**4. Major Depression**

MD has also attracted attention and is currently the second elucidated neuropsychiatric disease with respect to its reciprocal association with periodontitis. A recent cross-sectional study on 108 subjects reported that patients with periodontitis showed a significantly higher comorbidity rate of depression (62.5%) compared to periodontally healthy subjects (38.86%), excluding smokers, pregnan<sup>t</sup> women, subjects with systemic pathologies, and subjects taking antidepressants [49]. MD is susceptible to psychosocial factors and periodontitis could increase the risk for developing MD through the psychosocial e ffects that stem from periodontitis-causing oral troubles, such as halitosis, poor oral hygiene, and edentulousness [16]. Patients with malodorous wounds and poor oral hygiene often experience social isolation, depression, shame, and poor appetite, all of which have a negative impact on their QOL [50]. Also, tooth loss negatively a ffects the patients' QOL since it worsens not only chewing function, but also body image, self-esteem, and social status [16,51]. Because of all this, many early studies in this field were performed from a psychosocial viewpoint [52,53].

Although several studies have recently focused on the biological relationship between periodontitis and MD, most of them investigated periodontitis as an outcome influenced by MD [54,55]. The e ffects of antidepressants, which are known to possess anti-inflammatory and immunomodulatory properties [56,57], on chronic periodontitis have been studied in both MD animal models (systematically reviewed in [58]) and in MD patients [59,60]. The majority has established the therapeutic e ffects of antidepressants on chronic periodontitis. A recent cross-sectional study made by Gomes et al. (2018), who hypothesized that increased root canal LPS accompanying chronic apical periodontitis causes MD, showed that patients with periodontitis and MD had highly increased root canal endotoxin levels relative to patients with periodontitis without MD or normal controls. This study demonstrated a strong positive association between periodontitis or root canal endotoxin levels and the severity of MD, suggesting that the association between periodontitis and MD is attributable, at least in part, to root canal endotoxin levels [61]. In the study, periodontitis-related MD was accompanied with elevated

levels of oxidative and nitrosative stress index, including nitric oxide metabolites and hydroperoxides, which are supposed to play a role in the pathogenesis of MD [62]. A recent cohort study composed of a high methodological quality with more than 60,000 participants and a 10-year follow-up period also supports the feasible causal link of periodontitis to MD. The study showed a higher incidence of subsequent depression in the periodontitis group (*n* = 12,708) than in the non-periodontitis group (*n* = 50,832) (HR 1.73, 95% CI 1.58–1.89), after adjustment of sex, age and comorbidities [63]. This result suggests that periodontitis is an independent risk factor for subsequent MD regardless of sex, age, and the comorbidities except for diabetes, alcohol abuse, and cancer. On the other hand, in a meta-analysis on four cross-sectional studies [64–67] that were assessed as moderate-high quality of the evidence and considered periodontitis as the outcome and MD as the exposure, the pooled estimate does not show association between periodontitis and MD (OR 0.96, 95% CI 0.84–1.10) [68]. Therefore, more prospective cohort studies that test periodontitis as the independent variable and MD as the outcome, or interventional studies, such as studies that determine the e ffects of periodontal treatment on MD, are clearly warranted to elucidate the causal relationship between periodontitis and MD.
