive protein
binding assay in our hospital’s laboratory. The intraassay
coefficient of variation was 7%–10%.
2.3. Statistical analysis
Baseline characteristics of the smoker and nonsmoker groups
were compared using the chi-square test, analysis of variance,
student t test, Mann–Whitney U test and Fisher’s exact test, as
appropriate. As vitamin D levels were normally distributed in
smoker and nonsmoker groups (Kolmogorov–Smirnov one
sample test), the principal analysis was one-way ANOVA.
Similarly, vitamin D levels were also compared between the
depression group (HAMD-17 N 7) and normal group
(HAMD-17 ≤ 7) by one-way ANOVA. The difference of
smoke time and number of cigarettes between the depression
group and normal group was analyzed by analysis of
covariance, with the age being included as the covariate.
Correlation among vitamin D and clinical ratings (e.g. smoke
time, number of cigarettes smoked) was examined by Pearson
 W. Ren et al. / Comprehensive Psychiatry 65 (2015) 9–14 11

Table 1 3.2. Vitamin D levels and the relationship to

Clinical and demographic characteristics of the samples under study. depression symptoms
Variable Nonsmokers Smokers p
(78) (116) As was shown in Table 1, vitamin D levels were significantly
Age (years), mean ± SD 61.7 ± 11. 5 59.5 ± 10.0 0.176 lower in smokers than in nonsmokers (52.4 ± 20.8 vs 61.7 ±
BMI (kg/m 2), mean ± SD 24.4 ± 2.7 23.3 ± 3.1 0.052 19.2; F = 9.88, p = 0.002, ηp 2 = 0.05). Furthermore, patients
Education (years), median (IQR) 5 (1–8) 6 (3–9) 0.094 with depression symptoms showed lower vitamin D levels than
Marital status, married (%) 94.9 95.7 1.000 those with no depression symptoms (49.2 ± 19.6 vs 57.7 ±
Lesion location (%) 0.679
20.6; F = 5.03, p = 0.03, ηp 2 = 0.03). No associations were
Frontal lobe 9.0 5.2
Parietal lobe 0.0 0.9 found between the number of cigarettes, smoke time and
Temporal lobe 1.3 2.6 vitamin D levels.
Occipital lobe 3.8 7.8
Subcortical white matter 0.0 1.7
Basal ganglia 37.2 36.2
Brainstem 7.7 7.8 4. Discussion
Cerebellum 5.1 9.5
Other 35.9 28.4 To the best of our knowledge, this is the first study
Vascular risk factors 0.816
exploring the association of vitamin D levels with smoking in
History of hypertension 46.2 41.4
History of diabetes 14.1 12.9 patients with acute ischemic stroke. In present study, we found
History of hyperlipidemia 6.4 8.6 that smokers had significantly lower vitamin D levels and
CAD 6.4 4.3 more depression symptoms than nonsmokers, despite the
History of stroke 11.5 10.3 relatively small effect sizes. Furthermore, longer smoking time
Other 15.4 22.4
was associated with more depression symptoms, with a
PSQI, mean ± SD 5.0 ± 3.5 5.6 ± 3.7 0.250
Neuropsychological function moderate effect size.
NIHSS score, median (IQR) 3 (1–4) 3 (1–4) 0.983 Previous prospective studies have demonstrated that smokers
MMSE score, median (IQR) 24 (18.3–28) 26 (21–28) 0.386 are at increased risk of depression [26–29]. A 21-year
Vitamin D (nmol/L), mean ± SD 61.7 ± 19.2 52.4 ± 20.8 0.002 longitudinal study revealed that subjects with nicotine depen-
BMI: body mass index; CAD: coronary artery disease; PSQI: Pittsburgh Sleep dence had higher rates of depression disorders [30]. Our
Quality Index; NIHSS: National Institutes of Health Stroke Scale; MMSE: research in stroke patients also demonstrated that smokers had a
Mini-Mental State Examination; SD: standard deviation; IQR: interquartile range. higher risk of depression than nonsmokers, which was
consistent with previous studies. Besides, a longer smoke time
correlation coefficients. Phi (φ) was used in the chi-square test was found to be associated with more depression symptoms.
and partial eta squared (ηp 2) in the variance analysis to present There is significant literature describing the pathways that may
effect sizes with 0.01–0.06, 0.06–0.14, and 0.14 or higher explain the co-occurrence of depression and smoking. Cigarette
corresponding to small, moderate, and large effect sizes [25]. smoking is associated with the decreased serotonin function
Statistical analyses were performed in IBM SPSS [31], and extensive evidence of serotonergic abnormalities in
software (version 17.0; SPSS Inc., Chicago, IL, USA). All depression was found [32]. In addition, there is also evidence
p values were 2 tailed with the significance level set at 0.05. that inflammatory pathways could link smoking and depression.
Depressed smokers showed higher levels of pro-inflammatory
cytokines than nondepressed smokers, including interleukin-6,
tumor necrosis factor-alpha, and acute phase proteins such as
3. Results C-reactive protein [33]. Moreover, both cigarette smoking and
3.1. Symptoms and demographics depressive disorders are associated with increased levels of
oxidative stress [34,35].
As was shown in Table 1, no differences were found We also found that serum levels of vitamin D within 24 h
between the smokers and nonsmokers in the baseline after admission were significantly lower in smokers than
demographic and clinical data (all p N 0.05). nonsmokers, which was consistent with previous studies
The chi-square test showed that the frequency of depression [21,22,36]. The exact mechanisms by which smoke affect
in the smoker group was 23.3% (27/116), which was vitamin D metabolism are still not clear. It could possibly be
significantly higher than that in the nonsmoker group explained by the fact that smokers often had a less healthy
(11.5% = 9/78), with an odds ratios (OR) of 2.33 (95% CI: lifestyle (bad dietary habits, less physical activity) leading to
1.03–5.27; χ 2 = 4.25, df = 1, p = 0.039, φ = 0.15). Besides, reduced sun exposure and thus synthesis of vitamin D [37,38].
in the smoker group, patients with depression symptoms Induction of the 25(OH)D hydroxylating enzymes has been
smoked longer than those with no depression symptoms proposed, but not proven yet.
(40.1 ± 10.1 vs 37.2 ± 11.9 years; F = 6.51, p = 0.01, In addition, we also found that patients who had
ηp 2 = 0.06). However, no associations were found between depression symptoms showed lower vitamin D levels. As a
the number of cigarettes and depression symptoms. matter of fact, a growing number of studies have found that
12 W. Ren et al. / Comprehensive Psychiatry 65 (2015) 9–14
lower vitamin D levels were associated with depression
[15,39,40], which had reinforced our findings. Besides,
several randomized controlled trials had also confirmed the
positive effects of vitamin D supplementation in improving
the depression symptoms [41,42]. Meanwhile, a study by
Milaneschi et al. including 2386 subjects found that low
vitamin D levels were associated with the presence and
severity of depression, implying that hypovitaminosis D may
indicate an underlying biological vulnerability for depres-
sion [43]. Actually, vitamin D status could alter the risk of
depression by numerous biologically plausible mechanisms.
The deficiency of 25(OH)D may alter the brain morphology
and have an influence in synthesis levels of serotonin,
dopamine, nerve growth factor, norepinephrine, acetylcho-
line acetylase, testosterone, thyroid hormone, and tyrosine
hydroxylase messenger RNA [39,44,45], which have all
been implicated in the pathogenesis of depression. Besides,
receptors for vitamin D and the vitamin D–activating
enzyme 1α-hydroxylase are widely distributed in neuronal
and glial cells in various areas of the human brain, such as the
cingulate cortex, hypothalamus, hippocampus and substantia
nigra, which have been involved in the pathophysiology of
depression [46]. Moreover, in addition to the known effects of
vitamin D on calcium homeostasis, vitamin D also exerts a
neuroprotective function by its immunomodulatory and anti-
inflammatory effects [13,47,48]. It has been well documented
that acute ischemic stroke could trigger a central and peripheral
inflammatory response, characterized by upregulation of
proinflammatory cytokines and rapid infiltration of microglia
[49]. Previous studies had demonstrated that upregulation of
proinflammatory cytokines in the brain may be correlated with
depression [50]. Meanwhile, vitamin D may modulate the
association between inflammatory response and depression by
its effect on immune system [51,52]. Considering above,
vitamin D might play an important role in the development of
depression of patients with acute ischemic stroke.
In the present study, we found a significant relationship
between vitamin D levels and the depression symptoms of
patients with acute ischemic stroke, consistent with recent
researches which reported a significant association between
low serum 25(OH)D levels and depression post stroke [17,18].
Since smoking was associated with more depression symp-
toms and with lower vitamin D levels, vitamin D might be an
important mediating factor linking the cigarette smoking and
depression in patients with acute ischemic stroke. The
inflammatory response associated with vitamin D decline
might play a role in the association between cigarette smoking
and depression. Moreover, researches in animal models and in
vitro studies suggest that smoking may interfere with the
anti-inflammatory effects of vitamin D [53]. Besides, the
dysfunction of neurotransmitters such as serotonin might also
play a critical role in this three-way association. However, in
this study, we did not demonstrate dose–response relation-
ships between the number of cigarettes per day and the vitamin
D levels. Two possible explanations are listed here. Firstly, the
brand of cigarettes as well as the ways of smoking (frequency
of puff drawing, depth of inhalation, filter tips) was not known,
and the smoke composition varies greatly in various cigarette
brands. Therefore, the daily number of cigarettes may not
reflect the degree of exposure accurately. Secondly, as has
been mentioned above, the decline of vitamin D levels in
smokers might also be caused by other factors such as a less
healthy lifestyle (bad dietary habits, less physical activity)
instead of cigarette itself.
This study has several limitations. Firstly, as patients in
the following treatment were not allowed to smoke, all the
scales were assessed at admission to reduce the influence
caused by smoking cessation. Therefore, the present research
was designed as a cross-sectional study, which cannot
establish causal associations between smoking and vitamin
D. Secondly, our study lacked a normal control group. With
a normal control group, it would be better to determine
whether the changed vitamin D level in smokers with acute
ischemic stroke was associated with smoking or with the
illness itself. Thirdly, the sample was relatively small and
was limited to male patients. It is worthy of further study to
see whether our findings in the present research could
generalize to female subjects. Fourthly, the results in this
study only demonstrated small to moderate effect sizes,
which may somewhat impact the reliability of the conclu-
sions. A better designed research in a large sample size is
needed in the future to further study the underlying
associations among smoking, depression, and vitamin D
levels in patients with acute ischemic stroke. Lastly, some
information such as daily diet and level of activity which are
related to smoking and vitamin D levels were not collected in
the present study, which may affect the results to some
extent. These information will be needed in the future
research to further disentangle the effect of these factors.
In summary, higher rates of depression in smokers with
acute ischemic stroke may be associated with lower vitamin
D levels induced by smoking. A better understanding of the
relationship among smoking, vitamin D and depression may
help us to learn more about the risk factors for depression
and thus develop better interventions to improve the
outcomes of stroke patients.
Disclosure of conflicts of interest
All authors declare that they have no conflicts of interest.
Acknowledgment
This study was supported by the National Key Technologies
R&D Program in the 11th 5-year plan from the Ministry of
Science and Technology of the People’s Republic of China
(grant number: 2009BAI77B06) and Wenzhou Municipal
Sci-Tech Bureau Program (H20100021). These sources had no
further role in study design, data collection and analysis,
decision to publish, or preparation of the article.
 W. Ren et al. / Comprehensive Psychiatry 65 (2015) 9–14
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