- Email: [email protected]
Increased Risk of Depression in Patients with Parkinson Disease: A Nationwide Cohort Study
Increased Risk of Depression in Patients with Parkinson Disease: A Nationwide Cohort Study Yi-Ting Hsu, M.D., Chien-Chang Liao, Ph.D., Shih-Ni Chang, M.P.H., Yu-Wan Yang, M.D., Chon-Haw Tsai, M.D., Ta-Liang Chen, M.D., Fung-Chang Sung, Ph.D.
Objective: The association between Parkinson disease (PD) and depression remains unclear, particularly in the Asian population. The purpose of this study is to investigate the risk of depression in patients with PD using population-based data. Methods: Based on the National Health Insurance Research Database of Taiwan, we identified 1,698 patients with PD aged 40 years or older diagnosed in 2000e2003. With frequency matching procedure, we randomly selected 6,792 subjects without PD stratified by sex and age. Both cohorts were followed until the end of 2008 or diagnosis of depression. Risk of depression associated with PD was estimated in the multivariate Cox hazards regressions. Diabetes, hypertension, and hyperlipidemia were more prevalent at baseline in patients with PD. Results: Compared with the cohort without PD, the hazard ratio (HR) for depression in PD patients was 4.06 (95% CI: 3.15e5.23), which increased to 4.26 (95% CI: 3.29e5.51) after adjustment for age, sex, urbanization, income, and coexisting medical conditions. In the sex stratification, the HR of depression for men with PD was 4.42 (95% CI: 2.93e6.67) compared with men without PD. The HR for the association between PD and depression in women was 4.22 (95% CI: 3.02e5.88). Conclusion: This study suggests that patients with PD are at an elevated risk of depression, particularly for men. Integrated care for early identification and treatment of depression are crucial for patients with PD. (Am J Geriatr Psychiatry 2015; 23:934e940) Key Words: Cohort study, depression, Parkinson disease
INTRODUCTION Parkinson disease (PD) is a neurodegenerative disorder characterized by motor symptoms of tremor, bradykinesia, rigidity, and postural instability.
Nonmotor symptoms such as psychiatric, cognitive, and autonomic symptoms and depression and sleep disorders are often underestimated but have major impacts on PD patients. The prevalence of depression in patients with PD varies among populations, from
Received February 24, 2014; revised October 20, 2014; accepted October 30, 2014. From the Neuroscience Laboratory, Department of Neurology (Y-TH, Y-WY, C-HT) and Management Office for Health Data (C-CL, S-NC, F-CS), China Medical University Hospital, Taichung, Taiwan; School of Medicine (Y-TH, Y-WY, C-HT), School of Chinese Medicine (C-CL), and Department of Public Health (F-CS), China Medical University, Taichung, Taiwan; Department of Anesthesiology (C-CL, T-LC), Taipei Medical University Hospital, Taipei, Taiwan; School of Medicine (C-CL, T-LC), Taipei Medical University, Taipei, Taiwan. Send correspondence and reprint requests to Fung-Chang Sung, Ph.D., China Medical University College of Public Health, 91 Hsueh Shih Road, Taichung 404, Taiwan. e-mail: [email protected] Ó 2015 American Association for Geriatric Psychiatry http://dx.doi.org/10.1016/j.jagp.2014.10.011
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Hsu et al. 2.7% to more than 90%, possibly due to different methodologies and study populations.1 A comprehensive review of the 26 major studies concerning PD and depression indicates that the mean prevalence of depression is 40% among PD patients.2 Depression is known to have major impact on the quality of life, is an economic burden for PD patients, and is a risk factor for impaired cognitive functions.3e5 The relationship between depression and PD is an area of concern. Three large register studies have concluded that depressed patients are at a higher risk of PD.6e8 On the other hand, several cross-sectional studies have reported elevated prevalence of depression in patients with PD.9,10 The previous studies were either restricted to small populations or cross-sectional designs or lacked proper adjustments for potential confounding factors for depression.9e11 Few have focused on the longitudinal relationship between PD and subsequent risk of depression. The objective of the present study is to compare the risk of depression in people with and without PD in a nationwide retrospective cohort study using Taiwan’s National Health Insurance Research Database.
METHODS Data Sources This study used data from reimbursement claims of a universal National Health Insurance program, which was launched in March 1995 by incorporating 13 insurance programs in Taiwan. This insurance program provided healthcare to 99% of the population.12 The National Health Research Institutes (NHRI) had the responsibility for managing the insurance data. We obtained from NHRI the claims data of 1 million randomly selected subjects from 23 million insured individuals registered from 1996 to 2008, with the scrambled identifications of insured individuals and contracted healthcare institutions. The claims data included the registry of medical facilities, details of inpatient orders, ambulatory care, dental services, and prescriptions. Individuals’ identifiers in this dataset have been encrypted to protect the privacy and confidentiality of enrollee. Diagnoses were coded using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).
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Ethical Approval This study was conducted in accordance with the Helsinki Declaration. To protect personal privacy, the electronic database was decoded with patient identifications scrambled for further public access for research. According to NHRI regulations, informed consent is not required because of decoded and scrambled patient identification.13,14
Study Sample The study cohort was identified from the database using the primary diagnosis of PD (ICD-9 code 332) from 2000 to 2003. To ensure the validity of the diagnosis, only new patients with at least one visit with neurologist’s diagnoses of PD after the index date were eligible. For each PD case, four sex- and age-matched and depression-free subjects without a history of PD were randomly selected for comparison as the non-PD cohort. Both cohorts were followed until December 31, 2008 or upon the diagnosis of depression (ICD-9 codes 296.2 and 296.3) or censored for loss to follow-up or death. The National Health Insurance Research Database has been verified as a valid resource for populationbased research.15 In Taiwan, general physicians usually adopt the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM)-IV criteria or the Geriatric Depression Scale for diagnosing depression in daily medical practice. In the absence of a comprehensive clinical diagnostic interview, most neurologists or psychiatrists have been trained to use the DSM-IV for establishing depressive diagnoses according to standardized criteria. Based on the National Statistics of Regional Standard Classification, all subjects were grouped into four geographic areas (North, Central, South and East, and off-shore Islands) and three urbanization levels (low, moderate, and high). There are 359 townships and city districts in Taiwan. We calculated the population density (persons/km2) by dividing the population (persons) by the area (km2) for each of these administrative units according to the statistics from the Ministry of Interior, Taiwan. The first, second, and third tertiles were considered areas of low, moderate, and high urbanization, respectively.13,14
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Depression and Parkinson Disease Statistical Analysis Baseline distribution of age, sex, occupation, urbanization, residential area, and income were compared between the two cohorts. We used c2 tests to examine the categorical variables. Baseline comorbidities (diabetes, hypertension, and hyperlipidemia) between PD and non-PD cohorts were also examined by the c2 test. Because this is a retrospective cohort study with the calculation of person-years during the follow-up period, we selected the Cox proportional hazard model to estimate the risk of depression for PD and non-PD cohorts. We used an unadjusted Cox proportional hazard model to calculate the incidence rate ratio of depression associated with PD by sex and age. The multivariate Cox proportional hazards regression analysis with backward selection was performed to evaluate the hazard ratio (HR) and 95% confidence intervals (CIs) of depression in PD patients compared with non-PD subjects after adjusted for age, sex, urbanization, low income, and coexisting medical conditions. In this study, the proportional hazards assumption was evaluated by inspecting residual and log-log plots. The cumulative depression-free rates for both cohorts were estimated using the Kaplan-Meier method and the log-rank test to examine the difference. All analyses were performed using the SAS statistical software (version 9.1 for Windows; SAS Institute, Inc., Cary, NC). A two-tailed p <0.05 was considered statistically significant.
RESULTS Table 1 shows demographic characteristics and comorbidities between PD and non-PD cohorts. Distributions in age and sex were similar between the two cohorts. The PD patients had lower income and employment rates and tended to live in southern Taiwan. The PD patients were also more likely than non-PD cohort to have comorbidities of diabetes, hypertension, and hyperlipidemia. Table 2 shows the analysis of the incidence of depression in both cohorts developed in the follow-up period. The incidence in the PD cohort was 3.98 times greater than that in the non-PD cohort (10.3 versus 2.59 per 1,000 person-years). Men of the non-PD cohort had the lowest incidence of depression (2.02 per 1,000 personyears). The sex-specific PD to non-PD incidence rate ratio of depression was greater in women than in men.
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TABLE 1. Sociodemographic Factors, Coexisting Medical Conditions, and Depression in PD (N [ 1,698) and Non-PD (N [ 6,792) Cohorts
Sex Female Male Age, years 40e49 50e59 60e69 70 Urbanization Low Moderate High Very high Low income Medical conditions Hypertension COPD IHD Diabetes Stroke Hyperlipidemia Osteoporosis Asthma CHF IBD Renal dialysis Depression No Yes
Non-PD
PD
3,340 (49.2) 3,452 (50.8)
835 (49.2) 863 (50.8)
316 692 1,988 3,796
(4.7) (10.2) (29.3) (55.9)
79 173 497 949
(4.7) (10.2) (29.3) (55.9)
1,777 1,717 1,697 1,601 249
(26.2) (25.3) (25.0) (23.6) (3.7)
407 427 427 437 95
(24.0) (25.2) (25.2) (25.7) (5.6)
3,717 2,127 1,547 1,442 852 1,297 905 788 358 133 111
(54.7) (31.3) (22.8) (21.2) (12.5) (19.1) (13.3) (11.6) (5.3) (2.0) (1.6)
914 632 526 433 424 282 262 206 112 37 31
p
df Wald c2
1.0000 1
0.0
1.0000 3
0.0
0.1567 3
5.2
0.0003 1
13.0
(53.8) 0.5062 1 (37.2) <0.0001 1 (31.0) <0.0001 1 (25.5) 0.0001 1 (25.0) <0.0001 1 (16.6) 0.0184 1 (15.4) 0.0242 1 (12.1) 0.5435 1 (6.6) 0.0327 1 (2.2) 0.5612 1 (1.8) 0.5823 1 <0.0001 1 6,673 (98.3) 1577 (92.9) 119 (1.7) 121 (7.1)
0.4 21.6 49.5 14.4 164.2 5.6 5.1 0.4 4.6 0.3 0.3 142.8
Notes: Values are number of case with percents in parentheses. CHF: congestive heart failure; COPD: chronic obstructive pulmonary disease; IBD: inflammatory bowel disease; IHD: ischemic heart disease.
The unadjusted HR of depression for the PD cohort compared with the non-PD cohort was 4.06 (95% CI: 3.15e5.23) in model 1 (Table 3). After adjustments for age, sex, occupation, urbanization, and income, model 2 showed an adjusted HR of 4.02 (95% CI: 3.12e5.19). The HR increased to 4.27 (95% CI: 3.29e5.53) after further adjusting for coexisting medical conditions in model 3. The Kaplan-Meier analysis showed the depression-free rate was 6% lower in the PD cohort than in the non-PD cohort and was significant during the follow-up period (p <0.0001; log-rank test) (Fig. 1).
DISCUSSION This nationwide retrospective cohort study shows that PD patients are at an elevated risk of depression and
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Hsu et al.
TABLE 2. Risk of Depression for Cohorts With and Without PD No PD
Overall Sex Female Male Age, years 40e49 50e59 60e69 70
PD N
Cases
Person-Years
Incidencea
IRR
2.59
1698
121
11733
10.3
3.98
22613 23271
3.18 2.02
835 863
73 48
5750 5983
12.7 8.02
4.99 3.97
2205 4730 13554 25396
1.81 1.27 3.17 2.60
79 173 497 949
11 21 42 47
524 1193 3512 6504
21.0 17.6 12.0 7.23
11.6 13.8 3.78 2.78
N
Cases
Person-Years
Incidence
6,792
119
45884
3,340 3,452
72 47
316 692 1,988 3,796
4 6 43 66
a
Notes: IRR: PD cohort to non-PD cohort “incidence rate ratio.” a Per 1,000 person-years.
TABLE 3. Risk of Depression for Cohorts With and Without PDa
PD No Yes
c2 df p
Model 1b
Model 2b
Model 3b
HR (95% CI)
HR (95% CI)
HR (95% CI)
1.00 (reference) 4.06 (3.15e5.23) 139.9 1 <0.0001
1.00 (reference) 4.10 (3.18e5.29) 141.0 1 <0.0001
1.00 (reference) 4.26 (3.29e5.51) 165.2 1 <0.0001
FIGURE 1. Depression-free proportions estimated for PD and non-PD patients using the Kaplan-Meier method (log rank, df [ 1, c2 [ 18.17, p <0.0001).
a Sex stratification revealed that HRs for the association between PD and depression in women and men were 4.22 (95% CI: 3.02e5.88, df ¼ 1, c2 ¼ 111.3, p <0.0001) and 4.42 (95% CI: 2.93e6.67, df ¼ 1, c2 ¼ 64.4, p <0.0001), respectively, after adjusted all covariates except sex. b HR and 95% CI of depression associated with PD was calculated in the conditional (with backward selection) Cox proportional hazard models. Model 1: unadjusted. Model 2: covariates included age, sex, urbanization, and low income. Model 3: covariates in model 2 plus hypertension, chronic obstructive pulmonary disease, ischemic heart disease, diabetes, stroke, hyperlipidemia, osteoporosis, asthma, congestive heart failure, inflammatory bowel disease, and renal dialysis.
the risk remains significant after adjustments for sociodemographic factors and related coexisting diseases. This association seems similar in women and men. Lower socioeconomic status has been considered as a risk factor for chronic disease associated with worse health conditions, compared with higher socioeconomic status.16 Consistent with previous studies, we found that people with lower socioeconomic status are at higher risk of PD than those with higher socioeconomic status. From a public health perspective, PD, a chronic progressive and degenerative neurologic condition, imposes significant economic burden on both patients and public services.
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Metabolic syndrome is characterized by insulin resistance or overt diabetes, central obesity (large waist circumference), high blood pressure, and dyslipidemia.17 Cross-sectional studies consistently report positive associations between depression and metabolic syndrome.18,19 Diabetes mellitus, hypertension, and hyperlipidemia are significant factors associated with PD, which may confound the estimated risk for depression (Table 1). However, the whole magnitude of the observed association between PD and risk of depression is also sustained in a multivariate model. Another interesting issue is the causal relationship between metabolic syndrome and PD.
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Depression and Parkinson Disease A large prospective study among participants in two large cohorts (the Nurses’ Health Study and the Health Professionals Follow-up Study) also suggests that high total cholesterol is associated with an increased risk of PD.20 In contrast, another prospective cohort study suggests that PD risk is not significantly related to the history of hypertension, hypercholesterolemia, or diabetes but may modestly decline with increasing blood cholesterol levels.21 Some controversy still exists, however, and needs further investigation. Previous researchers have found the risk of depression in patients with PD is inconsistently related to gender.8,11 Studies failed to find gender differences in depression for PD patients because of the limitation of small sample sizes.22,23 The multicenter Priamo study, assessing nonmotor symptoms and their impact on the quality of life for PD patients, found a higher prevalence of depression in women.4 A population-based U.K. study concluded that increased relative risk of depression in PD patients is most pronounced in women and in individuals aged 40e69 years.11 However, our study showed a similar risk of depression in women and men with PD. Female preponderance in depression rates are related to genetic, hormonal, psychological, and sociocultural factors.23,24 However, our interpretation of the relationship between gender and depression in patients with PD may be limited. Because some patients may have treated depression, they may not have a sufficiently high score on a depression scale. Thus, these treated depressed patients may be included in the nondepressed group despite having, perhaps, a recurrent depressive disorder. Studies have investigated extensively the age at PD onset and the disease duration in association with depression for PD patients.25 In the present study, the absolute risk and relative risk of depression for PD patients decreased with age and became more pronounced in those aged 40e49 years. Also, the KaplanMeier survival curve explicitly showed the risk of depression increases with prolonged PD duration. PD may develop over several years before its clinical diagnosis, and diagnosis dates used in the current analysis are the first dates reported by the physician. However, depression almost inevitably emerged with disease progression and might dominate the clinical picture of advanced PD, which contributed to severe disability and impaired quality of life. We should pay
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more attention to the recognition and quantity of the important nonmotor symptoms and depression and provide available therapy. The current study supports the close association between PD and subsequent depression, with the risk of depression in PD patients at least threefold greater than that in non-PD individuals. The reason why there is a higher depression risk in PD is poorly understood, and the relationship is complex, but some hypotheses about depression and PD have been put forward. Depression is either a reactive process to the chronic, disabling symptoms of PD or is associated with brain pathologic changes of PD. These two hypotheses are not mutually exclusive. PD patients and their families clearly must make adjustments to manage this chronic disease because of the physical disability.26 Medication such as levodopa have both mood-improving and mood-lowering effects.26 In patients with more advanced disease, depression may be associated with “off-drug” fluctuations.27 However, it does not fully explain the high prevalence of depression. Sharing similar biologic mechanisms in PD and depression have thus been discussed. Two hypotheses about the pathophysiology between PD and depression have also been suggested. Two hypotheses proposed are the serotonergic hypotheses and the dopaminergic hypotheses, which considers degeneration of the mesolimbic and mesocortical structures of the dopaminergic system as the cause of depression.28e31 Some studies revealed that depression occurs before the diagnosis of PD and proposed that depression and PD share a common biologic factor.6e8 The cause of high risk in PD patients who are later diagnosed with depression may be of multifactorial etiology. We believe the development of depression is related to the neuroendocrine effects of the stress associated with living with PD.32 Those with PD may develop depressive symptoms because of loss of job, limited physical function, inability to participate in family activities, and poor quality of life.33 This is different from patients who have depressive disorders before the onset of PD. Another explanation for the association between PD and depression is that patients with PD receive more medical attention than non-PD people in the clinical setting. Because early detection of depressive symptoms by clinical workers in patients with PD may occur, diagnostic bias may partly explain the observed increased risk.11
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Hsu et al. The present study has some limitations. First, because this study used medical claims to identify diseases, the underestimation of comorbidities such as hypertension, diabetes, hyperlipidemia, depression, and PD should be considered, because some people with mild condition may not visit medical services. Second, diagnostic bias may also exist because more medical attention may be given to depressive symptoms in subjects with PD than those without. Third, the ICD-9 296.2 and 296.3 codes do not classify depression severity, and there is no accurate differentiation of depression severity in PD patients by the current ICD-9 code. However, the large population sample of longitudinal design is the strength of the present study, which aims to evaluate the relationship between depression and PD. Correcting for general risk factors like age, sex, socioeconomic status, occupation, and metabolic syndrome for depression highlights the importance of PD as a risk factor. In addition, although we required PD patients to have at least three medical visits with primary diagnosis, it remains possible that PD was diagnosed in some patients with drug-induced parkinsonism caused by neuroleptics, which are known to contribute to the metabolic syndrome. Finally, this study is limited to retrospective reimbursement claims without individual detailed biochemical data. In conclusion, there is a positive association between PD and subsequent risk for developing depression, stressing the importance of being aware of depression in PD patients, especially among younger people and men. From a public health perspective, it is important
to understand the strong association of this complication to enable clinicians and caregivers to adequately develop strategies for addressing the needs of PD patients. This study is based (in part) on data from the National Health Insurance Research Database provided by the NHRI. The interpretation and conclusions contained herein do not represent those of the NHRI. The study was supported by grants from the Executive Yuan National Science Council (NSC 99-2314-B039-016-MY2), China Medical University Hospital (DMR-99-176), and the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW103-TDU-Be212-113002). Supporters had no role in study design, data collection and analysis, decision to publish, or preparation of the article. Drs. Hsu and Liao and Drs. Chen and Sung contributed equally to this article. Author contributions are as follows: manuscript preparation: YTH and CCL; data analysis: CCL and SNC; interpretation of data: YTH, CCL, SNC, YWY, CHT, TLC, and FCS; revising the manuscript: YWY, CHT, TLC, and FCS; final approval of submission: YTH, CCL, SNC, YWY, CHT, TLC, and FCS. Ethical approval: Insurance reimbursement claims from the National Health Insurance Research Database are available for public access. To protect personal privacy, the electronic database with patient identifications was decoded and scrambled for further research access. Although informed consent was not required because of this privacy protection, the study was evaluated and approved by the NHRI.
References 1. Reijnders JS, Ehrt U, Weber WE, et al: A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord 2008; 23:183e189 2. Cummings JL: Depression and Parkinson’s disease: a review. Am J Psychiatry 1992; 149:443e454 3. Findley L, Aujla M, Bain PG, et al: Direct economic impact of Parkinson’s disease: a research survey in the United Kingdom. Mov Disord 2003; 18:1139e1145 4. Barone P, Antonini A, Colosimo C, et al: The PRIAMO study: A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease. Mov Disord 2009; 24: 1641e1649 5. Marder K, Tang MX, Cote L, et al: The frequency and associated risk factors for dementia in patients with Parkinson’s disease. Arch Neurol 1995; 52:695e701 6. Nilsson FM, Kessing LV, Bolwig TG: Increased risk of developing Parkinson’s disease for patients with major affective disorder: a register study. Acta Psychiatr Scand 2001; 104:380e386
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7. Schuurman AG, van den Akker M, Ensinck KT, et al: Increased risk of Parkinson’s disease after depression: a retrospective cohort study. Neurology 2002; 58:1501e1504 8. Leentjens AF, Van den Akker M, Metsemakers JF, et al: Higher incidence of depression preceding the onset of Parkinson’s disease: a register study. Mov Disord 2003; 18:414e418 9. Aarsland D, Bronnick K, Alves G, et al: The spectrum of neuropsychiatric symptoms in patients with early untreated Parkinson’s disease. J Neurol Neurosurg Psychiatry 2009; 80: 928e930 10. Kulisevsky J, Pagonabarraga J, Pascual-Sedano B, et al: Prevalence and correlates of neuropsychiatric symptoms in Parkinson’s disease without dementia. Mov Disord 2008; 23:1889e1896 11. Becker C, Brobert GP, Johansson S, et al: Risk of incident depression in patients with Parkinson disease in the UK. Eur J Neurol 2011; 18:448e453 12. Cheng TM: Taiwan’s new national health insurance program: genesis and experience so far. Health Aff 2003; 22:61e76
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Depression and Parkinson Disease 13. Liao CC, Shen WW, Chang CC, et al: Surgical adverse outcomes in patients with schizophrenia: a population-based study. Ann Surg 2013; 257:433e438 14. Liao CC, Chiu WT, Yeh CC, et al: Risk and outcomes for traumatic brain injury in patients with mental disorders. J Neurol Neurosurg Psychiatry 2012; 83:1186e1192 15. Cheng CL, Kao YH, Lin SJ, et al: Validation of the National Health Insurance Research Database with ischemic stroke cases in Taiwan. Pharmacoepidemiol Drug Saf 2011; 20:236e242 16. Mackenbach JP, Stirbu I, Roskam AJ, et al: Socioeconomic inequalities in health in 22 European countries. N Engl J Med 2008; 358:2468e2481 17. Fein O: The influence of social class on health status: American and British research on health inequalities. J Gen Intern Med 1995; 10:577e586 18. Koponen H, Jokelainen J, Keinanen-Kiukaanniemi S, et al: Metabolic syndrome predisposes to depressive symptoms: a populationbased 7-year follow-up study. J Clin Psychiatry 2008; 69:178e182 19. Skilton MR, Moulin P, Terra JL, et al: Associations between anxiety, depression, and the metabolic syndrome. Biol Psychiatry 2007; 62:1251e1257 20. Hu G, Antikainen R, Jousilahti P, et al: Total cholesterol and the risk of Parkinson disease. Neurology 2008; 70:1972e1979 21. Simon KC, Chen H, Schwarzschild M, et al: Hypertension, hypercholesterolemia, diabetes, and risk of Parkinson disease. Neurology 2007; 69:1688e1695 22. Tandberg E, Larsen JP, Aarsland D, et al: The occurrence of depression in Parkinson’s disease. A community-based study. Arch Neurol 1996; 53:175e179 23. Schrag A, Jahanshahi M, Quinn NP: What contributes to depression in Parkinson’s disease? Psychol Med 2001; 31:65e73
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24. Boorsma M, Joling K, Dussel M, et al: The incidence of depression and its risk factors in Dutch nursing homes and residential care homes. Am J Geriatr Psychiatry 2012; 20: 932e942 25. Aarsland D, Påhlhagen S, Ballard CG, et al: Depression in Parkinson disease: epidemiology, mechanisms and management. Nat Rev Neurol 2011; 8:35e47 26. McDonald WM, Richard IH, DeLong MR: Prevalence, etiology, and treatment of depression in Parkinson’s disease. Biol Psychiatry 2003; 54:363e375 27. Richard IH, Frank S, McDermott MP, et al: The ups and downs of Parkinson disease: a prospective study of mood and anxiety fluctuations. Cogn Behav Neurol 2004; 17:201e207 28. Mayeux R: The “serotonin hypothesis” for depression in Parkinson’s disease. Adv Neurol 1990; 53:163e166 29. Fibiger HC: The neurobiological substrates of depression in Parkinson’s disease: a hypothesis. Can J Neurol Sci 1984; 11: 105e107 30. Frisina PG, Haroutunian V, Libow LS: The neuropathological basis for depression in Parkinson’s disease. Parkinsonism Relat Disord 2009; 15:144e148 31. Remy P, Doder M, Lees A, et al: Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 2005; 128:1314e1322 32. Willis GL: Parkinson’s disease as a neuroendocrine disorder of circadian function: dopamine-melatonin imbalance and the visual system in the genesis and progression of the degenerative process. Rev Neurosci 2008; 19:245e316 33. Rod NH, Bordelon Y, Thompson A, et al: Major life events and development of major depression in Parkinson’s disease patients. Eur J Neurol 2013; 20:663e670
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Objective: The association between Parkinson disease (PD) and depression remains unclear, particularly in the Asian population. The purpose of this study is to investigate the risk of depression in patients with PD using population-based data. Methods: Based on the National Health Insurance Research Database of Taiwan, we identified 1,698 patients with PD aged 40 years or older diagnosed in 2000e2003. With frequency matching procedure, we randomly selected 6,792 subjects without PD stratified by sex and age. Both cohorts were followed until the end of 2008 or diagnosis of depression. Risk of depression associated with PD was estimated in the multivariate Cox hazards regressions. Diabetes, hypertension, and hyperlipidemia were more prevalent at baseline in patients with PD. Results: Compared with the cohort without PD, the hazard ratio (HR) for depression in PD patients was 4.06 (95% CI: 3.15e5.23), which increased to 4.26 (95% CI: 3.29e5.51) after adjustment for age, sex, urbanization, income, and coexisting medical conditions. In the sex stratification, the HR of depression for men with PD was 4.42 (95% CI: 2.93e6.67) compared with men without PD. The HR for the association between PD and depression in women was 4.22 (95% CI: 3.02e5.88). Conclusion: This study suggests that patients with PD are at an elevated risk of depression, particularly for men. Integrated care for early identification and treatment of depression are crucial for patients with PD. (Am J Geriatr Psychiatry 2015; 23:934e940) Key Words: Cohort study, depression, Parkinson disease
INTRODUCTION Parkinson disease (PD) is a neurodegenerative disorder characterized by motor symptoms of tremor, bradykinesia, rigidity, and postural instability.
Nonmotor symptoms such as psychiatric, cognitive, and autonomic symptoms and depression and sleep disorders are often underestimated but have major impacts on PD patients. The prevalence of depression in patients with PD varies among populations, from
Received February 24, 2014; revised October 20, 2014; accepted October 30, 2014. From the Neuroscience Laboratory, Department of Neurology (Y-TH, Y-WY, C-HT) and Management Office for Health Data (C-CL, S-NC, F-CS), China Medical University Hospital, Taichung, Taiwan; School of Medicine (Y-TH, Y-WY, C-HT), School of Chinese Medicine (C-CL), and Department of Public Health (F-CS), China Medical University, Taichung, Taiwan; Department of Anesthesiology (C-CL, T-LC), Taipei Medical University Hospital, Taipei, Taiwan; School of Medicine (C-CL, T-LC), Taipei Medical University, Taipei, Taiwan. Send correspondence and reprint requests to Fung-Chang Sung, Ph.D., China Medical University College of Public Health, 91 Hsueh Shih Road, Taichung 404, Taiwan. e-mail: [email protected] Ó 2015 American Association for Geriatric Psychiatry http://dx.doi.org/10.1016/j.jagp.2014.10.011
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Hsu et al. 2.7% to more than 90%, possibly due to different methodologies and study populations.1 A comprehensive review of the 26 major studies concerning PD and depression indicates that the mean prevalence of depression is 40% among PD patients.2 Depression is known to have major impact on the quality of life, is an economic burden for PD patients, and is a risk factor for impaired cognitive functions.3e5 The relationship between depression and PD is an area of concern. Three large register studies have concluded that depressed patients are at a higher risk of PD.6e8 On the other hand, several cross-sectional studies have reported elevated prevalence of depression in patients with PD.9,10 The previous studies were either restricted to small populations or cross-sectional designs or lacked proper adjustments for potential confounding factors for depression.9e11 Few have focused on the longitudinal relationship between PD and subsequent risk of depression. The objective of the present study is to compare the risk of depression in people with and without PD in a nationwide retrospective cohort study using Taiwan’s National Health Insurance Research Database.
METHODS Data Sources This study used data from reimbursement claims of a universal National Health Insurance program, which was launched in March 1995 by incorporating 13 insurance programs in Taiwan. This insurance program provided healthcare to 99% of the population.12 The National Health Research Institutes (NHRI) had the responsibility for managing the insurance data. We obtained from NHRI the claims data of 1 million randomly selected subjects from 23 million insured individuals registered from 1996 to 2008, with the scrambled identifications of insured individuals and contracted healthcare institutions. The claims data included the registry of medical facilities, details of inpatient orders, ambulatory care, dental services, and prescriptions. Individuals’ identifiers in this dataset have been encrypted to protect the privacy and confidentiality of enrollee. Diagnoses were coded using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).
Am J Geriatr Psychiatry 23:9, September 2015
Ethical Approval This study was conducted in accordance with the Helsinki Declaration. To protect personal privacy, the electronic database was decoded with patient identifications scrambled for further public access for research. According to NHRI regulations, informed consent is not required because of decoded and scrambled patient identification.13,14
Study Sample The study cohort was identified from the database using the primary diagnosis of PD (ICD-9 code 332) from 2000 to 2003. To ensure the validity of the diagnosis, only new patients with at least one visit with neurologist’s diagnoses of PD after the index date were eligible. For each PD case, four sex- and age-matched and depression-free subjects without a history of PD were randomly selected for comparison as the non-PD cohort. Both cohorts were followed until December 31, 2008 or upon the diagnosis of depression (ICD-9 codes 296.2 and 296.3) or censored for loss to follow-up or death. The National Health Insurance Research Database has been verified as a valid resource for populationbased research.15 In Taiwan, general physicians usually adopt the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM)-IV criteria or the Geriatric Depression Scale for diagnosing depression in daily medical practice. In the absence of a comprehensive clinical diagnostic interview, most neurologists or psychiatrists have been trained to use the DSM-IV for establishing depressive diagnoses according to standardized criteria. Based on the National Statistics of Regional Standard Classification, all subjects were grouped into four geographic areas (North, Central, South and East, and off-shore Islands) and three urbanization levels (low, moderate, and high). There are 359 townships and city districts in Taiwan. We calculated the population density (persons/km2) by dividing the population (persons) by the area (km2) for each of these administrative units according to the statistics from the Ministry of Interior, Taiwan. The first, second, and third tertiles were considered areas of low, moderate, and high urbanization, respectively.13,14
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Depression and Parkinson Disease Statistical Analysis Baseline distribution of age, sex, occupation, urbanization, residential area, and income were compared between the two cohorts. We used c2 tests to examine the categorical variables. Baseline comorbidities (diabetes, hypertension, and hyperlipidemia) between PD and non-PD cohorts were also examined by the c2 test. Because this is a retrospective cohort study with the calculation of person-years during the follow-up period, we selected the Cox proportional hazard model to estimate the risk of depression for PD and non-PD cohorts. We used an unadjusted Cox proportional hazard model to calculate the incidence rate ratio of depression associated with PD by sex and age. The multivariate Cox proportional hazards regression analysis with backward selection was performed to evaluate the hazard ratio (HR) and 95% confidence intervals (CIs) of depression in PD patients compared with non-PD subjects after adjusted for age, sex, urbanization, low income, and coexisting medical conditions. In this study, the proportional hazards assumption was evaluated by inspecting residual and log-log plots. The cumulative depression-free rates for both cohorts were estimated using the Kaplan-Meier method and the log-rank test to examine the difference. All analyses were performed using the SAS statistical software (version 9.1 for Windows; SAS Institute, Inc., Cary, NC). A two-tailed p <0.05 was considered statistically significant.
RESULTS Table 1 shows demographic characteristics and comorbidities between PD and non-PD cohorts. Distributions in age and sex were similar between the two cohorts. The PD patients had lower income and employment rates and tended to live in southern Taiwan. The PD patients were also more likely than non-PD cohort to have comorbidities of diabetes, hypertension, and hyperlipidemia. Table 2 shows the analysis of the incidence of depression in both cohorts developed in the follow-up period. The incidence in the PD cohort was 3.98 times greater than that in the non-PD cohort (10.3 versus 2.59 per 1,000 person-years). Men of the non-PD cohort had the lowest incidence of depression (2.02 per 1,000 personyears). The sex-specific PD to non-PD incidence rate ratio of depression was greater in women than in men.
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TABLE 1. Sociodemographic Factors, Coexisting Medical Conditions, and Depression in PD (N [ 1,698) and Non-PD (N [ 6,792) Cohorts
Sex Female Male Age, years 40e49 50e59 60e69 70 Urbanization Low Moderate High Very high Low income Medical conditions Hypertension COPD IHD Diabetes Stroke Hyperlipidemia Osteoporosis Asthma CHF IBD Renal dialysis Depression No Yes
Non-PD
PD
3,340 (49.2) 3,452 (50.8)
835 (49.2) 863 (50.8)
316 692 1,988 3,796
(4.7) (10.2) (29.3) (55.9)
79 173 497 949
(4.7) (10.2) (29.3) (55.9)
1,777 1,717 1,697 1,601 249
(26.2) (25.3) (25.0) (23.6) (3.7)
407 427 427 437 95
(24.0) (25.2) (25.2) (25.7) (5.6)
3,717 2,127 1,547 1,442 852 1,297 905 788 358 133 111
(54.7) (31.3) (22.8) (21.2) (12.5) (19.1) (13.3) (11.6) (5.3) (2.0) (1.6)
914 632 526 433 424 282 262 206 112 37 31
p
df Wald c2
1.0000 1
0.0
1.0000 3
0.0
0.1567 3
5.2
0.0003 1
13.0
(53.8) 0.5062 1 (37.2) <0.0001 1 (31.0) <0.0001 1 (25.5) 0.0001 1 (25.0) <0.0001 1 (16.6) 0.0184 1 (15.4) 0.0242 1 (12.1) 0.5435 1 (6.6) 0.0327 1 (2.2) 0.5612 1 (1.8) 0.5823 1 <0.0001 1 6,673 (98.3) 1577 (92.9) 119 (1.7) 121 (7.1)
0.4 21.6 49.5 14.4 164.2 5.6 5.1 0.4 4.6 0.3 0.3 142.8
Notes: Values are number of case with percents in parentheses. CHF: congestive heart failure; COPD: chronic obstructive pulmonary disease; IBD: inflammatory bowel disease; IHD: ischemic heart disease.
The unadjusted HR of depression for the PD cohort compared with the non-PD cohort was 4.06 (95% CI: 3.15e5.23) in model 1 (Table 3). After adjustments for age, sex, occupation, urbanization, and income, model 2 showed an adjusted HR of 4.02 (95% CI: 3.12e5.19). The HR increased to 4.27 (95% CI: 3.29e5.53) after further adjusting for coexisting medical conditions in model 3. The Kaplan-Meier analysis showed the depression-free rate was 6% lower in the PD cohort than in the non-PD cohort and was significant during the follow-up period (p <0.0001; log-rank test) (Fig. 1).
DISCUSSION This nationwide retrospective cohort study shows that PD patients are at an elevated risk of depression and
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Hsu et al.
TABLE 2. Risk of Depression for Cohorts With and Without PD No PD
Overall Sex Female Male Age, years 40e49 50e59 60e69 70
PD N
Cases
Person-Years
Incidencea
IRR
2.59
1698
121
11733
10.3
3.98
22613 23271
3.18 2.02
835 863
73 48
5750 5983
12.7 8.02
4.99 3.97
2205 4730 13554 25396
1.81 1.27 3.17 2.60
79 173 497 949
11 21 42 47
524 1193 3512 6504
21.0 17.6 12.0 7.23
11.6 13.8 3.78 2.78
N
Cases
Person-Years
Incidence
6,792
119
45884
3,340 3,452
72 47
316 692 1,988 3,796
4 6 43 66
a
Notes: IRR: PD cohort to non-PD cohort “incidence rate ratio.” a Per 1,000 person-years.
TABLE 3. Risk of Depression for Cohorts With and Without PDa
PD No Yes
c2 df p
Model 1b
Model 2b
Model 3b
HR (95% CI)
HR (95% CI)
HR (95% CI)
1.00 (reference) 4.06 (3.15e5.23) 139.9 1 <0.0001
1.00 (reference) 4.10 (3.18e5.29) 141.0 1 <0.0001
1.00 (reference) 4.26 (3.29e5.51) 165.2 1 <0.0001
FIGURE 1. Depression-free proportions estimated for PD and non-PD patients using the Kaplan-Meier method (log rank, df [ 1, c2 [ 18.17, p <0.0001).
a Sex stratification revealed that HRs for the association between PD and depression in women and men were 4.22 (95% CI: 3.02e5.88, df ¼ 1, c2 ¼ 111.3, p <0.0001) and 4.42 (95% CI: 2.93e6.67, df ¼ 1, c2 ¼ 64.4, p <0.0001), respectively, after adjusted all covariates except sex. b HR and 95% CI of depression associated with PD was calculated in the conditional (with backward selection) Cox proportional hazard models. Model 1: unadjusted. Model 2: covariates included age, sex, urbanization, and low income. Model 3: covariates in model 2 plus hypertension, chronic obstructive pulmonary disease, ischemic heart disease, diabetes, stroke, hyperlipidemia, osteoporosis, asthma, congestive heart failure, inflammatory bowel disease, and renal dialysis.
the risk remains significant after adjustments for sociodemographic factors and related coexisting diseases. This association seems similar in women and men. Lower socioeconomic status has been considered as a risk factor for chronic disease associated with worse health conditions, compared with higher socioeconomic status.16 Consistent with previous studies, we found that people with lower socioeconomic status are at higher risk of PD than those with higher socioeconomic status. From a public health perspective, PD, a chronic progressive and degenerative neurologic condition, imposes significant economic burden on both patients and public services.
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Metabolic syndrome is characterized by insulin resistance or overt diabetes, central obesity (large waist circumference), high blood pressure, and dyslipidemia.17 Cross-sectional studies consistently report positive associations between depression and metabolic syndrome.18,19 Diabetes mellitus, hypertension, and hyperlipidemia are significant factors associated with PD, which may confound the estimated risk for depression (Table 1). However, the whole magnitude of the observed association between PD and risk of depression is also sustained in a multivariate model. Another interesting issue is the causal relationship between metabolic syndrome and PD.
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Depression and Parkinson Disease A large prospective study among participants in two large cohorts (the Nurses’ Health Study and the Health Professionals Follow-up Study) also suggests that high total cholesterol is associated with an increased risk of PD.20 In contrast, another prospective cohort study suggests that PD risk is not significantly related to the history of hypertension, hypercholesterolemia, or diabetes but may modestly decline with increasing blood cholesterol levels.21 Some controversy still exists, however, and needs further investigation. Previous researchers have found the risk of depression in patients with PD is inconsistently related to gender.8,11 Studies failed to find gender differences in depression for PD patients because of the limitation of small sample sizes.22,23 The multicenter Priamo study, assessing nonmotor symptoms and their impact on the quality of life for PD patients, found a higher prevalence of depression in women.4 A population-based U.K. study concluded that increased relative risk of depression in PD patients is most pronounced in women and in individuals aged 40e69 years.11 However, our study showed a similar risk of depression in women and men with PD. Female preponderance in depression rates are related to genetic, hormonal, psychological, and sociocultural factors.23,24 However, our interpretation of the relationship between gender and depression in patients with PD may be limited. Because some patients may have treated depression, they may not have a sufficiently high score on a depression scale. Thus, these treated depressed patients may be included in the nondepressed group despite having, perhaps, a recurrent depressive disorder. Studies have investigated extensively the age at PD onset and the disease duration in association with depression for PD patients.25 In the present study, the absolute risk and relative risk of depression for PD patients decreased with age and became more pronounced in those aged 40e49 years. Also, the KaplanMeier survival curve explicitly showed the risk of depression increases with prolonged PD duration. PD may develop over several years before its clinical diagnosis, and diagnosis dates used in the current analysis are the first dates reported by the physician. However, depression almost inevitably emerged with disease progression and might dominate the clinical picture of advanced PD, which contributed to severe disability and impaired quality of life. We should pay
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more attention to the recognition and quantity of the important nonmotor symptoms and depression and provide available therapy. The current study supports the close association between PD and subsequent depression, with the risk of depression in PD patients at least threefold greater than that in non-PD individuals. The reason why there is a higher depression risk in PD is poorly understood, and the relationship is complex, but some hypotheses about depression and PD have been put forward. Depression is either a reactive process to the chronic, disabling symptoms of PD or is associated with brain pathologic changes of PD. These two hypotheses are not mutually exclusive. PD patients and their families clearly must make adjustments to manage this chronic disease because of the physical disability.26 Medication such as levodopa have both mood-improving and mood-lowering effects.26 In patients with more advanced disease, depression may be associated with “off-drug” fluctuations.27 However, it does not fully explain the high prevalence of depression. Sharing similar biologic mechanisms in PD and depression have thus been discussed. Two hypotheses about the pathophysiology between PD and depression have also been suggested. Two hypotheses proposed are the serotonergic hypotheses and the dopaminergic hypotheses, which considers degeneration of the mesolimbic and mesocortical structures of the dopaminergic system as the cause of depression.28e31 Some studies revealed that depression occurs before the diagnosis of PD and proposed that depression and PD share a common biologic factor.6e8 The cause of high risk in PD patients who are later diagnosed with depression may be of multifactorial etiology. We believe the development of depression is related to the neuroendocrine effects of the stress associated with living with PD.32 Those with PD may develop depressive symptoms because of loss of job, limited physical function, inability to participate in family activities, and poor quality of life.33 This is different from patients who have depressive disorders before the onset of PD. Another explanation for the association between PD and depression is that patients with PD receive more medical attention than non-PD people in the clinical setting. Because early detection of depressive symptoms by clinical workers in patients with PD may occur, diagnostic bias may partly explain the observed increased risk.11
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Hsu et al. The present study has some limitations. First, because this study used medical claims to identify diseases, the underestimation of comorbidities such as hypertension, diabetes, hyperlipidemia, depression, and PD should be considered, because some people with mild condition may not visit medical services. Second, diagnostic bias may also exist because more medical attention may be given to depressive symptoms in subjects with PD than those without. Third, the ICD-9 296.2 and 296.3 codes do not classify depression severity, and there is no accurate differentiation of depression severity in PD patients by the current ICD-9 code. However, the large population sample of longitudinal design is the strength of the present study, which aims to evaluate the relationship between depression and PD. Correcting for general risk factors like age, sex, socioeconomic status, occupation, and metabolic syndrome for depression highlights the importance of PD as a risk factor. In addition, although we required PD patients to have at least three medical visits with primary diagnosis, it remains possible that PD was diagnosed in some patients with drug-induced parkinsonism caused by neuroleptics, which are known to contribute to the metabolic syndrome. Finally, this study is limited to retrospective reimbursement claims without individual detailed biochemical data. In conclusion, there is a positive association between PD and subsequent risk for developing depression, stressing the importance of being aware of depression in PD patients, especially among younger people and men. From a public health perspective, it is important
to understand the strong association of this complication to enable clinicians and caregivers to adequately develop strategies for addressing the needs of PD patients. This study is based (in part) on data from the National Health Insurance Research Database provided by the NHRI. The interpretation and conclusions contained herein do not represent those of the NHRI. The study was supported by grants from the Executive Yuan National Science Council (NSC 99-2314-B039-016-MY2), China Medical University Hospital (DMR-99-176), and the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW103-TDU-Be212-113002). Supporters had no role in study design, data collection and analysis, decision to publish, or preparation of the article. Drs. Hsu and Liao and Drs. Chen and Sung contributed equally to this article. Author contributions are as follows: manuscript preparation: YTH and CCL; data analysis: CCL and SNC; interpretation of data: YTH, CCL, SNC, YWY, CHT, TLC, and FCS; revising the manuscript: YWY, CHT, TLC, and FCS; final approval of submission: YTH, CCL, SNC, YWY, CHT, TLC, and FCS. Ethical approval: Insurance reimbursement claims from the National Health Insurance Research Database are available for public access. To protect personal privacy, the electronic database with patient identifications was decoded and scrambled for further research access. Although informed consent was not required because of this privacy protection, the study was evaluated and approved by the NHRI.
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