Mental Health Impact of Post-Herpetic Neuralgia: A Retrospective Cohort Study from 33,201 Patients Using TriNetX Network Database

Mental Health Impact of Post-Herpetic Neuralgia: A Retrospective Cohort Study from 33,201 Patients Using TriNetX Network Database | 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 Research Article Mental Health Impact of Post-Herpetic Neuralgia: A Retrospective Cohort Study from 33,201 Patients Using TriNetX Network Database Mao-Hsuan Yang, Yu-Ping Hsiao, Yu-Hsun Wang, Li-Hua Huang, Yun-Shan Du, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8560550/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background Postherpetic neuralgia (PHN) is known to cause pain and affect quality of life. Nonetheless, its association with subsequent mental disorders or severe psychiatric conditions remain underexplored, especially in large and diverse populations. The aim of this study is to identify the risks mental disorders in patients with PHN, with a large-scale, real-world dataset in TriNetX. Methods This retrospective cohort study utilized the TriNetX U.S. Collaborative Network and included patients aged ≥ 18 years with new diagnosis of herpes zoster from 2016 to 2023. Patients were divided into PHN and non-PHN groups. The PHN group comprised patients diagnosed with PHN within one month after the diagnosis of herpes zoster, while the non-PHN group comprised those without PHN. Participants diagnosed with any mental disorders before the diagnosis of herpes zoster or up to one month after it were excluded. Each group included 33201 patients after propensity score matching. Risks of mental disorders were compared between the two groups over a 6-month follow-up. Subgroup analyses were conducted across age, sex, race, herpes zoster vaccination, and disease site. Results Our results suggested that patients with PHN had a significantly higher risk of developing mental disorders (hazard ratio [HR]: 1.23, 95% confidence interval [CI]: 1.13–1.34), especially in younger patients aged 18–64 (HR: 1.30, 95% CI: 1.15–1.47). Among categories of mental disorders, significant elevated risks for PHN patients were observed in mood disorders (HR: 1.25, 95% CI: 1.10–1.42), anxiety-related conditions (HR: 1.17, 95% CI: 1.06–1.30), and behavioral syndromes (HR: 1.35, 95% CI: 1.03–1.75). Subgroup analysis showed increased risks of mental disorders for females (HR: 1.17, 95% CI: 1.05–1.30), White patients (HR: 1.17, 95% CI: 1.06–1.30), and Black patients (HR: 1.34, 95% CI: 1.01–1.77), and patients with ocular herpes zoster (HR: 1.63, 95% CI: 1.20–2.21). Conclusions This retrospective cohort study showed a significantly elevated risk for PHN participants to develop mental disorders, particularly in younger adults, females, and White and Black racial groups. Our results also underlined the severe psychological effect of mental disorders associated with PHN. Clinicians should consider early psychological evaluation and intervention for PHN patients. Postherpetic neuralgia mental disorders herpes zoster anxiety depression Figures Figure 1 Figure 2 1 Background Postherpetic neuralgia (PHN) is a chronic complication of herpes zoster caused by varicella-zoster virus (VZV) inactivation( 1 , 2 ). Herpes zoster typically presents as an acute vesicular rash, but some patients may develop chronic neuropathic pain, which is defined as PHN. Patients with PHN may experience hyperalgesia and allodynia( 3 ). PHN is known to impair physical functioning( 4 ), disrupt sleep( 5 ), and reduce quality of life( 6 , 7 ). Growing evidence has shown that chronic neuropathic pain syndromes, including PHN, are associated with elevated risks of mental disorders such as anxiety, depression, somatization, somatic symptoms, personality disorders, hypochondriasis, and stress-related conditions( 8 – 15 ). Despite the emerging evidence of the association of chronic neuropathic pain and mental disorders, large-scale population-based cohort studies on mental health outcomes for PHN patients remain limited. We searched Pubmed for studies targeting the association between PHN and mental disorders. Several articles have examined the psychological burden of herpes zoster( 8 , 10 , 16 , 17 ), but few have specifically focused on PHN. Furthermore, most existing research has been limited by small sample sizes or single-institution data. To bridge these gaps, we conducted a retrospective cohort study using TriNetX, a US Collaborative Network encompassing over 250 million patients across over 200 healthcare organizations. In this research, we aimed to evaluate the 6-month follow-up data to compare the risks of mental disorders, including mood, anxiety-related, and behavioral conditions, between patients diagnosed with PHN and a matched cohort without PHN. Our study provides a comprehensive assessment of the psychiatric impact of PHN based on a large-scale, real-world, and demographically diverse database from TriNetX. 2 Methods 2.1 Data collection This study is a retrospective cohort study utilizing electronic health records obtained from TriNetX. The data used in this study were analyzed on September 23, 2024, from the TriNetX US Collaborative Network, which provides access to electronic medical records from approximately 117 million patients across 65 healthcare organizations. The data were anonymized from electronic health records provided by healthcare institutions, primarily including hospitals, primary care providers, and specialists. The dataset encompassed demographics, diagnoses (using the International Classification of Diseases, Tenth Revision, Clinical Modification, ICD-10-CM), medications (normalized prescription data via RxNorm), procedures (classified under the International Classification of Diseases, Tenth Revision, Procedure Coding System, ICD-10-PCS, or Current Procedural Terminology, CPT), and laboratory tests (identified by Logical Observation Identifier Names and Codes, LOINC). This retrospective analysis is exempt from the need for informed consent as it represents a secondary analysis of pre-existing data, does not involve any intervention or interaction with human subjects, and has been de-identified in accordance with the standards outlined in Section § 164.514(a) of the HIPAA Privacy Rule. The de-identification process has received formal validation by a qualified expert, as stipulated in Section § 164.514(b)( 1 ) of the HIPAA Privacy Rule. This research obtained approval from the Institutional Review Board (IRB No: CS1-24143). 2.2 Study participants Figure 1 illustrates the cohort construction flow chart. The study population comprised individuals aged ≥ 18 years with a new diagnosis of herpes zoster (ICD-10-CM = B02) from 2016 to 2023. The exposure group (PHN group) included patients diagnosed with PHN (ICD-10-CM = B02.2) within one month after the diagnosis of herpes zoster. The comparison group (non-PHN group) included subjects without a diagnosis of postherpetic neuralgia after the diagnosis of herpes zoster. The index date was defined as the first date of diagnosis of herpes zoster. Both groups excluded patients diagnosed with mental disorders (ICD-10-CM = F01-F99) before the index date or up to 1 month after the diagnosis of herpes zoster. Baseline characteristics were extracted from records spanning one year prior to the index date up to one day before the index date. Demographic factors included age, sex, race, and BMI. Medical utility, comorbidities, and medications were also collected. The relevant codes are listed in Supplementary table I. Propensity score matching was conducted to address differences in baseline characteristics between the two groups and to minimize the impact of confounding factors. Matching was performed at a 1:1 ratio using the built-in function in TriNetX, considering age, sex, race, healthcare utilization, comorbidities, and medications. A greedy nearest neighbor matching algorithm with a caliper of 0.1 pooled standard deviations was employed. The primary outcome of interest in this study was to estimate the risk of mental disorders, including mood disorders (ICD-10-CM: F30-F39), anxiety disorders, dissociative disorders, stress-related disorders, somatoform disorders, and other non-psychotic mental disorders (ICD-10-CM: F40-F48), as well as behavioral syndromes associated with physiological disturbances and physical factors (ICD-10-CM: F50-F59) and personality disorders (ICD-10-CM: F60-F69) between the postherpetic neuralgia and non-postherpetic neuralgia groups. The follow-up duration was set at six months. Subjects were tracked until the onset of mental disorders or the last recorded event in the US collaborative network. 2.3 Statistical analysis Statistical analyses were performed using the TriNetX platform. The balance of baseline characteristics between the matched cohorts was assessed using standardized mean differences (SMD), with variables having an SMD of less than 0.1 considered well-matched. Kaplan-Meier survival curves and Cox proportional hazards models were employed to compare the risk of mental disorders between the two groups, and hazard ratios (HRs) with 95% confidence intervals were calculated. Stratified analyses were conducted to assess the association between postherpetic neuralgia and mental disorders across subgroups defined by age, sex, race, and herpes zoster vaccination. Furthermore, cases were stratified based on specific herpes zoster diagnosis codes: zoster involvement of the brain (ICD-10-CM: B02.0, B02.1, B02.21, B02.22), zoster ocular disease (ICD-10-CM: B02.3), disseminated zoster (ICD-10-CM: B02.7), zoster with other complications (ICD-10-CM: B02.8), and zoster without complications (ICD-10-CM: B02.9). All analyses were executed on the TriNetX online platform, which employs R 4.0.2 as its underlying statistical software. 3 Results 3.1 Baseline Characteristics Table I presents demographic and clinical characteristics before and after propensity score matching. Initially, 33,230 PHN cases were compared with 212,667 non-PHN cases. After matching, 33,201 individuals remained in each cohort, with all covariates being well balanced. (Table I should be placed here during production.) 3.2 Kaplan-Meier Survival Analysis In Kaplan-Meier analysis (Fig. 2 ), PHN patients demonstrated an increased risk of mental disorders. Elevated risks were observed across several mental health outcomes, including mood disorders, anxiety conditions, and behavioral syndromes. These results highlighted the temporal relationship between PHN and mental disorders during the 6-month follow-up period. 3.3 Risk of Mental Disorders As summarized in Table II, PHN was associated with increased overall psychiatric risk (HR: 1.23, 95% CI: 1.13–1.34). Significantly higher risks were observed for “mood [affective] disorders” (HR: 1.25, 95% CI: 1.10–1.42), “anxiety, dissociative, stress-related, somatoform, and other nonpsychotic mental disorders” (HR: 1.17, 95% CI: 1.06–1.30), and “behavioral syndromes associated with physiological disturbances and physical factors” (HR: 1.35, 95% CI: 1.03–1.75). Subgroup analysis by specific neuralgia types identified a significant association only for “other postherpetic nervous system involvement” (B02.29; HR: 1.23, 95% CI: 1.12–1.36). (Table II should be placed here during production.) 3.4 Stratification Analyses Table III presents age, sex, and race subgroups. Significantly higher risks were identified in PHN patients aged 18–64 (HR: 1.30, 95% CI: 1.15–1.47) and a smaller increase in those aged ≥ 65 (HR: 1.13, 95% CI: 1.01–1.27). Females with PHN were more affected (HR: 1.17, 95% CI: 1.05–1.30). By race, White patients (HR: 1.17, 95% CI: 1.06–1.30) and Black or African American patients (HR: 1.34, 95% CI: 1.01–1.77) with PHN showed elevated risks. No difference was observed in individuals with herpes zoster vaccination. (Table III should be placed here during production.) Supplementary table II specifies mental health outcomes by subgroup. In patients aged 0–64, PHN was linked to mood disorders (HR: 1.24, 95% CI: 1.03–1.48) and anxiety-related disorders (HR: 1.37, 95% CI: 1.17–1.59). In patients aged ≥ 65, risks were not significant. Women with PHN had higher risks for mood (HR: 1.21, 95% CI: 1.03–1.43) and anxiety-related disorders (HR: 1.21, 95% CI: 1.06–1.37), while men demonstrated a higher risk of behavioral syndromes (HR: 1.84, 95% CI: 1.12–3.01). By race, White patients had greater risk of anxiety-related disorders (HR: 1.21, 95% CI: 1.07–1.38), whereas Black patients had higher risk of mood disorders (HR: 1.64, 95% CI: 1.09–2.48). 3.5 Disease Site Analysis As shown in Supplementary table III, PHN patients with ocular involvement (HR: 1.63, 95% CI: 1.20–2.21), other complications (HR: 1.56, 95% CI: 1.20–2.03), or no complications (HR: 1.44, 95% CI: 1.24–1.66) had significantly increased psychiatric risks. 4 Discussion In this cohort study, our results demonstrated increased risks for PHN patients to develop mental disorders, especially in younger adults and females. In stratification analysis (Table III), PHN patients of all ages had significantly higher risks of developing mental disorders compared to non-PHN patients, with the risk of patients aged 18–64 slightly higher than that of patients aged 65 and older. This result suggests that while older age has been identified as a risk factor for PHN( 4 , 18 ), younger individuals are more psychologically susceptible to chronic pain, which is consistent with previous studies( 19 – 21 ). In stratified analysis of mental sub-outcomes in different subgroups (Supplementary table II), female PHN patients demonstrated significantly increased risks in the categories of mood disorders and anxiety-related disorders. This result is consistent with a previous study, which demonstrated increased risks of anxiety and depression in female patients with PHN( 8 ). Another study showed an increased risk of PHN for women experiencing negative life events( 22 ). A recent meta-analysis also showed that among individuals with chronic pain, there was higher prevalence for younger adults and women to develop depression and anxiety( 23 ), further supporting our results. Several possible pathophysiological mechanisms linking PHN to mental disorders are presented. Firstly, a previous study( 17 ) demonstrated small-world brain functional networks in regions related to emotional processing can be altered by PHN, causing decreased local efficiency. Another research also utilized multimodal magnetic resonance imaging (MRI) to show that functional and structural changes can exist six months after relief of PHN( 10 ). Secondly, PHN is associated with central nervous inflammation caused by microglial activation, which is seen as the leading cause of anxiety, depression, and other mood disorders( 16 ). Previous studies have proved that BMP-4 can induce glial cell activation( 3 ) and release of pro-inflammatory cytokines (IL-1, IL-6, TNF-α), causing central sensitization and contributing to anxiety and depression( 16 , 24 ). Furthermore, the bidirectional relationship between chronic pain and depression is well established( 25 ). Both pain and depression affect similar brain areas, such as anterior cingulate cortex, amygdala, prefrontal cortex, thalamus, and hippocampus, which can be disrupted by PHN or other chronic pain symptoms( 10 , 26 ). A previous study demonstrated temporal lobe dysfunction in depressed PHN patients( 27 ). Moreover, PHN may cause dysregulation of the neurotransmitter systems shared by both pain modulation and mood regulation. Lastly, sleep disorders common in neuropathic pain and depression can worsen both conditions. Poor sleep quality is known to be positively associated with depression in patients with chronic pain( 28 ). Previous studies have also shown positive correlation between sleep shortage and PHN( 5 , 29 ). The nocturnal pain experienced by PHN patients can disrupt sleep quality and lead to a vicious cycle of fatigue and mental disorders( 25 , 30 – 33 ). Aside from mental disorders, there are other PHN sequelae that may severely impair daily functioning and quality of life. Common sequelae include sleep disturbances, physical inactivity, social withdrawal, and reduced productivity( 7 , 34 , 35 ). These chronic consequences can perpetuate a cycle of psychological distress, particularly anxiety and depression( 35 ), which is consistent with our findings. The chronicity of PHN also implicates challenges in treatment adherence and increases healthcare utilization over time, making early recognition and management critical. Given the association between PHN and increased risks of mental disorders, our findings underscore the importance of comprehensive management of PHN beyond pain control. Current treatment options for PHN include anticonvulsants (e.g., gabapentin, pregabalin)( 36 ), tricyclic antidepressants (e.g., amitriptyline, nortriptyline)( 37 ), topical agents (e.g., lidocaine patches, capsaicin), and opioids( 38 ). A recent study demonstrated significant reduction in scales of depression and anxiety in PHN patients treated with intravenous esketamine as opposed to analgesics alone( 39 ). Integrating psychiatric evaluation and therapy into the care plan of PHN patients may improve overall quality of life. Strengths and limitations There are several strengths to our study. We utilized a large, diverse, real-world dataset and applied PSM to minimize confounding. Detailed subgroup and stratified analyses were conducted to enhance the clinical relevance of our findings. Additionally, the study design excluded patients suffering from psychological conditions before the diagnosis of PHN, thus allowing for the assessment of temporal relationships between PHN and subsequent mental disorders. However, several limitations must be acknowledged. First, despite the use of PSM and validated diagnostic codes, unmeasured confounding and misclassification bias inherent to electronic health records can still exist. Secondly, mental disorders may have been underdiagnosed or unrecorded in some populations, potentially leading to underestimation of true effect sizes. Thirdly, as is seen in Table III, patients vaccinated against herpes zoster are relatively few in our study, which may lead to an underestimation of the effect of vaccination on mental health outcomes. Furthermore, the diagnosis record in TrinetX database does not include the intensity and duration of pain caused by PHN, making us unable to compare the different impacts they have on psychological conditions. Finally, medication usage, such as antiepileptics or opioids, may have affected mental health( 25 , 30 ) but was not assessed in our analyses. 5 Conclusion In summary, our study utilizes a large-scale, real-world, multicenter dataset to demonstrate a significant association between PHN and increased risks of mental disorders, particularly in subgroups of younger adults, females, and White and Black racial groups. Our study underscores the severe psychological effect of mental disorders associated with PHN. Aside from pain management, clinicians should consider routine psychological evaluation and early intervention programs for PHN patients, particularly those presenting with severe or prolonged symptoms, to improve overall outcomes and quality of life. Abbreviations BMI, body mass index; BMP-4, bone morphogenetic protein-4; CI, confidence interval; CPT, Current Procedural Terminology; HIV, human immunodeficiency virus; HRs, hazard ratios; ICD-10-CM, International Classification of Diseases, Tenth Revision, Clinical Modification; ICD-10-PCS, International Classification of Diseases, Tenth Revision, Procedure Coding System; IL-1, interleukin-1; IL-6, interleukin-6; IRB, Institutional Review Board; LOINC, Logical Observation Identifier Names and Codes; MRI, magnetic resonance imaging; NSAIDs, non-steroidal anti-inflammatory drugs; PHN, postherpetic neuralgia; SMD, standardized mean difference; TNF-α, tumor necrosis factor alpha; VZV, varicella-zoster virus. Declarations Ethics approval and consent to participate : Ethical approval was obtained from the Institutional Review Board of Chung Shan Medical University Hospital (IRB No: CS1-24143). All methodologies employed in this study were conducted in accordance with the Declaration of Helsinki. Funding sources: This study was supported by grants from Chung Shan Medical University Hospital (CSH-2014-C-034 and CSH-2023-D-003), National Taichung University of Science and Technology (NTCUST113-028), and the Ministry of Science and Technology, R.O.C. (MOST 112-2314-B-040-005- and 111-2314-B-025-001-). Conflicts of Interest: The authors declare no potential conflicts of interest. Clinical trial number: Not applicable. Consent for publication: Not applicable. Data availability: Research data supporting this publication can be accessed through the TriNetX platform, available at https://trinetx.com/. Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study. Author contributions: Yu-Hsun Wang collected the data, performed the analysis, and wrote the methods and results sections in the first draft. Mao-Hsuan Yang, Yu-Ping Hsiao and Yun-Shan Du assisted in writing and producing the final version of the manuscript. Tsu-Jung Wu and Li-Hua Wang contributed to the conception of the study and reviewed the final manuscript. All the authors contributed to the interpretation of the findings, approved the final manuscript, and agreed to be accountable for all aspects of the work. Acknowledgement: We extend our sincere gratitude to grants from Chung Shan Medical University (CSH-2014-C-034) and its faculty for assistance with using the TriNetX system that enabled this research. During the preparation of this work the authors used ChatGPT and Perplexity to check grammar and refine texts. After using these tools, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication. References Gan EY, Tian EA, Tey HL. Management of herpes zoster and post-herpetic neuralgia. Am J Clin Dermatol. 2013;14(2):77–85. Nalamachu S, Morley-Forster P. 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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-8560550","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":591310887,"identity":"c9e142bb-9661-4925-bd01-b79ccf589b96","order_by":0,"name":"Mao-Hsuan Yang","email":"","orcid":"","institution":"Chung Shan Medical University","correspondingAuthor":false,"prefix":"","firstName":"Mao-Hsuan","middleName":"","lastName":"Yang","suffix":""},{"id":591310888,"identity":"abb6dd30-4ada-40d3-a429-529b93a4a43d","order_by":1,"name":"Yu-Ping Hsiao","email":"","orcid":"","institution":"Chung Shan Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yu-Ping","middleName":"","lastName":"Hsiao","suffix":""},{"id":591310889,"identity":"cd08b742-a7d3-4256-9bb2-51cb4233975b","order_by":2,"name":"Yu-Hsun Wang","email":"","orcid":"","institution":"Chung Shan Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yu-Hsun","middleName":"","lastName":"Wang","suffix":""},{"id":591310890,"identity":"5f1265da-fbf8-4e28-8a4a-718595cf69cb","order_by":3,"name":"Li-Hua Huang","email":"","orcid":"","institution":"Chung Shan Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Li-Hua","middleName":"","lastName":"Huang","suffix":""},{"id":591310891,"identity":"4153c54f-3712-44f4-8ae4-59c7bacf5c96","order_by":4,"name":"Yun-Shan Du","email":"","orcid":"","institution":"Chung Shan Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yun-Shan","middleName":"","lastName":"Du","suffix":""},{"id":591310892,"identity":"23383c55-9796-4424-a5ad-2a7fbdd36293","order_by":5,"name":"Tzu-Jung Wu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIie3SoQrCUBTG8TsGWs5YPUOYr3DHwOqrTAyWbWBbUDHIknDrHsNoMBwRtNz1NZfM8wl0CwqW7dpE7j994fzaYUyn+8mAGVXycJuhTkyUpv8mCrI+sTbmZK1MbJGf0Vn3ZkLkxO6HJRtj0E6wiKd8vocoK+LAyG4XBl2EI3ilIzHaIXAT6Mxg0EVsyclK+awZioSFXmmlQVCPhiy6CRah76MkLytCfsyIAK5lO7GFHDlVQsN6eGVFK7e/pXbyUX17Uv+BV6uvhU6n0/1/T4rnP3K7Rv6jAAAAAElFTkSuQmCC","orcid":"","institution":"Chung Shan Medical University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Tzu-Jung","middleName":"","lastName":"Wu","suffix":""}],"badges":[],"createdAt":"2026-01-09 11:38:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8560550/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8560550/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102855751,"identity":"79add882-e20a-440d-90e0-f3109e786713","added_by":"auto","created_at":"2026-02-17 14:57:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":180004,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow-chart of subject selection. \u003c/strong\u003eThe study population comprised individuals aged ≥18 years with a new diagnosis of herpes zoster from 2016 to 2023. The postherpetic neuralgia (PHN) group included patients diagnosed with PHN within one month after the diagnosis of herpes zoster. The non-postherpetic neuralgia (non-PHN) group included subjects without a diagnosis of postherpetic neuralgia after the diagnosis of herpes zoster. The index date was defined as the first date of diagnosis of herpes zoster. Both groups excluded patients diagnosed with mental disorders before the index date or up to 1 month after the diagnosis of herpes zoster. Propensity score matching (PSM) was conducted across baseline characteristics. Each group included 33,201 patients after PSM.\u003c/p\u003e\n\u003cp\u003eFigure \u0026nbsp;is a 1.5 column-fitting image.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8560550/v1/ced3102b9413d5db813d4ee3.png"},{"id":102855740,"identity":"8ab500f2-cd1d-43b1-868e-5ec821f38374","added_by":"auto","created_at":"2026-02-17 14:57:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":57339,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier analysis for risks of mental disorders between PHN and non-PHN groups. Kaplan-Meier survival curves were employed to compare the risk of mental disorders between the two groups during the 6-month follow-up period. PHN patients demonstrated an overall increased risk of mental disorders. Significantly elevated risks were observed across several mental health outcomes, including mood disorders, anxiety-related conditions, and behavioral syndromes.\u003c/p\u003e\n\u003cp\u003eFigure \u0026nbsp;is a 1.5 column-fitting image.\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8560550/v1/ecb934b74b076ba14ab0cda6.png"},{"id":102965121,"identity":"2fe0354d-2107-4b3c-830a-a3dd4181f69d","added_by":"auto","created_at":"2026-02-19 04:30:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":785824,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8560550/v1/639467d0-e6db-4e93-ae02-209bf6e91767.pdf"},{"id":102963028,"identity":"96d31b7f-a147-4584-bb12-471aefb38cb8","added_by":"auto","created_at":"2026-02-19 04:12:54","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24393,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8560550/v1/45349dd68d8e9e5bd23d7e0b.docx"},{"id":102855758,"identity":"c2806235-4b9f-4646-afb9-69c8a43f69c1","added_by":"auto","created_at":"2026-02-17 14:57:28","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":32331,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8560550/v1/2540d33943d93870300d77f8.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Mental Health Impact of Post-Herpetic Neuralgia: A Retrospective Cohort Study from 33,201 Patients Using TriNetX Network Database","fulltext":[{"header":"1 Background","content":"\u003cp\u003ePostherpetic neuralgia (PHN) is a chronic complication of herpes zoster caused by varicella-zoster virus (VZV) inactivation(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Herpes zoster typically presents as an acute vesicular rash, but some patients may develop chronic neuropathic pain, which is defined as PHN. Patients with PHN may experience hyperalgesia and allodynia(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). PHN is known to impair physical functioning(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), disrupt sleep(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), and reduce quality of life(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Growing evidence has shown that chronic neuropathic pain syndromes, including PHN, are associated with elevated risks of mental disorders such as anxiety, depression, somatization, somatic symptoms, personality disorders, hypochondriasis, and stress-related conditions(\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13 CR14\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Despite the emerging evidence of the association of chronic neuropathic pain and mental disorders, large-scale population-based cohort studies on mental health outcomes for PHN patients remain limited.\u003c/p\u003e \u003cp\u003eWe searched Pubmed for studies targeting the association between PHN and mental disorders. Several articles have examined the psychological burden of herpes zoster(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), but few have specifically focused on PHN. Furthermore, most existing research has been limited by small sample sizes or single-institution data. To bridge these gaps, we conducted a retrospective cohort study using TriNetX, a US Collaborative Network encompassing over 250\u0026nbsp;million patients across over 200 healthcare organizations.\u003c/p\u003e \u003cp\u003eIn this research, we aimed to evaluate the 6-month follow-up data to compare the risks of mental disorders, including mood, anxiety-related, and behavioral conditions, between patients diagnosed with PHN and a matched cohort without PHN. Our study provides a comprehensive assessment of the psychiatric impact of PHN based on a large-scale, real-world, and demographically diverse database from TriNetX.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Data collection\u003c/h2\u003e \u003cp\u003eThis study is a retrospective cohort study utilizing electronic health records obtained from TriNetX. The data used in this study were analyzed on September 23, 2024, from the TriNetX US Collaborative Network, which provides access to electronic medical records from approximately 117\u0026nbsp;million patients across 65 healthcare organizations. The data were anonymized from electronic health records provided by healthcare institutions, primarily including hospitals, primary care providers, and specialists. The dataset encompassed demographics, diagnoses (using the International Classification of Diseases, Tenth Revision, Clinical Modification, ICD-10-CM), medications (normalized prescription data via RxNorm), procedures (classified under the International Classification of Diseases, Tenth Revision, Procedure Coding System, ICD-10-PCS, or Current Procedural Terminology, CPT), and laboratory tests (identified by Logical Observation Identifier Names and Codes, LOINC). This retrospective analysis is exempt from the need for informed consent as it represents a secondary analysis of pre-existing data, does not involve any intervention or interaction with human subjects, and has been de-identified in accordance with the standards outlined in Section \u0026sect;\u0026nbsp;164.514(a) of the HIPAA Privacy Rule. The de-identification process has received formal validation by a qualified expert, as stipulated in Section \u0026sect;\u0026nbsp;164.514(b)(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) of the HIPAA Privacy Rule. This research obtained approval from the Institutional Review Board (IRB No: CS1-24143).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Study participants\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the cohort construction flow chart. The study population comprised individuals aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years with a new diagnosis of herpes zoster (ICD-10-CM\u0026thinsp;=\u0026thinsp;B02) from 2016 to 2023. The exposure group (PHN group) included patients diagnosed with PHN (ICD-10-CM\u0026thinsp;=\u0026thinsp;B02.2) within one month after the diagnosis of herpes zoster. The comparison group (non-PHN group) included subjects without a diagnosis of postherpetic neuralgia after the diagnosis of herpes zoster. The index date was defined as the first date of diagnosis of herpes zoster. Both groups excluded patients diagnosed with mental disorders (ICD-10-CM\u0026thinsp;=\u0026thinsp;F01-F99) before the index date or up to 1 month after the diagnosis of herpes zoster. Baseline characteristics were extracted from records spanning one year prior to the index date up to one day before the index date. Demographic factors included age, sex, race, and BMI. Medical utility, comorbidities, and medications were also collected. The relevant codes are listed in Supplementary table I.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePropensity score matching was conducted to address differences in baseline characteristics between the two groups and to minimize the impact of confounding factors. Matching was performed at a 1:1 ratio using the built-in function in TriNetX, considering age, sex, race, healthcare utilization, comorbidities, and medications. A greedy nearest neighbor matching algorithm with a caliper of 0.1 pooled standard deviations was employed. The primary outcome of interest in this study was to estimate the risk of mental disorders, including mood disorders (ICD-10-CM: F30-F39), anxiety disorders, dissociative disorders, stress-related disorders, somatoform disorders, and other non-psychotic mental disorders (ICD-10-CM: F40-F48), as well as behavioral syndromes associated with physiological disturbances and physical factors (ICD-10-CM: F50-F59) and personality disorders (ICD-10-CM: F60-F69) between the postherpetic neuralgia and non-postherpetic neuralgia groups. The follow-up duration was set at six months. Subjects were tracked until the onset of mental disorders or the last recorded event in the US collaborative network.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using the TriNetX platform. The balance of baseline characteristics between the matched cohorts was assessed using standardized mean differences (SMD), with variables having an SMD of less than 0.1 considered well-matched. Kaplan-Meier survival curves and Cox proportional hazards models were employed to compare the risk of mental disorders between the two groups, and hazard ratios (HRs) with 95% confidence intervals were calculated. Stratified analyses were conducted to assess the association between postherpetic neuralgia and mental disorders across subgroups defined by age, sex, race, and herpes zoster vaccination. Furthermore, cases were stratified based on specific herpes zoster diagnosis codes: zoster involvement of the brain (ICD-10-CM: B02.0, B02.1, B02.21, B02.22), zoster ocular disease (ICD-10-CM: B02.3), disseminated zoster (ICD-10-CM: B02.7), zoster with other complications (ICD-10-CM: B02.8), and zoster without complications (ICD-10-CM: B02.9). All analyses were executed on the TriNetX online platform, which employs R 4.0.2 as its underlying statistical software.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Baseline Characteristics\u003c/h2\u003e \u003cp\u003eTable I presents demographic and clinical characteristics before and after propensity score matching. Initially, 33,230 PHN cases were compared with 212,667 non-PHN cases. After matching, 33,201 individuals remained in each cohort, with all covariates being well balanced.\u003c/p\u003e \u003cp\u003e \u003cem\u003e(Table I should be placed here during production.)\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Kaplan-Meier Survival Analysis\u003c/h2\u003e \u003cp\u003eIn Kaplan-Meier analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), PHN patients demonstrated an increased risk of mental disorders. Elevated risks were observed across several mental health outcomes, including mood disorders, anxiety conditions, and behavioral syndromes. These results highlighted the temporal relationship between PHN and mental disorders during the 6-month follow-up period.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Risk of Mental Disorders\u003c/h2\u003e \u003cp\u003eAs summarized in Table II, PHN was associated with increased overall psychiatric risk (HR: 1.23, 95% CI: 1.13\u0026ndash;1.34). Significantly higher risks were observed for \u0026ldquo;mood [affective] disorders\u0026rdquo; (HR: 1.25, 95% CI: 1.10\u0026ndash;1.42), \u0026ldquo;anxiety, dissociative, stress-related, somatoform, and other nonpsychotic mental disorders\u0026rdquo; (HR: 1.17, 95% CI: 1.06\u0026ndash;1.30), and \u0026ldquo;behavioral syndromes associated with physiological disturbances and physical factors\u0026rdquo; (HR: 1.35, 95% CI: 1.03\u0026ndash;1.75). Subgroup analysis by specific neuralgia types identified a significant association only for \u0026ldquo;other postherpetic nervous system involvement\u0026rdquo; (B02.29; HR: 1.23, 95% CI: 1.12\u0026ndash;1.36).\u003c/p\u003e \u003cp\u003e \u003cem\u003e(Table II should be placed here during production.)\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Stratification Analyses\u003c/h2\u003e \u003cp\u003eTable III presents age, sex, and race subgroups. Significantly higher risks were identified in PHN patients aged 18\u0026ndash;64 (HR: 1.30, 95% CI: 1.15\u0026ndash;1.47) and a smaller increase in those aged\u0026thinsp;\u0026ge;\u0026thinsp;65 (HR: 1.13, 95% CI: 1.01\u0026ndash;1.27). Females with PHN were more affected (HR: 1.17, 95% CI: 1.05\u0026ndash;1.30). By race, White patients (HR: 1.17, 95% CI: 1.06\u0026ndash;1.30) and Black or African American patients (HR: 1.34, 95% CI: 1.01\u0026ndash;1.77) with PHN showed elevated risks. No difference was observed in individuals with herpes zoster vaccination.\u003c/p\u003e \u003cp\u003e \u003cem\u003e(Table III should be placed here during production.)\u003c/em\u003e \u003c/p\u003e \u003cp\u003eSupplementary table II specifies mental health outcomes by subgroup. In patients aged 0\u0026ndash;64, PHN was linked to mood disorders (HR: 1.24, 95% CI: 1.03\u0026ndash;1.48) and anxiety-related disorders (HR: 1.37, 95% CI: 1.17\u0026ndash;1.59). In patients aged\u0026thinsp;\u0026ge;\u0026thinsp;65, risks were not significant. Women with PHN had higher risks for mood (HR: 1.21, 95% CI: 1.03\u0026ndash;1.43) and anxiety-related disorders (HR: 1.21, 95% CI: 1.06\u0026ndash;1.37), while men demonstrated a higher risk of behavioral syndromes (HR: 1.84, 95% CI: 1.12\u0026ndash;3.01). By race, White patients had greater risk of anxiety-related disorders (HR: 1.21, 95% CI: 1.07\u0026ndash;1.38), whereas Black patients had higher risk of mood disorders (HR: 1.64, 95% CI: 1.09\u0026ndash;2.48).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Disease Site Analysis\u003c/h2\u003e \u003cp\u003eAs shown in Supplementary table III, PHN patients with ocular involvement (HR: 1.63, 95% CI: 1.20\u0026ndash;2.21), other complications (HR: 1.56, 95% CI: 1.20\u0026ndash;2.03), or no complications (HR: 1.44, 95% CI: 1.24\u0026ndash;1.66) had significantly increased psychiatric risks.\u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eIn this cohort study, our results demonstrated increased risks for PHN patients to develop mental disorders, especially in younger adults and females.\u003c/p\u003e \u003cp\u003eIn stratification analysis (Table III), PHN patients of all ages had significantly higher risks of developing mental disorders compared to non-PHN patients, with the risk of patients aged 18\u0026ndash;64 slightly higher than that of patients aged 65 and older. This result suggests that while older age has been identified as a risk factor for PHN(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), younger individuals are more psychologically susceptible to chronic pain, which is consistent with previous studies(\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn stratified analysis of mental sub-outcomes in different subgroups (Supplementary table II), female PHN patients demonstrated significantly increased risks in the categories of mood disorders and anxiety-related disorders. This result is consistent with a previous study, which demonstrated increased risks of anxiety and depression in female patients with PHN(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Another study showed an increased risk of PHN for women experiencing negative life events(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). A recent meta-analysis also showed that among individuals with chronic pain, there was higher prevalence for younger adults and women to develop depression and anxiety(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), further supporting our results.\u003c/p\u003e \u003cp\u003eSeveral possible pathophysiological mechanisms linking PHN to mental disorders are presented. Firstly, a previous study(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) demonstrated small-world brain functional networks in regions related to emotional processing can be altered by PHN, causing decreased local efficiency. Another research also utilized multimodal magnetic resonance imaging (MRI) to show that functional and structural changes can exist six months after relief of PHN(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Secondly, PHN is associated with central nervous inflammation caused by microglial activation, which is seen as the leading cause of anxiety, depression, and other mood disorders(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Previous studies have proved that BMP-4 can induce glial cell activation(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) and release of pro-inflammatory cytokines (IL-1, IL-6, TNF-α), causing central sensitization and contributing to anxiety and depression(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Furthermore, the bidirectional relationship between chronic pain and depression is well established(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Both pain and depression affect similar brain areas, such as anterior cingulate cortex, amygdala, prefrontal cortex, thalamus, and hippocampus, which can be disrupted by PHN or other chronic pain symptoms(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). A previous study demonstrated temporal lobe dysfunction in depressed PHN patients(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Moreover, PHN may cause dysregulation of the neurotransmitter systems shared by both pain modulation and mood regulation. Lastly, sleep disorders common in neuropathic pain and depression can worsen both conditions. Poor sleep quality is known to be positively associated with depression in patients with chronic pain(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Previous studies have also shown positive correlation between sleep shortage and PHN(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). The nocturnal pain experienced by PHN patients can disrupt sleep quality and lead to a vicious cycle of fatigue and mental disorders(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan additionalcitationids=\"CR31 CR32\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAside from mental disorders, there are other PHN sequelae that may severely impair daily functioning and quality of life. Common sequelae include sleep disturbances, physical inactivity, social withdrawal, and reduced productivity(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). These chronic consequences can perpetuate a cycle of psychological distress, particularly anxiety and depression(\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e), which is consistent with our findings. The chronicity of PHN also implicates challenges in treatment adherence and increases healthcare utilization over time, making early recognition and management critical.\u003c/p\u003e \u003cp\u003eGiven the association between PHN and increased risks of mental disorders, our findings underscore the importance of comprehensive management of PHN beyond pain control. Current treatment options for PHN include anticonvulsants (e.g., gabapentin, pregabalin)(\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e), tricyclic antidepressants (e.g., amitriptyline, nortriptyline)(\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e), topical agents (e.g., lidocaine patches, capsaicin), and opioids(\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). A recent study demonstrated significant reduction in scales of depression and anxiety in PHN patients treated with intravenous esketamine as opposed to analgesics alone(\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Integrating psychiatric evaluation and therapy into the care plan of PHN patients may improve overall quality of life.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStrengths and limitations\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThere are several strengths to our study. We utilized a large, diverse, real-world dataset and applied PSM to minimize confounding. Detailed subgroup and stratified analyses were conducted to enhance the clinical relevance of our findings. Additionally, the study design excluded patients suffering from psychological conditions before the diagnosis of PHN, thus allowing for the assessment of temporal relationships between PHN and subsequent mental disorders.\u003c/p\u003e \u003cp\u003eHowever, several limitations must be acknowledged. First, despite the use of PSM and validated diagnostic codes, unmeasured confounding and misclassification bias inherent to electronic health records can still exist. Secondly, mental disorders may have been underdiagnosed or unrecorded in some populations, potentially leading to underestimation of true effect sizes. Thirdly, as is seen in Table III, patients vaccinated against herpes zoster are relatively few in our study, which may lead to an underestimation of the effect of vaccination on mental health outcomes. Furthermore, the diagnosis record in TrinetX database does not include the intensity and duration of pain caused by PHN, making us unable to compare the different impacts they have on psychological conditions. Finally, medication usage, such as antiepileptics or opioids, may have affected mental health(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) but was not assessed in our analyses.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eIn summary, our study utilizes a large-scale, real-world, multicenter dataset to demonstrate a significant association between PHN and increased risks of mental disorders, particularly in subgroups of younger adults, females, and White and Black racial groups. Our study underscores the severe psychological effect of mental disorders associated with PHN. Aside from pain management, clinicians should consider routine psychological evaluation and early intervention programs for PHN patients, particularly those presenting with severe or prolonged symptoms, to improve overall outcomes and quality of life.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBMI, body mass index; BMP-4, bone morphogenetic protein-4; CI, confidence interval; CPT, Current Procedural Terminology; HIV, human immunodeficiency virus; HRs, hazard ratios; ICD-10-CM, International Classification of Diseases, Tenth Revision, Clinical Modification; ICD-10-PCS, International Classification of Diseases, Tenth Revision, Procedure Coding System; IL-1, interleukin-1; IL-6, interleukin-6; IRB, Institutional Review Board; LOINC, Logical Observation Identifier Names and Codes; MRI, magnetic resonance imaging; NSAIDs, non-steroidal anti-inflammatory drugs; PHN, postherpetic neuralgia; SMD, standardized mean difference; TNF-\u0026alpha;, tumor necrosis factor alpha; VZV, varicella-zoster virus.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e:\u003c/em\u003e\u003c/strong\u003e Ethical approval was obtained from the Institutional Review Board of Chung Shan Medical University Hospital (IRB No: CS1-24143). All methodologies employed in this study were conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding sources:\u003c/em\u003e\u003c/strong\u003e This study was supported by grants from Chung Shan Medical University Hospital (CSH-2014-C-034 and CSH-2023-D-003), National Taichung University of Science and Technology (NTCUST113-028), and the Ministry of Science and Technology, R.O.C. (MOST 112-2314-B-040-005- and 111-2314-B-025-001-).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConflicts of Interest:\u003c/em\u003e\u003c/strong\u003e The authors declare no potential conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eClinical trial number:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cem\u003eNot applicable.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cem\u003eNot applicable.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eData availability:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eResearch data supporting this publication can be accessed through the TriNetX platform, available at https://trinetx.com/. Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthor contributions:\u003c/em\u003e\u003c/strong\u003e Yu-Hsun Wang collected the data, performed the analysis, and wrote the methods and results sections in the first draft. Mao-Hsuan Yang, Yu-Ping Hsiao and Yun-Shan Du assisted in writing and producing the final version of the manuscript. Tsu-Jung Wu and Li-Hua Wang contributed to the conception of the study and reviewed the final manuscript. All the authors contributed to the interpretation of the findings, approved the final manuscript, and agreed to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgement:\u003c/em\u003e\u0026nbsp;\u003c/strong\u003eWe extend our sincere gratitude to grants from Chung Shan Medical University (CSH-2014-C-034) and its faculty for assistance with using the TriNetX system that enabled this research. During the preparation of this work the authors used ChatGPT and Perplexity to check grammar and refine texts. After using these tools, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGan EY, Tian EA, Tey HL. Management of herpes zoster and post-herpetic neuralgia. 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Z Gesundh Wiss. 2012;20(4):441\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOster G, Harding G, Dukes E, Edelsberg J, Cleary PD. Pain, medication use, and health-related quality of life in older persons with postherpetic neuralgia: results from a population-based survey. J Pain. 2005;6(6):356\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGross GE, Eisert L, Doerr HW, Fickenscher H, Knuf M, Maier P, et al. S2k guidelines for the diagnosis and treatment of herpes zoster and postherpetic neuralgia. J Dtsch Dermatol Ges. 2020;18(1):55\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaguil A, Kane S, Mercado M, Lauters R. Herpes Zoster and Postherpetic Neuralgia: Prevention and Management. Am Fam Physician. 2017;96(10):656\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLim DZJ, Tey HL, Salada BMA, Oon JEL, Seah ED, Chandran NS et al. Herpes Zoster and Post-Herpetic Neuralgia-Diagnosis, Treatment, and Vaccination Strategies. Pathogens. 2024;13(7).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQiu L, Chen X, Fu J, Chen X, Wang X. Intravenous patient-controlled analgesia with esketamine improves early depressive symptoms in patients with postherpetic neuralgia: a single-center retrospective cohort study. BMC Psychiatry. 2024;24(1):582.\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Postherpetic neuralgia, mental disorders, herpes zoster, anxiety, depression","lastPublishedDoi":"10.21203/rs.3.rs-8560550/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8560550/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePostherpetic neuralgia (PHN) is known to cause pain and affect quality of life. Nonetheless, its association with subsequent mental disorders or severe psychiatric conditions remain underexplored, especially in large and diverse populations. The aim of this study is to identify the risks mental disorders in patients with PHN, with a large-scale, real-world dataset in TriNetX.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study utilized the TriNetX U.S. Collaborative Network and included patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years with new diagnosis of herpes zoster from 2016 to 2023. Patients were divided into PHN and non-PHN groups. The PHN group comprised patients diagnosed with PHN within one month after the diagnosis of herpes zoster, while the non-PHN group comprised those without PHN. Participants diagnosed with any mental disorders before the diagnosis of herpes zoster or up to one month after it were excluded. Each group included 33201 patients after propensity score matching. Risks of mental disorders were compared between the two groups over a 6-month follow-up. Subgroup analyses were conducted across age, sex, race, herpes zoster vaccination, and disease site.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOur results suggested that patients with PHN had a significantly higher risk of developing mental disorders (hazard ratio [HR]: 1.23, 95% confidence interval [CI]: 1.13\u0026ndash;1.34), especially in younger patients aged 18\u0026ndash;64 (HR: 1.30, 95% CI: 1.15\u0026ndash;1.47). Among categories of mental disorders, significant elevated risks for PHN patients were observed in mood disorders (HR: 1.25, 95% CI: 1.10\u0026ndash;1.42), anxiety-related conditions (HR: 1.17, 95% CI: 1.06\u0026ndash;1.30), and behavioral syndromes (HR: 1.35, 95% CI: 1.03\u0026ndash;1.75). Subgroup analysis showed increased risks of mental disorders for females (HR: 1.17, 95% CI: 1.05\u0026ndash;1.30), White patients (HR: 1.17, 95% CI: 1.06\u0026ndash;1.30), and Black patients (HR: 1.34, 95% CI: 1.01\u0026ndash;1.77), and patients with ocular herpes zoster (HR: 1.63, 95% CI: 1.20\u0026ndash;2.21).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study showed a significantly elevated risk for PHN participants to develop mental disorders, particularly in younger adults, females, and White and Black racial groups. Our results also underlined the severe psychological effect of mental disorders associated with PHN. Clinicians should consider early psychological evaluation and intervention for PHN patients.\u003c/p\u003e","manuscriptTitle":"Mental Health Impact of Post-Herpetic Neuralgia: A Retrospective Cohort Study from 33,201 Patients Using TriNetX Network Database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-17 14:55:48","doi":"10.21203/rs.3.rs-8560550/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-01T21:05:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"158402799702987925529203387694831304962","date":"2026-04-15T12:06:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-05T20:17:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-02T12:09:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"36977944380561184402325247535952529646","date":"2026-02-24T18:07:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"300312071439669337558250812803512312951","date":"2026-02-14T10:13:08+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-12T10:08:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-10T06:43:12+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-20T07:23:57+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-19T09:37:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Psychiatry","date":"2026-01-19T09:20:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-psychiatry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bpsy","sideBox":"Learn more about [BMC Psychiatry](http://bmcpsychiatry.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bpsy/default.aspx","title":"BMC Psychiatry","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"70988fa6-cd2c-410d-ab47-6ef46d689fca","owner":[],"postedDate":"February 17th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-01T21:05:26+00:00","index":75,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-17T14:55:49+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-17 14:55:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8560550","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8560550","identity":"rs-8560550","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}