The Effects of Psychological Stress, Depression and Inadequate Coping Behaviors on the Progression of Periodontal Disease

Introduction

Periodontopathic bacteria lead to destruction of the tooth supporting tissues causing periodontitis. Risk factors such as psychologic stress, behavioral habits, systemic diseases, socioeconomic factors influence periodontal disease onset and progression. Research also suggested that stress, depression, and ineffective coping may contribute to the development of periodontitis.¹

Stress and depression are more common in subjects experiencing high financial strain and with inadequate coping strategies, this can lead to more plaque accumulation. Stress and depression associated periodontal disease may be related to psycho-neuroimmunologic changes, at-risk health behavior, or a combination of both. The relationship between stress or depression and immune-regulated inflammation is complex. The polypeptides released from the sympathetic noradrenaline and sensory peptidergic nerve fibers may be prompted by negative emotions which help in regulating inflammatory responses triggered by bacterial antigens.²

Coping is the response of subjects to control, reduce, or avoid the negative and unpleasant effects of stress. Subjects with financial strain who used emotion-focused coping strategies experienced even more periodontal tissue destruction. These emotion-focused coping strategies include consuming alcohol or drugs to make himself/herself feel better, admitting that he/she cannot deal with it and quit trying, and pretending that the problem has not really happened.³

Psychologic stresses lower the rate of activity of cellular immune response in three ways: 1) the HPA (hypothalamo-pituitary-adrenal) axis 2) sympathetic nervous system (SNS) and 3) the peripheral release of neuropeptides by the release of adrenaline and noradrenaline. Periodontitis is negatively influenced by coping behavior when in stress, leading to immune suppression. It is assumed that Cortisol, one of the stress-related biomarkers of the HPA axis, is positively associated with the extent and severity of periodontitis.¹

Chromogranin A (CgA) is a highly acidic protein, which is stored and released along with noradrenaline and adrenaline in the adrenal medulla by splanchnic stimulation. Chromogranins are multifunctional hormones, stored in the secretory granules in many neurons and paraneurons, that releases peptide hormones. When in stress response, chromogranin A is more stable than catecholamines in sympathetic-adrenomedullary (SAM) system activity.⁴

C - reactive protein (CRP) is the pentraxin family of calcium dependent ligand-binding plasma proteins, which helps to precipitate the somatic C-polysaccharide of Streptococcus pneumoniae, causing tissue damage.⁵

In parasympathetic withdrawal, stress provokes the cholinergic-inflammation pathway which may be implicated in stress-triggered Acute Coronary Syndrome (ACS). For example, pro-inflammatory cytokines IL-1 and IL-6 are released by circulating mononuclear cells, and the magnitude and duration of the stimulus provided by acute stress may be adequate to increase their levels. Parasympathetic withdrawal during naturalistic stress may shift the balance between inflammatory and proinflammatory cytokines. Depression is associated with increased CRP level and hence patients with antidepressant therapy have decreased CRP levels.⁶

Variation in periodontal disease severity cannot be fully explained by systemic conditions, genetics, smoking, oral hygiene, or age. Therefore, researchers have posited that psychosocial factors, like depression and stress may account for the remaining variability. As per our knowledge, no study has explored the specific contribution of altered dental hygiene to the psychologic stress-periodontitis association. Hence, an attempt was made in this study to extend the research on stress/ depression and periodontal disease by measuring oral hygiene behaviors, psychologic variables and correlating with the markers such as salivary cortisol (CORT), salivary chromogranin A (CgA) and salivary C- Reactive proteins (CRP).

Materials and Methods

Subjects

One hundred patients, 50 healthy individuals (M=35, F=15) and 50 recall periodontal patients (M=30, F=20) of age ranging between 30-80 years were recruited from the Department of Periodontology, AECS Maaruti College of Dental Sciences, Bangalore.

The sample included 50 healthy individuals and 50 patients with a history of non-surgical periodontal therapy. In some cases, this was augmented with surgical intervention, followed by continued enrollment in maintenance regimen. The inclusion of recall patients ensured that all patients were receiving regular periodontal monitoring and maintenance. Patients taking steroids (prednisone) and any other antibiotics in the past three months were eliminated. Subjects with systemic diseases (cardiovascular disease) and smoking & alcohol consumption habits were excluded from this study. Patients were explained about the study and after their approval, were asked to read carefully and sign the consent form. The design of the study and procedures for obtaining informed consent were approved by the Ethical Committee of AECS Maaruti College of Dental Sciences.

Inclusion criteria

Group I: Fifty healthy individuals with no history of periodontitis / any other systemic diseases / absence of chronic stress or depression.

Group II: Fifty periodontitis patients with a history of non-surgical periodontal therapy, followed by continued enrollment in maintenance regimen for about 2-3 weeks and who were in stress (assessed by stress questionnaire) during this maintenance phase (the use of recall patients ensured that all patients were receiving regular periodontal monitoring and maintenance).

Exclusion criteria

Patients taking steroids (prednisone) and any antibiotics in the past three months. Patients diagnosed with diabetes, other systemic diseases (cardiovascular disease, respiratory diseases) and smokers were excluded.

Questionnaire

The questionnaire was completed through a structured interview. Socio-demographic characteristics including age, gender and marital status were recorded. Questionnaire used included health and oral hygiene survey, stress by Derogatis stress profile,⁷ depression by Center for Epidemiologic Studies Depression scale.⁸

Health and oral hygiene survey

The health and oral hygiene survey included questions about age, family history of periodontal disease, smoking, and frequency of brushing and flossing. Participants also indicated whether they neglected oral hygiene during periods of stress or depression.

Derogatis Stress Profile (DSP)⁷

The DSP is a self-report measure designed to assess chronic stress. This 77-item inventory assessed 11 components of stress, including vocational environment, domestic environment, health environment, time pressure, driven behavior, attitude posture, relaxation potential, role definition, hostility, anxiety, and depression. Participants rated each statement from 0 (not at all true of me) to 4 (extremely true of me).

Center for Epidemiologic Studies Depression (CES-D)⁸

The CES-D is a 20-item self-report measure of depression. Participants were instructed to indicate how frequently they behaved in a certain way in the past week. Items included, “I was bothered by things that usually don’t bother me”, and “I felt hopeful about the future.”

Laboratory tests

Participants provided a sample of saliva prior to their clinical examination. Saliva was collected by graduated pipettes into a vial. The sample was centrifuged and was frozen at -200 C. Salivary cortisol level was determined by Enzyme immunoassay method (BRIO SEAC, DRG, GERMANY). Salivary chromogranin A level was determined by Enzyme immunoassay method (YKO70 HUMAN CGA EIA KIT, YANAIHARA INSTITUTE, SHIZUOKA, JAPAN. Salivary CRP level was determined by Immunoturbidometric method (BS300, DIASYS, GERMANY).

Clinical examination

All the participants underwent clinical periodontal examination. Periodontal clinical examination was performed by using a graduated William’s periodontal probe. The periodontal parameters assessed included Gingival index (GI) of Loe and Silness,⁹ Plaque Index (PI) of Silness and Loe,¹⁰ Probing pocket depth (PPD) and Clinical attachment level (CAL).

Statistical analysis

The SPSS software (SPSS Inc 20, Chicago, II, USA) was used for data analysis. Statistical analysis was carried out in the present study. Significance was assessed at 5% level of significance. Analysis of variance (ANOVA) was used to determine the significance of study parameters between the study groups. Student-t test (two tailed, independent) was used to determine the significance of study parameters on a continuous scale between two groups (inter group analysis). Multiple comparisons of each parameter were carried out between the groups by using Mann-Whitney U test.

Results

About 38.1% of the patients (Group I = 5%, Group II = 33.1%) had a family history of periodontal disease (Table 1). About 83% patients (Group I, Group II) brushed their teeth twice a day (2.2 ± 0.84, 1.34 ± 0.43) (Table 1). About 61.2% of the patients (Group I = 8%, Group II = 53.2%) neglected brushing while under stress (Table 1). An overall p-value of <0.001was obtained for all the periodontal parameters (PI, GI, PD and CAL) and DSP, CES-D, CORT, CgA, CRP levels suggesting statistical significance in both the groups included in the study (Table 2).

A statistically significant increase in PI scores (p value <0.001), GI scores (p value <0.001), and an increase in number of sites of PD >5 mm and CAL >3 mm, an increase in DSP, CES-D scores (p value <0.001) and CORT, CgA, CRP levels (p value <0.001) were seen in group II (recall periodontal patients) when compared to group I (healthy individuals). This infers that subjects in group I (healthy individuals) showed good oral hygiene and satisfactory gingival conditions with low inflammatory response. Patients in group II (recall periodontal patients) who were in stress and depression during the maintenance phase neglected oral hygiene measures and hence there was an increased inflammatory response when compared to healthy individuals.

A statistically significant (p value <0.001) decrease in brushing frequency and increase in DSP, CES-D scores (p value <0.001), CORT, CgA, CRP levels (p value <0.001) were seen in group II (recall periodontal patients) when compared to group I (healthy individuals) (Table 3). This infers that recall periodontal patients in group II showed negligence towards brushing during maintenance phase; hence had poor oral hygiene with increased inflammatory response to periodontitis when compared to healthy individuals.

Our results showed significant and positive correlations among all periodontal parameters (PI, GI, PD, CAL) and DSP, CES-D scores, salivary levels of CORT, CgA, CRP (Table 3). Further, a statistically significant and positive correlation existed between PD >5 mm and CORT (r =0.306, P = 0.029), PD >5 mm and CgA (r = 0.626, p = 0.004), PD >5 mm and CRP (r = 0.333, p = 0.017), PD >5 mm and DSP (r =0.358, p=0.026), PD >5 mm and CES-D (r =0.442, p=0.032) (Tables 4, 5). Multiple regressions were used to predict periodontal disease severity from depression (CES-D), stress (DSP), and CORT, CgA, CRP while controlling for brushing and other confounding factors like age (Tables 6, 7).

Discussion

Stress is a human condition that is universally present, but to a varying degree and with different effect on each individual. In day today life challenges, it is necessary to cope with stress for good health.¹¹

Stress stimulates the hypothalamus to produce corticotrophic releasing hormone (CRH), which activates the pituitary gland to release adrenocorticotropic hormone (ACTH), which in turn releases the corticosteroids from adrenal cortex. Glucocorticoids causes reduction in the number of circulating lymphocytes, monocytes, eosinophils and also inhibits the accumulation of eosinophils, macrophages, and neutrophils at inflammatory sites. Hence, cortisol inhibits the action of degranulation, secretion and chemotaxis.¹²

Glucocorticoids inhibit the immune response cascade by inhibiting lymphocyte proliferation, macrophage-antigen presentation, and lymphocyte differentiation to effector cells. Corticosteroids also inhibit the production of cytokines including IL-1, 2, 3 and 6, TNF α and granulocyte and monocyte colony-stimulating factors.¹² CgA is a pluripotent pro-hormone that causes modulation of homeostatic processes such as inflammation and the first phase of microbial invasion.

In the present study, we revealed that salivary CgA levels in all periodontitis patients positively correlated with the number of teeth with deep periodontal pockets. This observation was consistent with that of previous studies,^1,13 which also demonstrated a positive correlation between salivary CgA and the extent of periodontitis. The activation of the SNS in inflammatory diseases may be expected to alter trafficking of inflammatory cells, the production of inflammatory mediators, tissue injury and tissue repair. Like catecholamines, CgA modifies the production of pro- and anti-inflammatory mediators and thus influences disease activity. N-terminal fragment of CgA, is released by bovine polymorphonuclear neutrophils (PMNs) upon stress.¹³ Since PMNs form the first line of innate immunity against bacterial attack in periodontal disease, it is also possible that CgA-fragments are locally produced by human PMNs in periodontitis. It has been suggested that accumulated PMNs at the sites of inflammation, which are stimulated by lipopolysaccharides, provide CgA peptides.¹⁴ These peptides have endocrine effects, such as the inhibition of TNF-α induced extravasation or the stimulation of histamine release.

C-reactive protein is secreted and synthesized by hepatocytes in response to cytokines such as Interleukin-6 (IL-6) and considered to be an inflammatory marker. Interleukin-6 production is also stimulated by other cytokines such as TNF-α and Interleukin-1. These elevated CRP levels reflect certain low-grade infections associated with CHD, like periodontitis and infections caused by Cytomegalovirus and Chlamydia pneumonia.⁶

The correlations between stress and depression scores such as DSP, CES-D, salivary stress markers CORT, CgA and inflammatory marker such as CRP supported the hypothesized association between psychosocial variables and periodontal disease. Individuals experiencing psychologic stress or depression may have decreased cell-mediated immune activity as measured by natural killer cell function and lymphocyte responses to mitogenic stimulation.¹⁵ Activation of HPA axis increases the progression of periodontitis through dysregulation of circulating cortisol which affects immune function. In contrast, the development of periodontal disease also alters the host’s resistance to periodontopathic bacteria.16 In our study, we found a positive relationship between stress scores, depression scores, salivary CgA, cortisol, and the PD >5 mm, CAL >3 mm. There was an increase in number of sites with PD >5 mm and CAL >3 mm which was statistically significant (p<0.001).

The regression model reported that salivary markers of stress were strongly associated with PD >5 mm. Also, analyses predicting the number of teeth with CAL >3 mm, cortisol, CgA, CRP were significant predictors after adjusting for age, and brushing frequency. Furthermore, in our study, salivary CgA levels had a positive relation with periodontal disease; this might be due to the release of hormone in saliva by sympathetic nerve endings. Increased level of cortisol and chromogranin-A upregulate the expression of MMP-1, 2, 7, & 11 and TIMP-1 in human gingival fibroblasts, which results in increased periodontal breakdown.

Previous studies^2,17,18 have indicated that depressed patients have increased baseline inflammation and exaggerated inflammatory responses accompanying their flattened cortisol patterns. In contrast, those with acute stress may experience elevated cortisol and related lymphocytic dysregulation, allowing the proliferation of subgingival bacteria but without the proinflammatory changes. The present study suggested that depression and cortisol are positively associated with severe periodontal outcomes, whereas everyday stress and cortisol are positively associated with milder forms of periodontal disease.

In addition, we found that salivary CgA levels in all periodontitis patients positively correlated with the number of teeth with deep periodontal pockets. Neuro-endocrine immune functions were altered in chronic periodontitis patients mainly due to increased secretion of these peptides in saliva interpreting immune activity which in turn is directly related to increased systemic stress.

Within the limits of our study, we found higher salivary cortisol, CgA, CRP levels in recall periodontal (maintenance phase) patients than in controls. Hence, we suggest that even recall (maintenance phase) patients may develop an increased risk of periodontal disease due to negligence of oral hygiene during stress.

Conclusion

Salivary levels of stress-markers could be related to the pathogenesis of periodontal disease and hence, it strongly suggests that stress, distress, and inadequate coping are important risk indicators for periodontal disease. Systemic diseases associated with periodontal disease such as diabetes, cardiovascular disease, and osteoporosis may share psychosocial stress as a common risk factor. Hence, a continuing research is required to establish a strong association between periodontal disease and psycho-neuro-immunologic variables like stress and depression and enhance the preventive measures in oral health. Future studies should include the assessment of other markers such as, TNF-α, MMP.

Conflict of Interest and Sources of Funding Statement

The authors declare that there are no conflicts of interest related to this study. Self-funded.