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Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 September 2015
Received in revised form
24 January 2016
Accepted 29 January 2016
Background: Accelerated telomere shortening is associated with stress-related cell damage and aging.
Patients with depression have been shown to have shortened life expectancy and to be associated with
multiple age-related systemic diseases. Previous studies have examined leukocyte telomere length (LTL)
in patients with depression, but have shown inconsistent results.
Methods: We conducted meta-analyses by pooling relevant results strictly from all eligible caseecontrol
studies for cross-sectional comparison of LTL between depressive patients and control subjects (16
studies involving 7207 subjects). The effect sizes (shown as Hedges' g) of each individual study were
synthesized by using a random effects model.
Results: Our analysis revealed telomere length is signicantly shorter in subjects with depression in
comparison to healthy controls (Hedges' g 0.42, p 1 105, corresponding to r 0.21). Signicant
heterogeneity among studies examining LTL in subjects with depression was found (Q 116.07, df 16,
I2 86.21%, p < 1 108), which can possibly be explained by methods used in measuring telomere
length (Q 18.42, df 2, p 1 104). There was no signicant publication bias, nor moderating effect
of age, female percentage, or illness duration of depression on synthesized results.
Conclusions: Our results support the hypothesis that depression is associated with accelerated cell aging.
Future studies are required to clarify whether the association is mediated through environmental stress,
and whether effective treatment can halt cell aging.
2016 Elsevier Ltd. All rights reserved.
Keywords:
Depression
Meta-analysis
Stress
Telomere
1. Introduction
Telomeres, complexes composed of both tandem repeated
guanine-rich DNA and specied proteins, cap the ends of eukaryotic
chromosomes. They protect DNA from damage and related consequences of genome instability when cells undergo repetitive
mitotic divisions (Blackburn, 2001, 2005). The rate of telomere
shortening can be decreased by the cellular enzyme telomerase, an
RNA-dependent DNA polymerase (Blackburn, 2005). The function
of telomerase is to maintain telomere length by synthesizing
telomeric repeat sequences to the ends of chromosomal DNA during cell replication to maintain a healthy cell status (Epel et al.,
* Corresponding author. Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, 123, Dapi Road, Niaosong District, Kaohsiung City 833, Taiwan.
E-mail addresses: paoyenilin@gmail.com, py1029@adm.cgmh.org.tw (P.-Y. Lin),
ychuang01@gmail.com (Y.-C. Huang), chifa.hung@gmail.com (C.-F. Hung).
1
Drs. Pao-Yen Lin and Yu-Chi Huang contributed equally as the rst authors.
http://dx.doi.org/10.1016/j.jpsychires.2016.01.015
0022-3956/ 2016 Elsevier Ltd. All rights reserved.
2006; Kim et al., 2003), and telomerase activity is positively associated with telomere length (Lin et al., 2010; Wolkowitz et al.,
2012). Normal human somatic cells are reported to have 5e15
kilobase pairs (kbp) in telomere length, which shortens on average
15e20 bp per year through cell division (Allsopp et al., 1992;
Bekaert et al., 2005). Cells will be susceptible to senescence and
apoptosis when telomeres length becomes critically short, between
0 and 2.8 kbp (Allsopp and Harley, 1995; Blackburn, 2005).
Telomere length is proposed to be a valuable biomarker of aging
(Bekaert et al., 2005; O'Donovan et al., 2012), which is related to
declining physiological integrity, the following functional impairment and susceptibility to death (Lopez-Otin et al., 2013). Aside
from normal aging, mounting evidences suggest that telomere
length is not only related to individual's age-related physical illnesses, such as cardiovascular disease (CVD) (Fitzpatrick et al.,
2007; Haycock et al., 2014), cancer (Campisi, 2005; Ma et al.,
2011), Alzheimer disease (Hochstrasser et al., 2012), cancer mortality or all-cause mortality (Cawthon et al., 2003; Rode et al., 2015;
Weischer et al., 2013), but also associated with major depressive
85
86
Comprehensive Meta-Analysis software, version 2 (Biostat, Englewood, NJ, USA). Two-sided p values < 0.05 were considered statistically signicant. We reported the methods and the results of
meta-analyses by following the MOOSE checklist (Stroup et al.,
2000).
3. Results
Our literature search resulted in 98 results for initial consideration in the meta-analysis. By examining their titles and abstracts,
45 studies were excluded because they were review articles
(n 15), non-human studies (n 13), not measuring telomere
length (n 13), or comments on other studies or case reports
(n 4). When we examined the text of remaining 53 studies by
inclusion criteria, 26 of them were excluded because they did not
include patients with depression, 3 studies were excluded because
they measured brain telomere length (Szebeni et al., 2014; Teyssier
et al., 2011, 2010), 5 studies were excluded because they did not
provide caseecontrol comparison of telomere length (Chen et al.,
2014; Hoen et al., 2013; Lin et al., 2015; Malan et al., 2011; Shalev
et al., 2014), and 3 studies were excluded because they overlapped with other studies (Puterman et al., 2013; Revesz et al.,
2014; Wolkowitz et al., 2011). Finally, 16 studies were included in
the current meta-analysis (Garcia-Rizo et al., 2013; Georgin-Lavialle
et al., 2014; Hartmann et al., 2010; Hoen et al., 2011; Karabatsiakis
et al., 2014; Liu et al., 2014; Lung et al., 2007; Needham et al., 2015;
Schaakxs et al., 2015; Simon et al., 2006, 2015; Teyssier et al., 2012;
Tyrka et al., 2016; Verhoeven et al., 2014; Wikgren et al., 2012;
Wolkowitz et al., 2015). In these studies, the study by Garcia-Rizo
et al. (2013) measured telomere DNA content, instead of telomere
length. Telomere content was directly proportional to telomere
length measured by the southern blot, so this study was included.
In addition, the study by Karabatsiakis et al. (2014) contained patients with depression history, with or without current depressive
symptoms, so it was regarded to provide two individual comparisons. The characteristics of the included studies were described in
Table 1.
First, we compared the LTL between patients with depression
(n 3414) and controls (n 3793), extracted from included
studies. The study by Simon et al. (2015) used both western blot
and PCR for examining LTL. We used the data from the southern
blot method in the main analysis because it contained a larger
sample size. Our analysis showed a signicant decrease in telomere
length in the patient group (Hedges' g 0.42, 95% CI 0.60
to 0.25, p 1 105) (Fig. 2A). Sensitivity analysis showed that
the signicant difference in telomere length was not inuenced by
any single study. Through the funnel plot, the distribution of
included studies seems to bias toward more negative ES (Fig. 2B),
and a trend of publication bias was found by using Egger's analysis
(t 1.83, df 15, p 0.09).
In addition, signicant heterogeneity existed among the studies
included in this analysis (Q 116.07, df 16, I2 86.21%,
p < 1 108). Next, we examined whether the heterogeneity
resulted from age, gender distribution, duration of illness, or the
methods used in measuring telomere length. In our metaregression analysis, the ESs from all included studies were not
signicantly moderated by mean age (Fig. 3A) (point estimate of
slope 0.00, p 0.89), percentage of female subjects (Fig. 3B)
(point estimate of slope 0.38, p 0.49), or duration of illness
(Fig. 3C) (point estimate of slope 0.00, p 0.85). When we
separated the studies by methods measuring telomere length, the
studies (Garcia-Rizo et al., 2013; Hartmann et al., 2010; Lung et al.,
2007; Simon et al., 2006, 2015) using the southern blot (Hedges'
g 0.62, 95% CI 1.12 to 0.13, p 0.01), using PCR (GeorginLavialle et al., 2014; Hoen et al., 2011; Liu et al., 2014; Needham
et al., 2015; Schaakxs et al., 2015; Simon et al., 2015; Teyssier
et al., 2012; Tyrka et al., 2016; Verhoeven et al., 2014; Wikgren
et al., 2012; Wolkowitz et al., 2015) (Hedges' g 0.21, 95%
CI 0.35 to 0.08, p 0.002), and using FISH (Karabatsiakis et al.,
2014) (Hedges' g 1.17, 95% CI 1.60 to 0.73, p < 1 106), all
showed signicant decrease in LTL in subjects with depression
(Fig. 4A). But there was a signicant difference in the ESs from
studies using the three different methods (Q 18.42, df 2,
p 0.0001).
Considering that telomere length can be inuenced by various
medical and other psychiatric disorders (Kong et al., 2013; Nilsson
et al., 2013; Shalev et al., 2013), we also performed the analysis
comparing LTL between patients with MDD diagnosed by DSM
87
Table 1
Summary of characteristics of included studies in current meta-analysis.
Study
Country
Patients, N
Controls, N
Diagnosis of
psychiatric
disorders
Mean age,
years
Proportion
of females
Methods
measuring
telomere
length
Simon et al.,
2006
USA
15 MDD subjects
44 healthy
controls
MDD (DSM-IV)
NA
Leukocytes
Southern
blot
Taiwan
MDD, 53.3%
Controls,
43.2%
MDD, 64.0%
Controls,
56.7%
MDD, 61.1%
Controls,
45.0%
MDD, 30.6%
Controls,
15.3%
25.7
Lung et al.,
2007
MDD, 50.3
Controls,
50.5
MDD, 44.5
Controls,
45.3
MDD, 49.1
Controls,
49.1
MDD, 61.7
Controls,
68.1
NA
NA
Peripheral blood
Southern
blot
15.4
MDD 100%
Control NA
Leukocytes
Southern
blot
NA
MDD 48.1%
Leukocytes
Control 10.5%
PCR
MDD, 39.5
Controls,
37.6
MDD, 60.4
Controls,
58.9
MDD, 30.7
Controls,
27.8
NA
MDD, 100%
Controls,
100%
MDD, 60.4%
Controls,
50.3%
MDD, 40.0%
Controls,
37.8%
NA
11.4
Leukocytes
PCR
Leukocytes
PCR
NA
70.6% (SSRI
and BZDs)
Control NA
Depression
89.0%
Control NA
MDD 0%
Leukocytes
Southern
blota
NA
NA
PBMCs
PCR
With
current
depression,
53.8;
Without
current
depression,
53.1;
Controls,
51.1
Depression,
54.8
Controls,
53.2
With
current
depression,
100%;
Without
current
depression,
100%;
Controls,
100%
Depression,
43.5%
Controls,
57.0%
With current
depression,
22.3b;
Without
current
depression,
15.9b
With current
depression
45.0%;
Without
current
depression
41.7%;
Control 0%
NA
NA
Leukocytes
Remitted
MDD, 43.5
Current
MDD, 40.7
Controls,
40.5
Depression,
MDD or
depressed affect 30.3
only (CIDI based Controls,
29.2
on DSM-IV)
Depression,
MDD or
70.6
dysthymia
Controls,
(DSM-IV)
70.1
DSM-IV
MDD, 41.3
Controls,
41.3
Remitted
MDD, 70.3%
Current
MDD, 67.4%
Controls,
60.2%
Depression,
58.6%
Controls,
56.0%
Depression,
66.2%
Controls,
61.7%
MDD, 53.6%
Controls,
53.6%
Remitted
MDD15.1b;
Current MDD
13.6b
Leukocytes
Remitted
MDD,
&23.0%;
Current MDD
&44.7%;
Control 0.4%
Peripheral blood
Depression
10.1%
Control 3.3%
MDD (DSM-IVTR)
MDD, 63%
Controls,
59%
NA
MDD (DSM-IIIR)
MDD (DSM-IV)
MDD (DSM-IV)
Wikgren
Sweden
et al., 2012
91 MDD subjects
MDD (DSM-IV)
Garcia-Rizo
Spain
et al., 2013
9 MDD subjects
France
GeorginLavialle
et al., 2014
8 subjects with
mastocytosis have
moderate-severe
depression
Hoen et al.,
2011
USA
451
community
controls
48 healthy
controls
7 subjects with
mastocytosis
have mild
depression
50 healthy
controls
Liu et al.,
2014
54 T2D patients
without
depression; 46
non-T2D
subjects
without
depression
510 controls
China
17 T2D patients
with depression; 6
non-T2D subjects
with depression
Verhoeven
Netheret al., 2014 lands
802 remitted
MDD; 1095
current MDD
Needham
USA
et al., 2015
Schaakxs
Netheret al., 2015 land
Simon et al.,
2015
USA
Wolkowitz
USA
et al., 2015
19 MDD subjects
17 healthy
controls
MDD (DSM)
BDI-IIS19
indicating
moderatesevere
depression
Unipolar
disorder (ICD10); BDIS14 or
&13 as with or
without current
depression
HADS-DS10
indicating
depression
MDD (DSM-IV)
MDD, 37.5
Controls,
37.9
27.9
NA
PCR
PCR
PCR
21.5b
PCR
21.8
Free of AD at Leukocytes
study entry;
Lifetime AD
use for over 6
months
(39.1%)
Leukocytes
All subjects
free of
psychotropics
Southern
blot
PCR
PCR
88
Table 1 (continued )
Study
Tyrka et al.,
2016
Country Patients, N
USA
59 subjects with
lifetime
depressive
disorder
(including 48
subjects with
lifetime MDD)
Controls, N
113 subjects
without
psychiatric
disorders or
childhood
adversity
Diagnosis of
psychiatric
disorders
Mean age,
years
NA
MDD or
depressive
disorder (DSMIV)
Proportion
of females
NA
NA
for at least 6
weeks
NA
Leukocytes
Methods
measuring
telomere
length
PCR
Abbreviations: AD, Antidepressant; BDI, Beck Depression Inventory; BZDs, benzodiazepines; CHD, coronary heart disease; CIDI, Composite International Diagnostic Interview;
DSM, diagnostic and statistical manual of mental disorders; FISH, uorescence in situ hybridization; HADS-D, Depression Subscale of Hospital Anxiety and Depression Scale;
MDD, major depressive disorder; MINI, Mini-International Neuropsychiatric Interview; NA, not available; PBMC, peripheral blood mononuclear cell; PCR, polymerase chain
reaction; SSRI, serotonin reuptake inhibitors; T2D, type 2 diabetes.
a
For measuring telomere content.
b
Mean illness duration equals mean age minus mean age at rst depressive episode.
2010; Lung et al., 2007; Schaakxs et al., 2015; Simon et al., 2006,
2015; Teyssier et al., 2012; Verhoeven et al., 2014; Wikgren et al.,
2012; Wolkowitz et al., 2015). The analysis also showed a
Fig. 2. (A) Forest plot showing effective sizes (Hedges' g) and 95% condent intervals (CIs) from individual studies and pooled results comparing telomere length between subjects
with depression and controls. (B) Funnel plot examining publication bias in studies comparing telomere length between subjects with depression and controls. The plot describes
the effect sizes (Hedges' g) of studies vs. their precision (inverse of standard error).
89
Fig. 3. Plots showing regression between the effect sizes (Hedges' g) of studies and (A) mean age of study subjects, (B) percentage of females in study subjects, and (C) duration of
illness of patients with depression. Each circle represents one study. Circle size is proportional to their precision (inverse of standard error).
4. Discussion
The goal of the present study was to investigate LTL, which is
thought to be one marker of cellular aging, in patients with MDD in
comparison to healthy control groups by performing meta-analysis
on the available data. Our major nding shows that the patients
with depression had signicantly shorter LTL than control subjects,
with a moderate difference. Consistent with the main results of
previous meta-analyses (Ridout et al., 2015; Schutte and Malouff,
2015), our nding supports the hypothesis that depression is
associated with accelerated cell aging. In terms of the magnitude of
the difference of LTL between patients and control subjects, our
study shows an ES as Hedges' g 0.42, p 1 105
90
Fig. 4. (A) Forest plot showing effective sizes (Hedges' g) and 95% CIs from individual studies and pooled results of studies using different methods (polymerase chain reaction (PCR)
vs. southern blot vs. uorescent in situ hybridization (FISH)) measuring telomere length. (B) Forest plots showing effective sizes (Hedges' g) and 95% condent intervals (CIs) from
individual studies and pooled results comparing telomere length between subjects with major depressive disorder (MDD) and controls.
marginal moderating effect of gender on MDD patients and telomere length by conducting analysis of age-controlled depression
and healthy samples without presentation of major physical illnesses in order to eliminate confounding factors. In addition, the
age distribution in this study ranged from 30.7 years (Garcia-Rizo
et al., 2013) to 70.6 years (Schaakxs et al., 2015), and those samples had more potential to reect the age spectrum of depression
patients. The results revealed that the ES from 10 studies which
included DSM-diagnosed MDD patients (n 2876) and controls
(n 1811) was marginally moderated by the percentage of female
subjects (point estimate of slope 1.65, p 0.06). The nding may
implicate that the more signicant association between depression
and telomere length would be observed in samples which included
a higher percentage of females. Among the potential biological
factors in regulating the maintenance of telomere length, estrogen
was hypothesized to mediate telomere length in women by
increasing telomerase activity (Kyo et al., 1999; Muezzinler et al.,
2013). Following of this hypothesis, women beyond reproductive
years may be more susceptible to LTL shortening than men while
the protective effect from estrogen is attenuated. But further prospective studies are warranted to investigate thorough pathophysiology about the gender effect on telomere length among
patients with depression.
Higher perceived psychological stress and chronic stress are
associated with accelerating aging of telomere length shortening
and the psychopathology of MDD (Hammen, 2005; Liu and Alloy,
2010). The complex mechanisms of HPA axis, brain-derived neurotrophic factor, oxidative or inammatory stress, excitotoxicity,
neurosteroids, mitochondrial DNA, LTL and telomerase are suggested to link MDD to biochemical mediators related to cell
dysfunction or damage (Cai et al., 2015; Kinser and Lyon, 2013).
With these above pathogenetic processes, a depression model can
be formed which states that depression is not only a brain disease
but also a whole body disease (Wolkowitz et al., 2010), which also
reects the elevated allostatic load and wear and tear on the body
and brain (McEwen, 2003). Lifetime duration of depression and the
chronicity of perceived stress were proposed to be correlated to the
shortening of telomere length (Epel et al., 2004; Wolkowitz et al.,
2011). However, the conicting results were also reported
(Hartmann et al., 2010; Wikgren et al., 2012). In this meta-analysis
study, we explored the association of illness duration and ES and no
signicant moderating effect of illness duration was detected (point
estimate of slope 0.01, p 0.36). This result may be interpreted
that the lifetime illness duration may not explain the prognosis of
MDD due to heterogeneity of treatment response (Kota et al., 2015)
and self-resilience against the stress (Puterman and Epel, 2012),
which are taken into account for LTL shortening. Further investigations are needed to further explore the association among
depression status, the duration of active depression, or remission
duration and LTL.
Aside from MDD, anxiety disorders are also suggested to be
related to shorter LTL (Hoen et al., 2013; O'Donovan et al., 2011a),
especially while under active course (Verhoeven et al., 2015). Comorbid anxiety disorders are related to more severity of depressive
symptoms and worsened outcomes in patients with MDD
(DeVeaugh-Geiss et al., 2010; Smits et al., 2009), and it could inuence the LTL and enhance or mask the true effect of MDD on LTL.
On the other hand, early onset of MDD is one predictive factor of
comorbid anxiety disorder and is related to irritability tendency in
clinical mood manifestation, in comparison to late-onset MDD
(Moscati et al., 2016; Parker et al., 2003). Due to the high comorbidity rate (53%) between MDD and anxiety disorders (Moscati
et al., 2016), we cannot rule out that MDD patients had comorbid
anxiety disorders in this study. However, there was no enough information about age of onset in MDD, comorbid anxiety disorders
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