Abstract
Population-based cohort study investigating the risk of depression and other psychiatric disorders for patients with overactive bladder (OAB) syndrome is unavailable. This study investigated the subsequent risk of psychiatric disorders among patients with OAB in an Asian population. Using data from the National Health Insurance Research Database of Taiwan, we established a cohort with 811 patients in an exposed group with OAB between January 1, 2000 and December 31, 2000, and a non-exposed group, without OAB, of 2433 patients without OAB matched by age and year of diagnosis. The occurrence of psychiatric disorders and Cox regression model measured adjusted HRs (aHR) were monitored until the end of 2013. The overall incidence of psychiatric disorders was 41.7% higher in the exposed group with OAB than in the non-exposed group without OAB (14.2% vs 10.1%, p<0.001), with an aHR of 1.34 (95% CI 1.12 to 1.80, p<0.001) for the OAB cohort. OAB was associated with the increased risk of dementia, anxiety, depressive, sleep, and psychotic disorders, with aHRs as 1.53 (p=0.040), 1.61 (p<0.001), 2.10 (p<0.001), 1.43 (p<0.001), and 2.49 (p=0.002), respectively. The risk of psychiatric disorders, including depression and anxiety, is significantly higher in patients with OAB than in those without OAB. Evaluation of psychiatric status in patients with OAB is strongly recommended.
Significance of this study
What is already known about this subject?
Previous studies have found that patients with overactive bladder (OAB) syndrome are at increased risk of anxiety disorder, depressive disorder, obstructive sleep apnea, and post-traumatic stress disorder.
The association between OAB and a range psychiatric disorders has not yet been studied.
What are the new findings?
Compared with previous research about the association between OAB and affective, sleep and other mental health problems, this population-based study focused on investigating whether OAB was associated with the risk of psychiatric disorders.
OAB was associated with the risk of psychiatric disorders (adjusted HR (aHR): 1.34, 95% CI 1.12 to 1.80, p<0.001), when adjusting for sex, age, monthly income, urbanization level, geographic region, and comorbidities.
OAB was associated with an increased risk of developing dementia, anxiety, depressive, sleep, and psychotic disorders, with aHRs as 1.53 (p=0.040), 1.61 (p<0.001), 2.10 (p<0.001), 1.43 (p<0.001), and 2.49 (p=0.002), respectively.
How might these results change the focus of research or clinical practice?
If the risk of psychiatric disorders in OAB is a causal association, then the results would remind the clinicians who care patients with OAB to provide careful monitoring of these patients’ mental conditions in the clinical practice.
Introduction
Overactive bladder (OAB) syndrome is defined as ‘urgency, with or without urge incontinence, usually with frequency and nocturia, in the absence of infection or other proven pathology.1 2 Community studies had showed that the prevalence of OAB was estimated to be around 16%–17% in different countries.3 4 Several researchers found that patients with OAB had suffered from this disabling condition associated with the considerable negative impact on their quality of life, quality of sleep, and mental health, such as guilty feelings, depression, loss of feeling of esteem, and fears.5 6
Some studies have revealed that OAB was associated with postpartum depression,7 obstructive sleep apnea,8 and one study about the female veterans also found that OAB was associated with post-traumatic stress disorder (PTSD), anxiety, and depression.9 However, whether OAB was associated with the risk of psychiatric disorders has not been studied. We hypothesized that we could examine whether OAB was associated with a range of psychiatric disorders by using the National Health Insurance Research Database (NHIRD), a nationwide, population-based registry. The present study is also to investigate the impact of medications for OAB on the association with the psychiatric disorders.
Materials and methods
Data sources
The National Health Insurance (NHI) Program was launched in Taiwan in 1995, and as of June 2009, it included contracts with 97% of the medical providers, with approximately 23 million beneficiaries, or more than 99% of the entire population of Taiwan.10 Several studies have demonstrated the accuracy and validity of the diagnoses in the NHIRD.11–13 The NHIRD uses the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes to record diagnoses.14 The NHI Administration randomly reviews the records of ambulatory care visits and inpatient claims periodically to verify the accuracy of the diagnoses.15
Sampled study population
The present study used a retrospective, matched-cohort design. Patients with OAB were selected from 1 year between January 1, 2000 and December 31, 2000, according to the ICD-9-CM codes: 596.51. In Taiwan, OAB is defined as a ‘symptom syndrome’, marked by urgency, with or without urge incontinence, usually with frequency and nocturia, in the absence of an underlying metabolic or pathologic condition,1 and this definition was then formalized in the ‘Standardization of Terminology in Lower Urinary Tract Function: Report from the Standardization Sub-committee of the International Continence Society’.2 16 And the reason why we just enrolled patients with OAB and controls within 1 year, between January 1, 2000 and December 31, 2000 is to make sure all the subjects were followed up in the same period, similar to several previous studies.17–19 All diagnoses of OAB were made by board-certified urologists, and gynecologists (in female patients). Those diagnoses of psychiatric disorders in this study were made by board-certified psychiatrists. In addition, while we reviewed previous literatures about OAB research, using the NHIRD, the definitions of OAB in their studies were the records of OAB combined with antimuscarinic medications,20–22 ≦2 visits for OAB in 1 year,23–25 or ≧3 visits for OAB in 1 year.26 For obtaining relative confirmatory diagnosis of OAB, each enrolled patient was required to have made at least 3 outpatient visits within the 1 consecutive year study according to the OAB ICD-9-CM code.26 The patients diagnosed with psychiatric disorders before 2000, or before the first visit for OAB, and all patients aged <20 years were also excluded. In this study, we used data from the NHIRD to investigate the association between patients with OAB and psychiatric disorders over a 13-year period, from the 1 million Longitudinal Health Insurance Database in Taiwan (2000–2013). A total of 3244 enrolled patients, with 811 OAB subjects, and 2433 controls, with 1:3 age, sex, and index date-matched control group without OAB in this study (online supplementary figure S1).
Supplementary file 1
Covariates
The covariates were sex, age groups (20–29, 30–39, 40–49, 50–59, 60–69, ≧70 years), comorbidity, areas of residence (north, center, south, and east of Taiwan), urbanization levels of residence (levels 1–4), seasons, and monthly insurance premiums (in New Taiwan dollars (NT$); <18,000; 18,000–34,999; ≥35,000). Charlson Comorbidity Index (CCI) defined the comorbidity.27 28 The population and various indicators defined the urbanization levels. Level 1 was defined as a population >1,250,000; level 2 was defined as a population between 500,000 and 1,249,999; and urbanization levels 3 and 4 were defined as a population between 149,999 and 499,999, and <149,999, respectively.29 Since 1 study found that there are seasonal symptom changes in OAB,30 we included the seasons that the patients searched for medical help as covariates.
Antimuscarinic medications reimbursed by the NHI for OAB, such as trospium, imipramine, flavoxate, propiverine, oxybutynin, tolterodine, and solifenacin, were also collected from the database. The data of the defined daily dose (DDD) were obtained from the WHO Collaborating Centre for Drug Statistics Methodology (https://www.whocc.no/), and the duration of the usage of antimuscarinic medications was calculated by dividing the cumulative doses by the DDD of the antimuscarinic medications.
Outcome measurements
The data on all of the study subjects were collected for the time period between January 1, 2000 and December 31, 2000, until the onset of those psychiatric disorders, including dementia (ICD-9-CM 290.0, 290.10–290.13, 292.20–292.21, 290.3, 290.41–290.43, 290.8–290.9, and 331.0), anxiety disorders (ICD-9-CM 300), depressive disorders (ICD-9-CM 296.2–296.3, 300.4, and 311), bipolar disorders (ICD-9-CM 296.0, and 296.4–296.8), sleep disorders (ICD-9-CM 307.4 and 780.5), psychotic disorders (ICD-9-CM 295, and 297–298), adjustment disorders (ICD-9-CM 309, excluding 309.81), PTSD, and acute stress disorder (ICD-9-CM 308 and 309.81). Each patient with psychiatric disorders was required to have made at least 3 outpatient visits within the 1-year study period.
Statistical analysis
All statistical analyses were performed using the IBM Statistical Product and Service Solutions (SPSS) for Windows, V.22.0 (IBM). χ2 test and t-test were used to evaluate the distributions of the categorical and continuous variables, respectively. The Fisher’s exact test for the categorical variables was used to statistically examine the differences between the two cohorts. Cox regression model was used to determine the risk of psychiatric disorders, and the results were present as HR with a 95% CI. The difference in the risk of psychiatric disorders between the study and control groups was estimated using the Kaplan-Meier method with the log-rank test. A two-tailed p value <0.05 was considered to indicate the statistical significance.
Results
Sample characteristics
Table 1 shows that there was a marginal difference of CCI scores between the OAB cohort and the control group (0.19±0.68 and 0.15±0.49; p=0.032). The difference between the two groups was not statistically significant in the distribution of sex, age, and monthly income between these two groups. The OAB cohort inclined to search for medical help in the springs, live in the Northern Taiwan, and reside more in the places of urbanization level 1.
Kaplan-Meier model for the cumulative risk of psychiatric disorders
Of the total 3244 enrollees, 115 from the 811 (14.2%) in the OAB cohort, in comparison to 245 from the 2433 (10.1%). Kaplan-Meier survival analysis revealed the difference was statistically significant in the development of psychiatric disorders (log-rank, p<0.001, figure 1).
The risk of psychiatric disorders in OAB cohort
Table 2 shows that in the Cox regression model, the HR of the OAB cohort in the development of psychiatric disorders was 1.34 (adjusted HR, 95% CI 1.12 to 1.80, p<0.001), compared with the non- OAB cohort, after adjustment for sex, age, comorbidity (CCI scores), anticholinergic medications for OAB, seasons, residence/regions, and monthly incomes. Men were associated with a lower risk than women of developing psychiatric disorders. The groups with ages of 30 and older were associated with a lower risk than the younger group aged 20–29. Usage of medications for OAB was not associated with an increased risk of psychiatric disorders.
Subgroup analysis in the HR of psychiatric disorders in OAB cohort
Table 3 depicts that the OAB cohort was associated with an increased risk of psychiatric disorders, in comparison to the non-OAB cohort, regardless of sex, age, CCI scores, duration of OAB medications usage (1–29 days, ≧30 days), and residence/regions, in the subgroup analysis. The patients with OAB with monthly insurance premiums of NT$<18,000 and NT$18,000–34,999 were in association with an increased risk of psychiatric disorders.
Risk of different psychiatric disorders in OAB cohort
Table 4 reveals that OAB was associated with an increased risk of dementia, anxiety disorder, depressive disorders, sleep disorders, and psychotic disorders, with the adjusted HRs as 1.53 (p=0.040), 1.61 (p<0.001), 2.10 (p<0.001), 1.43 (p<0.001), and 2.49 (p=0.002), respectively.
The comparison of psychiatric outpatient visits between the OAB and OAB cohorts
The average psychiatric outpatient visits in the OAB cohort and non-OAB cohort were 6.20 (SD ±6.91) and 5.63 (SD ±7.84) times in the period before the psychiatric diagnoses were made or the end of the study (table 5). The difference between the two groups was not statistically significant (p=0.065).
The sensitivity test for the risk of psychiatric disorders in Cox regression model
Table 6 shows that even after excluding the psychiatric diagnoses in the first 2 years after OAB diagnosis, an adjusted HR was 1.29 (95% CI 1.10 to 1.77, p=0.001).
Discussion
Association between OAB and the risk of psychiatric disorders
The study showed that the adult patients with OAB had an increased risk of psychiatric disorders. Even after adjusting for covariates, the overall adjusted HR was 1.34 (adjusted HR, 95% CI 1.12 to 1.80, p<0.001). In other words, the adult patients with OAB had a 1.34-fold increased risk of developing psychiatric disorders. The Kaplan-Meier analysis revealed that the OAB cohort had a significantly higher cumulative risk of psychiatric disorders in comparison to the controls. The younger OAB subjects were at a higher risk of developing psychiatric disorders.
Comparison of this study to previous literatures
Several hospital or office-based studies have found that OAB was correlated with psychiatric disorders in female patients, including postpartum depression,7 and obsessive-compulsive disorder.31 One study showed that in 172 recently deployed female veterans, 375 (22%) have had OAB, and the incidence and adjusted OR of mental health outcomes included PTSD (19%; OR: 2.7), anxiety (21%; OR: 2.7), depression (10%; OR: 2.5) and prior sexual assault (27%; OR: 1.4).9 For the studies about urine incontinence, one of the symptoms of OAB, 1 study found that there is a bidirectional influence between urine incontinence and depression or anxiety symptoms,32 and another study found that women with depressive symptoms or a history of depression were more likely to report subsequent urine incontinence symptoms.33 One previous study using the NHIRD found that the adjusted HR for depressive disorder in OAB women who received antimuscarinics was 1.38, when compared with those OAB women who did not receive antimuscarinics.34 This is the first study on the topic whether OAB was associated with overall risk of psychiatric disorders, by using a nationwide, population-based data set, regardless of usage of antimuscarinics or not.
The prevalence of OAB in this study
In this claims data set, the prevalence within 2000 was only 0.048% (811 in 1,685,500 individuals), which was much lower than other studies.3 4 There are several possible explanations. First, this indicates the difference between questionnaire-collected information in the community and the diagnosis by specialists, such as urologist or gynecologists, as aforementioned, in the claims data set. Second, help-seeking behaviors might play a role: one previous study found that only 6% and 7% of female patients with urinary incontinence, or OAB-wet, in 1991 and 2007, respectively, had sought help from the healthcare system, even in the USA.35 Therefore, this claims data set treatment prevalence might represent patients who showed more need in seeking medical help in the population. We have compared the number of psychiatric outpatient visits between the OAB cohort and non-exposed group without OAB, to clarify whether the OAB cohort was being more likely to be evaluated and diagnosed with psychiatric services. Also there was no difference in psychiatric outpatient visits between these groups. Furthermore, even after excluding the psychiatric diagnoses in the first 2 years after OAB diagnosis, the OAB was associated with an increased risk of psychiatric disorders. However, we need more studies for the reason why the prevalence rate of OAB in the study is so low.
The impact of sex differences in the prevalence of OAB
In the OAB subjects, female subjects (54.3%) were slightly higher than male subjects (45.7%). This finding was compatible with the results of other studies, in that OAB was found to be a more frequent condition in women than in men. The subgroup analysis revealed that both female (adjusted HR=1.53, 95% CI 1.34 to 1.76, p<0.001) and male (adjusted HR=1.65, 95% CI 1.52 to 1.99, p<0.001) patients were associated with an increased risk of developing psychiatric disorders. This finding should, therefore, remind clinicians that both women and men could suffer from OAB, as well as the risk of subsequent psychiatric disorders.
Possible mechanisms for the increased risk of psychiatric disorders in patients with OAB
The underlying mechanisms of the association between OAB and psychiatric disorders remain unclear. One hypothesis mentioned that the central sensitization was an induced state of spinal hypersensitivity that was associated with a variety of chronic pain disorders that share many attributes with OAB.36 Several animal studies have revealed that stress might contribute to symptom exacerbation in many disease states, including functional disorders, including OAB.37–40 These facts hint that OAB and psychiatric disorder might share a common pathophysiology. For dementia, muscarinic receptors could play a role in both OAB and the cognitive function.41 This might also provide an explanations that antimuscarinics for OAB were not associated with the decreased risk of psychiatric disorders, since these medications only act on the bladder, and not on the central nervous systems.
Limitations
This study has several limitations. First, we used the insurance claims to identify the data patients with OAB or psychiatric disorders; however, no data on the severity, functional impairment, and impact on their partners or family were available. Second, no records of body mass index, genetic, and environmental factors were included in the data set. Third, the claims data set was not able to include the descriptions of the predominance in urine urgency, urge incontinence, and nocturia. Fourth, the numbers were low in some subgroups of psychiatric disorders, such as bipolar disorder, adjustment disorder, acute stress disorder and PTSD, therefore this fact limits the possibility in generalization of the association between OAB in these disorders.
Conclusion
This study has shown evidence to support that the OAB cohort has an increased risk of developing psychiatric disorders. Other large or national data sets should be completed to confirm this finding and to explore the underlying mechanisms. This finding should, indeed, remind clinicians that both women and men could suffer from OAB, as well as the risk of subsequent psychiatric disorders.
Acknowledgments
The authors thank Professors Chang-Huei Tsao, Yung-Fu Wu and Fu-Huang Lin for their help in the administrative work and academic guidance in supporting the completion in this study.
Footnotes
Contributors NST and WCC conceived the study, participated in its design and coordination, data interpretation, performed the statistical analysis and drafted the manuscript. WCC, CHC, HWY, HAC, RBL and YCK participated in the design of the study and data interpretation. CBY, SYH and WSC participated in the statistical analysis and data interpretation. NST wrote the paper. All authors have read and approved the final manuscript as submitted.
Funding This work was supported by Tri-Service General Hospital Research Foundation (grant numbers TSGH-C105-130, TSGH-C106-106, TSGH-C107-106, TSGH-C107-004).
Competing interests None declared.
Patient consent Not required.
Ethics approval This study was conducted in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). The Institutional Review Board of the Tri-Service General Hospital approved this study and waived the need of individual consents since all the identification data were encrypted in the NHIRD (IRB number 1-104-05-145 and 1-106-05-055).
Provenance and peer review Not commissioned; externally peer reviewed.