Olanzapine's Impact on Oral Health in Patients with Schizophrenia: Research Progress on Effects and Mechanisms

Olanzapine's Impact on Oral Health in Patients with Schizophrenia: Research Progress on Effects and Mechanisms | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Olanzapine's Impact on Oral Health in Patients with Schizophrenia: Research Progress on Effects and Mechanisms Liang Kong, Linghui Zhang, Qian This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8714864/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : Olanzapine, a first-line atypical antipsychotic used in over 60% of clinical cases, induces dose-dependent oral impairments (xerostomia, caries, periodontitis) with a 35%-78% incidence in long-term use (≥3 months). Existing studies lack large-sample evidence from East Asians, focus on single adverse reactions, and have fragmented intervention strategies, failing to meet precise diagnosis needs. Objective : This review summarizes olanzapine-induced oral damage characteristics and molecular mechanisms, proposes GRADE-graded individualized oral management plans, clarifies East Asians’ risk thresholds and intervention priorities, and provides evidence for clinical practice. Methods : Following PRISMA 2020 guidelines, we searched PubMed, Web of Science, CNKI (2018-2025), including 24 high-quality studies. Data from NHANES 2017-2020 (586 cases) and 4 Chinese studies (832 cases) were analyzed via random-effects models and multivariate regression. Outcome indicators followed WHO oral health survey methods and 2017 periodontal disease classification. Results : East Asians are more susceptible to olanzapine’s oral toxicity (xerostomia: 42%-75%; caries: 51.3%), with a sharp risk increase at ≥8 mg/day (OR=2.73, P<0.001). Core mechanisms include M1/M3 receptor blockade-induced salivary hyposecretion, hBD-2/NF-κB-mediated dysbiosis, and TNF-α/IL-6 inflammatory crosstalk. Conclusion : Olanzapine-induced oral impairments show significant ethnic heterogeneity, with higher sensitivity in East Asians linked to M1 receptor polymorphism and high-refined carbohydrate diets. Stomatological departments should establish specialized management for olanzapine users, including 4-monthly screenings and dose warnings for ≥8 mg/day, combined with targeted interventions. Epidemiology Olanzapine Schizophrenia Oral health Xerostomia Dental caries Periodontal disease Oral microbiota Clinical oral management Dose dependence East Asian population Figures Figure 1 Figure 2 Figure 3 1 Introduction Oral health, as a core component of overall health, directly affects nutrient intake, masticatory function, and social quality [ 4 ] . Due to impaired cognitive function and reduced self-care ability, patients with schizophrenia have an oral disease prevalence 2–3 times higher than that of the general population. As a first-line atypical antipsychotic in clinical practice, long-term use of olanzapine is a key inducing factor for oral damage [ 5 ] . With a clinical application coverage exceeding 60%, this drug has a low incidence of extrapyramidal reactions, but the incidence of oral adverse reactions such as xerostomia, dental caries, and periodontal disease caused by long-term use (≥ 3 months) is as high as 35%-78%, showing a dose-dependent progression [ 3 ] . These oral impairments do not exist in isolation: as an initiating factor, xerostomia creates conditions for the occurrence of dental caries and periodontal disease by reducing salivary cleaning and buffering functions; local inflammation caused by periodontal disease can aggravate patients' psychiatric symptoms through systemic pathways, forming a vicious cycle of "worsening oral health - aggravating psychiatric symptoms" [ 35 ] . However, existing studies have significant limitations: first, the research is fragmented, mostly focusing on single oral adverse reactions, lacking systematic integration of the spectrum of olanzapine-related oral damage; second, the efficiency of evidence translation is insufficient, only stopping at the correlation analysis between drugs and adverse reactions, without forming a standardized intervention plan directly applicable in stomatological clinics; third, the evidence related to racial differences is weak, and the research conclusions centered on European and American populations have adaptability gaps with the unique dietary structure (high intake of refined carbohydrates) and genetic background (M1 receptor polymorphism) of East Asian populations; fourth, the explanation of molecular mechanisms is insufficient, restricting the development of targeted oral intervention methods. These problems lead to the lack of uniform standards for the management of patients taking olanzapine in stomatological clinical practice, making precise prevention and treatment difficult to implement. Based on the PRISMA 2020 guidelines, this review systematically summarizes core Chinese and English literatures from 2018 to 2025, integrates data from the NHANES public database and large-sample Chinese local studies, comprehensively analyzes the multi-dimensional damage characteristics of olanzapine on oral health, deeply explains its molecular mechanisms and dose-effect relationships, with a focus on the racial specificity of East Asian populations. Combined with the GRADE evidence grading standards, it proposes a closed-loop "screening-intervention-follow-up" management strategy suitable for stomatological clinical practice, clarifies an operable simplified process for primary hospitals, fills the evidence-based gap in the oral health management of olanzapine users in East Asian populations, provides scientific guidance for stomatological departments to actively participate in the health management of this special group of patients, and ultimately improves the oral health level and quality of life of patients. 2 Methods This review strictly follows the PRISMA 2020 guidelines. The search strategy is consistent with the abstract. Databases including PubMed, Web of Science, Embase, CNKI (China National Knowledge Infrastructure), and Wanfang Database were searched using a combination of subject terms and free terms. Citations from included literatures and related reviews were manually supplemented to avoid omissions. English search included synonym replacements (e.g., "olanzapine", "atypical antipsychotics", "oral adverse effects", "xerostomia", "dental caries"), and Chinese search synchronized standardized terms (e.g., "olanzapine", "oral adverse reactions", "xerostomia", "dental caries", "periodontal disease") to improve search accuracy; the search period was from January 2018 to June 2025 to ensure research timeliness. Inclusion Criteria ① Studies focusing on olanzapine-related oral adverse reactions (including xerostomia, dental caries, periodontal disease, oral microbiota dysbiosis, etc.) with clear olanzapine dosage and duration of use; ② Study types including clinical controlled trials, cohort studies, cross-sectional studies, systematic reviews, or meta-analyses with complete and extractable data, and outcome indicators defined in accordance with the WHO Basic Methods for Oral Health Surveys (5th edition) and the International Classification of Periodontal Diseases (2017) (e.g., xerostomia defined as salivary flow rate < 0.3mL/min or subjective symptoms lasting ≥ 1 week; periodontal disease defined as periodontal pocket depth ≥3mm and attachment loss ≥1mm); ③ Published in core Chinese and English journals (English journals indexed by SCI/SSCI; Chinese journals indexed by Peking University Core Journals or CSCD (Chinese Science Citation Database)) between January 2018 and June 2025; ④ Study subjects were adult patients (≥ 18 years old) diagnosed with schizophrenia, receiving continuous olanzapine treatment for ≥ 3 months, without severe liver and kidney dysfunction, autoimmune diseases, or other underlying diseases affecting oral health (e.g., congenital salivary gland hypoplasia, oral tumors). Exclusion Criteria ① Case reports, case analyses, conference abstracts, and non-original studies (excluding reviews); ② Unavailable full text or missing key data (e.g., no control group, no statistical analysis results); ③ Failure to independently analyze the effect of olanzapine, combined with other drugs that clearly affect oral health (anticholinergics, chemotherapeutic drugs, immunosuppressants, etc.); ④ Study subjects were children and adolescents (< 18 years old), pregnant or lactating women, or patients with acute exacerbation of severe psychiatric symptoms requiring compulsory treatment. Literature screening was conducted using a double-blind method by two independent researchers who completed two rounds of screening: the first round was preliminary screening based on titles and abstracts to exclude literatures that clearly did not meet the inclusion criteria; the second round was full-text re-screening of preliminary qualified literatures to strictly verify the inclusion and exclusion criteria. When there was a disagreement between the two researchers, a consensus was reached through joint review of the original literature and discussion (consensus rate of 92%), without the need for third-party arbitration. Quality assessment was performed using targeted scales: JBI scale for systematic reviews/meta-analyses (11 items, total score 11, ≥ 8 points for high-quality studies) and NOS scale for cohort studies/cross-sectional studies (8 items, total score 8, ≥ 6 points for high-quality studies). Finally, 24 high-quality studies were included, including 20 English studies (3 systematic reviews, 2 meta-analyses, 6 cohort studies, 9 cross-sectional studies) and 4 Chinese studies (all cross-sectional studies published in Peking University Core Journals). To enhance the reliability of the results, this review adopted dual dataset verification: one was the NHANES 2017–2020 database (586 cases), and the other was the combined data from 4 Chinese studies published in Peking University Core Journals (832 cases). The baseline characteristics of the two groups were matched (no significant differences in age and medication dosage between groups, P > 0.05), and data calibration was performed using standardized effect sizes to ensure the consistency of outcome indicator detection methods. A random-effects model was used for data pooling, with acceptable heterogeneity (I²=32.6%, P = 0.21); statistical analyses were performed using SPSS 26.0 and Stata 15.0 software. After adjusting for confounding factors such as age, gender, duration of medication use, frequency of oral care, smoking history, and history of oral underlying diseases, the association was clarified through multivariate logistic regression. Publication bias was cross-validated using funnel plots, Egger's test, and Begger's test (P = 0.32), indicating no significant publication bias; a two-tailed P < 0.05 was considered statistically significant. Specific baseline data can be supplemented to the supplementary materials as needed. The literature screening process is shown in Fig. 1 to ensure the scientificity and transparency of study selection. 3 Olanzapine's Impact on Oral Health in Patients with Schizophrenia 3.1 Xerostomia Xerostomia is the most common and earliest oral adverse reaction of olanzapine, with an incidence rate increasing with the duration of medication use, reaching 35%-68% in long-term users (≥ 1 year) [ 6 ] . Clinical manifestations include dry oral mucosa, burning sensation, difficulty swallowing, and decreased taste; severe cases may present with chapped oral mucosa and ulcers, significantly affecting patients' eating and quality of life. Its core hazard lies in triggering a chain reaction as an "initiating factor": weakened salivary cleaning function leads to food residue and plaque accumulation; reduced buffering capacity lowers the oral pH below 5.2 (critical demineralization pH); decreased concentration of antibacterial components (lysozyme, lactoferrin) impairs mucosal defense ability, creating conditions for the occurrence of dental caries and periodontal disease. Therefore, it is regarded as a core early warning indicator for olanzapine-related oral health problems. It is important to note that the prevalence of xerostomia in Asian populations is significantly higher than that in European and American populations. Clinical data show that the prevalence in Asian populations is 42%-75% (average 61.3%), while the average incidence in European and American populations is 51.5%, with a statistically significant difference between groups (P < 0.01) [ 31 ] . A cross-sectional study including 320 patients compared the oral adverse reactions between olanzapine and risperidone, and the results showed that the salivary flow rate in the olanzapine group was (0.32 ± 0.15) mL/min, significantly lower than that in the risperidone group (0.48 ± 0.18) mL/min (P < 0.01) [7], indicating that olanzapine has a stronger inhibitory effect on salivary secretion. Combined analysis of 4 Chinese core studies showed that the average salivary flow rate of Chinese olanzapine users was (0.28 ± 0.13) mL/min, lower than that of European and American populations (0.32 ± 0.15) mL/min and Korean populations, suggesting that Chinese populations are more susceptible to olanzapine-induced salivary secretion inhibition. 3.2 Dental Caries Dental caries is the main organic oral damage in olanzapine users, whose occurrence is closely related to olanzapine-induced decreased salivary secretion and oral acidification, showing a significant dose-dependent relationship. Clinical data show that the DMFT index of olanzapine users is 12.3 ± 4.5, 1.8–2.5 times that of schizophrenia patients not taking medication [ 8 ] , and the incidence of root caries is significantly higher than that of coronal caries, which is different from the distribution law of dental caries in the general population. The core reason is that the decreased salivary flow rate caused by olanzapine makes root plaque more likely to accumulate and difficult to remove; at the same time, the reduced salivary buffering capacity fails to timely neutralize lactic acid produced by plaque metabolism, accelerating the demineralization of root cementum. In addition, olanzapine-induced preference for high-sugar diets and lack of oral care due to impaired cognitive function further aggravate the occurrence and progression of dental caries. Some long-term medication users may develop multiple dental caries, even involving key masticatory parts of permanent teeth, seriously affecting masticatory function and nutrient intake. Large-sample data from the NHANES 2017–2020 database provide strong evidence for the association between olanzapine and dental caries. Among 586 olanzapine users included in the database, the rate of high caries burden (DMFT ≥ 12, indicating moderate to severe caries damage) reached 42.3%, significantly higher than 21.7% of non-users (χ²=26.38, df = 1, P < 0.001). After adjusting for confounding factors in the multivariate logistic regression model, olanzapine remained an independent risk factor for dental caries (OR = 2.41, 95%CI: 1.68–3.46, P < 0.001) [ 27 ] . The risk of dental caries is particularly significant in East Asian populations. Combined analysis of 832 patients from 4 Chinese core studies showed that the incidence of dental caries in East Asian olanzapine users was 51.3%, significantly higher than 23.7% of non-users (P < 0.001), and the increase in DMFT index (2.1–2.8 times) was higher than that in European and American populations (1.8–2.5 times) [ 28 , 31 ] . Among them, the rate of high caries burden (DMFT ≥ 12) in Chinese populations reached 53.8%, and the incidence of root caries in Korean populations reached 38.6%, both significantly higher than the corresponding indicators in European and American populations [ 26 , 28 ] . This difference is closely related to M1 receptor gene polymorphism and high refined carbohydrate diet characteristics in East Asian populations. 3.3 Periodontal Disease Periodontal disease is another common oral adverse reaction in olanzapine users, including gingivitis and periodontitis, with an incidence rate second only to xerostomia and dental caries, reaching 45%-70% in long-term users [ 9 ] , and forming a bidirectional interaction with psychiatric symptoms. Clinical data show that the prevalence in Asian populations is 52%-78% (average 61.6%), and the average prevalence in European and American populations is 57.5%, with a statistically significant difference between groups (P < 0.05) [ 31 ] ; combined analysis of 4 Chinese core studies showed that the incidence of periodontal disease in Chinese olanzapine users was 65.2%, significantly higher than 38.6% of non-users (P < 0.001) [ 28 , 30 ] , with more severe damage. A 2-year cohort study including 150 patients showed that the average increase in periodontal pocket depth and attachment loss in olanzapine users at the end of follow-up was (0.8 ± 0.3) mm and (0.6 ± 0.2) mm, respectively, both significantly higher than those in the control group (P < 0.05) [ 10 ] , while the increase in relevant indicators in Chinese populations was more significant (average increase in periodontal pocket depth: 1.1 ± 0.4mm, average increase in attachment loss: 0.9 ± 0.3mm) [ 30 ] , suggesting that East Asian populations have more prominent sensitivity of periodontal tissues to olanzapine. The core mechanism of the interaction between periodontal disease and psychiatric symptoms lies in the TNF-α/IL-6 inflammatory pathway: local inflammation caused by periodontal disease activates systemic inflammatory response, and inflammatory factors interfere with the balance of neurotransmitters through the blood-brain barrier, aggravating schizophrenia symptoms; while the deterioration of psychiatric symptoms further reduces patients' oral care ability, exacerbating plaque accumulation and microbiota dysbiosis. This vicious cycle makes the intervention of periodontal disease not only a local oral problem but also a key link to improve the overall prognosis of patients, requiring active intervention and management by stomatological departments. 3.4 Oral Microbiota Dysbiosis Olanzapine induces oral microbiota dysbiosis through multiple pathways, disrupting the balance of oral microecology, which is one of the core mechanisms leading to various oral adverse reactions. As the most complex microecosystem in the human body, the balance of oral microbiota is closely related to oral health. Olanzapine interferes with its composition mainly through four pathways: first, xerostomia reduces salivary secretion, disrupting the living microenvironment, reducing the colonization ability of beneficial bacteria (e.g., Streptococcus salivarius); second, drug-induced preference for high-sugar diets increases salivary glucose content, providing nutrients for pathogenic bacteria; third, mild inhibition of the immune system impairs the defense function of oral mucosa; fourth, direct inhibition of the growth of beneficial bacteria, as salivary drug concentrations of 0.12–0.35 ng/mL can significantly inhibit the proliferation of Streptococcus salivarius [ 18 ] . Analysis based on Shannon index (species diversity) and Simpson index (species dominance) showed that the diversity of oral microbiota in olanzapine users was significantly reduced (Shannon index: 3.2 ± 0.5 vs 4.7 ± 0.6, P < 0.001; Simpson index: 0.78 ± 0.08 vs 0.62 ± 0.07, P < 0.001) [ 11 , 12 ] , and the stability of microbiota structure was decreased. Racial differences are also significant in oral microbiota dysbiosis: the co-abundance of Streptococcus mutans and Porphyromonas gingivalis is higher in Asian populations (r = 0.42, P < 0.001), and the correlation with olanzapine dosage is stronger (r = 0.45, P < 0.001) [ 26 , 34 ] . As a core cariogenic bacterium, the increased abundance of Streptococcus mutans can directly promote the demineralization of hard dental tissues; as a key pathogenic bacterium for periodontal disease, Porphyromonas gingivalis can activate inflammatory pathways by secreting lipopolysaccharide (LPS), aggravating periodontal tissue damage. The increased co-abundance of the two further amplifies the damaging effect of olanzapine on oral health in East Asian populations, and can be used as early warning biomarkers for dental caries and periodontal disease, providing targets for targeted oral interventions in stomatological clinics. 3.5 Subgroup Analysis of Asian Populations By integrating data from 4 Chinese core studies (832 cases, Chinese populations) and 1 Korean multi-center study (328 cases, Korean populations), an Asian population subgroup analysis cohort was constructed (total 1574 cases), which was compared with a European and American population cohort (586 cases, from the NHANES database and English literatures). The results showed that Asian populations had higher incidence of olanzapine-related oral adverse reactions and stronger dose sensitivity, with statistically significant racial differences, which ran through all dimensions of the adverse reaction spectrum. The subgroup analysis also controlled for confounding factors such as age, gender, duration of medication use, and frequency of oral care, and the results suggested that race is an independent modifying factor for olanzapine-related oral adverse reactions. Its mechanism is related to the synergistic effect of multiple factors including genetic background (M1 receptor polymorphism, differences in insulin resistance-related genes), dietary structure (high refined carbohydrate diet in East Asia), and living habits (differences in oral care cognition), providing a core basis for the formulation of individualized intervention plans for East Asian populations. Dose sensitivity analysis showed that when the olanzapine dose was ≥8mg/d in Asian populations, the salivary flow rate decreased significantly (P 10mg/d to show similar changes [ 31 ] . This difference in dose threshold provides a key reference for clinical risk stratification in stomatology. The core difference characteristics are shown in Tables 1 and 2 . Table 1 Quantitative table of racial differences in the incidence of xerostomia by olanzapine dosage Olanzapine dosage (mg/d) Xerostomia prevalence in Asian populations (%) Xerostomia prevalence in European-American populations (%) Inter-group difference P- value Risk variation features ≤ 4 32.5 28.7 >0.05 In the low-dose range, both groups exhibit reduced risk. 5–7 48.3 41.2 < 0.05 The risk for Asian populations starts to rise significantly. ≥ 8 (Asian threshold) 68.7 45.5 < 0.001 The risk among Asian populations has increased significantly (OR = 2.73). 9–10 72.1 50.3 10 (European-American threshold) 75.0 61.8 < 0.01 European-American populations reach significant risk; Asian populations near the peak. Note: Data are from the combined effect size of subgroup analysis (Asian populations n = 1574, European and American populations n = 586); P values for intergroup differences were calculated by multivariate logistic regression adjusting for age, duration of medication use, and frequency of oral care; risk change characteristics are based on OR values and 95%CI (Asian populations ≥8mg/d OR = 2.73, 95%CI: 1.92–3.88; European and American populations > 10mg/d OR = 2.31, 95%CI: 1.56–3.42). Table 2 Comparison of racial differences in olanzapine-related oral adverse reactions Types of Oral Adverse Reactions Asian Population (n = 1574) European-American Population (n = 586) P -value for Racial Differences Xerostomia Prevalence (%) 42–75 (M = 61.3) 35–68 (M = 51.5) < 0.01 Salivary Flow Rate (mL/min, x ± s) 0.28 ± 0.13 0.32 ± 0.15 < 0.05 Dental Caries Prevalence (%) 45.2–51.3 (M = 48.7) 32.6–42.3 (M = 37.5) < 0.001 DMFT Index (x ± s) 13.7 ± 5.2 12.3 ± 4.5 < 0.05 Periodontal Disease Prevalence (%) 52–78 (M = 61.6) 45–70 (M = 57.5) < 0.05 Increased Periodontal Pocket Depth (mm, x ± s) 1.1 ± 0.4 0.8 ± 0.3 < 0.05 Salivary hBD-2 Expression (Relative Value, x ± s) 0.62 ± 0.18 0.76 ± 0.21 < 0.01 Note: Data are from 20 English studies, 4 Chinese core studies (Chinese populations), 1 Korean multi-center study, and the NHANES 2017–2020 database; Chinese data were combined using a random-effects model (I²=32.6%, P = 0.21, acceptable heterogeneity); P values for racial differences were calculated by meta-analysis of combined effect sizes; hBD-2: Human β-defensin 2; DMFT index: Decayed, Missing, Filled Teeth Index, referring to the WHO Basic Methods for Oral Health Surveys (5th edition). 4 Potential Mechanisms of Olanzapine Affecting Oral Health 4.1 Cholinergic Receptor Blockade and Salivary Secretion Inhibition The core initiating mechanism of olanzapine-induced oral health damage is the selective blockade of M1/M3 cholinergic receptors on the surface of salivary gland acinar cells, interfering with the neurohumoral regulatory pathway and inhibiting the secretory function of acinar cells. The secretory activity of salivary glands mainly relies on cholinergic innervation. After acetylcholine binds to M1/M3 receptors, it activates the intracellular calcium signaling pathway to promote salivary secretion. As a non-selective receptor antagonist, olanzapine has a higher affinity for binding to M1/M3 receptors than acetylcholine, leading to blocked receptor activation and failure to initiate the calcium signaling pathway, resulting in significant inhibition of acinar cell secretory function [ 13 ] , directly causing decreased salivary flow rate and secretion volume, and further triggering a chain reaction of "weakened cleaning function - plaque accumulation - oral acidification - dental demineralization", promoting the occurrence of dental caries and periodontal disease [ 14 ] . The single nucleotide polymorphism at the rs1050244 locus of the M1 receptor in East Asian populations is the core genetic driver of racial differences. This polymorphism can change the spatial conformation of the M1 receptor, enhancing its binding affinity with olanzapine. The allele frequency of this polymorphism in Chinese populations reaches 38.6%, significantly higher than 22.3% in European and American populations (P < 0.01) [ 32 ] , making East Asian populations have a higher proportion of M1 receptor blockade in salivary glands and more significant inhibition of salivary secretion at the same olanzapine dosage. A genetic association study including 200 Chinese olanzapine users showed that the average decrease in salivary flow rate in carriers of the rs1050244 risk allele was 42.3%, significantly higher than 28.7% in non-carriers (P < 0.05), and the incidence of xerostomia reached 72.5% (51.3% in non-carriers, P < 0.05) [ 32 ] . This genetic characteristic fully explains the clinical phenotype of high incidence of xerostomia and higher dose sensitivity in East Asian populations, providing a molecular basis for setting a risk threshold of ≥8mg/d. 4.2 Glucose Metabolism Interference Olanzapine can interfere with the insulin signaling pathway, inducing hyperglycemia and insulin resistance; this effect synergizes with cholinergic receptor blockade to further aggravate oral health damage [ 15 ] . Its main action pathways include: first, blocking the negative feedback regulation of the hypothalamic-pituitary-adrenal axis, leading to increased cortisol secretion, promoting hepatic gluconeogenesis, and elevating blood glucose; second, inhibiting the phosphorylation of insulin receptor substrate (IRS), interfering with insulin signal transduction, reducing insulin sensitivity in peripheral tissues, and causing insulin resistance. In the state of hyperglycemia, salivary glucose content increases synchronously, providing sufficient energy for cariogenic bacteria such as Streptococcus mutans, promoting the proliferation of pathogenic bacteria and the secretion of acidic metabolites, and accelerating dental demineralization [ 16 ] ; at the same time, insulin resistance leads to decreased angiogenesis and collagen synthesis in periodontal tissues, reducing the repair ability and resistance of periodontal tissues, making them more susceptible to pathogenic bacteria invasion and aggravating periodontal inflammation and tissue damage [ 17 ] . Metabolomic detection provides direct evidence: the concentrations of glucose and fructose in the saliva of olanzapine users were (8.6 ± 2.3) mmol/L and (2.1 ± 0.8) mmol/L, respectively, significantly higher than those of non-users (4.2 ± 1.5) mmol/L and (1.0 ± 0.5) mmol/L (P < 0.001), and the concentrations of cariogenic bacterial metabolites (lactic acid, acetic acid) increased synchronously, with the oral pH dropping to 5.2 ± 0.3 [ 34 , 33 ] . Racial differences are also significant: the insulin resistance index (HOMA-IR) of East Asian populations is 3.8 ± 1.2, significantly higher than 3.1 ± 1.0 of European and American populations (P < 0.05), and the salivary glucose content is 18.7% higher [ 33 ] . This is closely related to the higher frequency of insulin resistance-related gene polymorphisms (e.g., IRS-1 rs1801132) and more frequent intake of high refined carbohydrate diets in East Asian populations, further amplifying the risk of dental caries and periodontal disease. 4.3 Changes in Oral Microbiota Composition and Molecular Pathway Regulation Olanzapine exacerbates oral microbiota dysbiosis through four pathways, forming a regulatory network of "microenvironmental changes - pathogenic bacteria proliferation - inflammation activation" [ 18 ] : first, xerostomia disrupts the living microenvironment of microbiota, reducing the colonization of beneficial bacteria and promoting the adhesion of pathogenic bacteria; second, preference for high-sugar diets provides nutrients for pathogenic bacteria; third, mild inhibition of the immune system impairs the clearance ability of pathogenic bacteria; fourth, direct inhibition of the growth of beneficial bacteria, disrupting the microecological balance. At the molecular level, olanzapine further exacerbates dysbiosis and inflammatory responses by regulating the hBD-2/NF-κB pathway. As a core inflammatory regulatory pathway, the NF-κB pathway can activate the expression of downstream inflammatory factors such as IL-6 and TNF-α, and simultaneously regulate the synthesis of antibacterial peptides (e.g., hBD-2). Olanzapine can inhibit the nuclear transcriptional activity of the NF-κB p65 subunit in oral mucosal epithelial cells, preventing its translocation into the nucleus, leading to blocked transcription of downstream target genes and a 35%-42% downregulation of hBD-2 expression (P < 0.01) [ 34 ] . As an important antibacterial peptide in oral mucosa, hBD-2 can specifically inhibit the proliferation of Streptococcus mutans and Porphyromonas gingivalis; its downregulation directly impairs the mucosal inhibitory ability against pathogenic bacteria, promoting microbiota dysbiosis. At the same time, transcriptomic detection shows that the expression of LL-37 and TNFAIP3 genes in oral mucosal tissues of olanzapine users is synchronously downregulated, while the expression of IL-6 and TNF-α genes is upregulated [ 35 , 34 ] , forming a vicious cycle of "antibacterial peptide inhibition - inflammation activation - pathogenic bacteria proliferation", accelerating periodontal tissue damage and dental caries progression. Metabolomic analysis confirmed that the glycolytic pathway and lactic acid production pathway of oral microbiota in olanzapine users are significantly activated (P < 0.001). Streptococcus mutans and Porphyromonas gingivalis produce a large amount of acidic substances such as lactic acid and acetic acid by enhancing glycolytic metabolism, reducing the oral pH to 5.2 ± 0.3 (below the critical pH for dental demineralization of 5.5), and accelerating the demineralization of enamel and cementum [ 35 , 33 ] . In addition, toxic substances such as lipopolysaccharide (LPS) and proteases produced by pathogenic bacteria can directly damage periodontal pocket epithelial cells, destroy the periodontal tissue barrier, and aggravate periodontal inflammation. The dose-dependent characteristic is significant: the co-abundance of Streptococcus mutans and Porphyromonas gingivalis increases with the increase of olanzapine dosage, and is positively correlated with the duration of medication use (r = 0.45, P < 0.001) [ 26 , 34 ] , providing a mechanism support for dose-based risk stratification in stomatology. 4.4 "Oral-Systemic" Crosstalk Effect of TNF-α/IL-6 Inflammatory Pathway Activation The TNF-α/IL-6 inflammatory pathway activated by oral microbiota dysbiosis is the core link connecting oral health and psychiatric symptoms, forming an "oral-systemic" crosstalk effect. Clinical detection shows that the concentrations of TNF-α and IL-6 in the saliva of olanzapine users are (18.7 ± 5.2) pg/mL and (23.5 ± 6.8) pg/mL, respectively, significantly higher than those of non-users (8.2 ± 3.1) pg/mL and (10.5 ± 4.2) pg/mL (all P < 0.001) [ 35 ] . These inflammatory factors not only play a role locally in the oral cavity but also enter the systemic circulation through damaged periodontal mucosa, activating systemic inflammatory response, and further affecting central nervous system function. Correlation analysis shows that salivary TNF-α and IL-6 concentrations are positively correlated with periodontal pocket depth (r = 0.48, P < 0.001), and simultaneously positively correlated with the severity score of psychiatric symptoms (r = 0.53, P < 0.001) [35], clarifying the mediating role of inflammatory factors. Lipopolysaccharide (LPS) produced by periodontal pathogenic bacteria is a key substance activating systemic inflammation. After entering the systemic circulation through damaged periodontal mucosa, it binds to TLR4 receptors on the surface of monocytes and macrophages, activating downstream inflammatory pathways and promoting the massive secretion of TNF-α and IL-6 [ 35 ] . These inflammatory factors enter the central nervous system through the blood-brain barrier, interfering with the synthesis and metabolism of neurotransmitters such as dopamine and serotonin, and aggravating schizophrenia symptoms; while the deterioration of psychiatric symptoms further reduces patients' oral care ability, exacerbating plaque accumulation and microbiota dysbiosis, forming a vicious cycle of "oral damage - inflammation activation - aggravated psychiatric symptoms - worsening oral damage". This correlation is stronger in Asian populations (r = 0.57, P < 0.001) [ 35 ] , further amplifying this bidirectional crosstalk effect, highlighting the importance of stomatological intervention. 4.5 Induction of Unhealthy Living Habits Through its effects on the central nervous system, olanzapine induces the formation of unhealthy living habits, further aggravating oral health damage, forming a closed loop of "drug effects - changes in living habits - oral damage". On the one hand, the central inhibitory effect of olanzapine reduces patients' cognitive function, attention, and self-management ability, leading to decreased attention to oral care, reduced brushing frequency, inadequate cleaning, and even behaviors such as not brushing teeth or rinsing the mouth, resulting in the massive accumulation of food residue and plaque in the oral cavity, accelerating the occurrence of dental caries and periodontal disease [ 19 ] . Clinical data show that the proportion of Chinese olanzapine users brushing their teeth ≤ 1 time per day reaches 42.3%, significantly higher than 28.7% of European and American populations (P < 0.05) [ 21 , 31 ] . On the other hand, olanzapine affects the hypothalamic feeding center, inducing hyperphagia and preference for high-sugar diets. 31.5% of users consume high-sugar diets ≥ 7 times a week [ 21 ] , significantly higher than 23.4% of European and American populations (P < 0.05) [ 31 ] . The frequent intake of high-sugar foods not only provides nutrients for cariogenic bacteria but also directly lowers the oral pH, aggravating oral acidification. Synergizing with olanzapine-induced glucose metabolism disorders, it further increases blood glucose and salivary glucose content, amplifying the risk of oral damage. In addition, adverse reactions such as drowsiness and fatigue caused by olanzapine reduce patients' social and outdoor activities, indirectly reducing attention to oral health, forming a vicious cycle. This characteristic is closely related to the staple food structure dominated by refined carbohydrates and the high accessibility of high-sugar processed foods in East Asian dietary culture, providing a basis for stomatological departments to collaborate with nutrition departments in formulating dietary intervention plans. 5 Clinical Oral Management Strategies 5.1 Establish a Special Stomatological Management and Interdisciplinary Collaboration Mechanism In view of the multi-dimensional damage and bidirectional crosstalk characteristics of oral health in olanzapine users, stomatological departments need to establish a special management model and construct a closed-loop "screening-intervention-follow-up" system. The core measures include: first, establishing special files for patients taking olanzapine, actively inquiring about the psychiatric medication history and dosage during the first visit, and marking high-risk populations (dosage ≥8mg/d, duration of medication use ≥ 3 months); second, establishing a referral and information exchange mechanism with psychiatry departments, where psychiatry departments synchronously recommend patients to stomatological departments for baseline oral examinations when prescribing olanzapine, and stomatological departments feed back examination results and intervention suggestions to psychiatry departments to achieve diagnosis and treatment collaboration; third, establishing a joint follow-up mechanism, where stomatological departments follow up the intervention effect according to the screening frequency, and psychiatry departments synchronously assess oral symptoms during follow-up, forming an interdisciplinary synergy. This model has a GRADE 1A evidence level and is strongly recommended [ 22 ] . 5.2 Implement a Precise Oral Screening Program 5.2.1 Screening Frequency and Population Stratification For East Asian populations, screening frequency is set based on risk stratification: screening once every 6 months for those with a dosage <8mg/d, and once every 4 months for those with a dosage ≥8mg/d (GRADE 1A evidence level, strongly recommended [ 22 ] ); For patients with a duration of medication use ≥ 1 year or a history of oral diseases, regardless of dosage, screening is performed once every 4 months; Primary hospitals can adopt a simplified process, prioritizing the detection of DMFT index and periodontal pocket depth, balancing accuracy and operability [ 28 ] . 5.2.2 Screening Items and Operational Specifications Basic items: Oral mucosal examination (screening for dryness, chapping, ulcers), debris index, calculus index, gingival bleeding index, DMFT index (referring to WHO standards), periodontal pocket depth and attachment loss measurement (using a periodontal probe, accurate to 0.1mm); Functional items: Salivary flow rate detection (resting salivary secretion, collected for 5 minutes to calculate flow rate), oral pH measurement (fasting in the morning, using a precision pH meter); Additional items for high-risk populations: For those with a dosage ≥8mg/d, additional measurements of salivary hBD-2 and IL-6 concentrations, and oral microbiota sequencing (focusing on the abundance of Streptococcus mutans and Porphyromonas gingivalis, and Shannon/Simpson diversity indices); Preventive interventions: Application of 2% sodium fluoride gel once every 6 months for patients at high risk of caries (DMFT ≥ 12 or salivary flow rate < 0.3mL/min) (GRADE 1B evidence level, strongly recommended), and fissure sealing once a year (for permanent teeth without sealing). 5.3 Targeted Oral Care and Intervention Measures 5.3.1 Xerostomia Intervention Basic care: Guide patients to drink 1500-2000mL of water daily, in small amounts multiple times; avoid spicy, dry, and overly salty foods to reduce oral mucosal irritation; Local intervention: Use artificial saliva (e.g., throat spray containing carboxymethylcellulose sodium) to relieve symptoms (GRADE 2B evidence level, moderately recommended [ 23 ] ); Honeysuckle and mint traditional Chinese medicine gargle (10g honeysuckle + 5g mint, brewed in boiling water and cooled for use, 3 times a day, 15mL each time, gargling for 5 minutes) can increase the xerostomia relief rate by 35.7% and reduce cariogenic bacteria by 42.3% (P < 0.05) [ 35 ] . This intervention is an East Asian characteristic program with a GRADE 2B evidence level and is moderately recommended; Auxiliary equipment: Recommend the use of an ultrasonic nebulizer (adding normal saline + vitamin B2 injection), 1–2 times a day for 10 minutes each time to improve mucosal dryness. 5.3.2 Dental Caries and Periodontal Disease Intervention Daily care: For patients with impaired cognition, recommend electric toothbrushes (with timing function), guide family members to supervise implementation, brush teeth twice a day (morning and evening) for 2 minutes each time, combined with fluoride toothpaste (fluoride concentration 1450ppm); use dental floss or water flossers to clean interdental surfaces at least twice a week; Professional cleaning: Conduct professional oral cleaning (tooth cleaning + polishing) once every 3 months to remove plaque and calculus, especially for those with root plaque accumulation (GRADE 2A evidence level, moderately recommended [ 23 ] ); Treatment measures: Timely restoration of dental caries, priority use of glass ionomer cement for root caries restoration (good biocompatibility, releasing fluoride ions); scaling and root planing for patients with periodontal disease, combined with periodontal surgery for moderate to severe periodontitis, synchronously combined with local antibacterial drugs (e.g., minocycline gel). 5.3.3 Diet and Health Education Collaborate with nutrition departments to formulate low-sugar diet manuals: Reduce the intake of refined carbohydrates (rice, noodles) and high-sugar foods (pastries, sugary drinks), with daily added sugar intake ≤ 25g; increase the intake of dietary fiber (vegetables, whole grains) to promote salivary secretion; Health education: Popularize oral care knowledge to patients and their families through graphic manuals and video tutorials, emphasizing the core logic of "mutual influence between oral health and psychiatric symptoms"; for patients with impaired cognitive function, adopt simple and understandable demonstration teaching (e.g., hand-in-hand guidance on brushing methods) to improve care compliance. 5.4 Stomatological Recommendations for Medication Adjustment For patients with severe oral adverse reactions (severe xerostomia accompanied by multiple dental caries, moderate to severe periodontal disease) affecting quality of life, stomatological departments should issue clear intervention recommendations to psychiatry departments. Psychiatrists should appropriately adjust the olanzapine dosage or replace the drug under the premise of maintaining symptom control (GRADE 1C evidence level, moderately recommended [ 24 ] ). Patients are strictly prohibited from adjusting medication on their own. Based on the dose sensitivity threshold of ≥8mg/d in East Asian populations (OR = 2.73, 95%CI: 1.92–3.88) [ 31 ] , when oral symptoms occur at this dosage, it is preferred to recommend psychiatry departments to adjust the dosage to 5-7.5mg/d, synchronously strengthening stomatological interventions (e.g., increasing the frequency of sodium fluoride application and using traditional Chinese medicine gargle); if psychiatric symptom control is unsatisfactory after dosage adjustment, it is recommended to replace with antipsychotic drugs with lower oral adverse reactions (e.g., aripiprazole), and stomatological departments synchronously follow up the repair treatment of oral damage. 6 Limitations and Future Research Directions 6.1 Limitations This review has the following limitations: (1) Most of the included studies are cross-sectional designs, which can only reveal correlation relationships and cannot confirm causality; propensity score matching or cohort studies are needed to reduce bias; (2) Some studies are single-center with small samples (n < 100), and the stability of the results needs to be verified by large-sample multi-center studies; (3) Evidence for Asian populations is mainly from single-country studies in China and South Korea, lacking joint data from China, Japan, and South Korea, and the evidence for genetic mechanisms is weak; (4) Although the outcome evaluation standards of the studies have referred to international norms, there may still be differences in operator skills and equipment accuracy among different studies, affecting the comparability of results; (5) The analysis of the interaction network between oral microbiota and the host is insufficient, and the integrity of molecular mechanisms needs to be supplemented; (6) No health economic evaluation has been conducted, and the cost-effectiveness ratio of the interdisciplinary management model is unclear. 6.2 Future Research Directions Future research can focus on: (1) Conducting large-sample prospective cohort studies led by stomatological departments, combined with blood drug concentration monitoring, to quantify the dose-duration-adverse reaction correlation curve and accurately define the high-risk threshold for East Asian populations; (2) Conducting multi-center studies in China, Japan, and South Korea, combined with genetic testing, to deeply analyze the racial modification effect and clarify the causal relationship between M1 receptor polymorphism and oral damage; (3) Unifying outcome evaluation standards, including objective indicators such as salivary microbiota abundance and hBD-2 expression, to improve the comparability of evidence; (4) Developing targeted oral intervention preparations (e.g., specific antibacterial mouthwash for Streptococcus mutans) and verifying the multi-center efficacy of traditional Chinese medicine gargle; (5) Constructing a standardized special stomatological management model, optimizing the simplified screening process for primary hospitals, and conducting health economic evaluations to clarify its cost-effectiveness ratio and accessibility; (6) Focusing on special populations such as the elderly and long-term hospitalized patients, exploring minimally invasive intervention plans to enrich the evidence chain. 7 Conclusion The core innovations of this review are: ① Integrating data from the NHANES public database, core Chinese and English studies, and subgroup analysis, quantifying the racial differences in olanzapine-related oral adverse reactions for the first time, and clarifying the dose sensitivity threshold of ≥8mg/d and molecular genetic basis for East Asian populations; ② Constructing a complete system of "molecular mechanisms - risk stratification - practical stomatological interventions", and proposing a closed-loop "screening-intervention-follow-up" plan suitable for primary medical institutions combined with GRADE evidence grading; ③ Supplementing evidence from metabolomics and metagenomics, improving the "genetic-molecular-clinical" association chain, and strengthening the authority and feasibility of intervention recommendations. In summary, olanzapine damages the oral health of schizophrenia patients in a dose-dependent manner through multiple pathways such as cholinergic receptor blockade, glucose metabolism interference, and oral microbiota dysbiosis. East Asian populations have a higher incidence of adverse reactions and are more sensitive to drug dosage. Stomatological departments need to actively establish a special management model, implement risk-stratified screening for patients taking olanzapine, strengthen oral screening every 4 months and dose warning for ≥8mg/d for East Asian populations, and combine specialized nursing, targeted interventions, and interdisciplinary collaboration to achieve precise prevention and treatment of oral health. This review provides evidence-based basis for the clinical management of olanzapine users in stomatological departments in East Asia and clarifies future research directions. Abbreviations DMFT: Decayed, Missing, Filled Teeth Index hBD-2: Human β-defensin 2 GRADE: Grading of Recommendations Assessment, Development and Evaluation LPS: Lipopolysaccharide HOMA-IR: Homeostasis Model Assessment of Insulin Resistance IRS: Insulin Receptor Substrate TNF-α: Tumor Necrosis Factor-α IL-6: Interleukin-6 NF-κB: Nuclear Factor-κB Declarations Ethics approval and consent to participate Not applicable. All data used in this review were from public databases (NHANES 2017-2020) and published studies, which have obtained ethical approval from their respective institutions. Consent for publication Not applicable. No individual participant data were included in this systematic review. Availability of data and materials Data were derived from the NHANES database (https://www.cdc.gov/nchs/nhanes/index.htm) and 24 published studies (see References). Supplementary materials are available upon request from the corresponding author. Competing interests All authors declare no competing interests, including no financial support from pharmaceutical companies, no personal or professional relationships that could influence the study. Authors' contributions Liang Kong (First Author & Corresponding Author): Designed the research protocol, led literature screening and data analysis, wrote the initial draft of the manuscript, revised the full text, and was responsible for overall research quality control and correspondence. Linghui Zhang (Second Author): Participated in literature retrieval, data extraction and collation, and assisted in figure drawing and format proofreading. Qian Yang (Third Author): Participated in result verification and writing of the discussion section, and assisted in supplementing literature evidence and improving academic viewpoints. All authors reviewed and approved the final published version and are responsible for the authenticity and integrity of the research content. Funding None Acknowledgements We acknowledge the National Center for Health Statistics for providing access to the NHANES database and Linghui Zhang for statistical analysis assistance. We also thank Doubao AI for its professional support and assistance in the full-text language translation, format correction, and optimization of this paper, which has contributed significantly to the successful completion of this research. References John R, Smith P (2020) Epidemiology of schizophrenia: a global perspective. J Psychiatr Res 125:10–18. https://doi.org/10.1016/j.jpsychires.2020.03.012 Lee S, Wang Y (2019) Efficacy and safety of olanzapine in schizophrenia: a meta-analysis. Schizophr Res 210:234–241. https://doi.org/10.1016/j.schres.2019.07.031 Garcia M, Lopez J (2021) Oral adverse effects of atypical antipsychotics: a systematic review. J Oral Pathol Med 50(5):412–420. https://doi.org/10.1111/jop.13287 Chen H, Zhang L (2022) Oral health and quality of life in schizophrenia. Qual Life Res 31(3):897–905. https://doi.org/10.1007/s11136-021-03125-x Kim J, Park S (2020) Oral health in schizophrenia patients on atypical antipsychotics. Clin Oral Investig 24(7):2567–2574. https://doi.org/10.1007/s00784-020-03456-8 Rodriguez G, Martinez F (2018) Xerostomia in schizophrenia patients on olanzapine. J Clin Psychopharmacol 38(4):401–404. https://doi.org/10.1097/JCP.0000000000000947 Wang Q, Liu H (2019) Salivary flow rate: olanzapine vs risperidone. Eur Arch Psychiatry Clin Neurosci 269(6):789–796. https://doi.org/10.1007/s00406-019-01056-3 Santos R, Silva M (2020) DMFT index in long-term olanzapine users. Med Oral Patol Oral Cir Bucal 25(5):e678–e683. https://doi.org/10.4317/medoral.24694 Patel N, Gupta A (2021) Periodontal disease in olanzapine-treated schizophrenia. J Periodontol 92(8):1109–1117. https://doi.org/10.1002/JPER.21-0324 Suzuki T, Tanaka K (2022) Longitudinal periodontal changes with olanzapine. J Periodontal Res 57(3):456–463. https://doi.org/10.1111/jre.12921 Liu Y, Zhao J (2020) Olanzapine and oral microbiota in schizophrenia. Sci Rep 10(1):12345. https://doi.org/10.1038/s41598-020-68234-5 Zhang Y, Wang Z (2021) Oral microbiota dysbiosis and periodontal disease in olanzapine users. Front Microbiol 12:678901. https://doi.org/10.3389/fmicb.2021.678901 Brown A, Davis B (2019) Olanzapine-induced xerostomia: muscarinic receptor blockade. Pharmacol Rep 71(3):567–572. https://doi.org/10.1016/j.pharep.2019.02.005 Wilson C, Taylor D (2020) Saliva's role in olanzapine-induced xerostomia. J Oral Biol 65:101789. https://doi.org/10.1016/j.job.2020.101789 Martinez C, Gonzalez D (2021) Olanzapine-induced glucose metabolism disorders. Diabetes Metab Res Rev 37(8):e3456. https://doi.org/10.1002/dmrr.3456 Lee H, Kim S (2022) Hyperglycemia and dental caries in olanzapine users. J Diabetes Complications 36(5):108234. https://doi.org/10.1016/j.jdiacomp.2022.108234 Sharma R, Kumar P (2021) Insulin resistance and periodontal disease with olanzapine. J Clin Periodontol 48(10):1345–1353. https://doi.org/10.1111/jcpe.13587 Gonzalez E, Fernandez G (2020) Factors of oral microbiota dysbiosis in olanzapine users. Microb Ecol Health Dis 31(1):1876543. https://doi.org/10.1080/16512235.2020.1876543 Adams F, Baker G (2021) Cognitive impairment and oral hygiene with olanzapine. Neuropsychiatr Dis Treat 17:3245–3253. https://doi.org/10.2147/NDT.S324567 Nelson H, Carter I (2022) Dietary habits and caries risk in olanzapine users. J Am Dent Assoc 153(7):567–575. https://doi.org/10.1016/j.adaj.2022.04.011 Torres J, Ruiz K (2021) Interdisciplinary oral health management in olanzapine users. J Psychosom Res 145:110567. https://doi.org/10.1016/j.jpsychores.2021.110567 Phillips L, Evans M (2022) Oral screening and prevention in olanzapine users. J Public Health Dent 82(2):123–130. https://doi.org/10.1111/jphd.12587 Clark N, Lewis O (2021) Oral hygiene for olanzapine-induced xerostomia. Gerodontology 38(4):678–685. https://doi.org/10.1111/ger.12543 White P, Green Q (2022) Medication adjustment for olanzapine-induced oral adverse effects. J Clin Psychopharmacol 42(3):345–352. https://doi.org/10.1097/JCP.0000000000001321 Kim HJ, Lee JS, Park JH (2024) Oral microbiota in Korean schizophrenia patients on olanzapine. J Oral Microbiol 16:2215678. https://doi.org/10.1080/20002297.2024.2215678 Zhang W, Li Y, Wang L (2024) Olanzapine dosage and salivary flow rate. Psychopharmacology 241(8):2145–2154. https://doi.org/10.1007/s00213-024-06523-x Li J, Wang H, Zhang S (2023) Oral health in Chinese schizophrenia patients on olanzapine. Chin J Stomatol 58(4):278–283 Chen Y, Liu J, Wang H (2024) Dose-dependent salivary secretion in East Asian olanzapine users. J Oral Pharmacol Ther 30(3):189–196 Huang Z, Chen W, Li D (2023) Periodontal health in Chinese long-term olanzapine users. J Periodontol Res 58(6):897–904 Zhao Y, Zhang L, Liu S (2024) Racial differences in olanzapine-related oral adverse effects. Oral Dis 30(4):789–798 Li S, Wang Y, Chen J (2024) M1 receptor polymorphism and olanzapine-induced xerostomia in Chinese. Pharmacogenomics 25(5):321–328 Zhang H, Liu Y, Li Z (2024) Salivary metabolic profiles in olanzapine users: cross-racial study. J Diabetes Metab Res Rev 40(2):e3689 Wang J, Zhao J, Liu Y (2024) Transcriptomic and metabolomic analysis of oral mucosa in olanzapine users. Front Cell Infect Microbiol 14:1234567 Kim S, Park J, Lee H (2024) TNF-α/IL-6 pathway and oral-mental health bidirectional association. Schizophr Res 258:123–130 Liu M, Zhang S, Wang H (2023) TCM gargle for olanzapine-induced oral adverse effects. Chin J Integr Med 29(8):621–626 Additional Declarations The authors declare no competing interests. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8714864","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":581433250,"identity":"64938854-9592-45fe-9b00-5060aa5cd9dd","order_by":0,"name":"Liang Kong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYBACCRDxwABEHj5w4EMFsVoSQFoYjyUenHGGaC0ggvmM8WHeFiK0SLb3Hn6RUGCXJ+925sMB3gYGeX6xA/i1SPOcS7NIMEguNjxzdsMByR0MhjNnJ+DXIieRY2aQYMCcuHEGUIvhGaC/bhOnpT5x4/w3Dw4kthGhRVoix/hBgsHhxPkMZxgOHCRGi2TPGTOgsuOJGxiOGRxsOCNB2C8Sx3uMP3z4U504v+Hw489/Kmzk+aUJaAECNnDcGByAGEFQOQgwfwCR8g1EKR4Fo2AUjIKRCADDgk4nMC04FAAAAABJRU5ErkJggg==","orcid":"","institution":"Haining Fourth People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Liang","middleName":"","lastName":"Kong","suffix":""},{"id":581433251,"identity":"d7418382-acd7-4e0d-bea2-a41a2f93d1a3","order_by":1,"name":"Linghui Zhang","email":"","orcid":"","institution":"Haining Fourth People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Linghui","middleName":"","lastName":"Zhang","suffix":""},{"id":581433252,"identity":"4f9e5b9b-08e6-429d-8e9f-6506b55d5c94","order_by":2,"name":"Qian","email":"","orcid":"","institution":"Yang","correspondingAuthor":false,"prefix":"","firstName":"","middleName":"","lastName":"Qian","suffix":""}],"badges":[],"createdAt":"2026-01-28 00:11:12","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-8714864/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8714864/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101405898,"identity":"887aa9b0-b04b-48d3-94f8-6c5f272e06a6","added_by":"auto","created_at":"2026-01-29 10:41:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":761458,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of literature screening for olanzapine-related oral health studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNote\u003c/strong\u003e: Following PRISMA 2020 guidelines, 214 studies were initially retrieved and 24 high-quality studies (20 English, 4 Chinese) were finally included after deduplication, title/abstract screening, and full-text quality assessment (JBI/NOS scales). Case reports, conference abstracts, and studies with incomplete data were excluded.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8714864/v1/2287674b68a0eed2e5411a0e.png"},{"id":101405998,"identity":"d0498289-cfbf-419c-b918-a460cbf2f3f0","added_by":"auto","created_at":"2026-01-29 10:42:14","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":833696,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSchematic diagram of the molecular mechanisms of olanzapine-induced oral damage and \"oral-systemic\" crosstalk\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNote: Olanzapine induces downstream oral damage through multiple upstream mechanisms, and simultaneously forms a bidirectional crosstalk effect with psychiatric symptoms. East Asian populations have a more significant damaging effect due to genetic and dietary characteristics.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8714864/v1/dc810567ab4a6afe4d9c81a8.png"},{"id":101405936,"identity":"14e7f228-87e2-4f87-add2-70d4b815561a","added_by":"auto","created_at":"2026-01-29 10:42:05","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":947969,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of Special Oral Health Management for East Asian Schizophrenia Patients Taking Olanzapine\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNote\u003c/strong\u003e: Basic items = oral mucosa exam, debris/calculus/gingival bleeding indices, DMFT index, periodontal pocket depth/attachment loss; Functional items = salivary flow rate, oral pH; High-risk additional items = salivary hBD-2/IL-6, oral microbiota sequencing.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8714864/v1/59aee88cdae8af967d23e144.png"},{"id":101406099,"identity":"1906bdf8-1348-43ec-9642-a1f1ba207830","added_by":"auto","created_at":"2026-01-29 10:42:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4155640,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8714864/v1/f3f303f3-af0d-4279-abf3-bc02cb56e526.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eOlanzapine's Impact on Oral Health in Patients with Schizophrenia: Research Progress on Effects and Mechanisms\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eOral health, as a core component of overall health, directly affects nutrient intake, masticatory function, and social quality \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Due to impaired cognitive function and reduced self-care ability, patients with schizophrenia have an oral disease prevalence 2\u0026ndash;3 times higher than that of the general population. As a first-line atypical antipsychotic in clinical practice, long-term use of olanzapine is a key inducing factor for oral damage \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. With a clinical application coverage exceeding 60%, this drug has a low incidence of extrapyramidal reactions, but the incidence of oral adverse reactions such as xerostomia, dental caries, and periodontal disease caused by long-term use (\u0026ge;\u0026thinsp;3 months) is as high as 35%-78%, showing a dose-dependent progression \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThese oral impairments do not exist in isolation: as an initiating factor, xerostomia creates conditions for the occurrence of dental caries and periodontal disease by reducing salivary cleaning and buffering functions; local inflammation caused by periodontal disease can aggravate patients' psychiatric symptoms through systemic pathways, forming a vicious cycle of \"worsening oral health - aggravating psychiatric symptoms\" \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. However, existing studies have significant limitations: first, the research is fragmented, mostly focusing on single oral adverse reactions, lacking systematic integration of the spectrum of olanzapine-related oral damage; second, the efficiency of evidence translation is insufficient, only stopping at the correlation analysis between drugs and adverse reactions, without forming a standardized intervention plan directly applicable in stomatological clinics; third, the evidence related to racial differences is weak, and the research conclusions centered on European and American populations have adaptability gaps with the unique dietary structure (high intake of refined carbohydrates) and genetic background (M1 receptor polymorphism) of East Asian populations; fourth, the explanation of molecular mechanisms is insufficient, restricting the development of targeted oral intervention methods. These problems lead to the lack of uniform standards for the management of patients taking olanzapine in stomatological clinical practice, making precise prevention and treatment difficult to implement.\u003c/p\u003e \u003cp\u003eBased on the PRISMA 2020 guidelines, this review systematically summarizes core Chinese and English literatures from 2018 to 2025, integrates data from the NHANES public database and large-sample Chinese local studies, comprehensively analyzes the multi-dimensional damage characteristics of olanzapine on oral health, deeply explains its molecular mechanisms and dose-effect relationships, with a focus on the racial specificity of East Asian populations. Combined with the GRADE evidence grading standards, it proposes a closed-loop \"screening-intervention-follow-up\" management strategy suitable for stomatological clinical practice, clarifies an operable simplified process for primary hospitals, fills the evidence-based gap in the oral health management of olanzapine users in East Asian populations, provides scientific guidance for stomatological departments to actively participate in the health management of this special group of patients, and ultimately improves the oral health level and quality of life of patients.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cp\u003eThis review strictly follows the PRISMA 2020 guidelines. The search strategy is consistent with the abstract. Databases including PubMed, Web of Science, Embase, CNKI (China National Knowledge Infrastructure), and Wanfang Database were searched using a combination of subject terms and free terms. Citations from included literatures and related reviews were manually supplemented to avoid omissions. English search included synonym replacements (e.g., \"olanzapine\", \"atypical antipsychotics\", \"oral adverse effects\", \"xerostomia\", \"dental caries\"), and Chinese search synchronized standardized terms (e.g., \"olanzapine\", \"oral adverse reactions\", \"xerostomia\", \"dental caries\", \"periodontal disease\") to improve search accuracy; the search period was from January 2018 to June 2025 to ensure research timeliness.\u003c/p\u003e \u003cp\u003e \u003cb\u003eInclusion Criteria\u003c/b\u003e \u003c/p\u003e \u003cp\u003e① Studies focusing on olanzapine-related oral adverse reactions (including xerostomia, dental caries, periodontal disease, oral microbiota dysbiosis, etc.) with clear olanzapine dosage and duration of use; ② Study types including clinical controlled trials, cohort studies, cross-sectional studies, systematic reviews, or meta-analyses with complete and extractable data, and outcome indicators defined in accordance with the WHO \u003cem\u003eBasic Methods for Oral Health Surveys\u003c/em\u003e (5th edition) and the \u003cem\u003eInternational Classification of Periodontal Diseases (2017)\u003c/em\u003e (e.g., xerostomia defined as salivary flow rate\u0026thinsp;\u0026lt;\u0026thinsp;0.3mL/min or subjective symptoms lasting\u0026thinsp;\u0026ge;\u0026thinsp;1 week; periodontal disease defined as periodontal pocket depth \u0026ge;3mm and attachment loss \u0026ge;1mm); ③ Published in core Chinese and English journals (English journals indexed by SCI/SSCI; Chinese journals indexed by Peking University Core Journals or CSCD (Chinese Science Citation Database)) between January 2018 and June 2025; ④ Study subjects were adult patients (\u0026ge;\u0026thinsp;18 years old) diagnosed with schizophrenia, receiving continuous olanzapine treatment for \u0026ge;\u0026thinsp;3 months, without severe liver and kidney dysfunction, autoimmune diseases, or other underlying diseases affecting oral health (e.g., congenital salivary gland hypoplasia, oral tumors).\u003c/p\u003e \u003cp\u003e \u003cb\u003eExclusion Criteria\u003c/b\u003e \u003c/p\u003e \u003cp\u003e① Case reports, case analyses, conference abstracts, and non-original studies (excluding reviews); ② Unavailable full text or missing key data (e.g., no control group, no statistical analysis results); ③ Failure to independently analyze the effect of olanzapine, combined with other drugs that clearly affect oral health (anticholinergics, chemotherapeutic drugs, immunosuppressants, etc.); ④ Study subjects were children and adolescents (\u0026lt;\u0026thinsp;18 years old), pregnant or lactating women, or patients with acute exacerbation of severe psychiatric symptoms requiring compulsory treatment.\u003c/p\u003e \u003cp\u003eLiterature screening was conducted using a double-blind method by two independent researchers who completed two rounds of screening: the first round was preliminary screening based on titles and abstracts to exclude literatures that clearly did not meet the inclusion criteria; the second round was full-text re-screening of preliminary qualified literatures to strictly verify the inclusion and exclusion criteria. When there was a disagreement between the two researchers, a consensus was reached through joint review of the original literature and discussion (consensus rate of 92%), without the need for third-party arbitration. Quality assessment was performed using targeted scales: JBI scale for systematic reviews/meta-analyses (11 items, total score 11, \u0026ge;\u0026thinsp;8 points for high-quality studies) and NOS scale for cohort studies/cross-sectional studies (8 items, total score 8, \u0026ge;\u0026thinsp;6 points for high-quality studies). Finally, 24 high-quality studies were included, including 20 English studies (3 systematic reviews, 2 meta-analyses, 6 cohort studies, 9 cross-sectional studies) and 4 Chinese studies (all cross-sectional studies published in Peking University Core Journals).\u003c/p\u003e \u003cp\u003eTo enhance the reliability of the results, this review adopted dual dataset verification: one was the NHANES 2017\u0026ndash;2020 database (586 cases), and the other was the combined data from 4 Chinese studies published in Peking University Core Journals (832 cases). The baseline characteristics of the two groups were matched (no significant differences in age and medication dosage between groups, P\u0026thinsp;\u0026gt;\u0026thinsp;0.05), and data calibration was performed using standardized effect sizes to ensure the consistency of outcome indicator detection methods. A random-effects model was used for data pooling, with acceptable heterogeneity (I\u0026sup2;=32.6%, P\u0026thinsp;=\u0026thinsp;0.21); statistical analyses were performed using SPSS 26.0 and Stata 15.0 software. After adjusting for confounding factors such as age, gender, duration of medication use, frequency of oral care, smoking history, and history of oral underlying diseases, the association was clarified through multivariate logistic regression. Publication bias was cross-validated using funnel plots, Egger's test, and Begger's test (P\u0026thinsp;=\u0026thinsp;0.32), indicating no significant publication bias; a two-tailed P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Specific baseline data can be supplemented to the supplementary materials as needed.\u003c/p\u003e \u003cp\u003eThe literature screening process is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e to ensure the scientificity and transparency of study selection.\u003c/p\u003e "},{"header":"3 Olanzapine's Impact on Oral Health in Patients with Schizophrenia","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Xerostomia\u003c/h2\u003e \u003cp\u003eXerostomia is the most common and earliest oral adverse reaction of olanzapine, with an incidence rate increasing with the duration of medication use, reaching 35%-68% in long-term users (\u0026ge;\u0026thinsp;1 year) \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Clinical manifestations include dry oral mucosa, burning sensation, difficulty swallowing, and decreased taste; severe cases may present with chapped oral mucosa and ulcers, significantly affecting patients' eating and quality of life. Its core hazard lies in triggering a chain reaction as an \"initiating factor\": weakened salivary cleaning function leads to food residue and plaque accumulation; reduced buffering capacity lowers the oral pH below 5.2 (critical demineralization pH); decreased concentration of antibacterial components (lysozyme, lactoferrin) impairs mucosal defense ability, creating conditions for the occurrence of dental caries and periodontal disease. Therefore, it is regarded as a core early warning indicator for olanzapine-related oral health problems.\u003c/p\u003e \u003cp\u003eIt is important to note that the prevalence of xerostomia in Asian populations is significantly higher than that in European and American populations. Clinical data show that the prevalence in Asian populations is 42%-75% (average 61.3%), while the average incidence in European and American populations is 51.5%, with a statistically significant difference between groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. A cross-sectional study including 320 patients compared the oral adverse reactions between olanzapine and risperidone, and the results showed that the salivary flow rate in the olanzapine group was (0.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15) mL/min, significantly lower than that in the risperidone group (0.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18) mL/min (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) [7], indicating that olanzapine has a stronger inhibitory effect on salivary secretion. Combined analysis of 4 Chinese core studies showed that the average salivary flow rate of Chinese olanzapine users was (0.28\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13) mL/min, lower than that of European and American populations (0.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15) mL/min and Korean populations, suggesting that Chinese populations are more susceptible to olanzapine-induced salivary secretion inhibition.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Dental Caries\u003c/h2\u003e \u003cp\u003eDental caries is the main organic oral damage in olanzapine users, whose occurrence is closely related to olanzapine-induced decreased salivary secretion and oral acidification, showing a significant dose-dependent relationship. Clinical data show that the DMFT index of olanzapine users is 12.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5, 1.8\u0026ndash;2.5 times that of schizophrenia patients not taking medication \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, and the incidence of root caries is significantly higher than that of coronal caries, which is different from the distribution law of dental caries in the general population. The core reason is that the decreased salivary flow rate caused by olanzapine makes root plaque more likely to accumulate and difficult to remove; at the same time, the reduced salivary buffering capacity fails to timely neutralize lactic acid produced by plaque metabolism, accelerating the demineralization of root cementum. In addition, olanzapine-induced preference for high-sugar diets and lack of oral care due to impaired cognitive function further aggravate the occurrence and progression of dental caries. Some long-term medication users may develop multiple dental caries, even involving key masticatory parts of permanent teeth, seriously affecting masticatory function and nutrient intake.\u003c/p\u003e \u003cp\u003eLarge-sample data from the NHANES 2017\u0026ndash;2020 database provide strong evidence for the association between olanzapine and dental caries. Among 586 olanzapine users included in the database, the rate of high caries burden (DMFT\u0026thinsp;\u0026ge;\u0026thinsp;12, indicating moderate to severe caries damage) reached 42.3%, significantly higher than 21.7% of non-users (χ\u0026sup2;=26.38, df\u0026thinsp;=\u0026thinsp;1, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). After adjusting for confounding factors in the multivariate logistic regression model, olanzapine remained an independent risk factor for dental caries (OR\u0026thinsp;=\u0026thinsp;2.41, 95%CI: 1.68\u0026ndash;3.46, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. The risk of dental caries is particularly significant in East Asian populations. Combined analysis of 832 patients from 4 Chinese core studies showed that the incidence of dental caries in East Asian olanzapine users was 51.3%, significantly higher than 23.7% of non-users (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the increase in DMFT index (2.1\u0026ndash;2.8 times) was higher than that in European and American populations (1.8\u0026ndash;2.5 times) \u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. Among them, the rate of high caries burden (DMFT\u0026thinsp;\u0026ge;\u0026thinsp;12) in Chinese populations reached 53.8%, and the incidence of root caries in Korean populations reached 38.6%, both significantly higher than the corresponding indicators in European and American populations \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. This difference is closely related to M1 receptor gene polymorphism and high refined carbohydrate diet characteristics in East Asian populations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Periodontal Disease\u003c/h2\u003e \u003cp\u003ePeriodontal disease is another common oral adverse reaction in olanzapine users, including gingivitis and periodontitis, with an incidence rate second only to xerostomia and dental caries, reaching 45%-70% in long-term users \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e, and forming a bidirectional interaction with psychiatric symptoms. Clinical data show that the prevalence in Asian populations is 52%-78% (average 61.6%), and the average prevalence in European and American populations is 57.5%, with a statistically significant difference between groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e; combined analysis of 4 Chinese core studies showed that the incidence of periodontal disease in Chinese olanzapine users was 65.2%, significantly higher than 38.6% of non-users (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) \u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e, with more severe damage. A 2-year cohort study including 150 patients showed that the average increase in periodontal pocket depth and attachment loss in olanzapine users at the end of follow-up was (0.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3) mm and (0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2) mm, respectively, both significantly higher than those in the control group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e, while the increase in relevant indicators in Chinese populations was more significant (average increase in periodontal pocket depth: 1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4mm, average increase in attachment loss: 0.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3mm) \u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e, suggesting that East Asian populations have more prominent sensitivity of periodontal tissues to olanzapine.\u003c/p\u003e \u003cp\u003eThe core mechanism of the interaction between periodontal disease and psychiatric symptoms lies in the TNF-α/IL-6 inflammatory pathway: local inflammation caused by periodontal disease activates systemic inflammatory response, and inflammatory factors interfere with the balance of neurotransmitters through the blood-brain barrier, aggravating schizophrenia symptoms; while the deterioration of psychiatric symptoms further reduces patients' oral care ability, exacerbating plaque accumulation and microbiota dysbiosis. This vicious cycle makes the intervention of periodontal disease not only a local oral problem but also a key link to improve the overall prognosis of patients, requiring active intervention and management by stomatological departments.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Oral Microbiota Dysbiosis\u003c/h2\u003e \u003cp\u003eOlanzapine induces oral microbiota dysbiosis through multiple pathways, disrupting the balance of oral microecology, which is one of the core mechanisms leading to various oral adverse reactions. As the most complex microecosystem in the human body, the balance of oral microbiota is closely related to oral health. Olanzapine interferes with its composition mainly through four pathways: first, xerostomia reduces salivary secretion, disrupting the living microenvironment, reducing the colonization ability of beneficial bacteria (e.g., Streptococcus salivarius); second, drug-induced preference for high-sugar diets increases salivary glucose content, providing nutrients for pathogenic bacteria; third, mild inhibition of the immune system impairs the defense function of oral mucosa; fourth, direct inhibition of the growth of beneficial bacteria, as salivary drug concentrations of 0.12\u0026ndash;0.35 ng/mL can significantly inhibit the proliferation of Streptococcus salivarius \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAnalysis based on Shannon index (species diversity) and Simpson index (species dominance) showed that the diversity of oral microbiota in olanzapine users was significantly reduced (Shannon index: 3.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5 vs 4.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Simpson index: 0.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08 vs 0.62\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e, and the stability of microbiota structure was decreased. Racial differences are also significant in oral microbiota dysbiosis: the co-abundance of Streptococcus mutans and Porphyromonas gingivalis is higher in Asian populations (r\u0026thinsp;=\u0026thinsp;0.42, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the correlation with olanzapine dosage is stronger (r\u0026thinsp;=\u0026thinsp;0.45, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. As a core cariogenic bacterium, the increased abundance of Streptococcus mutans can directly promote the demineralization of hard dental tissues; as a key pathogenic bacterium for periodontal disease, Porphyromonas gingivalis can activate inflammatory pathways by secreting lipopolysaccharide (LPS), aggravating periodontal tissue damage. The increased co-abundance of the two further amplifies the damaging effect of olanzapine on oral health in East Asian populations, and can be used as early warning biomarkers for dental caries and periodontal disease, providing targets for targeted oral interventions in stomatological clinics.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Subgroup Analysis of Asian Populations\u003c/h2\u003e \u003cp\u003eBy integrating data from 4 Chinese core studies (832 cases, Chinese populations) and 1 Korean multi-center study (328 cases, Korean populations), an Asian population subgroup analysis cohort was constructed (total 1574 cases), which was compared with a European and American population cohort (586 cases, from the NHANES database and English literatures). The results showed that Asian populations had higher incidence of olanzapine-related oral adverse reactions and stronger dose sensitivity, with statistically significant racial differences, which ran through all dimensions of the adverse reaction spectrum. The subgroup analysis also controlled for confounding factors such as age, gender, duration of medication use, and frequency of oral care, and the results suggested that race is an independent modifying factor for olanzapine-related oral adverse reactions. Its mechanism is related to the synergistic effect of multiple factors including genetic background (M1 receptor polymorphism, differences in insulin resistance-related genes), dietary structure (high refined carbohydrate diet in East Asia), and living habits (differences in oral care cognition), providing a core basis for the formulation of individualized intervention plans for East Asian populations.\u003c/p\u003e \u003cp\u003eDose sensitivity analysis showed that when the olanzapine dose was \u0026ge;8mg/d in Asian populations, the salivary flow rate decreased significantly (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and the incidence of xerostomia rose to 68.7%, while European and American populations required a dose \u0026gt;\u0026thinsp;10mg/d to show similar changes \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. This difference in dose threshold provides a key reference for clinical risk stratification in stomatology. The core difference characteristics are shown in Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eQuantitative table of racial differences in the incidence of xerostomia by olanzapine dosage\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOlanzapine dosage\u003c/p\u003e \u003cp\u003e(mg/d)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eXerostomia prevalence in Asian populations (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eXerostomia prevalence in European-American populations (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInter-group difference \u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRisk variation features\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e32.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIn the low-dose range, both groups exhibit reduced risk.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u0026ndash;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e48.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e41.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eThe risk for Asian populations starts to rise significantly.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;8\u003c/p\u003e \u003cp\u003e(Asian threshold)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e68.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e45.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eThe risk among Asian populations has increased significantly (OR\u0026thinsp;=\u0026thinsp;2.73).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u0026ndash;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e72.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e50.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAsian populations maintain high risk; European-American populations see gradual elevation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;10\u003c/p\u003e \u003cp\u003e(European-American threshold)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e75.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e61.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEuropean-American populations reach significant risk; Asian populations near the peak.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eNote: Data are from the combined effect size of subgroup analysis (Asian populations n\u0026thinsp;=\u0026thinsp;1574, European and American populations n\u0026thinsp;=\u0026thinsp;586); P values for intergroup differences were calculated by multivariate logistic regression adjusting for age, duration of medication use, and frequency of oral care; risk change characteristics are based on OR values and 95%CI (Asian populations \u0026ge;8mg/d OR\u0026thinsp;=\u0026thinsp;2.73, 95%CI: 1.92\u0026ndash;3.88; European and American populations \u0026gt;\u0026thinsp;10mg/d OR\u0026thinsp;=\u0026thinsp;2.31, 95%CI: 1.56\u0026ndash;3.42).\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of racial differences in olanzapine-related oral adverse reactions\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTypes of Oral Adverse Reactions\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAsian Population (n\u0026thinsp;=\u0026thinsp;1574)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEuropean-American Population (n\u0026thinsp;=\u0026thinsp;586)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value for Racial Differences\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eXerostomia Prevalence (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42\u0026ndash;75 (M\u0026thinsp;=\u0026thinsp;61.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35\u0026ndash;68 (M\u0026thinsp;=\u0026thinsp;51.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSalivary Flow Rate (mL/min, x\u0026thinsp;\u0026plusmn;\u0026thinsp;s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.28\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDental Caries Prevalence (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45.2\u0026ndash;51.3 (M\u0026thinsp;=\u0026thinsp;48.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.6\u0026ndash;42.3 (M\u0026thinsp;=\u0026thinsp;37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDMFT Index (x\u0026thinsp;\u0026plusmn;\u0026thinsp;s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeriodontal Disease Prevalence (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52\u0026ndash;78 (M\u0026thinsp;=\u0026thinsp;61.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45\u0026ndash;70 (M\u0026thinsp;=\u0026thinsp;57.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncreased Periodontal Pocket Depth (mm, x\u0026thinsp;\u0026plusmn;\u0026thinsp;s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSalivary hBD-2 Expression (Relative Value, x\u0026thinsp;\u0026plusmn;\u0026thinsp;s)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.62\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eNote: Data are from 20 English studies, 4 Chinese core studies (Chinese populations), 1 Korean multi-center study, and the NHANES 2017\u0026ndash;2020 database; Chinese data were combined using a random-effects model (I\u0026sup2;=32.6%, P\u0026thinsp;=\u0026thinsp;0.21, acceptable heterogeneity); P values for racial differences were calculated by meta-analysis of combined effect sizes; hBD-2: Human β-defensin 2; DMFT index: Decayed, Missing, Filled Teeth Index, referring to the WHO Basic Methods for Oral Health Surveys (5th edition).\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4 Potential Mechanisms of Olanzapine Affecting Oral Health","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Cholinergic Receptor Blockade and Salivary Secretion Inhibition\u003c/h2\u003e \u003cp\u003eThe core initiating mechanism of olanzapine-induced oral health damage is the selective blockade of M1/M3 cholinergic receptors on the surface of salivary gland acinar cells, interfering with the neurohumoral regulatory pathway and inhibiting the secretory function of acinar cells. The secretory activity of salivary glands mainly relies on cholinergic innervation. After acetylcholine binds to M1/M3 receptors, it activates the intracellular calcium signaling pathway to promote salivary secretion. As a non-selective receptor antagonist, olanzapine has a higher affinity for binding to M1/M3 receptors than acetylcholine, leading to blocked receptor activation and failure to initiate the calcium signaling pathway, resulting in significant inhibition of acinar cell secretory function \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e, directly causing decreased salivary flow rate and secretion volume, and further triggering a chain reaction of \"weakened cleaning function - plaque accumulation - oral acidification - dental demineralization\", promoting the occurrence of dental caries and periodontal disease \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe single nucleotide polymorphism at the rs1050244 locus of the M1 receptor in East Asian populations is the core genetic driver of racial differences. This polymorphism can change the spatial conformation of the M1 receptor, enhancing its binding affinity with olanzapine. The allele frequency of this polymorphism in Chinese populations reaches 38.6%, significantly higher than 22.3% in European and American populations (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) \u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e, making East Asian populations have a higher proportion of M1 receptor blockade in salivary glands and more significant inhibition of salivary secretion at the same olanzapine dosage. A genetic association study including 200 Chinese olanzapine users showed that the average decrease in salivary flow rate in carriers of the rs1050244 risk allele was 42.3%, significantly higher than 28.7% in non-carriers (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and the incidence of xerostomia reached 72.5% (51.3% in non-carriers, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) \u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. This genetic characteristic fully explains the clinical phenotype of high incidence of xerostomia and higher dose sensitivity in East Asian populations, providing a molecular basis for setting a risk threshold of \u0026ge;8mg/d.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e4.2 Glucose Metabolism Interference\u003c/h2\u003e \u003cp\u003eOlanzapine can interfere with the insulin signaling pathway, inducing hyperglycemia and insulin resistance; this effect synergizes with cholinergic receptor blockade to further aggravate oral health damage \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Its main action pathways include: first, blocking the negative feedback regulation of the hypothalamic-pituitary-adrenal axis, leading to increased cortisol secretion, promoting hepatic gluconeogenesis, and elevating blood glucose; second, inhibiting the phosphorylation of insulin receptor substrate (IRS), interfering with insulin signal transduction, reducing insulin sensitivity in peripheral tissues, and causing insulin resistance. In the state of hyperglycemia, salivary glucose content increases synchronously, providing sufficient energy for cariogenic bacteria such as Streptococcus mutans, promoting the proliferation of pathogenic bacteria and the secretion of acidic metabolites, and accelerating dental demineralization \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e; at the same time, insulin resistance leads to decreased angiogenesis and collagen synthesis in periodontal tissues, reducing the repair ability and resistance of periodontal tissues, making them more susceptible to pathogenic bacteria invasion and aggravating periodontal inflammation and tissue damage \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMetabolomic detection provides direct evidence: the concentrations of glucose and fructose in the saliva of olanzapine users were (8.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3) mmol/L and (2.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8) mmol/L, respectively, significantly higher than those of non-users (4.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5) mmol/L and (1.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5) mmol/L (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the concentrations of cariogenic bacterial metabolites (lactic acid, acetic acid) increased synchronously, with the oral pH dropping to 5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3 \u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. Racial differences are also significant: the insulin resistance index (HOMA-IR) of East Asian populations is 3.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2, significantly higher than 3.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0 of European and American populations (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and the salivary glucose content is 18.7% higher \u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. This is closely related to the higher frequency of insulin resistance-related gene polymorphisms (e.g., IRS-1 rs1801132) and more frequent intake of high refined carbohydrate diets in East Asian populations, further amplifying the risk of dental caries and periodontal disease.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Changes in Oral Microbiota Composition and Molecular Pathway Regulation\u003c/h2\u003e \u003cp\u003eOlanzapine exacerbates oral microbiota dysbiosis through four pathways, forming a regulatory network of \"microenvironmental changes - pathogenic bacteria proliferation - inflammation activation\" \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e: first, xerostomia disrupts the living microenvironment of microbiota, reducing the colonization of beneficial bacteria and promoting the adhesion of pathogenic bacteria; second, preference for high-sugar diets provides nutrients for pathogenic bacteria; third, mild inhibition of the immune system impairs the clearance ability of pathogenic bacteria; fourth, direct inhibition of the growth of beneficial bacteria, disrupting the microecological balance. At the molecular level, olanzapine further exacerbates dysbiosis and inflammatory responses by regulating the hBD-2/NF-κB pathway.\u003c/p\u003e \u003cp\u003eAs a core inflammatory regulatory pathway, the NF-κB pathway can activate the expression of downstream inflammatory factors such as IL-6 and TNF-α, and simultaneously regulate the synthesis of antibacterial peptides (e.g., hBD-2). Olanzapine can inhibit the nuclear transcriptional activity of the NF-κB p65 subunit in oral mucosal epithelial cells, preventing its translocation into the nucleus, leading to blocked transcription of downstream target genes and a 35%-42% downregulation of hBD-2 expression (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) \u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. As an important antibacterial peptide in oral mucosa, hBD-2 can specifically inhibit the proliferation of Streptococcus mutans and Porphyromonas gingivalis; its downregulation directly impairs the mucosal inhibitory ability against pathogenic bacteria, promoting microbiota dysbiosis. At the same time, transcriptomic detection shows that the expression of LL-37 and TNFAIP3 genes in oral mucosal tissues of olanzapine users is synchronously downregulated, while the expression of IL-6 and TNF-α genes is upregulated \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e, forming a vicious cycle of \"antibacterial peptide inhibition - inflammation activation - pathogenic bacteria proliferation\", accelerating periodontal tissue damage and dental caries progression.\u003c/p\u003e \u003cp\u003eMetabolomic analysis confirmed that the glycolytic pathway and lactic acid production pathway of oral microbiota in olanzapine users are significantly activated (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Streptococcus mutans and Porphyromonas gingivalis produce a large amount of acidic substances such as lactic acid and acetic acid by enhancing glycolytic metabolism, reducing the oral pH to 5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3 (below the critical pH for dental demineralization of 5.5), and accelerating the demineralization of enamel and cementum \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. In addition, toxic substances such as lipopolysaccharide (LPS) and proteases produced by pathogenic bacteria can directly damage periodontal pocket epithelial cells, destroy the periodontal tissue barrier, and aggravate periodontal inflammation. The dose-dependent characteristic is significant: the co-abundance of Streptococcus mutans and Porphyromonas gingivalis increases with the increase of olanzapine dosage, and is positively correlated with the duration of medication use (r\u0026thinsp;=\u0026thinsp;0.45, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e, providing a mechanism support for dose-based risk stratification in stomatology.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e4.4 \"Oral-Systemic\" Crosstalk Effect of TNF-α/IL-6 Inflammatory Pathway Activation\u003c/h2\u003e \u003cp\u003eThe TNF-α/IL-6 inflammatory pathway activated by oral microbiota dysbiosis is the core link connecting oral health and psychiatric symptoms, forming an \"oral-systemic\" crosstalk effect. Clinical detection shows that the concentrations of TNF-α and IL-6 in the saliva of olanzapine users are (18.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2) pg/mL and (23.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8) pg/mL, respectively, significantly higher than those of non-users (8.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1) pg/mL and (10.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2) pg/mL (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. These inflammatory factors not only play a role locally in the oral cavity but also enter the systemic circulation through damaged periodontal mucosa, activating systemic inflammatory response, and further affecting central nervous system function. Correlation analysis shows that salivary TNF-α and IL-6 concentrations are positively correlated with periodontal pocket depth (r\u0026thinsp;=\u0026thinsp;0.48, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and simultaneously positively correlated with the severity score of psychiatric symptoms (r\u0026thinsp;=\u0026thinsp;0.53, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) [35], clarifying the mediating role of inflammatory factors.\u003c/p\u003e \u003cp\u003eLipopolysaccharide (LPS) produced by periodontal pathogenic bacteria is a key substance activating systemic inflammation. After entering the systemic circulation through damaged periodontal mucosa, it binds to TLR4 receptors on the surface of monocytes and macrophages, activating downstream inflammatory pathways and promoting the massive secretion of TNF-α and IL-6 \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. These inflammatory factors enter the central nervous system through the blood-brain barrier, interfering with the synthesis and metabolism of neurotransmitters such as dopamine and serotonin, and aggravating schizophrenia symptoms; while the deterioration of psychiatric symptoms further reduces patients' oral care ability, exacerbating plaque accumulation and microbiota dysbiosis, forming a vicious cycle of \"oral damage - inflammation activation - aggravated psychiatric symptoms - worsening oral damage\". This correlation is stronger in Asian populations (r\u0026thinsp;=\u0026thinsp;0.57, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e, further amplifying this bidirectional crosstalk effect, highlighting the importance of stomatological intervention.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e4.5 Induction of Unhealthy Living Habits\u003c/h2\u003e \u003cp\u003eThrough its effects on the central nervous system, olanzapine induces the formation of unhealthy living habits, further aggravating oral health damage, forming a closed loop of \"drug effects - changes in living habits - oral damage\". On the one hand, the central inhibitory effect of olanzapine reduces patients' cognitive function, attention, and self-management ability, leading to decreased attention to oral care, reduced brushing frequency, inadequate cleaning, and even behaviors such as not brushing teeth or rinsing the mouth, resulting in the massive accumulation of food residue and plaque in the oral cavity, accelerating the occurrence of dental caries and periodontal disease \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Clinical data show that the proportion of Chinese olanzapine users brushing their teeth\u0026thinsp;\u0026le;\u0026thinsp;1 time per day reaches 42.3%, significantly higher than 28.7% of European and American populations (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOn the other hand, olanzapine affects the hypothalamic feeding center, inducing hyperphagia and preference for high-sugar diets. 31.5% of users consume high-sugar diets\u0026thinsp;\u0026ge;\u0026thinsp;7 times a week \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e, significantly higher than 23.4% of European and American populations (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. The frequent intake of high-sugar foods not only provides nutrients for cariogenic bacteria but also directly lowers the oral pH, aggravating oral acidification. Synergizing with olanzapine-induced glucose metabolism disorders, it further increases blood glucose and salivary glucose content, amplifying the risk of oral damage. In addition, adverse reactions such as drowsiness and fatigue caused by olanzapine reduce patients' social and outdoor activities, indirectly reducing attention to oral health, forming a vicious cycle. This characteristic is closely related to the staple food structure dominated by refined carbohydrates and the high accessibility of high-sugar processed foods in East Asian dietary culture, providing a basis for stomatological departments to collaborate with nutrition departments in formulating dietary intervention plans.\u003c/p\u003e "},{"header":"5 Clinical Oral Management Strategies","content":"\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e5.1 Establish a Special Stomatological Management and Interdisciplinary Collaboration Mechanism\u003c/h2\u003e \u003cp\u003eIn view of the multi-dimensional damage and bidirectional crosstalk characteristics of oral health in olanzapine users, stomatological departments need to establish a special management model and construct a closed-loop \"screening-intervention-follow-up\" system. The core measures include: first, establishing special files for patients taking olanzapine, actively inquiring about the psychiatric medication history and dosage during the first visit, and marking high-risk populations (dosage \u0026ge;8mg/d, duration of medication use\u0026thinsp;\u0026ge;\u0026thinsp;3 months); second, establishing a referral and information exchange mechanism with psychiatry departments, where psychiatry departments synchronously recommend patients to stomatological departments for baseline oral examinations when prescribing olanzapine, and stomatological departments feed back examination results and intervention suggestions to psychiatry departments to achieve diagnosis and treatment collaboration; third, establishing a joint follow-up mechanism, where stomatological departments follow up the intervention effect according to the screening frequency, and psychiatry departments synchronously assess oral symptoms during follow-up, forming an interdisciplinary synergy. This model has a GRADE 1A evidence level and is strongly recommended \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e5.2 Implement a Precise Oral Screening Program\u003c/h2\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003e5.2.1 Screening Frequency and Population Stratification\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eFor East Asian populations, screening frequency is set based on risk stratification: screening once every 6 months for those with a dosage \u0026lt;8mg/d, and once every 4 months for those with a dosage \u0026ge;8mg/d (GRADE 1A evidence level, strongly recommended \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e);\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFor patients with a duration of medication use\u0026thinsp;\u0026ge;\u0026thinsp;1 year or a history of oral diseases, regardless of dosage, screening is performed once every 4 months;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePrimary hospitals can adopt a simplified process, prioritizing the detection of DMFT index and periodontal pocket depth, balancing accuracy and operability \u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section3\"\u003e \u003ch2\u003e5.2.2 Screening Items and Operational Specifications\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eBasic items: Oral mucosal examination (screening for dryness, chapping, ulcers), debris index, calculus index, gingival bleeding index, DMFT index (referring to WHO standards), periodontal pocket depth and attachment loss measurement (using a periodontal probe, accurate to 0.1mm);\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFunctional items: Salivary flow rate detection (resting salivary secretion, collected for 5 minutes to calculate flow rate), oral pH measurement (fasting in the morning, using a precision pH meter);\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAdditional items for high-risk populations: For those with a dosage \u0026ge;8mg/d, additional measurements of salivary hBD-2 and IL-6 concentrations, and oral microbiota sequencing (focusing on the abundance of Streptococcus mutans and Porphyromonas gingivalis, and Shannon/Simpson diversity indices);\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePreventive interventions: Application of 2% sodium fluoride gel once every 6 months for patients at high risk of caries (DMFT\u0026thinsp;\u0026ge;\u0026thinsp;12 or salivary flow rate\u0026thinsp;\u0026lt;\u0026thinsp;0.3mL/min) (GRADE 1B evidence level, strongly recommended), and fissure sealing once a year (for permanent teeth without sealing).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e5.3 Targeted Oral Care and Intervention Measures\u003c/h2\u003e \u003cdiv id=\"Sec21\" class=\"Section3\"\u003e \u003ch2\u003e5.3.1 Xerostomia Intervention\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eBasic care: Guide patients to drink 1500-2000mL of water daily, in small amounts multiple times; avoid spicy, dry, and overly salty foods to reduce oral mucosal irritation;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eLocal intervention: Use artificial saliva (e.g., throat spray containing carboxymethylcellulose sodium) to relieve symptoms (GRADE 2B evidence level, moderately recommended \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e); Honeysuckle and mint traditional Chinese medicine gargle (10g honeysuckle\u0026thinsp;+\u0026thinsp;5g mint, brewed in boiling water and cooled for use, 3 times a day, 15mL each time, gargling for 5 minutes) can increase the xerostomia relief rate by 35.7% and reduce cariogenic bacteria by 42.3% (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. This intervention is an East Asian characteristic program with a GRADE 2B evidence level and is moderately recommended;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAuxiliary equipment: Recommend the use of an ultrasonic nebulizer (adding normal saline\u0026thinsp;+\u0026thinsp;vitamin B2 injection), 1\u0026ndash;2 times a day for 10 minutes each time to improve mucosal dryness.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section3\"\u003e \u003ch2\u003e5.3.2 Dental Caries and Periodontal Disease Intervention\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eDaily care: For patients with impaired cognition, recommend electric toothbrushes (with timing function), guide family members to supervise implementation, brush teeth twice a day (morning and evening) for 2 minutes each time, combined with fluoride toothpaste (fluoride concentration 1450ppm); use dental floss or water flossers to clean interdental surfaces at least twice a week;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eProfessional cleaning: Conduct professional oral cleaning (tooth cleaning\u0026thinsp;+\u0026thinsp;polishing) once every 3 months to remove plaque and calculus, especially for those with root plaque accumulation (GRADE 2A evidence level, moderately recommended \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e);\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTreatment measures: Timely restoration of dental caries, priority use of glass ionomer cement for root caries restoration (good biocompatibility, releasing fluoride ions); scaling and root planing for patients with periodontal disease, combined with periodontal surgery for moderate to severe periodontitis, synchronously combined with local antibacterial drugs (e.g., minocycline gel).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003e5.3.3 Diet and Health Education\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eCollaborate with nutrition departments to formulate low-sugar diet manuals: Reduce the intake of refined carbohydrates (rice, noodles) and high-sugar foods (pastries, sugary drinks), with daily added sugar intake \u0026le;\u0026thinsp;25g; increase the intake of dietary fiber (vegetables, whole grains) to promote salivary secretion;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eHealth education: Popularize oral care knowledge to patients and their families through graphic manuals and video tutorials, emphasizing the core logic of \"mutual influence between oral health and psychiatric symptoms\"; for patients with impaired cognitive function, adopt simple and understandable demonstration teaching (e.g., hand-in-hand guidance on brushing methods) to improve care compliance.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003e5.4 Stomatological Recommendations for Medication Adjustment\u003c/h2\u003e \u003cp\u003eFor patients with severe oral adverse reactions (severe xerostomia accompanied by multiple dental caries, moderate to severe periodontal disease) affecting quality of life, stomatological departments should issue clear intervention recommendations to psychiatry departments. Psychiatrists should appropriately adjust the olanzapine dosage or replace the drug under the premise of maintaining symptom control (GRADE 1C evidence level, moderately recommended \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e). Patients are strictly prohibited from adjusting medication on their own.\u003c/p\u003e \u003cp\u003eBased on the dose sensitivity threshold of \u0026ge;8mg/d in East Asian populations (OR\u0026thinsp;=\u0026thinsp;2.73, 95%CI: 1.92\u0026ndash;3.88) \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e, when oral symptoms occur at this dosage, it is preferred to recommend psychiatry departments to adjust the dosage to 5-7.5mg/d, synchronously strengthening stomatological interventions (e.g., increasing the frequency of sodium fluoride application and using traditional Chinese medicine gargle); if psychiatric symptom control is unsatisfactory after dosage adjustment, it is recommended to replace with antipsychotic drugs with lower oral adverse reactions (e.g., aripiprazole), and stomatological departments synchronously follow up the repair treatment of oral damage.\u003c/p\u003e "},{"header":"6 Limitations and Future Research Directions","content":"\u003cdiv id=\"Sec26\" class=\"Section2\"\u003e \u003ch2\u003e6.1 Limitations\u003c/h2\u003e \u003cp\u003eThis review has the following limitations: (1) Most of the included studies are cross-sectional designs, which can only reveal correlation relationships and cannot confirm causality; propensity score matching or cohort studies are needed to reduce bias; (2) Some studies are single-center with small samples (n\u0026thinsp;\u0026lt;\u0026thinsp;100), and the stability of the results needs to be verified by large-sample multi-center studies; (3) Evidence for Asian populations is mainly from single-country studies in China and South Korea, lacking joint data from China, Japan, and South Korea, and the evidence for genetic mechanisms is weak; (4) Although the outcome evaluation standards of the studies have referred to international norms, there may still be differences in operator skills and equipment accuracy among different studies, affecting the comparability of results; (5) The analysis of the interaction network between oral microbiota and the host is insufficient, and the integrity of molecular mechanisms needs to be supplemented; (6) No health economic evaluation has been conducted, and the cost-effectiveness ratio of the interdisciplinary management model is unclear.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section2\"\u003e \u003ch2\u003e6.2 Future Research Directions\u003c/h2\u003e \u003cp\u003eFuture research can focus on: (1) Conducting large-sample prospective cohort studies led by stomatological departments, combined with blood drug concentration monitoring, to quantify the dose-duration-adverse reaction correlation curve and accurately define the high-risk threshold for East Asian populations; (2) Conducting multi-center studies in China, Japan, and South Korea, combined with genetic testing, to deeply analyze the racial modification effect and clarify the causal relationship between M1 receptor polymorphism and oral damage; (3) Unifying outcome evaluation standards, including objective indicators such as salivary microbiota abundance and hBD-2 expression, to improve the comparability of evidence; (4) Developing targeted oral intervention preparations (e.g., specific antibacterial mouthwash for Streptococcus mutans) and verifying the multi-center efficacy of traditional Chinese medicine gargle; (5) Constructing a standardized special stomatological management model, optimizing the simplified screening process for primary hospitals, and conducting health economic evaluations to clarify its cost-effectiveness ratio and accessibility; (6) Focusing on special populations such as the elderly and long-term hospitalized patients, exploring minimally invasive intervention plans to enrich the evidence chain.\u003c/p\u003e \u003c/div\u003e"},{"header":"7 Conclusion","content":"\u003cp\u003eThe core innovations of this review are: ① Integrating data from the NHANES public database, core Chinese and English studies, and subgroup analysis, quantifying the racial differences in olanzapine-related oral adverse reactions for the first time, and clarifying the dose sensitivity threshold of \u0026ge;8mg/d and molecular genetic basis for East Asian populations; ② Constructing a complete system of \"molecular mechanisms - risk stratification - practical stomatological interventions\", and proposing a closed-loop \"screening-intervention-follow-up\" plan suitable for primary medical institutions combined with GRADE evidence grading; ③ Supplementing evidence from metabolomics and metagenomics, improving the \"genetic-molecular-clinical\" association chain, and strengthening the authority and feasibility of intervention recommendations.\u003c/p\u003e \u003cp\u003eIn summary, olanzapine damages the oral health of schizophrenia patients in a dose-dependent manner through multiple pathways such as cholinergic receptor blockade, glucose metabolism interference, and oral microbiota dysbiosis. East Asian populations have a higher incidence of adverse reactions and are more sensitive to drug dosage. Stomatological departments need to actively establish a special management model, implement risk-stratified screening for patients taking olanzapine, strengthen oral screening every 4 months and dose warning for \u0026ge;8mg/d for East Asian populations, and combine specialized nursing, targeted interventions, and interdisciplinary collaboration to achieve precise prevention and treatment of oral health. This review provides evidence-based basis for the clinical management of olanzapine users in stomatological departments in East Asia and clarifies future research directions.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul\u003e\n \u003cli\u003eDMFT: Decayed, Missing, Filled Teeth Index \u0026nbsp;\u003c/li\u003e\n \u003cli\u003ehBD-2: Human \u0026beta;-defensin 2 \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eGRADE: Grading of Recommendations Assessment, Development and Evaluation \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eLPS: Lipopolysaccharide \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHOMA-IR: Homeostasis Model Assessment of Insulin Resistance \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eIRS: Insulin Receptor Substrate \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTNF-\u0026alpha;: Tumor Necrosis Factor-\u0026alpha; \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eIL-6: Interleukin-6 \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNF-\u0026kappa;B: Nuclear Factor-\u0026kappa;B \u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. All data used in this review were from public databases (NHANES 2017-2020) and published studies, which have obtained ethical approval from their respective institutions. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. No individual participant data were included in this systematic review. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData were derived from the NHANES database (https://www.cdc.gov/nchs/nhanes/index.htm) and 24 published studies (see References). Supplementary materials are available upon request from the corresponding author. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no competing interests, including no financial support from pharmaceutical companies, no personal or professional relationships that could influence the study. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLiang Kong (First Author \u0026amp; Corresponding Author): Designed the research protocol, led literature screening and data analysis, wrote the initial draft of the manuscript, revised the full text, and was responsible for overall research quality control and correspondence. Linghui Zhang (Second Author): Participated in literature retrieval, data extraction and collation, and assisted in figure drawing and format proofreading. Qian Yang (Third Author): Participated in result verification and writing of the discussion section, and assisted in supplementing literature evidence and improving academic viewpoints. All authors reviewed and approved the final published version and are responsible for the authenticity and integrity of the research content.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge the National Center for Health Statistics for providing access to the NHANES database and Linghui Zhang for statistical analysis assistance. We also thank Doubao AI for its professional support and assistance in the full-text language translation, format correction, and optimization of this paper, which has contributed significantly to the successful completion of this research.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJohn R, Smith P (2020) Epidemiology of schizophrenia: a global perspective. J Psychiatr Res 125:10\u0026ndash;18. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jpsychires.2020.03.012\u003c/span\u003e\u003cspan address=\"10.1016/j.jpsychires.2020.03.012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee S, Wang Y (2019) Efficacy and safety of olanzapine in schizophrenia: a meta-analysis. 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Schizophr Res 258:123\u0026ndash;130\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu M, Zhang S, Wang H (2023) TCM gargle for olanzapine-induced oral adverse effects. Chin J Integr Med 29(8):621\u0026ndash;626\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Olanzapine, Schizophrenia, Oral health, Xerostomia, Dental caries, Periodontal disease, Oral microbiota, Clinical oral management, Dose dependence, East Asian population","lastPublishedDoi":"10.21203/rs.3.rs-8714864/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8714864/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Olanzapine, a first-line atypical antipsychotic used in over 60% of clinical cases, induces dose-dependent oral impairments (xerostomia, caries, periodontitis) with a 35%-78% incidence in long-term use (≥3 months). Existing studies lack large-sample evidence from East Asians, focus on single adverse reactions, and have fragmented intervention strategies, failing to meet precise diagnosis needs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e: This review summarizes olanzapine-induced oral damage characteristics and molecular mechanisms, proposes GRADE-graded individualized oral management plans, clarifies East Asians’ risk thresholds and intervention priorities, and provides evidence for clinical practice.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: Following PRISMA 2020 guidelines, we searched PubMed, Web of Science, CNKI (2018-2025), including 24 high-quality studies. Data from NHANES 2017-2020 (586 cases) and 4 Chinese studies (832 cases) were analyzed via random-effects models and multivariate regression. Outcome indicators followed WHO oral health survey methods and 2017 periodontal disease classification.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: East Asians are more susceptible to olanzapine’s oral toxicity (xerostomia: 42%-75%; caries: 51.3%), with a sharp risk increase at ≥8 mg/day (OR=2.73, P\u0026lt;0.001). Core mechanisms include M1/M3 receptor blockade-induced salivary hyposecretion, hBD-2/NF-κB-mediated dysbiosis, and TNF-α/IL-6 inflammatory crosstalk.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Olanzapine-induced oral impairments show significant ethnic heterogeneity, with higher sensitivity in East Asians linked to M1 receptor polymorphism and high-refined carbohydrate diets. Stomatological departments should establish specialized management for olanzapine users, including 4-monthly screenings and dose warnings for ≥8 mg/day, combined with targeted interventions.\u003c/p\u003e","manuscriptTitle":"Olanzapine's Impact on Oral Health in Patients with Schizophrenia: Research Progress on Effects and Mechanisms","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-29 10:39:37","doi":"10.21203/rs.3.rs-8714864/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4672ef53-aa78-46f9-b482-a9fc30773544","owner":[],"postedDate":"January 29th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61856779,"name":"Epidemiology"}],"tags":[],"updatedAt":"2026-01-29T10:39:37+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-29 10:39:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8714864","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8714864","identity":"rs-8714864","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}