Risk factors for depression in patients with Parkinson's disease: A nationwide nested case-control study.

OBJECTIVES: Patients with Parkinson's disease (PD) have higher prevalence of depression than the general population; however, the risk factors for depression in PD remain uncertain. METHODS/
DESIGN: Using the 2000-2010 Taiwan National Health Insurance Research Database, we selected 1767 patients aged ≧ 40 years with new-onset PD during 2000-2009. Among them, 324 patients with a new incidence of depression were enrolled as cases and 972 patients without depression were randomly selected as controls. The groups were frequency-matched at a ratio of 1:3 by age, sex, and index year. Thus, this nested case-control study compared differences between the cases and the controls. Logistic regression models were used to identify risk factors for depression in PD.
RESULTS: Compared with the controls, the odds ratio (OR) of anxiety disorders in the cases was 1.53 (95% confidence interval [95% CI], 1.16-2.02; P = 0.003), after adjusting for the confounding factors of age, sex, index year, geographic region, urban level, monthly income, and other coexisting medical conditions. The OR for sleep disturbances in the cases was 1.49 (95% CI, 1.14-1.96; P = 0.004) compared to the controls, after adjusting these confounding factors. Hence, the risk factors for depression in PD were nonsignificantly associated with physical comorbidities.
CONCLUSIONS: In the present study, depression in PD was significantly associated with anxiety disorders and sleep disturbances. Integrated care for early identification and treatment of neuropsychiatric comorbidities is crucial in patients with new-onset PD so as to prevent further PD degeneration.

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease, consisting of both motor and non-motor symptoms. Some non-motor symptoms, including certain cognitive, autonomic, and psychiatric disorders, can precede and even deteriorate the motor symptoms of PD. Depression is one of the most common non-motor symptoms observed in patients with PD, but it is often underestimated in clinical practice [1, 2]. This condition worsens the disability, impairs quality of life, increases the burden on caregivers and society, and may herald dementia with a shortened life expectancy [3-5].

Increasing evidence has suggested that the risk factors for depression in patients with PD are both non-specific (e.g., age, sex, and history of anxiety and/or depression before PD diagnosis) and PD-specific (e.g., the severity of motor symptoms, disease duration, disease stage, the extent of limitations in disease-related activities of daily living, daily levodopa equivalents dose, and the presence of non-motor symptoms such as sleep disturbance, anxiety, hallucinations, and memory-related problems) [6-11]. A previous cross-sectional study showed that non-specific risk factors may be more prominent risk markers of depression in PD than PD-specific factors [6]. Some studies with a longitudinal design and a sample of < 200 patients have reported that a low education level and family history of depression are risk factors for depression in patients with PD [12, 13]. However, these studies have not only been restricted to small-to-medium samples or cross-sectional design, but lacked proper adjustments for potential confounding factors for depression as well.

To determine the risk factors for depression in patients with PD, we conducted a nested population-based cohort study using data derived from the Taiwan National Health Insurance Research Database (NHIRD). The risk factors for depression in PD were determined amongst subjects with depression of varying severity compared to those without depression. Data regarding comorbid anxiety were also included in the analysis.

Materials and methods

Data source and ethics

This study used data from the Taiwan NHIIRD, which was developed and is managed by Taiwan National Health Insurance Program (NHIP). Since its inception in March 1995, the NHIP has provided healthcare to approximately 99% of the residents of Taiwan [14]. We accessed the 2000–2010 NHIRD, which contains data on 1 million randomly selected patients (nearly 5% of the total Taiwanese population) drawn in 2010. The NHIRD includes the demographic characteristics, diagnoses, and prescription claims data of each patient. The prescription claims data contain medication types, prescription dates, medication dosage and the duration of use.

This study was exempt from full review by the Institutional Review Board at Kaohsiung Medical University Hospital (KMUHIRB-EXEMPT(I)-20150043). Informed consent was waived because of the use of previously stored de-identified medical information from the NHIRD.

Study subjects and design

This nested case-control study [15] used the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code to identify patients with new-onset PD from January 1, 2000 to December 31, 2009. Study patients were those diagnosed by a neurologist for more than three consecutive visits with first-onset PD (ICD-9-CM code 332.0) who also received anti-PD medication (levodopa, carbidopa, bromocriptine mesylate, pergolide mesylate, amantadine, selegiline, cabergoline, ropinirole, or pramipexole) [16, 17]. The date (year) of first-onset PD was defined as the index date (year). PD patients aged < 40 years on their index date or those who had ever had been diagnosed with dementia, stroke, psychosis, or depression before their index date were excluded. Of all study patients, PD patients with an incidence of depression (ICD-9-CM codes 296.2–296.3, 296.82, 300.4, and 311) diagnosed by a neurologist or psychiatrists after their index date were selected as cases. PD patients without depression were randomly selected as controls after they were frequency-matched to a depressed subject at a ratio of 1:3 according to age, sex, and index year. The flowchart of the nested case-control study is depicted in Fig 1. The ICD-9-CM and Anatomical Therapeutic Chemical (ATC) codes used are provided in S1 Table.

Fig 1

Flowchart of the nested case-control study from prescriptions in the 2000–2010 Taiwan National Health Insurance Research Database.

Abbreviations: PD, Parkinson Disease; NIHRD, National Health Insurance Research Database; ICD, International Classification of Diseases.

Covariates

We referred to the diagnosis and prescription files of PD inpatients and outpatients before the index date [18] to ascertain their history of diabetes mellitus, hypertension, chronic pulmonary disease, osteoporosis, chronic heart failure, chronic kidney disease, chronic liver disease, cancer, anxiety disorders, and sleep disturbances by using the ICD-9-CM codes and ATC codes [16, 17, 19]. In addition, sleep disturbances (ICD-9-CM codes 780.5 and 307.4) and hypnotic medications prescribed at bedtime for at least 1 month were the primary focus so as to increase the accuracy of the diagnosis (S1 Table).

Statistical analyses

We conducted the chi-square test to compare the distribution of sociodemographic characteristics and potential confounding factors between the cases and controls. Logistic regression models were used to analyze the effect of a single and multiple covariates in terms of predicting the risk of depression in PD. All statistical analyses were performed using SAS statistical software (version 9.3, SAS Institute, Cary, NC). A two-tailed P-value < 0.05 was considered statistically significant.

Results

After excluding patients who did not meet the study criteria, 1767 patients with new-onset PD between 2000 and 2009 were selected. Among them, 324 (18.3%) patients with an incidence of depression were enrolled as cases; the mean (stand deviate, SD) time interval between PD and depression occurred was 2.4 (2.3) years. We eventually matched 324 cases with 972 controls whose new-onset PD patients without depression were randomly selected as controls after they were frequency-matched with cases at a ratio of 1:3 based on age, sex, and index year (Fig 1). In our study, the mean (SD) follow-up times after PD was 4.5 (3.0) years. Table 1 shows the distribution of sociodemographic characteristics and coexisting medical conditions of the cases and controls. A significantly higher percentages of cases had anxiety disorders (36.1% vs. 28.2%, P = 0.007) and sleep disturbances (38.9% vs. 31.0%, P = 0.009) compared with controls. The differences between cases and controls were nonsignificant for the other coexisting medical conditions and all sociodemographic characteristics.

Table 1

Characteristics of Parkinson’s disease patients with depression (cases) and the controls.

	The casesa PD with depression (n = 324)		The controlsa PD without depression (n = 972)
Characteristics	n	(%)	n	(%)	p value
Sociodemographic characteristics
Sex
Male	148	45.7	444	45.7	1.000
Female	176	54.3	528	54.3
Age (years)
40–49	13	4.0	39	4.0	1.000
50–59	35	10.8	105	10.8
60–69	86	26.5	258	26.5
> 70	190	58.6	570	58.6
Geographic region
Northern	134	41.4	432	44.4	0.616
Central	85	26.2	248	25.5
Southern and Eastern	105	32.4	292	30.1
Urban level
Urban and suburban	232	71.6	673	62.2	0.422
Rural	92	28.4	299	30.8
Monthly income (NT$)
High (>30,000)	28	8.6	116	11.9	0.102
Low (<30,000)	296	91.4	856	88.1
Coexisting medical conditions
Emergencyb
No	213	65.7	682	70.2	0.136
Yes	111	34.3	290	29.8
PD with dementiac	44	13.6	168	17.3	0.119
CCI score
0	50	15.4	141	14.5	0.363
1–2	124	38.3	337	34.7
>2	150	46.3	492	50.8
Comorbidities
Diabetes mellitus	109	33.6	334	34.4	0.813
Hypertension	202	62.3	575	59.2	0.310
Chronic pulmonary disease	147	45.4	482	49.6	0.188
Osteoporosis	93	28.7	272	28.0	0.803
Chronic heart failure	3	0.9	7	0.7	0.718
Chronic kidney disease	64	19.8	172	17.7	0.406
Chronic liver disease	103	31.8	301	31.0	0.782
Cancer	8	2.5	43	4.4	0.117
Anxiety disorders	117	36.1	274	28.2	0.007
Sleep disturbance	126	38.9	301	31.0	0.009

Abbreviations: CCI, Charlson Comorbidity Index; NT$, new Taiwan dollars; PD, Parkinson disease.

aValues are numbers (percentage) of column totals of patients.

bVisiting the emergency before diagnosis of PD.

cDementia occurred at least one year after diagnosis of PD.

Table 2 lists the adjusted odds ratios (adjusted ORs) for depression in the study patients. After adjusting for age, sex, index year, geographic region, urban level, monthly income, emergency visits before PD diagnosis, PD with dementia, the Charlson Comorbidity Index score, and other comorbidities, anxiety disorders and sleep disturbances were the only two factors that significantly affected depression in patients with PD, with an adjusted OR of 1.53 (95% confidence interval [95% CI], 1.16–2.02; P = 0.003) for anxiety disorders and 1.49 (95% CI, 1.14–1.96; P = 0.004) for sleep disturbances. The association with depression in patients with PD was non-significant for all physical comorbidities, including diabetes, hypertension, chronic pulmonary disease, osteoporosis, chronic heart failure, chronic kidney disease, chronic liver disease, and cancer (all P > 0.05).

Table 2

Risk factors for depression in the study patients with Parkinson’s disease (n = 1296).

Variables	Adjusted ORa	95% CIa	p value
Comorbidities
Diabetes mellitus	1.05	(0.78–1.42)	0.743
Hypertension	1.21	(0.91–1.59)	0.188
Chronic pulmonary disease	0.88	(0.66–1.17)	0.375
Osteoporosis	1.05	(0.77–1.42)	0.753
Chronic heart failure	1.29	(0.33–5.02)	0.719
Chronic kidney disease	1.24	(0.88–1.75)	0.218
Chronic liver disease	1.10	(0.83–1.46)	0.508
Cancer	0.56	(0.27–1.28)	0.180
Anxiety disorders	1.53	(1.16–2.02)	0.003
Sleep disturbance	1.49	(1.14–1.96)	0.004

Abbreviations: CCI, Charlson Comorbidity Index; CI, confidence interval; OR, odds ratio; PD, Parkinson’s disease.

aAdjusted for age, sex, the index year, geographic region, urban level, monthly income, emergency visits before PD diagnosis, PD with dementia, PD with psychosis, CCI score, and other comorbidities.

Discussion

We conducted a nationwide nested case-control study to determine the risk factors for depression in patients with PD. There were 1767 patients with new-onset PD identified from 2000 to 2009 in this analysis. Overall, 324 (18.3%) patients with PD had an incidence of depression; the mean (SD) time to depression occurrence was 2.4 (2.3) years. The results revealed that the comorbidities of anxiety disorders and sleep disturbances were risk factors for depression in patients with PD, independent of physical comorbidities.

In the present study, the incidence of depression in Taiwanese patients with PD was 18.3%, as assessed from clinical visit records. The result corresponds with the incidence found in a previous 5-year longitudinal prospective cohort study, which showed that approximately 20% of PD patients suffer from depression [20]. Hence, our incidence seems to be below the average incidence value (about 35%) of international reports [21]. Apart from differences in the methods used to assess depression, differences in study populations, and varying statistical measures [13, 21], this lower incidence is most likely due to the lack of awareness of depression in PD of clinicians, the patients, and their families. The overlapping symptoms of PD and depression—such as psychomotor retardation, facial expression, fatigue, insomnia, and poor food intake—may make it difficult to the diagnose depression in patients with PD [22, 23]. Primary care physicians, particularly neurologists treating movement disorders and psychiatrists in Taiwan, should consider developing consensus on the diagnosis of depression in PD patients.

In this study, we analyzed the associated between depression in PD and its comorbidities. Four previous studies with a cross-sectional design and sample sizes < 250 patients with PD have analyzed this association [6, 8, 11, 12]. Wichowicz et al [11] reported that typical risk factors for depression in patients with PD are strongly associated with a family history of depression and weakly associated with somatic comorbidities; however, these researchers did not assess anxiety and sleep disturbances [12]. Another Polish population-based study concluded that sleep disturbances and the disease severity of PD were the two risk factors significantly associated with depression in PD [11]. In addition, two other studies found that comorbidities, including anxiety, a family history of depression, sleep disturbances, memory-related problems, hallucinations, and postural hypotension were more commonly identified in PD patients with depression than in those without depression, whereas the incidence of physical disorders such as head injury and hypertension differed nonsignificantly between these two types of patients [6, 8]. The results of the present study were consistent with those of previous research, which found that depression in PD is strongly associated with the neuropsychiatric comorbidities of anxiety disorders and sleep disturbances, but nonsignificantly associated with physical comorbidities. These neuropsychiatric comorbidities are among the non PD-specific risk factors for depression in PD, which were associated with a three-fold greater risk of depression than PD-specific factors in PD [6]. Early prediction of risk factors for depression in PD is key to preventing further PD degeneration. However, future studies must determine the extent to which treatment for such neuropsychiatric comorbidities effectively prevents subsequent PD degeneration.

The etiology of depression in PD is most likely multifactorial, with a possible contribution from both psychosocial stress and brain-related changes [24, 25, 26]. At the time of initial PD diagnosis, patients and their families must make adjustments to address this chronic progressive and debilitating brain disorder, which may lead to loss of jobs, marital discord, increasing withdrawal, and a worsening quality of life. Some patients, particularly those with early-onset PD, exhibit certain aspects of a reactive emotion such as sadness, anxiety, and sleep disturbances. Increasing evidence has recently implied that depression in PD is secondary to brain-related changes, and is a reaction to psychosocial stress and the associated disability [24]. Brain-related changes may result from the severity and course of PD, the adverse effects of medications, or the comorbidities of the disorder [1, 24, 25]. Furthermore, we found that these brain-related changes were strongly associated with neuropsychiatric comorbidities, namely anxiety disorders and sleep disturbances, and weakly associated with physical comorbidities. Anxiety is a common non-motor symptom in PD, with a reported prevalence of 25% to 49% [27, 28]. Moreover, 14% to 40% of PD patients are diagnosed with anxiety comorbid with depression [27, 29]. We found a similar prevalence of anxiety disorders in PD patients with depression (36%) and in those without depression (28.2%). Growing evidence has shown that dopaminergic treatment has the potential not only to improve depression in patients with PD [28], but also to induce neuropsychiatric disorders (e.g., mania, psychosis, impulsive control disorder, and dopamine dysregulation syndrome) [30], implying that dopaminergic neuron loss is likely to occur in PD patients with depression and anxiety. Extra-striatal and non-dopaminergic neurotransmitter systems have become increasingly recognized for their role in the course of PD [31]. Serotonergic raphe nuclei and the noradrenergic locus coeruleus implicated in depression have a disposition to lewy body [32, 33], which precedes basal midbrain involvement in PD [31]. Both anxiety and depression have been observed to induce similar changes in norepinephrine and serotonin systems; anxiety disorders may occur earlier than depression, and even before motor symptoms appear in PD. This progression may explain the occurrence of depression and anxiety in PD during the premotor phase [34]. Elevated inflammatory cytokine, soluble interleukin 2 receptor (sIL-2R) and tumor necrosis factor-α, may be associated with depression and anxiety in PD, which also imply the underlying neuro-inflammatory process may contribute to the development of depression and anxiety in PD [35]. This study found anxiety to be a crucial risk factor for depression in PD; this finding is consistent with those reported in previous anatomical, pathological, and pharmacological studies.

Sleep disturbances are among the most common non-motor symptoms of PD [36]. Sleep disturbances such as sleep fragmentations and early awakenings can lead to poor sleep quality and excessive daytime sleepiness, which may exacerbate motor performance and degrade the quality of life of patients with PD [37, 38]. A previous study found strong genotypic correlations between sleep disorders and depression in PD; however, the causality remains unknown [39]. The present study can only confirm the association between sleep disturbance and depression in PD.

Strength and limitation in the study

The strengths of our study were the use of nationwide population-base data and the large sample. We analyzed the risk factors for depression in patients with new-onset PD. The results are relevant for PD patients with comorbid depression, particularly in the ethnic Chinese population. To increase the accuracy of PD diagnosis, an ambulatory care expenditure database (containing diagnoses by neurologists using ICD-9-CM codes) and a prescription claims database (containing PD treatment medications) were used to confirm the PD diagnosis. Furthermore, covariates, including underlying common physical and psychiatric disorders, were considered. Despite its retrospective nature, we used a nested case-control design to analyze the national population-based database, and avoided two major potential biases, namely selection bias and recall bias.

Our study has certain limitations, and hence, could not control for all potential biases. First, the prevalence of PD, depression, and comorbidities, such as sleep disturbances, may have been underestimated in medical claims, because certain patients experiencing mild symptoms of such disorders are unlikely to visit medical services. Consecutive outpatient visits and medications by neurologists may warrant symptomatic effects of dopaminergic treatment but could exclude the possibility of partial response in atypical parkinsonism patients such as multiple system atrophy or progressive supranuclear palsy. Moreover, we could not assess the polysomnography data to confirm the diagnosis of sleep disorders such as rapid eye movement disorder, restless leg syndrome, and obstructive sleep apnoea, symptoms typically observed in patients with PD. Second, information on other risk factors contributing to depression in PD, such as biochemistry data, current alcohol consumption, head injury and the severity of PD and other comorbidities such as apathy executive dysfunction or mild cognitive impairment, were unavailable in the database. Alcohol consumption is widely known for its positive association with depression. We were unable to explain the positive association observed in the study because of the lack of data. Other lifestyle-related risk factors for depression, including coffee consumption, exposure to herbicides, and a childhood history of traumas such as child abuse, were not included in our study. Finally, various aspects of depression in PD were also unavailable in the study, because we used the ICD-9-CM Diagnosis Coding System for depression diagnosis. Further, we can consider the following two systems as a diagnostic nomenclature of depression in PD: the Diagnostic and Statistical of Mental Disorders (5th Edition) by American Psychiatric Association and the provisional diagnostic criteria for depression in PD proposed by the NINDS/NIMH Work Group [40].

Conclusions

The findings of the present study demonstrate that the risk factors for depression in patients with PD are significantly associated with the comorbidities of anxiety disorders and sleep disturbances, but nonsignificantly associated with physical comorbidities. Based on our findings and previously reported evidence, physicians should emphasize the early identification and treatment of neuropsychiatric comorbidities in patients with new-onset PD so as to prevent further PD degeneration.

ICD-9-CM codes and ATC codes used in this study.

(DOC)

Click here for additional data file.

27 May 2020

PONE-D-20-09123

Risk factors for depression in patients with Parkinson’s disease: A nationwide nested case-control study

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Reviewer #1: Thank you for the opportunity to comment on this article describing a nested case-control study of depression in Taiwanese Parkinson's disease patients. The article is clearly written and the methods are well-described. The conclusions are that anxiety and sleep disorders are more common in PD cases who have co-morbid depression compared to those who do not. This finding aligns with other reports; the results are unremarkable.

There are a few limitations of the study that should be further discussed by the authors:

1. An exclusion criteria for the PD with depression group is the diagnosis of depression that precedes PD presentation. To my mind this is problematic as it is well-accepted that many PD patients report a history of depressive symptoms many years before the presentation of motor Parkinsonism. This criteria may significantly lead to an under-estimation of the frequency of depression in this disease group. Can the authors comment?

2. The inclusion of prescriptions of dopaminergic Parkinson medication as a means of refining diagnosis is understandable - was there a need for a symptomatic response to the medication in the inclusion criteria?

3. It is very possible that symptoms of depression (that may warrant a DSM diagnosis of depression) may not have been screened for in the patients in the PD without depression group. While the authors touch on this in the discussion, it is very important to note that absence of evidence is not evidence of absence. How did the authors address this situation?

Further, despite formal diagnosis, some PD cases are prescribed anti-anxiolytics and anti-depressive medications "to help them sleep or relax". Was there an attempt to look at medication usage in this group to confirm that they were not on such medications?

4. Both anxiety and sleep disturbance (particularly REM behavioural sleep disorder) are recognised parts of the spectrum of PD symptoms. Can the authors comment on when these were recognised in the PD cases with respect to PD diagnoses? Did the study also consider other diagnoses prior to the incident diagnosis of PD (eg head injury was one that would be interesting to consider).

Finally, was there any investigation of disease severity (by any measure) or Quality of Life for patients in either group? Such information would highlight the importance of recognising and treating depression in PD patients.

The dataset accessed as part of this report is a valuable one and further analyses are likely to provide important insights into Parkinson's disease.

Reviewer #2: Next, some observations:

1. There are several symptoms that share apathy and depression, how did the researchers control this confounding factor?

2. Up to 20% of patients with Parkinson's disease de novo may have mild cognitive impairment. In that sense, it should be clear that these patients were excluded.

3. Patients with Parkinson's disease and subjective cognitive complaints may have executive dysfunction, which could increase suspicion of depression/apathy. How did the researchers control for this confounding factor?

4. It is important to comment on the likelihood of patients with low levels of education, as in that case, cognitive tests should report on their adaptation and validation.

Reviewer #3: Manuscript Number: PONE-D-20-09123.

Title: Risk factors for depression in patients with Parkinson’s disease: A nationwide nested case-control study.

The authors report a nested case-control study for risk factors of depression in Parkinson’s disease among 324 patients with depression and 972 patients without depression, using the 2000–2010 Taiwan National Health Insurance Research Database. They found an odds ratio of 1.53 (95% confidence interval, 1.16–2.02; P = 0.003) for anxiety disorders after adjusting for the confounding factors of age, sex, index year, geographic region, urban level, monthly income, and other coexisting medical conditions. For sleep disturbances, the odds ratio was 1.49 (95% confidence interval, 1.14–1.96; P = 0.004) compared to the controls, after adjusting these confounding factors. I enjoyed reading this interesting manuscript. I have only a few suggestions.

Major points.

1. Various kinds of depression.

Authors presented ICD codes for various kinds of depression. However, these codes could not be so apparent for readers to describe various aspects of depression in Parkinson’s disease. We can consider the following two systems as a diagnostic nomenclature of depression in Parkinson’s disease.

1-1. One, the Diagnostic and Statistical Manual of Mental Disorders (5th Edition) by American Psychiatric Association classifies depression according to its etiology and symptom severity. This system comprises of major depression, minor depression, dysthymia, adjustment disorder, and depressive disorder due to Parkinson’s disease.

1-2. The other, the provisional diagnostic criteria for depression in Parkinson's disease proposed by the NINDS/NIMH Work Group classifies depression according to the presence or absence of symptoms and severity. This system includes major depression, minor depression, dysthymia, and subsyndromal depression.

1-3. I would like to ask authors for supplementing these systems in addition to the ICD codes. If not possible, I’d like to suggest that this aspect could be pointed out as a limitation of this study.

2. Risk factors versus association factors.

If anxiety disorder and sleep disorder are risk factors to develop depression, we can observe a temporal order of preceding risk factors and resulting depression. If not, anxiety disorder and sleep disorder could be ascribed as association factors. Please clarify this point.

Minor points.

3. Page 35. Figure 1.

In the box of “Excluded due to”, ICD 300.3.

In the box of “PD patients with an incidence of”, ICD 300.4.

Please check 300.3.

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Reviewer #1: Yes: George D. Mellick

Reviewer #2: Yes: Nilton Custodio

Reviewer #3: No

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11 Jun 2020

Reviewer #1: Thank you for the opportunity to comment on this article describing a nested case-control study of depression in Taiwanese Parkinson's disease patients. The article is clearly written and the methods are well-described. The conclusions are that anxiety and sleep disorders are more common in PD cases who have co-morbid depression compared to those who do not. This finding aligns with other reports; the results are unremarkable.

There are a few limitations of the study that should be further discussed by the authors:

1. An exclusion criteria for the PD with depression group is the diagnosis of depression that precedes PD presentation. To my mind this is problematic as it is well-accepted that many PD patients report a history of depressive symptoms many years before the presentation of motor Parkinsonism. This criteria may significantly lead to an under- estimation of the frequency of depression in this disease group. Can the authors comment?

ANS: Thanks for your comments.

As depression may be a risk factor and a common prodromal symptom of PD patients, it is possible for our study to under-estimate our PD patients with coincided depression, which may be another explanation for the relatively low incidence of depression in our PD patients. Because of the convenience of our insurance system, in Taiwan citizens who suffered from depression can be treated earlier than those in other countries. In the same time, many clinicians have also observed many patients are diagnosed with drug-induced parkinsonism due to doctoral shopping for treating their symptoms. To clarify the temporality of association in the risk factors for depression in patients with PD, we decided to exclude patients with past history of depression in order to minimize the inclusion of patients with drug-induced parkinsonism, which may complicate the interpretations of the results.

2. The inclusion of prescriptions of dopaminergic Parkinson medication as a means of refining diagnosis is understandable - was there a need for a symptomatic response to the medication in the inclusion criteria?

ANS: Thank you for this comment.

To ensure the symptomatic response to the medications are sustainable for defining our diagnosis, we include patients with more than 3 consecutive outpatient visits with medications by neurologists. However, it is still possible that we were not be able to completely exclude patients with multiple system atrophy, progressive supranuclear palsy or other atypical parkinsonism. We would revise our article and point out the limitations. See them in detail on the Line 12 of Page 8 in the Materials and Methods section and on the Lines 7-10 of Page 17 in the “Strength and limitation in the study” of the Discussion section.

3. It is very possible that symptoms of depression (that may warrant a DSM diagnosis of depression) may not have been screened for in the patients in the PD without depression group. While the authors touch on this in the discussion, it is very important to note that absence of evidence is not evidence of absence. How did the authors address this situation?
Further, despite formal diagnosis, some PD cases are prescribed anti-anxiolytics and anti-depressive medications "to help them sleep or relax". Was there an attempt to look at medication usage in this group to confirm that they were not on such medications?

ANS:

As many PD patients with depression may also respond to dopaminergic medications like dopamine agonists, PD with subclinical depression may not be screened by the clinicians because of the pharmacological effects. We hope the article may contribute to the increasing attention on the issue and the development of the consensus of screening depressive PD patients with validated scale and correct diagnosis.

Further, we believed that this comment often happened in the clinic. In our health insurance system, it is required that the consistency of prescription medications and diagnosis code. In our study, we have excluded dementia, stroke, psychosis, and depression before PD diagnosis. So the anti-anxiolytics and anti-depressive medications could be ignored.

4. Both anxiety and sleep disturbance (particularly REM behavioural sleep disorder) are recognised parts of the spectrum of PD symptoms. Can the authors comment on when these were recognised in the PD cases with respect to PD diagnoses? Did the study also consider other diagnoses prior to the incident diagnosis of PD (eg head injury was one that would be interesting to consider).

ANS: Thanks for your comments.

Anxiety and sleep disturbances were diagnosed before the index date of PD diagnosis and depression diagnosis (in depressive PD group) using both ICD codes and ATC codes in order to confirm the diagnosis and the diagnosis should be made by neurologists or psychiatrists with regular outpatient follow-ups. We did not put head injury prior to PD diagnosis to investigate the association but it would be a very interesting topics to be investigated.

Finally, was there any investigation of disease severity (by any measure) or Quality of Life for patients in either group? Such information would highlight the importance of recognising and treating depression in PD patients.

ANS: Thanks for your comment.

No, we did not assess and confirm quality of life for our patients because all the data had been delinked to avoid personal identity as we mentioned in the limitations.

But considering disease severity in terms of the initial dosage of dopaminergic medications, mean Levodopa equivalent daily dose of depressive and non-depressive groups were 116.26 ± 32.35 mg and 143.81 ± 59.34 mg respectively without significant difference. (data not shown) In addition, comorbidity score or emergency visits before PD diagnosis did not differ significantly between two groups.

The dataset accessed as part of this report is a valuable one and further analyses are likely to provide important insights into Parkinson's disease.

Reviewer #2: Next, some observations:

1. There are several symptoms that share apathy and depression, how did the researchers control this confounding factor?

ANS: Thank you for important comments.

Like depression, apathy is also a common non-motor symptom in Parkinson’s disease (PD), but is often under-recognized. Apathy is defined as a lack of motivation characterized by reduced emotional expression and diminished goal-oriented behavior. Apathy may share similar feature with depression. Apathetic PD patients may represent as decreased self-generated activities as a consequence of decreased rewarding experiences, but depressive PD patients describe the increase or enhancement of sadness, feelings of guilt, recurrent (and even involuntary intrusion of) negative thoughts and/or feelings, helplessness, hopelessness, pessimism, self-criticism, anxiety, and even suicidal ideation. Differentiation of apathy from depression would be difficult and may be mainly based on a well-structured clinical interview. Common treatment for depression would use serotonin and/or norepinephrine reuptake inhibitors would worsen symptoms of isolated apathetic patients.

In our nationwide database, we did not routinely re-check the symptoms of apathy and cannot arrange complete neuropsychological examinations to evaluate the symptoms of depression and apathy.

2. Up to 20% of patients with Parkinson's disease de novo may have mild cognitive impairment. In that sense, it should be clear that these patients were excluded.

ANS: Thanks for your comments.

Mild cognitive impairment is not uncommon in PD patients. With the restriction of insurance regulations, our clinicians would not be able to routinely arrange yearly neuropsychological examinations for de Novo PD patients except for patients with complaints of subjective memory impairment or other signs or symptoms of cognitive decline. It’s possible for us to exclude PD patients with mild cognitive impairment without regular neuropsychological examinations. However, we exclude PD patients with prior diagnosis of dementia to avoid the inclusion of atypical parkinsonism like Lewy body disease. We have revised our articles in the description of limitations. See them on the Lines 15, 16 of Page 17 of the Discussion section.

3. Patients with Parkinson's disease and subjective cognitive complaints may have executive dysfunction, which could increase suspicion of depression/apathy. How did the researchers control for this confounding factor?

ANS: Thanks for your comments.

Executive dysfunction, part of mild cognitive impairment, is common in PD patients and the symptoms may be improved after dopaminergic medications. With the restriction of insurance regulations, our clinicians/researches would not be able to routinely arrange yearly neuropsychological examinations for de Novo PD patients except for patients with complaints of subjective memory impairment or other signs or symptoms of cognitive decline. It’s possible for us not being able to exclude PD patients with mild cognitive impairment. However, we exclude PD patients with prior diagnosis of dementia to avoid the inclusion of patients with dementia and atypical parkinsonism like Lewy body disease. We have revised our articles in the description of limitations. See them on the Lines 15, 16 of Page 17 of the Discussion section.

4. It is important to comment on the likelihood of patients with low levels of education, as in that case, cognitive tests should report on their adaptation and validation.

ANS: Thanks for your comments.

In our demographic data, we have shown that our PD patients were from different geographic regions of Taiwan with difference economic levels. There is no significant difference between the cases and control. With the restriction of insurance regulations, we would not be able to gain their educational levels and to routinely arrange neuropsychological examinations for patients every year, except for patients with complaints of subjective memory impairment or other signs or symptoms of cognitive decline.

Reviewer #3: Manuscript Number: PONE-D-20-09123.

Title: Risk factors for depression in patients with Parkinson’s disease: A nationwide nested case-control study.

The authors report a nested case-control study for risk factors of depression in Parkinson’s disease among 324 patients with depression and 972 patients without depression, using the 2000–2010 Taiwan National Health Insurance Research Database. They found an odds ratio of 1.53 (95% confidence interval, 1.16–2.02; P = 0.003) for anxiety disorders after adjusting for the confounding factors of age, sex, index year, geographic region, urban level, monthly income, and other coexisting medical conditions. For sleep disturbances, the odds ratio was 1.49 (95% confidence interval, 1.14–1.96; P = 0.004) compared to the controls, after adjusting these confounding factors. I enjoyed reading this interesting manuscript. I have only a few suggestions.

Major points.

1. Various kinds of depression.
Authors presented ICD codes for various kinds of depression. However, these codes could not be so apparent for readers to describe various aspects of depression in Parkinson’s disease. We can consider the following two systems as a diagnostic nomenclature of depression in Parkinson’s disease.

1.1. One, the Diagnostic and Statistical Manual of Mental Disorders (5th Edition) by American Psychiatric Association classifies depression according to its etiology and symptom severity. This system comprises of major depression, minor depression, dysthymia, adjustment disorder, and depressive disorder due to Parkinson’s disease.

ANS: Thank you very much for this key point.

We believed that the Diagnostic and Statistical Manual of Mental Disorders (5th Edition) by American Psychiatric Association can help psychiatrists and neurologist for further clarifying the etiology and symptom severity of depression, particularly in PD with depression. However, we had the limitations in this study because we used the 2000-2010 database, diagnosed using ICD-9-CM system. In this study, we can only divide depressions into “296.2-296.3--major depressive affective disorders”, “atypical depressive disorder”, “300.4--Dysthymic disorder”, and “311--depressive disorder, not elsewhere classified”. See them in S1_Table in detail.

1.2. The other, the provisional diagnostic criteria for depression in Parkinson's disease proposed by the NINDS/NIMH Work Group classifies depression according to the presence or absence of symptoms and severity. This system includes major depression, minor depression, dysthymia, and subsyndromal depression.

1.3. I would like to ask authors for supplementing these systems in addition to the ICD codes. If not possible, I’d like to suggest that this aspect could be pointed out as a limitation of this study.

ANS: Thank you for supplying for a simple and clear diagnostic tool to clarifying the etiology and symptom severity of depression in Parkinson’s disease. With the restriction of insurance regulations, we only added this information and a new reference in the limitation of the Discussion section. See it in detail on the Lines 3-8 of Page 18 in the Discussion section and on the Lines 1-5 of Page 28 in the Reference section.

2. Risk factors versus association factors.

If anxiety disorder and sleep disorder are risk factors to develop depression, we can observe a temporal order of preceding risk factors and resulting depression. If not, anxiety disorder and sleep disorder could be ascribed as association factors. Please clarify this point.

ANS: Thanks for key point of risk and association factors.

In this study, we favored that anxiety disorder and sleep disorder are risk factors by time-order. Anxiety and sleep disturbances were diagnosed before the index date of PD diagnosis and depression diagnosis (in depressive PD group) using both ICD codes and ATC codes in order to confirm the diagnosis and the diagnosis should be made by neurologists or psychiatrists with regular outpatient follow-ups. (See it in detail on the Lines 10-13, Page 9 of the Materials and Methods section.) With some limitations of our study, we think that anxiety disorder and sleep disturbances may be recognized as risk factors for PD patients who develop depression after initial diagnosis.

Minor points.

2. Page 35. Figure 1.

In the box of “Excluded due to”, ICD 300.3.

In the box of “PD patients with an incidence of”, ICD 300.4. Please check 300.3.

ANS: Thanks for your comments.

We have revised ICD 300.3 to 300.4 in the Figure 1

Submitted filename: Response to reviewers_Depression in PD.doc

Click here for additional data file.

8 Jul 2020

Risk factors for depression in patients with Parkinson’s disease: A nationwide nested case-control study

PONE-D-20-09123R1

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Reviewer #2: Congratulations on resolving the observations which have improved the nature of the publication for the benefit of readers.

Reviewer #3: Manuscript Number: PONE-D-20-09123.

Title: Risk factors for depression in patients with Parkinson’s disease: A nationwide nested case-control study.

Thank you very much for sending a revised manuscript. The authors have made a substantial revision of their manuscript and adequately responded to my suggestions. Thank you again for your valuable manuscript.

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Reviewer #2: Yes: Nilton Custodio

Reviewer #3: Yes: Jong-Min Kim

13 Jul 2020

PONE-D-20-09123R1

Risk factors for depression in patients with Parkinson’s disease: A nationwide nested case-control study

Dear Dr. Tsai:

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