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Journal of Psychiatric Research 76 (2016) 84e93

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Journal of Psychiatric Research


journal homepage: www.elsevier.com/locate/psychires

Shortened telomere length in patients with depression: A metaanalytic study


Pao-Yen Lin a, b, *, 1, Yu-Chi Huang a, 1, Chi-Fa Hung a
a
b

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

P.-Y. Lin et al. / Journal of Psychiatric Research 76 (2016) 84e93

disorder (MDD) (Hartmann et al., 2010).


MDD has been recognized as a serious public health problem
causing detrimental impact and excess medical costs (Ferrari et al.,
2013). MDD has worldwide high point and lifetime prevalence of
4.4% and nearly 16.2% respectively (Ferrari et al., 2013; Kessler et al.,
2007). The patients with MDD not only suffer from psychological
impact, but also endure excess risks for age-related physical diseases, including CVD, stroke, diabetes, metabolic syndrome, dementia, and related mortality (Brown et al., 2004; Irwin and Miller,
2007; McCusker et al., 2007; Musselman et al., 1998). Among them,
the risk of cardiac death was increased by 68% in those with
depression (Gasse et al., 2014). The association among depression
and accelerated age-related physical and functional decline supports the concept of premature telomere length shortening over
time in patients with MDD.
In the past decade, clinical investigations have shown shortened
telomere length in leukocytes in patients with depression (Cai et al.,
2015; Hartmann et al., 2010; Simon et al., 2006; Wikgren et al.,
2012). It was estimated that telomere length shortening may
represent 4e10 years of accelerated aging in subjects with MDD
(Simon et al., 2006; Verhoeven et al., 2014). But some conicting
results were also discovered (Ladwig et al., 2013; Teyssier et al.,
2012). The discrepancy in their results may be related to differences in study design, including sample population, diagnosis
assessment of psychiatric disorders, and methods in measuring
telomere length. In addition, individual studies with small sample
sizes may have insufcient statistical power to detect small but
signicant effects. Recently, two meta-analytic studies have
examined the relationship between depression and telomere
length (Ridout et al., 2015; Schutte and Malouff, 2015). The study by
Schutte and Malouff (2015), including 25 studies with 21,040 participants, found that depression was associated with shorter
leukocyte telomere length (LTL). The latest meta-analysis by Ridout
et al. (2015), expanding the subjects to 38 studies with 34,347
participants and including samples from saliva and brain tissues,
conrmed the association between depression and shorter telomere length. However, the signicance of these studies was
undermined by their inclusion of many studies examining the
correlation between LTL and the degree of depressive symptoms in
the general population, rather than direct comparison between
clinically-diagnosed depression and control subjects. And high
heterogeneity among studies may have resulted from pooling of
correlation studies and caseecontrol studies and including samples
other than leukocytes. In addition, various self-report assessments
of depression may have contributed to the publication bias in
estimating the magnitude of the effect size.
In this study, we aimed to conduct a meta-analysis to pool
relevant results strictly from all eligible caseecontrol studies to
analyze LTL in patients with depression, and examine the overall
difference in LTL between patients with depression and healthy
controls and determine possible moderating effects to account for
the difference.
2. Methods
2.1. Literature search
To identify eligible studies, two independent reviewers (P.-Y. Lin
and Y.-C. Huang) searched for studies available by July 2015 in the
electronic databases of PubMed at the National Library of Medicine,
Scopus, and Google Scholar. The search was performed by using the
search terms (telomere) AND (depression), without special limitation in language. The references of relevant articles and review
articles in this area were searched for citations not indexed in above
databases. The titles and abstracts of studies obtained by this search

85

strategy were screened by the independent reviewers to determine


if the studies were potentially eligible for inclusion in this metaanalysis, and to exclude studies that were apparently noneligible, such as review articles, non-human studies, and studies
not mentioning telomere. In case of disagreement in eligibility, we
reached agreement through consensus.
2.2. Inclusion criteria of studies in the meta-analysis
The included manuscripts passing the initial screening were
examined based on the inclusion criteria used in this meta-analysis,
including studies that: (1) included patients with depression, (2)
used samples from leukocyte DNA, (3) measured telomere length,
(4) included caseecontrol comparison between subjects with
depression and control subjects, and (5) dataset that did not
overlap with other studies. There is no limitation about the type of
diagnostic criteria of depression, if it clearly described cases and
non-cases in the manuscript. In addition, leukocytes are the predominant nuclear cells in peripheral blood, and the main leukocyte
subtypes include neutrophils, monocytes, and lymphocytes. Hence,
the telomere samples which were designated from peripheral
blood or peripheral blood mononuclear cell (PBMC) was regarded
as equivalent to being from leukocytes. When dataset from two
studies overlapped, we included only the study with the larger
sample size between them. The process of study selection was
described in Fig. 1.
2.3. Meta-analytic methods
The rst purpose was to compare LTL between patients with
depression and controls. The diagnoses of depression were based
on criteria provided in individual studies.
For each identied study, the effect sizes (ESs) expressing the
difference in telomere length between patients and controls were
described as standardized mean differences (SMDs) based on
Hedges' adjusted g, where values greater than 0 indicated that the
telomere was longer in patients. The means and standard deviations of telomere length of both patients and controls were used
to derive the ES from each included study. When these data could
not be available from these articles, we contacted the authors to
acquire the data or derived the ES from other statistical parameters,
such as t value or p value. The ESs of individual studies were synthesized by the random effects model (Shadish and Haddock, 1994).
The signicance of the pooled ES was determined by the z-test.
Sensitivity analyses were performed in the analysis that resulted in
signicant difference to determine if any individual study was
responsible for the signicant result. Each study was individually
removed and the signicance was re-tested.
Heterogeneity was examined to determine whether the group
of ESs came from a homogeneous source and assessed by Q statistics, their related p-value, and the I2 statistic, which is the percentage of the variability in the estimate of effects that is due to
heterogeneity rather than random error. A larger value of I2 statistic
indicates higher heterogeneity. A rejection of homogeneity suggests that there may be systemic differences existing among the
included studies. In addition, we used Egger's regression to statistically test for evidence of publication bias (Egger et al., 1997). To
examine whether mean age, gender distribution (percentage of
females), or duration of illness of included subjects moderates the
ES, we performed meta-regression by using the unrestricted
maximum likelihood method. In addition, we examined the pooled
effect in separate groups of studies based on the methods used for
measuring telomere length (southern blot, polymerase chain reaction (PCR), or uorescent in situ hybridization (FISH)).
Statistics in meta-analyses were performed by applying

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P.-Y. Lin et al. / Journal of Psychiatric Research 76 (2016) 84e93

Fig. 1. Flowchart describing the process of study selection.

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

P.-Y. Lin et al. / Journal of Psychiatric Research 76 (2016) 84e93

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

Mean Illness Proportion of Sampling source


AD use
duration,
years

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%

CD4, CD8, and


FISH
CD20 lymphocytes

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

253 MDD subjects 411


community
controls
Hartmann
Germany 54 MDD subjects 20 healthy
et al., 2010
controls

MDD (DSM-IIIR)
MDD (DSM-IV)

MDD (DSM-IV)

206 CHD subjects 746 CHD


subjects
with current
without
depression
current
depression
17 MDD subjects 16 healthy
controls

MDD (DSM-IVTR and MINI)

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

Teyssier et al., France


2012

451
community
controls
48 healthy
controls
7 subjects with
mastocytosis
have mild
depression

Karabatsiakis Germany Patients with


et al., 2014
lifetime
depression; 20
with current
depression; 24
without current
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

198 subjects with 966 subjects


MDD or depressed without
depressive
affect only
symptoms
355 subjects with 128 neverdepressed
current late life
controls
depression

Schaakxs
Netheret al., 2015 land

Simon et al.,
2015

USA

Wolkowitz
USA
et al., 2015

166 MDD subjects 166 healthy


controls

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

MDD &76.9% Leukocytes

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

(continued on next page)

88

P.-Y. Lin et al. / Journal of Psychiatric Research 76 (2016) 84e93

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

Mean Illness Proportion of Sampling source


AD use
duration,
years

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.

(Diagnostic and Statistical Manual of Mental Disorders) criteria and


without major systemic diseases (n 2876) and healthy controls
(n 1811) from 10 studies (Garcia-Rizo et al., 2013; Hartmann et al.,

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).

P.-Y. Lin et al. / Journal of Psychiatric Research 76 (2016) 84e93

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).

signicant decrease in telomere length in MDD patients (Hedges'


g 0.33, 95% CI 0.57 to 0.09, p 0.007) (Fig. 4B). However,
signicant heterogeneity still existed among the studies (Q 73.99,
df 9, I2 87.84%, p < 1  106). Sensitivity analysis showed that
the signicant difference in the telomere length was not inuenced
by any single study. Meta-regression analysis showed the ESs from
all included studies were marginally moderated by the percentage
of female subjects (point estimate of slope 1.65, p 0.06), but not
by mean age (point estimate of slope 0.00, p 0.60) and duration
of illness (point estimate of slope 0.01, p 0.36). In addition, we
detected no publication bias in the analysis of telomere length in
MDD (t 0.50, df 8, p 0.63).

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

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P.-Y. Lin et al. / Journal of Psychiatric Research 76 (2016) 84e93

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.

(corresponding to r 0.21, p 1  105), which is larger than the


ES in Schutte and Malouff (2015) (r 0.14, p < 0.01) and that in
Ridout et al. (2015) (cohen's d 0.34, p < 1  104). The difference
may result mainly from the difference in inclusion criteria. These
two previous meta-analyses included all relevant reports that
present a relationship between depression and telomere length.
Furthermore, the study by Ridout et al. (2015) even included relevant studies providing telomere length from saliva and brain tissues. On the other hand, our study included relevant results strictly
from all eligible caseecontrol studies for cross-sectional comparison in LTL between depressive patients and controls. The number of
included studies of our meta-analysis (16 studies) is fewer than that
of the previous studies (25 studies in Schutte and Malouff (2015)
and 38 studies in Ridout et al. (2015)). But our result provided a
computed difference in the LTL between groups, rather than the
association between telomere length and depression as in other
meta-analyses. In addition, our strict inclusion criteria prevented us
from pooling overly heterogeneous studies together, thus providing
a clear foundation to explain the results.

Telomere length is associated with gender difference, and


women are reported to have longer telomeres than men (Broer
et al., 2013). However, this difference is not consistently revealed
in studies of depression. One prospective longitudinal study reported accelerated LTL erosion among men aged 11e38 years with
depression, generalized anxiety disorder and post-traumatic stress
disorder. But, the above signicance was not found among women
with the same diagnoses and age window (Shalev et al., 2014). This
result could not be generalized to the whole depression population
due to limited age distribution, especially in ages beyond women's
reproductive years. One meta-analysis concluded the signicant
association between depression and telomere length in female
samples (Schutte and Malouff, 2015), but the other meta-analysis
did not replicate this gender difference (Ridout et al., 2015). However, these two meta-analytic studies also revealed a borderline
signicant association between the mean age of samples and effect
size, and the confounding factor related to age was not controlled
while analyzing the moderating effect of gender (Ridout et al.,
2015; Schutte and Malouff, 2015). In our study, we reported a

P.-Y. Lin et al. / Journal of Psychiatric Research 76 (2016) 84e93

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

91

and the related stage for assessing possible moderating factors of


LTL in advance. Further research is needed to discuss the impacts of
different age-of-onset MDD and comorbid anxiety disorders on LTL.
Previous studies examining the telomere length shortening in
individuals with comorbidity of MDD and physical diseases show
inconsistent ndings (Georgin-Lavialle et al., 2014; Hoen et al.,
2011). These ndings may indicate that physical or age-related
diseases may further complicate and confound the study results.
Ridout et al. (2015) had reported signicant moderator effect of
chronic comorbid medical condition on telomere length (Ridout
et al., 2015). In our study, signicant LTL shortening was analyzed
while comparing MDD patients with or without physical illnesses
to the healthy controls. However, methods for assessing depression,
severity of depression, follow-up duration, healthy controls selection and varied sample size may all contribute to heterogeneity
among selected studies in this analysis.
We found signicant differences in ESs by using different
methods for determining telomere length. A reliable method to
detect telomeric DNA and measure telomere length is critical to
provide accurate information for telomere biology (Aubert et al.,
2012). Although various methods used in assessing telomere
length, namely quantitative uorescence in situ hybridization
(qFISH), Southern blot and qPCR showed signicant telomere
shortening in subjects with depression, signicantly larger effect
was observed in studies using qFISH and Southern blot than those
using qPCR. The qFISH arrays uses directly uorescently labeled
(CCCTAA)3 peptide nucleic acid (PNA) probes to be highly afnity to
DNA oligonucleotide probes (Aubert et al., 2012). qFISH image
analysis software was then used to capture and measure the uorescent intensity signal which correlates to telomere length, and
thus a high resolution method to detect telomere length at specic
chromosome ends could be available (Aubert et al., 2012; Poon and
Lansdorp, 2001). The Southern blot measures both the canonical
(strictly TTAGGG repeats) and noncanonical components of telomeres to determine the length of terminal restriction fragment
(TRF) to present telomere length (Aviv et al., 2011; Kimura et al.,
2010). The method of quantitative PCR (qPCR)-based method only
measures the canonical component of telomeres to quantify telomere signals length (T) in a DNA sample, relative to a single copy
gene signal (S) and express in T/S ratios for average telomere length
(Cawthon, 2009; Elbers et al., 2014). Both Southern blot and the
qPCR showed good reliability in measuring telomere length (Aviv
et al., 2011), but the inter-assay coefcient of variation (CV), presented for the measurement error, was reported to be lower in the
method of Southern blots (Aviv et al., 2011; Elbers et al., 2014). Our
meta-analysis showed a larger effect from the studies using
Southern blot, supporting that qFISH arrays and Southern blot,
although more laborious and time-consuming technically
(Baerlocher et al., 2002), had higher measurement reliability than
qPCR.
Our meta-analysis has some limitations. First, the nding of this
meta-analysis suggested the cross-sectional correlation between
LTL shortening and depression, but cannot explain a possible causal
relation. There is no sufcient evidence to reveal that if subjects
born with shorter LTL are more vulnerable to develop depressive
disorder. Further prospective researches are warranted to investigate the underlying LTL-regulating mechanism and the possible
stress-mediating effect which predisposes depressed patients to
LTL shortening. Second, this meta-analysis selected studies which
investigated LTL in relation to categorical diagnoses rather than
dimensional diagnoses. Therefore, the results may not be applied to
the generalized population. Third, small sample size may present
limitations in meta-analysis results. Larger sample size is needed
for further investigating the correlation of LTL in patients with
depression. Finally, several biological or healthy-related behavioral

92

P.-Y. Lin et al. / Journal of Psychiatric Research 76 (2016) 84e93

and psychological factors associated with LTL shortening were not


well controlled, including patterns of antidepressant (Savolainen
et al., 2012), childhood maltreatment (Tyrka et al., 2010), comorbid anxiety disorders (Hoen et al., 2013; O'Donovan et al., 2011b;
Verhoeven et al., 2015), ethnicity (Elbers et al., 2014; Hartmann
et al., 2010), heritability (Prescott et al., 2011), smoking (Valdes
et al., 2005), alcohol (Pavanello et al., 2011), obesity (Lee et al.,
2011), or exercise (Savela et al., 2013) in original studies.
Conclusions
Our study showed shorter telomere length in patients with
depression, thus suggesting an important role of a biomarker of LTL
in this disorder. With these results, future studies are required to
clarify whether the association is mediated through psychological
stress or cytotoxic processes, and whether effective treatments can
halt accelerated cell aging.
Authors' contributions
Dr. Lin and Dr. Huang performed literature search and organization, and completed the rst draft. Dr. Lin conducted statistical
analysis and prepared gures. Dr. Hung helped with data interpretation and critical revision of the manuscript. Dr. Lin and Dr.
Huang contributed equally as the rst authors to this study.
Role of funding source
The funding agent had no role in the study design, in the
collection, analysis and interpretation of data, in the report writing,
and in the decision to submit the article for publication.
Conicts of interest
All authors declare no biomedical conict of interest.
Acknowledgments
Authors thank Kaohsiung Chang Gung Memorial Hospital
(CMRPG8D1191) for supporting our study.
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