Annals of Epidemiology 24 (2014) 206e213

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Original article

Psychiatric diseases predated the occurrence of Parkinson disease: a retrospective cohort study Hsiu-Li Lin MD a, Herng-Ching Lin PhD b, Yi-Hua Chen PhD c, * a

Department of Neurology, General Cathay Hospital, Sijhih Branch, New Taipei City, Taiwan School of Health Care Administration, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan c School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 3 October 2013 Accepted 24 December 2013 Available online 1 January 2014

Purpose: The influence of mental illness early in life on the subsequent risk of Parkinson disease (PD) and its clinical picture remain obscure. This study investigated the effects of psychiatric diseases on a subsequent PD diagnosis. Methods: We used the Longitudinal Health Insurance Database 2000 of Taiwan to identify 73,597 patients who visited ambulatory care centers or were hospitalized with a first-time diagnosis of anxiety, affective disorders, or schizophrenia between 2001 and 2003 as the study cohort. We also randomly selected 220,791 enrollees matched with the study cohort for comparison. Each patient was individually tracked for 6 years to identify a subsequent PD diagnosis. Stratified Cox proportional hazard regressions were performed for the analysis. Results: The incidence rate of PD per 1000 person-years was 4.91 (95% confidence interval [CI], 4.71 e5.12) and 1.63 (95% CI, 1.56e1.70) for the psychiatric and comparison groups, respectively. Patients with psychiatric illnesses were more vulnerable to developing PD than nonpsychiatric individuals, exhibiting a 2.38-fold increased risk (95% CI, 2.23e2.53) after other covariates were considered. Furthermore, patients with schizophrenia exhibited the highest risk for developing PD. Conclusions: We suggest effective monitoring of patients with psychiatric disturbances for potential longterm neurodegenerative diseases. Ó 2014 Elsevier Inc. All rights reserved.

Keywords: Depression Anxiety Bipolar disorder Schizophrenia Parkinson disease

Introduction Parkinson disease (PD) is a progressive movement disorder that involves the degeneration of neurons in the substantia nigra and results in a decrease in dopamine activity. As the second most common neurologic disorder, PD affects approximately 79e187 per 105 persons in most populations [1e3]. Although PD commonly occurs late in life, a young onset is also possible. PD is characterized by tremors, rigidity, bradykinesia, disturbance of the gait and posture, and both cognitive and emotional alterations [2,3]. The etiology of PD remains largely unknown. The predominant evidence points to a multifactorial etiology, with a genetic susceptibility to the negative effects of environmental agents, trauma, or psychosocial impacts most likely to be involved [4]. Among an array of potential risk factors, certain factors observed in patients’ Disclosures: The authors have no conflicts of interest to declare. * Corresponding author. School of Public Health, College of Public Health and Nutrition, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan. Tel.: 8862-27361661 ext. 6528; fax: 886-2-27384831. E-mail address: [email protected] (Y.-H. Chen). 1047-2797/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.annepidem.2013.12.010

medical histories have been determined to increase the risk for PD, including a head injury [4e6], a prior diagnosis of psychoneurosis or psychosomatic diseases [7], depression, and a family history of neurologic illnesses [8]. Several studies have identified certain psychiatric illnesses, particularly anxiety and depression, as risk factors for PD. Anxiety has been suggested to be one of the earliest manifestations of PD in several case-control and cohort studies [9e11]. Studies have also reported that depression may precede PD symptoms [12e15]. Shiba et al. [11], in a case-control study, indicated that anxiety and depressive disorders are associated with a subsequent incidence of PD, with their underlying causative effects possibly being displayed many years before the onset of motor manifestations. Two other case-control studies have presented similar findings of a previous history of depression being a significant risk factor for the incidence of PD [15,16]. Despite their rarity, other mental disorders were also examined for possible links with PD because of their effects on the brain. Null associations of PD with both bipolar disorders and schizophrenia were determined in a case-control study in the United States [11].

H.-L. Lin et al. / Annals of Epidemiology 24 (2014) 206e213

It is possible that the underlying neurologic changes attributed to premorbid mental disorders may increase the susceptibility of the brain to PD [17]. However, the relevance of psychiatric illnesses, including schizophrenia, anxiety, and affective disorders, in the pathogenesis of PD remains unclear, and additional studies are needed to clarify this relationship [8,11]. Previous studies examining the risk factors of PD encountered challenges and limitations. Many previous investigations used a case-control study design, which may have led to considerable recall bias because of the difficulties in reconstructing psychiatric histories based on memory. Because PD is rare, a large-scale epidemiologic examination is required to generate a sufficient number of cases for valid statistical comparisons. The influence of mental illnesses early in life on the risk of subsequent PD and its clinical picture remain obscure. Thus, we investigated the effects of psychiatric diseases on a subsequent PD diagnosis in an Asian population (Taiwan). A 6-year follow-up period was used in this study because prodromal symptoms such as depression and anxiety may develop 4e6 years before PD motor symptoms appear [18]. This lag time may correspond to the proposed interval of 4.7 years from the beginning of neuronal loss to the onset of PD motor symptoms [19]. It was also suggested that the beginning of the disease process may predate the onset of motor symptoms by 6e7 years [20]. Finally, the effect of each major psychiatric disease (i.e., anxiety disorders, affective disorder [depressive and bipolar], and schizophrenia) associated with PD was separately examined. Materials and methods Database In this study, we used the Longitudinal Health Insurance Database 2000 (LHID2000), which was created by the Taiwan National Health Research Institutes for research purposes and is available to scientists in Taiwan. The database comprises monthly claims summaries consisting of inpatient and ambulatory care, a registry of contracted medical facilities, and a registry of board-certified specialists. The LHID2000 consists of all medical claims data and a registry of 106 beneficiaries, randomly sampled from 25.68 million enrollees (approximately 98.5% of the Taiwanese population) covered by the National Health Insurance program (NHIP). According to the Taiwan National Health Research Institutes, no statistically significant differences in age, sex, or health care costs exist between the 106 beneficiaries in the LHID2000 and all enrollees. The LHID2000, a nationwide populationebased data set, provides an exclusive opportunity to explore the risk of PD among patients with psychiatric diseases. Because the data set used in this study consisted of deidentified secondary data released to the public for research purposes, this study was exempt from full review by the Institutional Review Board. Study sample This study was designed as a retrospective cohort study. First, we identified 76,782 patients (exhibiting at least two consensusspecified psychiatric conditions) who visited ambulatory care centers or were hospitalized with a first-time diagnosis of anxiety disorders (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 300.0, 300.2, 300.3, 309.8, and 308.3), depressive disorders (ICD-9-CM codes 296.2, 296.3, 300.4, and 311), bipolar disorders (ICD-9-CM codes 296.0, 296.4, 296.5, 296.6, and 296.8), and schizophrenia (any ICD-9-CM 295 code other than 295.7 [schizoaffective disorder]) between January 1, 2001 and December 31, 2003. All patients aged less than 18 years

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(n ¼ 2591) were excluded to limit the sampled patients to an adult population. We assigned the patients’ first ambulatory care visit or hospitalization with a first-time diagnosis of an anxiety disorder, affective disorder, or schizophrenia as the index date. In other words, the index date of each patient was defined as the exact date, ranging from 2001 to 2003, of their first diagnosis of a specified psychiatric illness. We also excluded patients who had received a PD diagnosis (ICD-9-CM code 332) before the index date (n ¼ 594). Finally, 73,597 patients with anxiety disorders, affective disorders, or schizophrenia were included as the study cohort. The comparison cohort of this study was likewise extracted from the remaining beneficiaries in the LHID2000. Because PD is associated with aging and displays a possible male preponderance [17], age and sex were considered the key matching criteria. Specifically, we randomly selected 220,791 enrollees (three for every patient with an anxiety disorder, affective disorder, or schizophrenia) matched with the study cohort according to age group (74 years), sex, and the year of the index date. For the comparison patients, we assigned their first use of medical care in the index year (ranging from 2001 to 2003) as their index date, to ensure concordance with the index dates of the patients in the study cohort. We also ensured that all selected comparison patients had never received a diagnosis of an anxiety disorder, affective disorder, or schizophrenia since the beginning of the National Health Insurance (NHI) program. We also ensured that no selected comparison patients had received a PD diagnosis before their index date. Thereafter, each patient was individually tracked for 6 years starting from their index date to identify all patients who had received a PD diagnosis (ICD-9-CM code 332) during the follow-up period. In general, a PD diagnosis is based on the medical history and symptoms of the patient evaluated during a neurologic examination. In the assessment, the balance and coordination of the patient are observed, with at least two of the following four symptoms being displayed: tremors when the limb is at rest, slowness of movement, rigidity or stiffness in the limbs or torso, and poor balance. Brain scans such as computed tomography or magnetic resonance imaging are also used to rule out other neurologic diseases. In our study, to increase coding reliability and validity, we selected only patients who had been given at least two concordant PD diagnoses after clinical studies. Statistical analysis The SAS statistical package (SAS System for Windows, ver. 8.2; Cary, NC) was used to perform all statistical analyses. Incidence rates were used to measure and compare the risks of developing PD per population at risk per unit time for patients with and without psychiatric disorders. Person-time was used in the denominator to account for the different observation times among people. Stratified Cox proportional hazard regressions (stratified according to age and sex) were also performed to estimate the hazard of PD during the 6year follow-up period. We further examined the hazard of PD between the two cohorts by stratifying the patients according to the type of psychiatric illness diagnosed. A two-sided value of P .05 or less indicated a statistically significant difference. Results After matching according to sex and age group, patients with psychiatric diseases were more likely to reside in the central part of Taiwan (P < .001) than comparison patients (Table 1). Regarding comorbidities, patients with psychiatric diseases exhibited a higher prevalence of hypertension (31.5% vs. 20.0%), diabetes (13.6% vs. 9.7%), coronary heart disease (17.9% vs. 7.5%), obesity (0.6% vs. 0.3%),

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H.-L. Lin et al. / Annals of Epidemiology 24 (2014) 206e213

Table 1 Demographic characteristics of Taiwanese patients with psychiatric diseases and comparison patients in Taiwan in 2001e2003 (n ¼ 294,388) Variable

Sex Male Female Age (y) 18e44 45e54 55e64 65e74 75 Urbanization level 1 (most urbanized) 2 3 4 5 (least urbanized) Monthly income* NT$1e$15,840 NT$15,841e$25,000 NT$25,001 Geographical region Northern Central Southern Eastern Diabetes Hypertension Coronary heart disease Obesity Hyperlipidemia Alcohol abuse/alcohol dependence syndrome

Patients with psychiatric diseases (n ¼ 73,597)

Comparison patients (n ¼ 220,791)

Total no.

%

Total no.

%

45,303 28,294

61.6 38.4

135,909 84,882

61.6 38.4

32,267 15,858 10,680 9500 5292

43.8 21.6 14.5 12.9 7.2

96,801 47,574 32,040 28,500 15,876

43.8 21.6 14.5 12.9 7.2

21,273 21,184 11,719 10,710 8711

28.9 28.8 15.9 14.6 11.8

67,397 63,075 37,747 29,048 23,524

30.5 28.6 17.1 13.2 10.6

29,850 31,222 12,525

40.6 42.4 17.0

96,959 85,580 38,252

43.9 38.8 17.3

32,781 19,431 19,728 1657 10,011 23,205 13,237 455 12,538 610

44.5 26.4 26.8 2.3 13.6 31.5 17.9 0.6 17.0 0.8

105,788 50,911 58,639 5453 21,498 44,153 16,529 731 22,849 233

47.9 23.1 26.5 2.5 9.7 20.0 7.5 0.3 10.4 0.1

P

1.000

1.000

Psychiatric diseases predated the occurrence of Parkinson disease: a retrospective cohort study.

The influence of mental illness early in life on the subsequent risk of Parkinson disease (PD) and its clinical picture remain obscure. This study inv...
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