J Invest Clin Dent. 2017;e12291. wileyonlinelibrary.com/journal/jicd
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1 of 6 https://doi.org/10.1111/jicd.12291© 2017 John Wiley & Sons Australia, Ltd Received: 10 May 2017
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Accepted: 1 July 2017DOI: 10.1111/jicd.12291
R E V I E W A R T I C L E
Periodontics
Use of antidepressive agents as a possibility in the
management of periodontal diseases: A systematic review of
experimental studies
Francisco Wilker Mustafa Gomes Muniz
1|
Iracema Matos Melo
2|
Cassiano Kuchenbecker Rösing
1|
Geanne Matos de Andrade
3|
Ricardo Souza Martins
4|
Maria Mônica Studart Mendes Moreira
4|
Rosimary de Sousa Carvalho
41Department of Periodontology, Federal
University Rio Grande do Sul, Porto Alegre, Brazil
2Department of Periodontology, Federal
University of Ceará, Sobral, Brazil
3
Department of Physiology and Pharmacology, Medicine School, Federal University of Ceará, Fortaleza, Brazil
4Department of Periodontology, Federal
University of Ceará, Fortaleza, Brazil
Correspondence
Mr Francisco Wilker Mustafa Gomes Muniz, Department of Periodontology, Federal University Rio Grande do Sul, Porto Alegre, Brazil.
Email: wilkermustafa@gmail.com
Abstract
Antidepressant agents have anti- inflammatory functions that could be interesting as
adjuvants in periodontal therapy. The aim of the present study was to analyze the ef
-fect of antidepressive drugs in the management of periodontal disease. The MEDLINE,
Scopus, Embase, LILACS, and SciELO databases were searched. To be included, the studies had to be experimental studies; randomized, controlled; double- blinded; or blinded studies. A total of 565 articles were initially searched, of which five were se-lected for the systematic review. All studies used rats, and three different drugs were
evaluated: tianeptine, venlafaxine, and fluoxetine. Two of these studies evaluated the
effect of antidepressive agents in rats submitted to both ligature- induced periodontitis
and depression models, showing that depressive rats had greater alveolar bone loss
(ABL). Only the venlafaxine study was not able to find any significant ABL reduction in
the group that used this antidepressive drug. The other four studies showed
statistically- significant differences, favoring the group with the antidepressant agent. Treatments that are able to modulate the brain- neuroendocrine- immune system could
be used as an adjuvant to periodontal disease management. However, studies on hu
-mans and animals are scarce, limiting the conclusion of a positive effect in the present
systematic review.
K E Y W O R D S
animal, antidepressive agent, depression, periodontal disease, tricyclic
1
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INTRODUCTION
Periodontitis is an inflammatory disease caused by infection of oral
biofilm in the subgingival area, leading to an imbalance in the host
defense system.1 However, the sole presence of bacteria in these
areas is not capable of inducing extensive tissue destruction in all
individuals. This suggests that an adaptive individual response to
some bacterial loads in biofilm occurs without disease progression.2
Immune and inflammatory responses are critical to the pathogenesis
of periodontitis, and are modulated by a number of host- related fac-tors, such as neutrophil and cytokines activities.3,4
In this context, new therapeutic agents have been investigated
that modulate the host response. Thus, reports suggest that some
pharmacological agents, such as antiresorptive agents and drugs that
inhibit inflammatory mediators, reduce inflammatory parameters and
alveolar bone resorption in vivo.5-7
In addition, it has been reported that several diseases and sys
periodontal disease, such as diabetes.8 It is largely known that stress
has been associated as the second main etiological factor for necro
-tizing periodontitis.9,10 Researchers have tried to establish the rela
-tionship between chronic periodontitis and psychological factors. In their study, Johannsen et al11 showed that depressive women had larger plaque accumulation and higher levels of gingival inflamma -tion, interleukin (IL)- 6, and cortisol when compared to non- depressed women. Another cross- sectional study found, through a self- reported questionnaire, that patients with higher depression scores had severe clinical attachment loss than periodontally- healthy individuals.12 However, others studies failed to establish this relationship, conclud
-ing that periodontitis development is not associated with the analyzed
psychological factors.13-15
These controversial results can be confirmed in a systematic review that showed that 57% of the studies found a positive outcome between psychological factors/stress and periodontal disease, while only 14% reported a negative association, and approximately 29% observed a positive outcome only for some characteristics, and a neg
-ative relationship for others.16
Antidepressant treatment contributes to immune regulation, both in cellular and humoral immunity, in patients with major depressive
disorder.17 The xerostomia, related to antidepressive agents, might
play an important role in the periodontitis exacerbation.18 However,
one study found that amitriptyline, clomipramine, and maprotiline exert anti- inflammatory effects,19 which could benefit inflammation related to periodontal disease.
Additionally, the literature reports that tricyclic antidepressants (TCA) are able to reduce the production of pro- inflammatory cyto-kines, such as IL- 1β, tumor necrosis factor- α (TNF- α), and γ- interferon (IFN), meanwhile increasing the levels of another anti- inflammatory cytokine, such as IL- 10.20 Therefore, it can be hypothesized that those drugs could promote improvements in periodontal parameters.
Thus, the purpose of the present systematic review was to analyze
the effect of antidepressive agents in the management of periodontal
disease.
2
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MATERIALS AND METHODS
In the present systematic review, five databases were searched: MEDLINE- PubMed, Scopus, Embase, LILACS, and SciELO. Search terms included “antidepressive agents” OR “antidepressive agents,
second generation” OR “antidepressive agents, tricyclic” OR “antide -pressant” OR “depression” AND “periodontitis” OR “periodontal dis-ease” OR “periodontal diseases”. The literature search was conducted up to 11 June 2017.
Titles and abstracts resulting from the search, as described earlier,
were screened. Retrieval of papers was performed when the titles or
abstracts fulfilled the following criteria:
(a) intervention studies in both humans and animals; (b) randomized, double-blinded, or blinded studies; (c) intervention groups: use of any antidepressant drug;
(d) control groups: use of any placebo agent or controlled technique/ therapy;
(e) outcomes: any periodontal clinical parameter, such as probing depth and clinical attachment level. In case of experimental stud -ies, the measurement of alveolar bone loss (ABL) was necessary.
No language or publication date restrictions were applied. However,
observational studies, case reports, letters, and historical reviews were excluded from the search. Additionally, animal model studies that used any drug, including antidepressant agents, to induce depression were
also excluded. Studies without abstracts, but whose titles suggested that
they could be related to the objective of this systematic review, were also selected, so the full text could be screened for eligibility. All the refer-ences of every selected study were screened for possible eligible studies.
If any missing data were detected, efforts were made to find it by con
-tacting the authors through email.
In trying to reduce the potential bias in the review, screening and
data extraction were performed independently by two reviewers (FWMGM and IMM). Any discrepancies with regard to the exclu-sion and incluexclu-sion of the studies were solved by extensive discusexclu-sion
between the two reviewers. If there was still any doubt, another col -laborator (RSC) was involved in the process.
For data extraction and data synthesis, the authors developed
a spreadsheet specifically for this systematic review. Only studies
involving animals were selected for the present systematic review.
Therefore, the following parameters were extracted from each
selected study: author, country, number of animals involved, anti -depressant used, use of ligature (yes or no), intervention (if any) in the control group, number of days with the ligature placed, number of days the antidepressant was administered, measurement of ABL in each experimental group, and additional information. Due to high heterogeneity among the studies, no meta- analysis was performed.
3
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RESULTS
A total of 565 titles/abstracts were retrieved from the search, of which five were selected based on the criteria previously described (Figure 1). All of the selected studies were written in English, and no clinical trials/human studies were found.
All of the selected experimental studies used adult rats (Wistar or Fischer 344) in the study design. Three different antidepressive drugs were used: tianeptine,21,22 venlafaxine,23 and fluoxetine.24,25 The main
results of these studies are shown in Table 1.
Breivik et al21 evaluated the effect of chronic treatment with
tianeptine in a combined Wistar rat model of experimental periodon
-titis associated with a depression model: the olfactory bulbectomized (OB) rat model. In Breivik et al’s study, animals received two daily ip doses of tianeptine, a modified TCA, 10 mg/kg during the entire experimental period. After 29 days of the first drug administration, periodontitis was induced by ligature, and bulbectomy was performed.
Ligatures were placed around a tooth during the entire experiment,
serving as a retention device for oral microorganisms. Two hours before
injected with lipopolysaccharide (LPS) to induce a robust immune and stress response. Bone loss in OB rats treated with tianeptine was sig -nificantly lower when compared with bone loss in the non- depressed rats. In addition, OB rats treated with tianeptine were able to reduce TNF- α and enhance transforming growth factor(TGF)- β serum levels compared with control rats.
In another study, performed by Breivik et al,22 tianeptine was administered at a daily ip dose of 10 mg/kg for 35 days in the treat-ment group, and a saline solution was administered in the control
group. Both groups had periodontitis induced by ligature on the same day of the first drug administration. Thirty- five days after liga-ture placement, ABL in the treatment group was significantly reduced compared to the controls. In addition, tianeptine- treated rats showed significantly higher plasma levels of TNF- α and TGF- 1β. The treatment group also presented higher IL- 6 and IL- 10 plasma levels, but these values did not reach statistical significance compared to the controls.
One of the selected studies failed to find bone loss protection in rats with ligature- induced periodontitis associated with antidepressive agents.23 In that study, animals were treated orally with venlafaxine (10 or 50 mg/kg/d), a selective serotonin- reuptake inhibitors (SSRI), for 11 days. Ligature was placed 1 hour after the first drug administration. The group that received that lowest dose (10 mg/kg) showed smaller ABL compared to the control group, but these differences did not reach statistical signif -icance. However, the group that received the highest dose (50 mg/kg) showed enhanced ABL compared to the other two groups.
In Branco- de- Almeida et al’s24 study, fluoxetine was administered to Wistar rats by gavage at a dose of 20 mg/kg, 1 hour before liga -ture placement, and daily for 3 or 15 days, according to the analysis of inflammatory or morphometric parameters, respectively. Three days after ligature placement, fluoxetine significantly reduced IL- 1β and cyclooxygenase- 2 mRNA expression in gingival tissues compared to the ligature- alone group. After 15 days, the group treated with
fluoxetine showed significantly lower levels of ABL when compared to the control group.
In their study, Aguiar et al25 used fluoxetine in the context of con -ditioned fear stress (CFS), a depression model. Aguiar et al’s study used ligature- induced periodontitis for 40 days in all animals, and adminis-tered fluoxetine daily for 19 days at a dose of 20 mg/kg by gavage. Mean ABL was significantly higher in the group subjected only to CFS when compared to the non- stressed group. The stressed group treated with fluoxetine did not differ from the non- stressed group, showing that, even in presence of stress induction, fluoxetine decreased ABL.
4
|
DISCUSSION
The aim of the present study was to review the published literature
testing the effects of antidepressant drugs in periodontal disease. According to the methodological criteria, no human studies were found. This probably demonstrates that the topic is still incipient. This
lack of evidence is probably also related to the difficulties in designing ethically- acceptable clinical trials.
Furthermore, only five experimental studies were selected in the
present review, and just two of these evaluated the effect of antide -pressive agents in rats subjected to both ligature- induced periodon-titis and depression models.21,25 It should be emphasized that these
animal studies dealt with the etiopathogenesis of periodontal destruc -tion, rather than with therapeutic approaches. Additionally, no meta- analysis could be performed, as the studies were too different in terms
of design, drugs, and depression models used.
One of this studies observed that OB rats presented greater ABL compared with sham- operated rats.21 It has been hypothesized that some forms of depression increase pro- inflammatory cytokines in the brain.26 To consider this hypothesis correct, the antidepressant should
F I G U R E 1 Flowchart of the studies during the review
Potentially-relevant articles identified
with electronic search after
duplication elimination
n = 565
Potentially-relevant articles for
full-text analysis
n = 91
Excluded abstracts
n = 474
Excluded articles
• Observational study = 31
• Report cases = 5
• Review = 15
• Used a drug to induce depression = 2
• Uncontrolled study = 3
• No periodontal outcome was assessed = 9
• Antidepressant agents were not used = 21 Articles included for
methodological appraisal
alleviate the depressed mood and reduce the brain expression of pro- inflammatory cytokines.20,27 However, Breivik et al21 demonstrated
that OB rats responded to an in vivo LPS challenge, which provides
a useful model to easily assess central actions of cytokines,20 with reduced blood levels of TNF- α and increased levels of TGF- 1β.
The antidepressants addressed in the selected studies were tianep -tine, venlafaxine, and fluoxetine. Tianeptine is a TCA, whereas venla-faxine and fluoxetine are SSRI. In the literature, it seems that chronic treatment with TCA is more effective to attenuate LPS- induced sick-ness than treatment with SSRI in animal models, although SSRI can be
T A B L E 1 Main results of the selected studies
Study (Country) Therapy used
Experimental time and drug
administration Main results P- value
Breivik et al21 (Norway)
Experiment 1:
Group 1: Sham – OB + EP Group 2: OB + EP
Experiment 1: 62 d Experiment 1:
Group 1: mean ABL: 0.90 ± 0.13 mm Group 2: mean ABL: 1.06 ± 0.25 mm
<.01
Experiment 2:
Group 1: OB + EP + tianeptine 10 mg/kg
Group 2: OB + EP + saline Group 3: EP + saline
Experiment 2: 50 d tianeptine was administered twice daily starting 29 d before OB and EP
Experiment 2:
Group 1: mean ABL: 0.79 ± 0.08 mm Group 2: mean ABL: 0.96 ± 0.09 mm Group 3: mean ABL: 0.81 ± 0.05 mm
<.001 (between groups 1 & 2, & groups 2 & 3)
Breivik et al22
(Norway)
Only experiment 2 is described: Group 1: EP + tianeptine 10 mg/
kg
Group 2: EP + placebo solution
35 days Group 1: mean ABL: 0.88 ± 0.11 mm Group 2: mean ABL: 0.99 ± 0.07 mm
.03
Tianeptine was administered once daily for 35 d
Group 1 showed significantly higher levels of TNF- α and TGF- 1β
compared to group 2
.04 & <.01, respectively
Group 1 showed higher levels of IL- 6 and IL- 10 compared to group 2, but without statistical significance
.10
Carvalho et al23
(Brazil)
Group SO: sham-operated + pla-cebo solution
Group EPD: EP + placebo solution
Group Venla 10: EP + venlafaxine 10 mg/kg
Group Venla 50: EP + venlafaxine 50 mg/kg
11 d Group SO: mean ABL: 1.61 ± 1.36 mm Group EPD: mean ABL:
4.47 ± 1.98 mm Group Venla 10: mean ABL:
3.25 ± 1.26 mm Group Venla 50: mean ABL:
6.81 ± 3.31 mm
<.001 (between groups SO & EPD)
Venlafaxine was administered once daily for 11 d
Statistically- significant differences were not found between EPD and Venla 10 groups
<.05 (between Venla 10 & Venla 50 groups)
Venlafaxine (10 mg/kg) treatment did not prevent inflammatory parameters induced by experimen-tal periodontitis
Branco- de- Almeida et al24
(Brazil)
Group 1: Control rats (without ligature)
Group 2: EP + placebo solution Group 3: EP + fluoxetine 20 mg/
kg
3 & 15 d Group 3 showed significantly lower levels of ABL compared to group 2
<.05
Fluoxetine was administered once daily for 15 d
Group 3 reduced the expression of IL- 1β and COX- 2 mRNA induced in
the gingival tissues compared to group 2
<.05
Aguiar et al25
(Brazil)
Group A: EP + placebo solution (rat not stressed)
Group B: EP + fluoxetine 20 mg/ kg (rat not stressed) Group C: EP + CFS + placebo
solution
Group D: EP + CFS + fluoxetine 20 mg/kg
40 d Group C showed higher levels of
ABL compared to group A. For ABL, no statistical differences were found between groups A, B, and D
.006 CFS paradigm was
done from days 1 to 38
Fluoxetine was administered once daily from days 20 to 39
CFS and fluoxetine did not exert any effect on IL- 1β and IL- 6 levels
in the ligature site
.681 and .5, respectively
at least as effective as TCA in attenuating the effects of LPS on the hypothalamic- pituitary- adrenal axis.28 Alterations in LPS- induced cyto-kine production can occur in distinct pharmacological classes, such as TCA,29-31 SSRI,32 and tianeptine,27 leading to an increase in the anti- inflammatory cytokines and a decrease in the pro- inflammatory cytokines.27,29-32 These inflammatory modulations seem to be inca
-pable of preventing bone loss in all antidepressant studies that used ligature- induced periodontitis. From the five selected studies, four were able to show the reduction on ABL after treatment with fluoxe-tine and tianepfluoxe-tine.21,22,24,25 However, it seems that venlafaxine is not able to prevent bone loss in ligature- induced periodontitis rats.23 The group that received the higher dose of venlafaxine showed the high -est ABL. The main reasons for these discrepancies are the different study designs. The selected venlafaxine study did not use any depres
-sion model in their animals, and drug administration was done for only
11 days. Venlafaxine is an antidepressant that acts mainly by inhibiting
the reuptake of serotonin and noradrenaline,33 and only partially the
dopaminergic uptake.34 One study showed that, after a higher dose of venlafaxine (60 mg/kg) for 14 days, the generation of pro- inflammatory cytokines, such as IL- 12 p40, TNF- α, and IFN- γ, is suppressed.35 Despite its anti- inflammatory properties, it has been demonstrated that elderly people treated with venlafaxine had increased levels of β- isom-erized C- terminal cross- linking telopeptide of type I collagen, a marker of bone resorption, compared to baseline values,36 which could explain the absence of prevention and the increased ABL in the selected venla-faxine study. All of these characteristics might render venlavenla-faxine usage undesirable for the adjuvant treatment of any periodontal disease.
Specifically relating to tianeptine, a modified TCA, this drug reduced ABL in both OB rats and non- stressed rats.21,22 Although one study has shown that, after chronic tianeptine treatment, there is an altered balance between pro- and anti- inflammatory cytokines, which increased TNF- α expression in the spleen, as well as plasma lev -els,27 tianeptine normalized behavioral responses after LPS injection, and enhanced the plasma levels of TNF- α and TGF- β. Breivik et al22 explained the effect of tianeptine in experimental periodontitis, high
-lighting the possible role of glutamate. In fact, there is increasing evi
-dence that tianeptine also acts via the modulation of glutamatergic
transmission and glutamate turnover by serine phosphorylation of
α- amino- 3- hydroxy- 5- methyl- 4- isoxazolepropionic acid receptors,37 which could explain the biological effects of tianeptine, such as the inhibition of stress- induced reduction in cell proliferation and hippo-campal volume. It is also possible that tianeptine could have altered
the cytokine response, which is important in periodontal disease progression. In their study, Janda et al38 showed that tianeptine sup -pressed inducible nitric oxide synthase, resulting in the suppression
of nitric oxide production. Tianeptine also prevents the activation of nuclear factor- κB by controlling nuclear factor- κB- α.
Two selected studies on fluoxetine in the management of peri
-odontal disease used different study designs. One used CFS to induce
animal depression, and the other did not use any depression model
in the animals. However, these studies present similarities. Both used fluoxetine orally at a dose of 20 mg/kg/d, and both showed ABL pre-vention, favoring the groups that had used this antidepressant.24,25
Fluoxetine is one SSRI agent that has no significant clinical effects on
cognitive or psychomotor abilities, unlike some tricyclic antidepres
-sants.39 There are some possibilities for this ABL prevention, such as
osteoclast formation being inhibited, and osteoblast and osteoclast
apoptosis being induced, when fluoxetine is administered.40 Thus, fluoxetine could activate anti- inflammatory or immunomodulatory pathways, which might explain the effects on the ABL prevention. It is worth noting, however, that treatment with fluoxetine is associated
with a moderate and transient body weight loss.39
Overall, these results suggest that, with the exception of venlafaxine,
antidepressant treatments can change the responsiveness of the stress
response system and modulate susceptibility to periodontitis. This con
-tributes to the knowledge of pathogenesis, rather than for periodontal
therapy itself. It is important to highlight that some antidepressant drugs
are associated with poor oral health and xerostomia.41 Understanding
of the periodontal patient is perhaps part of the answer for the encoun
-tered effects. Despite the promising results in most of these studies,
there is an absence of evidence in the literature on human studies, which
limits any kind of direct translation. Through this systematic review, it
is possible to indicate that more studies in this field are necessary to
assess the actions of antidepressant agents in human periodontal tis -sues. Furthermore, the treatments that are capable of altering the brain- neuroendocrine- immune system could modulate the predisposition to periodontitis, therefore giving space for antidepressant drugs to be part
of the process of preventing and treating periodontal diseases.
Clinical trials are needed to confirm these findings and better
support the possibility of the use of these drugs in the management
of periodontal diseases. Further clinical trials should include patients
with depression and periodontitis diagnoses. To assess the effect of
antidepressant drugs in periodontal parameters, a minimum of two
groups should be involved; one with patients under pharmacological treatment, and another without it. Additionally, for the inclusion crite-ria, patients should be matched by age, sex, and smoking habit. It was
concluded that antidepressant agents, such as fluoxetine and tianep -tine, are able to prevent ABL in ligature- induced periodontitis in rats using different mechanisms of action.
ORCID
Francisco Wilker Mustafa Gomes Muniz
http://orcid.org/0000-0002-3945-1752
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