Increased risk of developing dementia in patients with bipolar disorder: a nested matched case control study

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1 Bipolar Disorders 2013: 15: Original Article 2013 John Wiley & Sons A/S Published by John Wiley & Sons Ltd. BIPOLAR DISORDERS Increased risk of developing dementia in patients with bipolar disorder: a nested matched case control study Wu K-Y, Chang C-M, Liang H-Y, Wu C-S, Wu EC-H, Chen C-H, Chau Y-L, Tsai H-J. Increased risk of developing dementia in patients with bipolar disorder: a nested matched case control study. Bipolar Disord 2013: 15: John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objective: The association between bipolar disorder and subsequent dementia risk is not well established. The objective of this study was to investigate whether patients with bipolar disorder were at an increased risk for developing dementia. Methods: A conditional logistic regression model was performed using data from the National Health Insurance Research Database, a nationwide dataset in Taiwan. The study sample included 9,304 patients with incident dementia first diagnosed between 2000 and 2009, and 55,500 gender-, age-, and index date-matched subjects without dementia. Cerebrovascular disease, diabetes, hypertension, head injury, chronic pulmonary disease, alcohol-related disorders, substance use disorders, and health system utilization were treated as covariates in the analyses. Results: After controlling for the covariates, bipolar disorder was significantly associated with an increased risk of subsequent dementia [adjusted odds ratio (aor) = 4.32, 95% confidence interval (CI): ]. An increased risk of developing dementia was observed in males and females alike (aor = 4.01, 95% CI: in males; aor = 4.55, 95% CI: in females). Moreover, a significantly increased risk was observed in subjects diagnosed with dementia before the age of 65 years (aor = 3.77, 95% CI: ). Conclusions: Findings from this study suggest a positive association between the presence of a lifetime history of bipolar disorder and an increased risk of developing dementia. Furthermore, our results also suggest that subjects with bipolar disorder tend to develop dementia in middle age. Going forward, it will be of importance to confirm our findings in different populations. Kuan-Yi Wu a, Chia-Ming Chang a, Hsin-Yi Liang a, Chi-Shin Wu b, Erin Chia-Hsuan Wu c, Chia-Hsiang Chen d,e, Yeuk-Lun Chau a and Hui-Ju Tsai f,g,h a Department of Psychiatry, Chang Gung Memorial Hospital, Lin-Kou and Chang Gung University, Lin-Kou, b Department of Psychiatry, Far Eastern Memorial Hospital, c Graduate Institute of Humanity in Medicine, Taipei Medical University, Taipei, d Institute of Medical Science, Tzu Chi University, Hua-Lan, e Division of Mental Health and Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan, f Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, g Department of Medical Genetics, College of Medicine, Kaohsiung Medical University, Kaohsiung, h Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan doi: /bdi Key words: bipolar disorder dementia presenile senile Received 18 May 2012, revised and accepted for publication 19 April 2013 Corresponding author: Hui-Ju Tsai, M.P.H., Ph.D. Division of Biostatistics and Bioinformatics Institute of Population Health Sciences National Health Research Institutes Zhunan Taiwan Fax: s: tsaihj@nhri.org.tw; h-tsai@northwestern. edu Numerous cross-sectional studies have suggested the presence of cognitive dysfunction in mixed-age patients with bipolar disorder during euthymic states (1, 2). Cognitive deficits have been identified in multiple cognitive domains, and have been associated with functional impairments (3 5). However, longitudinal assessments of cognition in bipolar patients have found a range of stability of the cogni- 787

2 Wu et al. tive dysfunction (6 9). Some studies observed stable cognitive deficits in middle-aged bipolar patients but no significant decline over three to six years of follow-up (8, 9); however, other groups found significant cognitive decline (6, 7). In addition, previous studies examining the relationship between unipolar depression and dementia suggested that subjects with a history of major depression may confer an increased risk for later development of dementia (10, 11). At present, the association between bipolar disorder and subsequent risk for dementia has not been well established. Limited studies have examined the association between bipolar disorder and dementia using a population-based design. For example, Kessing et al. (12 16) published a series of prospective studies using national registry data in Denmark. They found that patients who had previously been discharged from psychiatric hospitals with single or recurrent depression or with bipolar disorder had an increased risk of developing dementia, as compared to the general population (12), or to patients with a diagnosis of osteoarthritis or diabetes (14). In addition, Kessing et al. reported that patients with the diagnosis of bipolar disorder who had been treated with lithium at least once had an increased rate of dementia, as compared to subjects not exposed to lithium in outpatient settings (15, 16). Thus far, the association between bipolar disorder and dementia has been understudied. Using a subset of data derived from the National Health Insurance Research Data (NHIRD) in Taiwan, we aimed to address the following issues: (i) to assess the risk of developing dementia among patients with previously diagnosed bipolar disorder; (ii) to investigate whether there is a gender difference regarding dementia risk in bipolar patients; and (iii) to explore whether clinically identifiable dementia diagnoses evoke a pre-senile stage in bipolar patients. Materials and methods Data source Taiwan launched a single-payer National Health Insurance program (NHIP) in March Since 1996, the National Health Insurance reimbursement claims data have been managed by the National Health Research Institute (NHRI) in Taiwan. The National Health Insurance Research Data (NHIRD; index.htm), a medical claims database, was subsequently established and released for research purposes. Specifically, the NHIRD contains all claims data from the NHIP in Taiwan, including patients 788 demographic characteristics, disease diagnoses, prescription records, and medical expenditures. As of 2007, 22.6 million, or approximately 98.4% of the total population in Taiwan, were enrolled in the NHIP. Because of mega-data collected for longitudinal follow-up, the claims data of 1,000,000 beneficiaries were randomly sampled from the Year 2005 Registry for Beneficiaries of the NHIRD, which constituted a representative subset of NHIRD LHID2005. Of note, there was no significant difference in the distributions of gender, age, or average insured payroll-related amount between the subjects in this LHID2005 subset and the original NHIRD ( The present study, using data derived from this LHID2005 subset, covered the period from January 1, 2000 to December 31, We selected this particular study period to exclude disease diagnoses coded by A-codes, a simplified disease coding system used mainly for ambulatory care before 2000, and to avoid problems due to diagnostic validity and concordance between International Classification Diagnostic (ICD)-9-CM and A-codes. For data protection purposes, the confidential information on individuals was scrambled and encrypted before the NHIRD data were released to the researchers. This study protocol was approved by the Institutional Review Board at the National Health Research Institutes, and the investigators signed a written patient confidentiality agreement before using the NHIRD. Study population Case group. Eligible cases were subjects who had at least three consistent diagnoses of dementia (ICD-9- CM codes: , , 294.1, , or ) from either inpatient or outpatient claims data between January 1, 2000 and December 31, We defined the date of the first dementia claim as the index date of dementia, and excluded patients who had a dementia diagnosis in the year 2000 as new incident dementia cases. In order to avoid a misdiagnosis of dementia, we excluded patients who were younger than 45 years of age at the time of the first diagnosis of dementia. Moreover, we also excluded patients with a diagnosis of Down syndrome, a rare genetic disorder, because it is well known to be associated with cognitive impairment and subsequent early-onset dementia. Control group. The control subjects were defined as those with no record of a claim for a dementia diagnosis during the years For each

3 Bipolar disorder and dementia case, up to six control subjects without a dementia diagnosis during the study period were randomly matched for gender and age. If there were < 6 eligible subjects, they were all were included. Each comparison subject was assigned the same index date as that of the matched cases. As a result, the study population consisted of 9,304 subjects with dementia and 55,500 matched controls in our subsequent analysis (Fig. 1). Exposure variables Exposure variables were defined as patients with diagnosed bipolar disorder that is, those who were diagnosed with one of the following ICD-9- CM codes: 296.0x, 296.1x, 296.4x, 296.5x, 296.6x, 296.7x, , , or from either inpatient or outpatient claims records from 2000 to 2009, and only those who had had at least three consistent bipolar diagnoses in either inpatient or outpatient claims data were included. Only the patients whose diagnostic date of bipolar disorder was prior to their index date of dementia were included in the study. In addition, we excluded patients whose latency period between their first diagnostic date of bipolar disorder and the index date of dementia was within six months. In this situation, bipolar disorder was defined as the pro- Study database of NHIRD (n = 1,000,000) A study cohort during Inclusion criteria: Inpatient or outpatient diagnosis with ICD-9-CM of dementia At least three consistent diagnoses Subjects without any inpatient or outpatient diagnoses of dementia from Patients with dementia diagnosis during (n = 16,101) Exclusion criteria: < 45 years old Dementia diagnosis in 2000 Down syndrome (n = 5,529) Incident dementia in (n = 10,572) 1:6 matched controls by age, gender, and index year; if < 1:6, all eligible subjects were selected 1,269 non-matched cases a 9,304 incident cases 55,500 matched controls b Fig. 1. Flow chart of sampling procedure for the study sample (both case and control groups). NHIRD = National Health Insurance Research Data. a A total of 1,269 cases, whose ages ranged from 82 to 106 years, with no control matched by age, gender, or index year, was identified. b A total of 9,304 cases and 55,500 matched controls were included in this study. 789

4 Wu et al. drome of dementia in this study. As a result, a total of 127 patients with bipolar disorder were identified who had a diagnostic date that was prior to the index date of dementia. After excluding subjects with the six-month latent period between the diagnoses of bipolar disorder and dementia, 114 bipolar patients were included in the subsequent analyses. Potential confounding covariates Previous literature has identified potential risk factors for dementia, particularly midlife cardiovascular risk factors, medical comorbid factors, and psychiatric disorders associated with dementia (1, 17 19). Midlife cardiovascular risk factors and medical comorbidities consist of cerebrovascular diseases (ICD-9 codes: 430.xx-438.xx), diabetes (ICD-9 codes: 250.xx), hypertension and its complications (ICD-9 codes: 401.xx-405.xx), dyslipidemia (ICD-9 codes: 272.xx), head injury (ICD-9 codes: 800.xx 804.xx, 850.xx 854.xx, or 959.xx), chronic pulmonary disease (ICD-9 codes: 491.xx- 494.xx, 496.xx, 415.0, 416.8, 416.9); and psychiatric comorbidities include alcohol-related disorders (ICD-9 codes: 291.xx, 303.xx, 305.0x, 357.5x, 425.5x, 535.3x, 571.0x, or 571.1x-571.3x) and substance use disorders (ICD-9 codes: 292.xx, 304.xx, or 305.1x-305.9x). Health system utilization within the preceding year of the index date was also included and adjusted for the confounding effect in the analyses, such as the number of outpatient visits and the number of hospitalizations. Consequently, in addition to dyslipidemia, we treated these midlife cardiovascular risk factors, medical comorbidities, and psychiatric disorders as covariates in the regression models and examined the association between bipolar disorder and the risk of dementia. Data analysis Pearson chi-square tests were used for discrete variables and Student s t-tests for continuous variables, separately, to compare the differences between dementia cases and matched controls. The examined variables included: medical comorbidities, psychiatric illnesses, and health service utilization, individually. Next, we applied conditional logistic regression to examine the associations between bipolar disorder and the risk for dementia with and without covariates adjustment. Covariates included in the multiple conditional logistic regression models were those that showed a significant crude odds ratio (OR) in univariate conditional logistic analyses. To test whether there 790 was a gender difference, logistic regression analysis was performed to examine the interaction between gender and bipolar disorder. We further performed subgroup analyses stratified by gender, and by age of dementia onset (the senile stage defined as incident dementia at the age of 65 years and pre-senile stage defined as incident dementia aged < 65 years). Statistical significance was set at the level of p < All statistical analyses were carried out using the SAS 9.1 statistical package (SAS Institute, Inc., 1995; Cary, NC, USA). Results Characteristics of the study subjects The mean age and corresponding standard deviation (SD) of the study population was years, with an even gender distribution (50.6% female). Table 1 presents the distributions of demographic characteristics and selected comorbid medical and psychiatric disorders between the 9,304 dementia cases and the 55,500 matched controls. In total, 1.23% of dementia patients and 0.21% of comparison subjects had a previous diagnosis of bipolar disorder (Table 1). Compared to the matched controls, dementia patients had a significantly higher prevalence of examined medical comorbidities such as cerebrovascular disease (p < ), diabetes mellitus (p < ), hypertension (p < ), head injury (p < ), chronic pulmonary disease (p < ), and the psychiatric disorders we examined such as alcoholrelated disorders (p < ) and substancerelated disorders (p = 0.02) in the year before the index date. There was significant difference in dyslipidemia between the two groups. The number of outpatient (p < ) and inpatient (p < ) visits in the year before the index date was higher for the dementia cases than for the matched controls. Association of bipolar disorder with developing dementia When examining the association of bipolar disorder with the development of dementia, subjects with bipolar disorder had a 4.07-fold higher risk of dementia than the controls [adjusted odds ratio (aor) = 4.07; 95% CI: ] (Table 2). In addition, subjects with medical and/or psychiatric comorbidities also had a higher risk of developing dementia than the controls, but no significant association was found for subjects with dyslipidemia (Table 2).

5 Table 1. Demographic characteristics, medical comorbidities, psychiatric comorbidities, and health service utilization of study sample, Dementia patients (n = 9,304) Comparison group (n = 55,500) Chi-square p-value Gender, n (%) Female 4,716 (50.69) 28,089 (50.61) Male 4,588 (49.31) 27,411 (49.39) Age, years, mean SD a 0.34 Bipolar disorder, n (%) 114 (1.23) 115 (0.21) < Medical comorbidities, n (%) Cerebrovascular disease 3,195 (34.34) 5,342 (9.63) 4, < Chronic pulmonary disease 1,293 (13.90) 5,628 (10.14) < Diabetes mellitus 2,268 (24.38) 9,604 (17.30) < Dyslipidemia 1,168 (12.55) 6,931 (12.49) Head injury 395 (4.25) 702 (1.26) < Hypertension 5,249 (56.42) 25,953 (46.76) < Psychiatric comorbidities, n (%) Alcohol-related disorder 64 (0.69) 117 (0.21) < Substance-related disorder 29 (0.31) 104 (0.19) Health service utilization, mean SD Outpatient visit a < Inpatient visit a < SD = standard deviation. a Statistical significance was determined by Student s t-test. Bipolar disorder and dementia Table 2. Crude and adjusted odds ratio of developing dementia in patients with bipolar disorder Dementia patients (n = 9,304) Comparison group (n = 55,500) Crude odds ratio Adjusted odds ratio (95% CI) a,b (95% CI) a,b Bipolar disorder, n (%) 127 (1.37) 136 (0.25) 5.75 ( ) 4.07 ( ) Medical comorbidities, n (%) Cerebrovascular disease 3,195 (34.34) 5,342 (9.63) 5.01 ( ) 4.00 ( ) Chronic pulmonary disease 1,293 (13.90) 5,628 (10.14) 1.44 ( ) 1.01 ( ) Diabetes mellitus 2,268 (24.38) 9,604 (17.30) 1.56 ( ) 1.19 ( ) Dyslipidemia 1,168 (12.55) 6,931 (12.49) 1.01 ( ) Head injury 395 (4.25) 702 (1.26) 3.46 ( ) 2.93 ( ) Hypertension 5,249 (56.42) 25,953 (46.76) 1.50 ( ) 1.11 ( ) Psychiatric comorbidities, n (%) Alcohol-related disorder 64 (0.69) 117 (0.21) 3.34 ( ) 2.47 ( ) Substance-related disorder 29 (0.31) 104 (0.19) 1.69 ( ) 1.47 ( ) Health service utilization, mean SD Outpatient visit 38.9 (29.2) 27.9 (22.2) 1.02 ( ) 1.01 ( ) Inpatient visit 0.9 (2.00) 0.3 (0.90) 1.51 ( ) 1.30 ( ) CI = confidence interval; SD = standard deviation. a Statistical significance was determined in multiple conditional logistic regression with adjustment for covariates including cerebrovascular disease, diabetes mellitus, hypertension, head injury, chronic pulmonary disease, alcohol-related disorder, substance-related disorder, outpatient visit, and inpatient visit. b p < 0.05 is in boldface. Next, in the absence of a consensual definition for prodromal period, we further examined the association of bipolar disorder with the development of dementia after excluding subjects with a diagnosis of incipient dementia within one, two, three, and even five years of an initial diagnosis of bipolar disorder. Notably, the results in Supplementary Table 1 show that subjects with bipolar disorder had a higher risk of developing dementia than the controls across different latency periods (aor = 3.89; 95% CI: for one year; aor = 3.58; 95% CI: for two years; aor = 3.82; 95% CI: for three years; and aor = 4.15; 95% CI: for five years). Subgroup analyses Table 3 shows the results of subgroup analyses, grouped by gender and age of dementia onset, separately. Of note, the results indicate an increased 791

6 Wu et al. Table 3. The association between bipolar disorder and dementia, stratified by gender and age at dementia diagnosis Dementia patients Comparison group Total N Bipolar (%) Total N Bipolar (%) Crude odds ratio a,b (95% CI) Adjusted odds ratio a,b (95% CI) Gender c Male 4, (1.02) 27, (0.20) 5.14 ( ) 4.01 ( ) Female 4, (1.42) 28, (0.21) 7.03 ( ) 4.55 ( ) Age at dementia onset Pre-senile dementia (age < 65) 1, (1.90) 7, (0.34) 5.66 ( ) 3.77 ( ) Senile dementia (age 65) 8, (1.12) 48, (0.19) 6.23 ( ) 4.57 ( ) CI = confidence interval. a Statistical significance was determined in multiple conditional logistic regression with adjustment for covariates including cerebrovascular disease, diabetes mellitus, hypertension, head injury, chronic pulmonary disease, alcohol-related disorder, substance-related disorder, outpatient visit, and inpatient visit. b p < is in boldface. c Interaction between gender and bipolar disorder was non-significant using logistic regression analysis. risk of developing dementia in both males and females with bipolar disorder (aor = 4.01, 95% CI: in males; aor = 4.55, 95% CI: in females). Patients with bipolar disorder had a greater risk of developing pre-senile dementia (aor = 3.77, 95% CI: ) as well as a greater risk of developing senile dementia (aor = 4.57, 95% CI: ), separately, than the comparison group. We also examined the interaction between gender and bipolar disorder, but the results showed no significant interaction (data not shown). Discussion To date, limited studies have investigated the association between bipolar disorder and the risk of developing dementia. The present study is one of the first population-based studies to investigate this association. The major findings from this study suggest that subjects with a previous diagnosis of bipolar disorder may be at increased risk of subsequent dementia, even after controlling for pertinent risk factors. Importantly, this finding is consistent with the results reported by Kessing et al. (12 16) that patients with a previous diagnosis of bipolar disorder or with at least one lithium treatment had an increased risk of developing dementia in outpatient psychiatric hospital settings. Our results showed that 1.37% of the dementia patients and 0.25% of the control subjects had been previously diagnosed with bipolar disorder. Previous studies conducted in Taiwan, including one from a 1985 community survey the Taiwan Psychiatric Epidemiological Project (20) and another from the 2000 National Health Insurance study (21), both estimated prevalence rates for bipolar affective disorders to be %, which 792 is comparable to the observed prevalence rate in this study. Of note, the estimated prevalence rate (0.25%) was representative of the proportion of treated bipolar patients among the National Health Insurance (NHI) enrollees in Taiwan. As such, it might not be comparable to the lifetime prevalence rate of bipolar disorder in the general population. In addition, in the absence of a consensual definition for prodromal period, we defined six months as the prodromal interval between bipolar disorder and dementia in the present study. To test the robustness of our findings, we further repeated logistic regression analyses for four different prodromal intervals: one year, two years, three years, and five years, separately. Notably, the results presented in Supplementary Table 1 are remarkably consistent across the five different prodromal intervals: six months, one year, two years, three years, and five years, separately. The pathophysiology behind the link between bipolar disorder and the subsequent development of dementia largely remains unclear (13). Previous work has reported that a reduction in the frontal lobe volume may be associated with diffuse cognitive impairments in patients with bipolar disorder (22). In addition, a brain imaging study has suggested that bipolar patients may have abnormal brain structures in neural pathways (23). Several studies have proposed that the glucocorticoid cascade (24), vascular disease (25, 26), and even a trait marker of genetic vulnerability (27, 28) may play an important mechanistic role in neurodegenerative change over time for affective disorders including bipolar disorder. However, we found that patients with bipolar disorder, especially elderly patients, represented an etiologically heterogeneous group (i.e., different age at illness onset, different number of acute relapses, and different

7 Bipolar disorder and dementia medical comorbidities, etc.). It was likely that there were various causes of cognitive impairment in our elderly study population. Therefore, the findings in the present study provide solid evidence for further investigating the underlying neuropathophysiological and pathological mechanisms that link bipolar disorder with the development of dementia. Although our findings are compelling, several potential limitations should be noted. First, based on the use of the claims data, the reliability and validity of the diagnoses of bipolar disorder and dementia remain a major concern. A previous study found that the accuracy of dementia diagnosis was increased when the severity of cognitive impairment increased (29). To ensure the validity of dementia and bipolar disorder diagnoses in the present study, we included only patients who had had at least three consistent diagnoses (for both bipolar disorder and dementia) identified from outpatient and inpatient claim data, which was similar to the criteria used in other studies using the NHIRD source in Taiwan (30, 31). However, because of the NHIRD data protection policy, it was impossible to validate the subjects data in the medical records to confirm the diagnosis of bipolar disorders. In addition, subjects with a six-month latency period between diagnoses of bipolar disorder and dementia were identified as having the prodrome of dementia and were excluded from subsequent analysis. Second, detailed information on some clinical variables, such as various clinical subtypes of dementia, severity of bipolar disorder, and number of acute relapses, were not available in the NHIRD. Therefore, we could not further evaluate whether there was a gender difference for different clinical subtypes of dementia. Third, to control for potential detection bias, we treated cerebrovascular and related diseases and health system utilization within the preceding year of the index diagnosis as potentially important confounders, and adjusted for them as covariates in the analyses. We also excluded a directly etiological factor, Down syndrome, in all analyses. However, unadjusted confounding factors such as educational level, family history of dementia, and socioeconomic status may still partially affect the risk for dementia. Lastly, patients aged < 45 years at the time of the first dementia diagnosis were excluded from the study, and the study period was set from 2000 to 2009, a ten-year period. Therefore, we could not examine the potentially differential relationship between dementia and a diagnosis of bipolar disorder early versus late in life. It will be of interest to investigate this issue when data are available in the future. Conclusions The findings from the present study strongly document an association between the presence of bipolar disorder and the risk of developing dementia in all study subjects, both male and female. More importantly, patients with bipolar disorder exhibited clinically identifiable signs of both pre-senile and senile dementia. Further research, including biochemical and brain imaging studies, will be warranted to provide a better understanding of the pathophysiology of the early process and progression of bipolar disorder to dementia. Acknowledgements H-JT was supported in part by grants from the National Health Research Institutes (PI: Tsai, PH-099-PP-56, PH-100- PP-14, PH-101-PP-14, PH-101-SP-14). This study was based, in part, on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health, and managed by the National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of the Bureau of National Health Insurance, Department of Health, or National Health Research Institutes. We thank Tami R. Bartell at Lurie Children s Hospital of Chicago for English editing. Disclosures The authors of this paper do not have any competing interests to report. References 1. Bearden CE, Hoffman KM, Cannon TD. The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review. Bipolar Disord 2001; 3: Robinson LJ, Thompson JM, Gallagher P et al. A metaanalysis of cognitive deficits in euthymic patients with bipolar disorder. J Affect Disord 2006; 93: Quraishi S, Frangou S. Neuropsychology of bipolar disorder: a review. 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