J Clin Periodontol 2016; 43: 216–228 doi: 10.1111/jcpe.

12510

Systematic Review
Association between depression Milena Moreira Arau
2

jo1, Carolina
Castro Martins , Lidiane Cristina

vio
Machado Costa1, Lu
ıs Ota

and periodontitis: a systematic Miranda Cota1, Rodrigo Lamounier

Arau
jo Melo Faria1, Fabiano Arau
Cunha1 and Fernando Oliveira Costa1

jo

review and meta-analysis 1

Department of Dental Clinics, Oral
Pathology, and Oral Surgery, Federal
University of Minas Gerais, Belo Horizonte,
Brazil; 2Department of Pediatric Dentistry and
Orthodontics, Federal University of Minas
Ara

ujo MM, Martins CC, Costa LCM, Cota LOM, Faria RLAM, Cunha FA, Gerais, Belo Horizonte, Brazil
Costa FO. Association between depression and periodontitis: a systematic review
and meta-analysis. J Clin Periodontol 2016; 43: 216–228. doi: 10.1111/jcpe.12510

Abstract
Aim: The aim of this systematic review and meta-analysis was to assess the scien-
tific evidence on the association between depression and periodontitis.
Methods: An electronic search was conducted in three databases until October
2015 (PROSPERO-CRD42014006451). Hand searches and grey literature were
also included. Search retrieved 423 potentially studies. Two independent reviewers
selected the studies, extracted data and assessed risk bias through a modified ver-
sion of Newcastle–Ottawa scale. Meta-analysis was performed for the presence/
absence of periodontitis (dichotomic). Summary effect measures and odds ratio
(OR) 95% CI were calculated.
Results: After selecting the studies, 15 were included in the systematic review
(eight cross-sectional, six case–control and one cohort study). Six studies reported
that depression was associated with periodontitis, whereas nine studies did not.
The majority of studies had low risk of bias by methodological quality assess-
ment. Meta-analysis of seven cross-sectional studies showed no significant associ-
ation between depression and periodontitis (OR = 1.03, 95% CI = 0.75–1.41).
Conclusion: Findings from the present systematic review showed a great hetero-
Key words: aggressive periodontitis; chronic
geneity among the studies and the summary effect measure of the meta-analysis periodontitis; depressive disorders.periodontal
cannot affirm an association between depression and periodontitis. Future studies disease; periodontitis
with different designs in distinct populations should be conducted to investigate
this association. Accepted for publication 3 January 2016

Depression is a complex and multi-
factorial disorder with important
genetic and non-genetic contributory
Conflict of interest and source of
funding statement
The authors declare that there are no
conflicts of interest. This study was
supported by grants from the Minas
Gerais State Research Support
Foundation – Brazil (FAPEMIG
#21612).
factors (Tiemeier 2003, Levinson
2006). It is a common condition that
might occur on its own or in associa-
tion with other diseases. The elderly
are particularly at risk for depressive
illnesses, which can have a profound
adverse effect on the quality of life
of both individuals and their families
(Warren et al. 2014). This epidemio-
logical pattern of depressive disor-
ders in late life represents an
important public health problem
(Cadoret et al. 1977, Weissman et al.
1993, Gottfries 2001, Warren et al.
2014).
Periodontitis is an infectious
inflammatory condition of periodon-
tal tissues characterized by loss of
tooth support (Beck & L€ oe 1993).
The presence of inflammatory
mediators in the pathogenesis of
periodontitis called the attention to
the systemic impact of periodontitis
and its potential association with
other conditions (Esteves Lima et al.
2013).

216 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

The biological plausibility for the
association between depression and
periodontitis is supported by studies
showing how depression may affect
the host immune response, making
the individual more susceptible to
the development of unhealthy condi-
tions and affecting periodontal
health (Genco et al. 1998, Peruzzo et
al. 2007, Warren et al. 2014) Gluco-
corticoids released into the cortex of
the supra-renals can induce the
reduction in pro-inflammatory
cytokines secretion (interleukins,
prostaglandins and tumour necrosis
factor). On the other hand, cate-
cholamines (epinephrine and nore-
pinephrine) have the opposite effect,
stimulating the formation and activ-
ity of prostaglandins and proteolytic
enzymes, which can indirectly pro-
voke tissue destruction (Genco et al.
1998, Breivik & Thrane 2001).
Evidence of the association
between depression and periodontitis
are contradictory in the literature.
Some studies showed a positive asso-
ciation (Moss et al. 1996, Genco
et al. 1999, Ng & Leung 2006,
Johannsen et al. 2007, Rosania et al.
2009), but other studies did not
(Solis et al. 2004, 2014, Castro et al.
2006, Abahneh et al. 2010, Kham-
baty & Stewart 2013, Mendes et al.
2013). Besides these divergent
results, to the best of our knowledge,
there is no systematic review and
meta-analysis covering this topic.
Hence, the aim of this study was
to evaluate the scientific evidence on
the association between depression
and periodontitis in adult individuals.
The clinical question (PICO) was:
adults (P = patients); depression
(I = exposure/intervention); patients
without depression (C = compar-
ison); periodontitis (O = outcome).
Methods
The present systematic review was
registered in PROSPERO
(#CRD42014006451). It was con-
ducted in accordance with the guide-
lines of Transparent Reporting of
Systematic Reviews and Meta-Ana-
lysis – PRISMA Statement (Moher
et al. 2009).
To be eligible for the inclusion in
the present systematic review, studies
had to meet the following criteria:
cross-sectional, case–control or
cohort studies; clinical trials; studies
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
in humans; adult individuals; studies
that evaluated the presence of
depressive disorders associated with
periodontitis, the presence of control
patients without depression (healthy
conditions); studies reporting values
of clinical periodontal parameters
[probing depth (PD), clinical attach-
ment level (CAL) and bleeding on
probing (BOP)].
The exclusion criteria included:
case reports; reviews; other mental
or systemic diseases rather than
depression (psychotic, mental retar-
dation, schizophrenia, erectile dys-
function, eating disorder, down
syndrome, anorexia and bulimia,
alcohol and drug dependence, HIV,
Parkinson’s, epilepsy and halitosis);
absence of healthy control patients;
outcomes other than periodontitis.
Search strategy
Electronic and manual search, as
well as studies selection and quality
assessment, were performed by two
independent reviewers (L.C.M.C and
M.M.A).
An electronic search was con-
ducted until October 2015 on three
electronic databases: Medline through
Pubmed (http://www.ncbi.nlm.nih.gov
/pubmed), Web of Science (www.isikn
owledge.com), and Cochrane Library
(http://www.thecochranelibrary.com).
No restrictions were imposed regard-
ing language or date of publication.
The following search strategy was
used in Medline: ((periodontal disease
[Mesh] OR periodontitis [Mesh] OR
chronic periodontitis [Mesh] OR
aggressive periodontitis [Mesh]) AND
(anxiety [Mesh] OR Anxious [Mesh]
OR depression [Mesh] OR depressive
disorder [Mesh])); Web of Science:
((periodontal disease OR periodontitis
OR chronic periodontitis OR aggres-
sive periodontitis) AND (anxiety OR
Anxious OR depression OR depres-
sive disorder)); and Cochrane Library:
((periodontal diseases [Mesh] OR
periodontitis [Mesh] OR chronic peri-
odontitis [Mesh] OR aggressive peri-
odontitis [Mesh]) AND (anxiety
[Mesh] OR Anxious OR depression
[Mesh] OR depressive disorder
[Mesh])).
A manual search on the reference
list of the included studies was
carried for publications that were
not electronically identified. Refer-
ence Manager SoftwareÒ (Reference
Depression and periodontitis 217
Manager, Thomson Reuters, version
12.0.3) was used to organize the
studies.
A total of 449 potentially relevant
records were found: 251 references
from PubMed, 180 references from
Web of Science, 18 references from
Cochrane Library. After the dupli-
cate references were removed, a total
of 374 studies were selected based on
titles/abstracts. Two reviewers were
calibrated on the application of the
inclusion and exclusion criteria. As a
calibration exercise, the reviewers
thoroughly discussed the criteria and
applied them to a sample of 20% of
the retrieved studies to determine
inter-examiner agreement. After ade-
quate agreement was achieved
(kappa 0.87), all the studies were
independently read by the reviewers.
Disagreements were resolved by con-
sensus. If relevant data were missing
or if the paper was not available, the
primary authors were contacted for
additional information or article
request. A total of 348 studies were
excluded after selection on titles/ab-
stracts (Appendix 1. suppinfo), and
26 studies were selected for the full
text analysis. Among the 26 selected
studies, 11 studies (Appendix 2– sup-
pinfo) were excluded. Figure 1
describes the search process.
Quality assessment
A modified version of the New-
castle–Ottawa scale for case–control
studies (Wells et al. 2011) was used
for quality assessment of cross-sec-
tional and case–control studies
(Table 1). The cohort study was
evaluated by the Newcastle–Ottawa
scale for cohort studies (Wells et al.
2011) (Table 2). Studies’ quality was
rated on a scale from 0 (high risk of
bias) to 10 (low risk of bias) for
cross-sectional and case–control
studies, and 0 (high risk of bias) to 9
(low risk of bias) for cohort studies.
Those studies that presented sum-
mary score above the median were
considered to have low risk of bias.
The criteria were as follows: ade-
quate definition of cases, representa-
tion cases, selection of controls,
definition of controls, comparability
of cases and controls based on study
design, ascertainment of exposure,
same method of exposure for cases
and controls, and rate of non-
response. For cross-sectional and
218 Ara

ujo et al.
Fig. 1. Flow diagram.
case–control studies, each item could
be awarded one point, except the
items comparability (2 points could
be awarded for a maximum of two
adjusted confounders) and ascertain
of exposure (one point for secure
record to access of depression and
one point for blinding of periodontal
condition). Non-response rate could
be awarded just one point for cross-
sectional and case–control studies. A
case–control study awarded one
point if rate of non-respondents was
equal for cases and controls. A
cross-sectional study awarded one
point if non-response rate was
described. For cohort studies, each
item of the scale could be awarded
one point. Only the item comparabil-
ity could be awarded two points for
a maximum of two adjusted con-
founders in the analysis. Disagree-
ments between the reviewers in
relation to quality assessment were
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
resolved by consensus or consulting
a third reviewer.
Data extraction
The extraction of data was indepen-
dently performed by two reviewers
(C.C.M and F.O.C) and was based
on: study classification, country and
publication language, sample size, age
at examination, diagnostic criteria for
periodontitis, diagnostic criteria for
 Depression and periodontitis 221

Table 2. Quality assessment criteria used for cohort study through Newcastle–Ottawa Scale inflammation (Solis et al. 2004, 2014,
for cohort studies. Johannsen et al. 2006), subgingival
Cohort calculus (Moss et al. 1996, Genco
Moss et al. (1996) [157] et al. 1999) and number of present
teeth (Persson et al. 2003, Ng &
Selection Leung 2006). The following criteria
(1) Representativeness of the exposed cohort were less frequently used: papillary
(a) Truly representative of the average _____(describe) b*
bleeding index (Saletu et al. 2005),
in the community*
(b) Somewhat representative of the average ____ in
approximal plaque index (Saletu
the community* et al. 2005), bone loss in radiographs
(c) Selected group of users, e.g. nurses, volunteers (Saletu et al. 2005), vertical inter-
(d) No description of the derivation of the cohort proximal defects in panoramic radio-
(2) Selection of the non-exposed cohort graphs (Persson et al. 2003), calculus
(a) Drawn from the same community as the exposed a* (Ng & Leung 2006), gingival recession
cohort* (Ng & Leung 2006), Community Peri-
(b) No description of the derivation of the non-exposed odontal Index (Moss et al. 1996),
cohort dental plaque (Johannsen et al. 2006),
(3) Ascertainment of exposure
missing teeth (Solis et al. 2004, 2014),
(a) Secure record (e.g. surgical records)* a*
(b) Structured interview* radiographic alveolar crestal height
(c) Written self report (Genco et al. 1999), gingival bleeding
(d) No description (Moss et al. 1996) and Periodontal
(4) Demonstration that outcome of interest was not present Index (Luca et al. 2014).
at start of study
(a) Yes* b
Diagnostic criteria for depression
(b) No
Comparability Table 3 presents detailed informa-
(1) Comparability of cohorts on the basis of the design or tion of the diagnostic criteria for
analysis
depression. Instruments used for the
(a) Study controls for one confounder* a*
(b) Study does not control for confounder* b*
diagnostic of depression varied:
Outcome Geriatric Depression Scale (Persson
(1) Assessment of outcome et al. 2003, Mendes et al. 2013),
(a) Independent blind assessment* b* Zung Self-Rating Depression Scale
(b) Record linkage* (Saletu et al. 2005, Abahneh et al.
(c) Self report 2010), Diagnostic and Statistical
(d) No description Manual for Mental Disorders
(2) Was follow-up long enough for outcomes to occur (Johannsen et al. 2006, 2007, Solis
(a) Yes (select an adequate follow-up period for outcome of b et al. 2014), Multidimensional Cop-
interest)*
ing Inventory – COPE (Moss et al.
(b) No
(3) Adequacy of follow-up cohorts 1996, Ng & Leung 2006), Life
(a) Complete follow-up – all subjects accounted for * c Events Scale (Genco et al. 1999,
(b) Subjects lost to follow-up unlikely to introduce bias – Castro et al. 2006), Beck Depression
small number lost <20* Inventory (Solis et al. 2004, Castro
(c) Follow-up rate <80% et al. 2006), Brief Symptom Inven-
(d) No statement tory (Moss et al. 1996, Genco et al.
Summary Score (risk of bias) 6/9 (low) 1999), Daily Strains Scale (Moss
*awarded 1 point. et al. 1996), Hamilton Depression
Scale (Saletu et al. 2005, Luca et al.
pant age was defined by a mean son et al. 2003, Ng & Leung 2006, 2014, Solis et al. 2014) and World
value of 42 years in the case group Luca et al. 2014) that did not report Health Organization Composite
and 54.5 years in the control group CAL. Other common parameter was International Diagnostic Interview
(Johannsen et al. 2006). In another bleeding on probing (BOP) used in (CIDI-Auto) (Khambaty & Stewart
study, the participant age was five studies (Genco et al. 1999, Castro 2013). Some studies used combined
defined as ≥60 years (Mendes et al. et al. 2006, Johannsen et al. 2006, instruments: Life Event Question-
2013). The studies comprised sample 2007, Ng & Leung 2006), and naire, Social Readjustment Rating
sizes from 45 to 1,979 individuals. supragingival plaque used in three Scale, Symptom Checklist-90,
studies (Moss et al. 1996, Genco Depression Anxiety Stress Scales-
et al. 1999, Rosania et al. 2009). State, Depression Anxiety Stress
Diagnostic criteria for periodontitis
Other indexes were also used: gingival Scales-Trait, Problems of Every Day
Several diagnostic criteria for peri- index (Johannsen et al. 2007, Abah- Living Scale of Pearlin and Schooler
odontitis were used (Table 3). The neh et al. 2010, Luca et al. 2014, (Ng & Leung 2006); Derogatis Stress
most common used clinical parame- Solis et al. 2014), plaque index (Solis Profile, Center for Epidemiologic
ters were PD and CAL, both used in et al. 2004, 2014, Abahneh et al. Studies Depression Scale (Rosania
all studies, except three studies (Pers- 2010, Luca et al. 2014), gingival et al. 2009); Beck Anxiety Inventory,
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
220 Ara

ujo et al.

5/10 (high)
depression, exposure to risk factors

Johannsen

(2006)
et al.
(Table 3).

[91]

c
Statistical methods and data synthesis

Johannsen
The Comprehensive Meta-Analysis

(2007)

(high)
et al.

5/10
[57]

c
Program (Biostat, Englewood, USA)
was used for meta-analysis. A sensi-
Case–control tivity test was conducted to test con-

(2014)

(low)
6/10
et al.
sistency of data. Heterogeneity was
Solis

c
evaluated by I2 statistics (I2 statistics
quantifies the proportion of total
(2005)
Saletu

(low)
et al.

[101]

7/10
variation in the estimates of treat-

c
ment effect that is due to hetero-
geneity between studies) (Higgins &
Castro

(2006)

(low)
et al.

7/10
[99]

Thompson 2002), it was determined

c

a random effect model for moderate

to substantial heterogeneity (between
(2014)

(low)
7/10
et al.
Luca

a*

30 and 75%) and a fixed effect

model when heterogeneity was <30%
(Higgins & Green 2015). The fixed
Genco

(1999)

(low)
et al.

[150]

7/10
c

effect model considers that all stud-

ies in the meta-analysis share a com-
Persson

mon true effect, whereas the random

(2003)

(low)
et al.

[119]

effect model considers a variation in

7/10

true effects across studies (Boren-

c

stein et al. 2005). Meta-analysis was

Rosania

(2009)

(high)
et al.

7/10

not conducted if statistical hetero-

[71]

geneity (I2) was >75% (Higgins &

Green 2015). Outcome (periodonti-
Abahneh

tis) was dichotomized in the presence

(2010)

(low)
et al.

7/10
[56]
Cross-sectional

or absence as described by the

c

authors. Seven cross-sectional studies

(Genco et al. 1999, Persson et al.
Leung
(2006)
Ng &

(low)
8/10
[89]

2003, Solis et al. 2004, Ng & Leung

b*

2006, Abahneh et al. 2010, Kham-

baty & Stewart 2013, Mendes et al.
(2004)

(low)
et al.

[114]
Solis

8/10
b*

2013) were included in the quantita-

tive synthesis for meta-analysis.
Summary effect measures, 95% con-
Mendes

(2013)

(low)
et al.

8/10
[14]

fidence intervals (CI), odds ratio

b*

(OR) and p-values were described in

forest plots (Fig. 2).
Khambaty &
Stewart
(2013)

(low)
9/10
b*
[5]

Results

Search and selection results

(b) Non respondents described (only for
(a) Same rate for both groups (only for

Fifteen studies were included in the

(c) Rate different and no designation

present systematic review: eight cross-

sectional studies, six case–control
studies and one cohort study (Fig. 1).
cross-sectional studies)*

Summary Score (risk of bias)

case–control studies)*

General studies characteristics

Detailed information regarding pop-

ulation characteristics, sample size,
Table 1. (continued)

*awarded 1 point.

periodontal status, depression status

and study design is summarized in
Table 3.
The studies enrolled populations
from age groups between 15 and
82 years. In one study, the partici-
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
 Depression and periodontitis 221

Table 2. Quality assessment criteria used for cohort study through Newcastle–Ottawa Scale inflammation (Solis et al. 2004, 2014,
for cohort studies. Johannsen et al. 2006), subgingival
Cohort calculus (Moss et al. 1996, Genco
Moss et al. (1996) [157] et al. 1999) and number of present
teeth (Persson et al. 2003, Ng &
Selection Leung 2006). The following criteria
(1) Representativeness of the exposed cohort were less frequently used: papillary
(a) Truly representative of the average _____(describe) b*
bleeding index (Saletu et al. 2005),
in the community*
(b) Somewhat representative of the average ____ in
approximal plaque index (Saletu
the community* et al. 2005), bone loss in radiographs
(c) Selected group of users, e.g. nurses, volunteers (Saletu et al. 2005), vertical inter-
(d) No description of the derivation of the cohort proximal defects in panoramic radio-
(2) Selection of the non-exposed cohort graphs (Persson et al. 2003), calculus
(a) Drawn from the same community as the exposed a* (Ng & Leung 2006), gingival recession
cohort* (Ng & Leung 2006), Community Peri-
(b) No description of the derivation of the non-exposed odontal Index (Moss et al. 1996),
cohort dental plaque (Johannsen et al. 2006),
(3) Ascertainment of exposure
missing teeth (Solis et al. 2004, 2014),
(a) Secure record (e.g. surgical records)* a*
(b) Structured interview* radiographic alveolar crestal height
(c) Written self report (Genco et al. 1999), gingival bleeding
(d) No description (Moss et al. 1996) and Periodontal
(4) Demonstration that outcome of interest was not present Index (Luca et al. 2014).
at start of study
(a) Yes* b
Diagnostic criteria for depression
(b) No
Comparability Table 3 presents detailed informa-
(1) Comparability of cohorts on the basis of the design or tion of the diagnostic criteria for
analysis
depression. Instruments used for the
(a) Study controls for one confounder* a*
(b) Study does not control for confounder* b*
diagnostic of depression varied:
Outcome Geriatric Depression Scale (Persson
(1) Assessment of outcome et al. 2003, Mendes et al. 2013),
(a) Independent blind assessment* b* Zung Self-Rating Depression Scale
(b) Record linkage* (Saletu et al. 2005, Abahneh et al.
(c) Self report 2010), Diagnostic and Statistical
(d) No description Manual for Mental Disorders
(2) Was follow-up long enough for outcomes to occur (Johannsen et al. 2006, 2007, Solis
(a) Yes (select an adequate follow-up period for outcome of b et al. 2014), Multidimensional Cop-
interest)*
ing Inventory – COPE (Moss et al.
(b) No
(3) Adequacy of follow-up cohorts 1996, Ng & Leung 2006), Life
(a) Complete follow-up – all subjects accounted for * c Events Scale (Genco et al. 1999,
(b) Subjects lost to follow-up unlikely to introduce bias – Castro et al. 2006), Beck Depression
small number lost <20* Inventory (Solis et al. 2004, Castro
(c) Follow-up rate <80% et al. 2006), Brief Symptom Inven-
(d) No statement tory (Moss et al. 1996, Genco et al.
Summary Score (risk of bias) 6/9 (low) 1999), Daily Strains Scale (Moss
*awarded 1 point. et al. 1996), Hamilton Depression
Scale (Saletu et al. 2005, Luca et al.
pant age was defined by a mean son et al. 2003, Ng & Leung 2006, 2014, Solis et al. 2014) and World
value of 42 years in the case group Luca et al. 2014) that did not report Health Organization Composite
and 54.5 years in the control group CAL. Other common parameter was International Diagnostic Interview
(Johannsen et al. 2006). In another bleeding on probing (BOP) used in (CIDI-Auto) (Khambaty & Stewart
study, the participant age was five studies (Genco et al. 1999, Castro 2013). Some studies used combined
defined as ≥60 years (Mendes et al. et al. 2006, Johannsen et al. 2006, instruments: Life Event Question-
2013). The studies comprised sample 2007, Ng & Leung 2006), and naire, Social Readjustment Rating
sizes from 45 to 1,979 individuals. supragingival plaque used in three Scale, Symptom Checklist-90,
studies (Moss et al. 1996, Genco Depression Anxiety Stress Scales-
et al. 1999, Rosania et al. 2009). State, Depression Anxiety Stress
Diagnostic criteria for periodontitis
Other indexes were also used: gingival Scales-Trait, Problems of Every Day
Several diagnostic criteria for peri- index (Johannsen et al. 2007, Abah- Living Scale of Pearlin and Schooler
odontitis were used (Table 3). The neh et al. 2010, Luca et al. 2014, (Ng & Leung 2006); Derogatis Stress
most common used clinical parame- Solis et al. 2014), plaque index (Solis Profile, Center for Epidemiologic
ters were PD and CAL, both used in et al. 2004, 2014, Abahneh et al. Studies Depression Scale (Rosania
all studies, except three studies (Pers- 2010, Luca et al. 2014), gingival et al. 2009); Beck Anxiety Inventory,
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
 Table 3. Data extraction.
222

Author Study Country Sample size Age at Diagnosis criteria for Diagnosis criteria Exposure
classifications examination periodontal disease for depression

Genco et al. Cross-sectional USA 1,426 subjects (741 25–74 years Supragingival Plaque, BOP, Life Event Scale, Measures An increase in CAL was
Ara

(1999) women, 685 men) Subgingival calculus, PD, of Chronic Stress, BSI, significantly associated to
CAL (6 sites, 0 to 1 mm: Coping Styles and depression (OR: 1.51, 95%
healthy; 1.1 to 2.0 mm: low; Strategies CI: 1.02–2.2).
2.1 to 3.0 mm: moderate; 3.1
ujo et al.

to 4.0 mm: high; 4.1 to

8.0 mm: severe); radiographic
ACH (0.4 to 1.9 mm:
healthy; 2.0 to 2.9 mm: low;
3.0 to 3.9 mm: moderate; ≥
4.0 mm: severe.
Persson et al. Cross-sectional USA 701 subjects (414 60–75 years PD (≥5 mm), Number of GDS and Depression Depression was not associated
(2003) women, 287 men. standing teeth, Panoramic self-reported with periodontitis (OR: 0.85;
radiographic (vertical inter- 95% CI: 0.58–1.23).
proximal defects ≥ 3 mm)
Solis et al. Cross-sectional Brazil 153 subjects. 19–67 years PI, GI, PD (≥5 mm), CAL BDI Logistic regression analysis model
(2004) 106 controls (71 (≥6 mm); MT. that included age, plaque index,
women, 35 men) smoking and psychological
47 cases (28 factors showed that patients with
women, 19 men) depression symptoms (OR: 0.57,
95% CI: 0.15–2.21) were not at a
greater risk of developing
established periodontitis.
Ng & Leung Cross-sectional China 1,000 subjects, 531 25–64 years CAL, CI; BOP; REC; PD LEQ, SRRS, Problems of CAL was statistically associated
(2006) women and 469 were probed at six sites; and Everyday Living Scale of with SCL-90 (OR: 1.41, 95% CI:
men Number of standing teeth; Pearlin and Schooler; 1.17–2.78) and depression trait
The criteria for diagnosis of SCL-90; DASS-S; COPE; (OR: 1.62; 95% CI: 1.15–2.35).
periodontal disease were not cited. DASS-T
Rosania et al. Cross-sectional USA 45 subjects (31 45–82 years Recession, PD, CAL. The DSP, CES-D Depression were correlated with
(2009) women, 14 men) criteria for diagnosis of measures of periodontal disease
periodontal disease were (p = 0.018).
not cited.
Abahneh et al. Cross-sectional Jordan, 666 subjects 15–62 years PD, CAL, GIx, PI. The ZSDS There was no statistically
(2010) criteria for diagnosis of significant association between
periodontal disease were susceptibility to depression
not cited. symptoms and periodontal
parameters, including PD (OR
adjusted: 0.87. 95% CI: 0.56–
1.34), CAL (OR adjusted: 0.71.
0.48–1.05), PI and GI (p > 0.05).
Khambaty & Cross-sectional USA 1,979 subjects 20–39 years PD, CAL CIDI-Auto Depressive disorder were not
Stewart (2013) related to periodontal disease
(OR: 0.79, 95% CI: 0.31–1.97,
p = 0.61).

© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
 Table 3. (continued)
Author Study Country Sample size Age at Diagnosis criteria for Diagnosis criteria Exposure
classifications examination periodontal disease for depression

Mendes et al. Cross-sectional Brazil 200 subjects ≥60 years CPI, CAL (one site with PD ≥ GDS Findings showed no significant
(2013) 4 mm, and at last one site association between depression
with CAL ≥4 mm). and periodontal disease (OR:
0.837; 95% CI: 0.317–2.207).
Saletu et al. Case–control Austrian 81 subjects 23–70 years PD, CAL, PBI, API, HAMD, ZSDS. Partial correlation analyses
(2005) 40 cases with 32–64 years radiographically evident loss between psychometric measures
periodontitis; 16 of attachment (slight and dental variables revealed
women, 24 men periodontitis: attachment loss positive correlations of
41 controls; 18 of 1–2 mm and/or a bone periodontal disease severity/CAL
women, 23 men. loss of 10–30%, moderate with the depression/anxiety.
periodontitis: attachment loss (p < 0.05).
of up to 4 mm and/or a bone
loss of 30–50%; severe
periodontitis: attachment loss
of ≥5 mm and/or a bone loss
of ≥50%.
Castro et al. Case–control Brazil 165 subjects (96 35–60 years PD, CAL and BOP were LES, BAI, STAI, BDI The multivariate model showed
(2006) cases with probed at six sites, and no association between
periodontitis number of teeth. psychometric instrument for
69 controls) CAL ≥4 mm and BOP in at depression and the clinical
least 10 teeth, and parameters for periodontal

© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
PD ≥6 mm in at least 5 teeth. disease: BAI: (OR: 0.94; 95%
CI: 0.86–1.04); BDI: (OR: 0.96;
95% CI: 0.88–1.05); STAI for
anxiety trace (OR: 1.003; 95%
CI: 0.95–1.06)
Johannsen et al. Case–control Sweden 72 subjects, (43 Case group Dental plaque (lingual and DSM-IV Bonferroni’s test adjusted for age
(2006) women with stress- (42.0 years); buccal surfaces – 1 = plaque, and smoking showed that
related depression control group 0 = no plaque), GI from L€ oe, amount of plaque (p < 0.003)
and exhaustion (54.5 years). BOP, PD, CAL were probed and GI (p < 0.001) were higher
and 29 controls). at six sites, and number of in patients with depression when
teeth. compared with controls.
The criteria for diagnosis of
periodontal disease were not
cited.
Johannsen et al. Case–control Sweden 49 subjects (20 40–50 years PD, CAL, GIx, BOP, Number DSM-IV The depressed patients had
(2007) women with of standing teeth significantly higher gingival
depression, 29 inflammation (p < 0.001), and
women without deeper pockets (p < 0.003), than
depression) the healthy controls, after
adjusting for age and smoking.
Depression and periodontitis
223
 224
Ara

Table 3. (continued)
Author Study Country Sample size Age at Diagnosis criteria for Diagnosis criteria Exposure
classifications examination periodontal disease for depression
ujo et al.

Solis et al. Case–control Brazil 72 subjects (36 with 36 years (3) CAL, PD, PI, GIx, missing DSM-IV There was no statistically
(2014) major depressive teeth HAMD significant difference between
disorder, 36 cases and controls and any
without depression) periodontal parameter (CAL,
PD, PI, GIx, missing teeth,
p > 0.05).
Luca et al. Case–control Italy 90 subjects (50 56.1 (15.9) GIx, PI, PeIx rated in: HAMD Depressed patients had
(2014) depressed patients, 0–0.2 = excellent; significantly more chance to have
40 without 0.3–0.9 = good; fair PI (OR: 13.93; 95%
depression) 1.0–1.9 = fair; CI: 2.77–69.88); fair PeIx
2.0–4.9 = poor; (OR: 4.43; 95% CI: 1.42–13.75)
5.0–8.0 = very poor) compared to controls in bivariate
analysis.
Moss et al. Cohort USA 148 subjects (71 25–74 years Supragingival Plaque, GB, Daily Strains Scale, BSI, Depression trait of BSI was not
(1996) cases with Subgingival calculus, PD COPE different between cases and
periodontitis, 77 (two or more inter-proximal controls (OR: 1.28; 95%
controls) sites from different teeth with CI: 0.56–2.95).
CAL ≥6 mm and at last one
additional site with a
PD ≥5 mm. Antibody for
Bacteroides forsythus (IgG
BF); Porphyromonas
gingivalis (IgG PG) and
Actinobacillus
actinomycetemcomitans (IgG
AA).

CI, Calculus Index; BOP, bleeding on probing; REC, recession; PD, probing depth; CAL, clinical attachment level; GI, gingival inflammation; GIx, gingival index; PI, plaque index; MT,
missing teeth; GB, gingival bleeding; PBI, papillary bleeding index; ACH, radiographic alveolar crestal height; CPI, community periodontal index; PeIx, periodontal index; OHI-S, simplified
oral hygiene index; API, Lange approximal plaque index; LEQ, life event questionnaire; SRRS, social readjustment rating scale; SCL-90, Symptom Checklist-90; DASS-S, depression anxiety
stress scales-state; COPE, COPE inventory; DASS-T, depression anxiety stress scales-trait; LES, life events scale; BAI, beck anxiety inventory; STAI, state-trait anxiety inventory; BDI, beck
depression inventory; DSM-IV, diagnostic and statistical manual of mental disorders, 4th edition; HAMD, Hamilton depression scale; GDS, geriatric depression scale; BSI, brief symptom
inventory; HADS, depression subscale of the hospital anxiety and depression scale; DSP, Derogatis stress profile; CES-D, centre for epidemiologic studies depression scale; CIDI-Auto,
World Health Organization Composite International Diagnostic Interview, auto version 2.1; ZSDS, Zung Self-Rating Depression Scale; DSM-IV, Diagnostic and Statistical Manual for
Mental Disorders, Fourth Edition.

© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Fig. 2. Meta-analysis of seven cross-sectional studies evaluating depression and peri-
odontitis. Outcome was a dichotomous variable (the presence/absence of periodonti-
tis). Sensitivity test conducted did not change the summary effect model. I2 = 60.34%.
Random effect model.
State-Trait Anxiety Inventory
(Castro et al. 2006); Measures of
Chronics Stress, Coping Styles and
Strategies (Genco et al. 1999).
Quality assessment
Quality criteria for methodological
assessment are shown in Table 1 for
cross-sectional and case–control
studies and in Table 2 for cohort
studies. Most studies had low risk of
bias and reached a score from 8 to 7
points, except two case–control stud-
ies (Johannsen et al. 2006, 2007) that
had high risk of bias. These studies
are from the same research group
and scored 5 points. The studies pre-
sented a case–control design where
cases were defined from an insurance
company with employees with his-
tory of depression, whereas controls
were from the general population
(risk of bias in selection of cases;
controls were not from the same
community as cases). The studies fail
to ascertain depression in controls
(risk of bias once controls were not
submitted to a validated instrument
to guarantee they were free of
depression). There was no blinding
of examiners for periodontal and
depression condition and rate of
non-respondents was different for
cases and controls.
Major bias of cross-sectional and
case–control studies were: risk of
bias in selection of samples. The
majority of studies used convenience
samples from dental schools, hospi-
tals, insurance companies, advertise-
ment recruitment and
neighbourhood. Only one study
(Khambaty & Stewart 2013) used a
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
representative sample from US
NHANES. No study mentioned
blinding of examiners and many
studies did not report non-response
rate (Genco et al. 1999, Persson
et al. 2003, Saletu et al. 2005, Castro
et al. 2006, Johannsen et al. 2006,
2007, Rosania et al. 2009, Abahneh
et al. 2010).
Favourable points in those stud-
ies were that all adjusted the con-
founders in the statistical analysis:
age, gender, smoking and educa-
tional level. Periodontal condition
was defined by clinical examination
and depression was evaluated by
instruments (except Johannsen et al.
2006, 2007 where controls were not
submitted to depression tests).
Moss et al. 1996 derived from a
cohort sample. The study started
from a sample of subjects followed
based on the periodontal status, not
on the exposure (depression).
Depression was single evaluated at
the time of the study raising the
characteristic of a cross-sectional
design nested in a cohort sample.
There is no statement that the out-
come of interest (periodontitis) was
not present at the start of the study.
Moreover, the follow-up period does
not guarantee that there was time
enough for depression to occur.
Data synthesis
Six of the selected studies reported a
positive significant association
between depression and clinical
parameters for periodontitis
(p < 0.05), being three cross-sec-
tional (Genco et al. 1999, Saletu
et al. 2005, Ng & Leung 2006,
Depression and periodontitis 225
Rosania et al. 2009) and three case–
control studies (Johannsen et al.
2007, Luca et al. 2014).
Nine studies showed no associa-
tion between depression and peri-
odontitis, being five cross-sectional
(Persson et al. 2003, Solis et al.
2004, Abahneh et al. 2010, Kham-
baty & Stewart 2013, Mendes et al.
2013), three case–control (Castro
et al. 2006, Johannsen et al. 2006,
Luca et al. 2014, Solis et al. 2014),
and one cohort study (Moss et al.
1996). Johannsen et al. (2006)
showed no significant association for
BOP, PD, CAL and number of
teeth, but for dental plaque and gin-
gival inflammation there was a sig-
nificant difference.
Meta-analysis
Figure 2 shows the meta-analysis of
seven cross-sectional studies (Genco
et al. 1999, Persson et al. 2003, Solis
et al. 2004, Ng & Leung 2006,
Abahneh et al. 2010, Khambaty &
Stewart 2013, Mendes et al. 2013).
There was no significant association
between depression and periodontitis
(OR = 1.03, 95% CI = 0.75–1.41).
Meta-analysis for case–control stud-
ies was performed (Castro et al.
2006, Luca et al. 2014) but the high
statistical heterogeneity (87.48%)
precluded meta-analysis.
Discussion
A robust, and presumably causal,
association exists between stressful
life events and major depressive epi-
sodes. The neurobiology underlying
stress and depression is thought to
result from molecular and cellular
abnormalities that interact with
genetic and environmental factors
(Warren et al. 2014).
Several pathophysiologic mecha-
nisms may explain the association of
chronic stress and depression with
systemic diseases (Joels & Baram
2009, Miller et al. 2009, Shelton
et al. 2011, Warren et al. 2014).
Studies demonstrated that stress and
depression are associated with atro-
phy and loss of function of limbic
brain regions that control mood and
depression, including the prefrontal
cortex and the hippocampus
(Krishnan & Nestler 2008, McEwen
2008, Duman & Voleti 2012). More-
over, animal studies suggested that
226 Ara

ujo et al.
chronic stress induces vascular
inflammation through elevations in
circulating proinflammatory cytoki-
nes (Warren et al. 2014).
Therefore, chronic stress and
depression have been hypothesized
to reduce immune responsiveness,
resulting in a higher rate of infection
with pathogenic organisms and a
greater degree of periodontal tissue
destruction. In general, the evidence
is consistent with the hypothesis that
stress can modify the host immune
defence and permit the progression
of periodontal infections in patients
susceptible to periodontitis (Warren
et al. 2014). However, substantial
evidence also indicates that these
conditions can mediate risk for dis-
ease, including periodontitis, through
changes in health-related behaviours,
such as oral hygiene, smoking and
diet (Genco et al. 1998, Alekseju-
niene et al. 2002).
In this study, the meta-analysis of
seven cross-sectional studies showed
absence of association between
depression and periodontitis. Meta-
analysis had high statistical
(I2 = 60.34%) and clinical hetero-
geneity, as studies diagnosed peri-
odontitis from several clinical
periodontal parameters. Also, instru-
ments and cut-off points used to
detect depression varied among the
studies, showing also methodological
heterogeneity. The statistical,
methodological and clinical hetero-
geneity weakens the evidence of the
summary effect measure. Hence,
the meaningful interpretation of the
meta-analysis should be cautious.
Moreover, meta-analysis of observa-
tional studies may be subject to vari-
ations if potential biases of included
studies could be adjusted (Thompson
et al. 2011). In other words, if there
were no potential biases in the
included studies, the outcome of
meta-analysis would be different.
For this reason, an overall quantita-
tive conclusion using meta-analysis
can be avoided because of the intan-
gible nature of some of the biases,
the incompatibility of methods of
presenting results in different
articles, and the fact that relevant
information is often missing in publi-
cations (Thompson et al. 2011). A
qualitative synthesis would be more
reliable than the result of meta-ana-
lysis. However, even qualitatively,
results of individual studies raise
doubts of the role of depression on
periodontitis due great methodologi-
cal and clinical differences among
studies.
The included studies were pre-
dominantly in English language.
Although some language bias can be
expected, the included studies were
conducted in several countries with
different cultures, demonstrating
geographical diversity.
Results of nine individual studies
were in agreement with meta-analy-
sis, five studies cross-sectional
(Persson et al. 2003, Solis et al.
2004, Abahneh et al. 2010, Kham-
baty & Stewart 2013, Mendes et al.
2013), three case–control studies
(Castro et al. 2006, Johannsen et al.
2006, Solis et al. 2014) and one
cohort study (Moss et al. 1996).
Cross-sectional studies have the
lower level of scientific evidence
when compared to case–control and
cohort studies. Although cross-sec-
tional designs are not the best way
to define causal risk factors,
(Thompson et al. 2011), that does
not invalidate their findings.
Other methodological limitations
relation to the studies included in
the present systematic review and
meta-analysis should be considered,
such as different criteria for
periodontitis definition, different
instruments for measuring depres-
sion, sample size and age of the
participants.
The methodological approaches
used in studies were quite different.
These differences may be responsible
for the conflicting results among
some studies. Such differences
involved different levels of severity
of periodontitis and the clinical
parameters used for periodontal con-
dition.
Several periodontal parameters
were statistically associated with
depression: CAL (Genco et al. 1999,
Saletu et al. 2005, Ng & Leung
2006, Rosania et al. 2009), dental
plaque (Johannsen et al. 2006),
gingival inflammation (Johannsen
et al. 2006, 2007), deep pockets
(Johannsen et al. 2007) and peri-
odontal index (Luca et al. 2014).
Even though the several clinical peri-
odontal parameters hampers a more
robust conclusion of the association
between depression and periodonti-
tis, CAL seems to be the most
common clinical parameter associ-
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
ated with depression. Most positive
association was derived mainly from
cross-sectional studies (Genco et al.
1999, Ng & Leung 2006, Rosania
et al. 2009) and a single case–control
(Saletu et al. 2005).
There is a great disagreement
regarding the establishment of clear
criteria to determine periodontitis
(Blaizot et al. 2009) and different
levels of periodontal attachment loss
and inflammation that are essential
to guarantee a clear difference in
exposure among groups. In the eval-
uated studies, several criteria were
applied to characterize periodontitis.
Examples of different criteria to
define periodontitis were reported by
Costa et al. (2009) that demon-
strated a high impact on the preva-
lence and extent of periodontitis.
Beck & L€ oe (1993) stated that a
periodontitis definition might include
reliable extent and severity indicators
of attachment loss. In this sense,
efforts should be directed towards
standardizing periodontitis defini-
tions in these association studies.
In the selected studies, several
instruments have been used to
determine depression; some with the
purpose of diagnosing, measuring or
even identifying symptoms of depres-
sion which determines controversial
characterization of the real state of
depression: BDI (Genco et al. 1999,
Solis et al. 2004), GDS (Persson
et al. 2003, Mendes et al. 2013),
SCL-90 (Ng & Leung 2006), ZSDS
(Abahneh et al. 2010) and CIDI-
Auto (Khambaty & Stewart 2013).
Moreover, distinct cut-off points in
these instruments were adopted in
some studies. It is also important to
note that depression can have a
greater character of temporality,
being a disease of acute, intermittent,
or chronic evolution. This fact
hampers a real interpretation of
depression as an exposure.
Another critical issue in some
selected studies is related to the age of
participants that can be a potential
confounder in the association under
investigation. Some studies such as
Abahneh et al. (2010), Solis et al.
(2004), Khambaty & Stewart (2013),
and Ng & Leung (2006) included
young individuals in their sample,
varying from 15 to 25 years old.
Regarding methodological qual-
ity, all studies except one (Khambaty
& Stewart 2013) presented a conve-

nience sample that do not ensure
representativeness of the results. No
study reported blinding of examiners
for periodontal status or depression
and many did not report attrition
bias (Moss et al. 1996, Genco et al.
1999, Persson et al. 2003, Saletu
et al. 2005, Castro et al. 2006,
Johannsen et al. 2006, 2007, Rosania
et al. 2009, Abahneh et al. 2010,
Solis et al. 2014). Favourable char-
acteristics were the adjustment of
confunders in statistical analysis of
data and the low risk of bias in the
majority of included studies.
Because both periodontitis and
depression are chronic and multifac-
torial diseases, studies should control
for several potentially confounders
and use sufficient sample size to
determine statistical power. Also, it
is suggested that future studies
should employ both continuous and
categorical assessments of periodon-
tal status (Ide & Papapanou 2013).
Although CAL showed association
with depression in many studies, the
great variety of clinical periodontal
parameters hampers a more definite
conclusion.
Conclusions
Findings from the present system-
atic review showed a great hetero-
geneity among the studies and the
summary effect measure of the
meta-analysis cannot affirm an asso-
ciation between depression and peri-
odontitis. However, the statistical,
methodological and clinical hetero-
geneity weakens the evidence of this
measure. Future prospective studies
with standard methodologies and
designs in distinct populations
should be conducted to investigate
this association.
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Clinical Relevance
Scientific rationale for the study:
Periodontitis and depression are
common chronic diseases occurring
worldwide. This systematic review
and meta-analysis explored the
cross-sectional, case–control and
cohort studies on the association
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Supporting Information
Additional Supporting Information
may be found in the online version
of this article:
between depression and periodonti-
tis.
Principal findings: There are clinical
and methodological heterogeneity
among the studies. The majority of
studies had low risk of bias by
methodological quality assessment.
Meta-analysis of seven cross-sec-
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Appendix S1. Studies excluded on
basis of titles and/or abstracts.
Appendix S2. Studies excluded on
basis of full text – exclusion criteria.
Address:
Fernando Oliveira Costa
Department of Periodontology
School of Dentistry
Federal University of Minas Gerais
Ant^
onio Carlos Avenue, 6627, Pampulha.
PO Box 359
Zip Code 31270-901
Belo Horizonte, Minas Gerais
Brazil
E-mail: focperio@uol.com.br
tional studies showed no significant
association between depression and
periodontitis.
Practical implications: More well-
conducted studies are needed to
confirm the association between
depression and periodontitis.