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. 2021 Jan 22;16(1):e0245864. doi: 10.1371/journal.pone.0245864

Risk factors for neuropsychiatric symptoms in patients with Parkinson’s disease during COVID-19 pandemic in Japan

Fukiko Kitani-Morii 1,2, Takashi Kasai 2,*, Go Horiguchi 3, Satoshi Teramukai 3, Takuma Ohmichi 2, Makiko Shinomoto 2, Yuzo Fujino 2, Toshiki Mizuno 2
Editor: Kensaku Kasuga4
PMCID: PMC7822544  PMID: 33481879

Abstract

The worsening of neuropsychiatric symptoms such as depression, anxiety, and insomnia in patients with Parkinson’s disease (PD) has been a concern during the COVID-19 pandemic, because most people worked in self-isolation for fear of infection. We aimed to clarify the impact of social restrictions imposed due to the COVID-19 pandemic on neuropsychiatric symptoms in PD patients and to identify risk factors associated with these symptoms. A cross-sectional, hospital-based survey was conducted from April 22, 2020 to May 15, 2020. PD patients and their family members were asked to complete paper-based questionnaires about neuropsychiatric symptoms by mail. PD patients were evaluated for motor symptoms using MDS-UPDRS part 2 by telephone interview. A total of 71 responders (39 PD patients and 32 controls) completed the study. Although there was no difference in the age distribution, the rate of females was significantly lower in PD patients (35%) than controls (84%) (P < 0.001). Participants with clinical depression (PHQ-9 score ≥ 10) were more common in PD patients (39%) than controls (6%) (P = 0.002). Multivariate logistic regression analysis revealed that an MDS-UPDRS part 2 score was correlated with the presence of clinical depression (PHQ-9 score ≥ 10) and clinical anxiety (GAD-7 score ≥ 7) (clinical depression: OR, 1.31; 95% CI, 1.04–1.66; P = 0.025; clinical anxiety: OR, 1.36; 95% CI, 1.07–1.72; P = 0.013). In the presence of social restrictions, more attention needs to be paid to the neuropsychiatric complications of PD patients, especially those with more severe motor symptoms.

Introduction

The pandemic of coronavirus disease 2019 (COVID-19) and subsequent state of emergency forced people to focus on the infection and lower the priority of care for chronic diseases. Older people, who often have underlying medical conditions, have an increased mental burden, because they were reported to be at a higher risk for severe disease [1]. While Japan’s state of emergency did not introduce legal penalties for leaving the house, there was concern that self-isolation and social distancing, which were strongly advocated, would worsen physical inactivity and mental instability, especially in the elderly [2, 3].

Parkinson’s disease (PD) is one of the most frequent neurodegenerative diseases that is predominant in the elderly. In addition to motor symptoms like bradykinesia, rigidity, and tremor, non-motor symptoms such as depression, anxiety, and sleep disturbance occur from the early to advanced stages of PD [4–6]. There was concern that the increased mental burden and restrictions placed on exercise due to the COVID-19 pandemic negatively affect both motor and non-motor symptoms [7]. Indeed, several groups from around the world have reported higher rates of neuropsychiatric problems in PD patients due to the social restrictions imposed following the surge of infections [8–13]. Notably, a report from Netherland clearly showed that PD patients with more COVID-19 related stressors had more PD symptoms through increased mental stress [14]. However, we need to accumulate more cases from diverse regions to more closely examine the impact of the COVID-19 pandemic on PD patients, because there are regional differences in the severity of the infection and social restrictions.

The purpose of this study was to assess the severity of depression, anxiety, and insomnia in PD patients in Japan experiencing social stresses caused by the COVID-19 pandemic, and to identify factors associated with severe non-motor features and subjective worsening of motor and non-motor symptoms.

Materials and methods

Study design and participants

The study protocol was reviewed and approved by the institutional ethics review boards of Kyoto Prefectural University of Medicine in accordance with the Helsinki Declaration (ERB-G-12). Written informed consent was provided by all survey participants. No minors were among the participants. According to a priori power analysis (with 95% power and 5% type I error rate) of the results of previous studies [8–10], the minimum number for the sample was found to be 41 patients for the comparative study of the prevalence of psychiatric symptoms during COVID-19 pandemic in PD and control groups. This study was a cross-sectional, single hospital-based survey conducted from April 22, 2020 to May 15, 2020. Japan’s state of emergency was imposed from April 7, 2020 to May 22, 2020. PD patients who regularly visited the outpatient clinic of Kyoto Prefectural University of Medicine were asked to participate in this study. The family members of each PD patient were recruited to the study as controls. Participants were asked to complete paper-based questionnaires by mail and respond to a telephone interview.

Outcomes measures and patients’ characteristics

We assessed symptoms of depression, anxiety, and insomnia both in PD patients and controls using the Japanese version of questionnaires such as the 9-item Patient Health Questionnaire (PHQ-9), 7-item Generalized Anxiety Disorder (GAD-7), and 7-item Insomnia Severity Index (ISI), respectively [15–18]. The scores for each assessment method were classified into the following categories: PHQ-9, normal (0–4), mild (5–9), moderate (10–14), moderate to severe (15–19), and severe (20–27) depression; GAD-7, normal (0–4), mild (5–9), moderate (10–14), and severe (15–21) anxiety; ISI, normal (0–7), subthreshold (8–14), moderate (15–21), and severe (22–28) insomnia (15–18). The cutoff values for PHQ-9, GAD-7, and ISI were 10, 7, and 15, respectively. Participants with scores higher than the cutoff were considered to have “clinical depression”, “clinical anxiety”, and “clinical insomnia”. In addition, all participants were asked if they had experienced a subjective worsening of motor performance, anxiety, and insomnia.

PD patients were further evaluated based on the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 2, which assesses the patient’s subjective motor experiences of daily living [19]. The questions and possible responses were read out over the phone, and the patient responded accordingly. The following information was obtained from medical records of PD patients: sex, age, whether they lived alone, duration of PD, Hoehn & Yahr (HY) stage, non-motor symptoms (such as cognitive impairment, hallucinations, and rapid eye movement sleep behavior disorder [RBD]), medications such as L-DOPA, dopamine agonist, psychiatric medicines (including selective serotonin reuptake inhibitor, serotonin noradrenaline reuptake inhibitor, and tricyclic/tetracyclic antidepressant, atypical antipsychotics), and sleeping pills. Controls provided the following information: sex, age, and whether they lived alone.

Statistical analysis

PHQ-9, GAD-7, and ISI scores are expressed as the median and interquartile (IQR) because they do not show a normal distribution. A Mann-Whitney U test was adopted to compare each questionnaire score between PD patients and controls. For PD patients, uni- and multivariate logistic regression analyses were performed to determine potential risk factors for clinical depression, anxiety, and insomnia, and subjective worsening of motor and non-motor symptoms. The relationship between risk factors (sex, age [< 70, 70–79, ≥ 80], duration of PD [years, < 5 or ≥ 5], HY stage [0–2 or ≥ 3], scores of MDS-UPDRS part 2 [Note: this scale was treated as continuous variables in the analysis], L-DOPA dose [mg, < 600 or ≥ 600], and use of dopamine agonist) and outcomes are expressed as odds ratios (ORs) and 95% confidence intervals (CIs). Univariate logistic regression analysis was performed for all variables. For the multivariate model, the L-DOPA dose and use of dopamine agonists were adopted as variables if their P-value was greater than 0.2 on univariate analysis in addition to basic characteristics (including sex, age, duration of PD, HY stage, and scores of MDS-UPDRS part 2). Data analysis was performed using SPSS version 26 (IBM, Armonk, NY, USA) and SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA) under the supervision of statisticians. A P-value of less than 0.05 indicated significance, and all reported P-values were 2-sided.

Results

Participants’ characteristics

A total of 88 patients and their family members (44 PD patients and 44 controls) were invited to participate in the study, and 71 (80%) responders completed the survey. Of the 71 participants, 39 (54%) were PD patients and 32 (45%) were controls. The response rates for PD patients and controls were 88 and 72%, respectively. The rate of females was significantly lower in PD patients (PD patients vs. controls: 14 [35%] vs. 27 [84%], P < 0.001). There was no significant difference in age between PD patients and controls (mean age ± standard deviation of PD patients vs. controls: 72.3 ± 10.9 vs. 66.4 ± 13.8, P = 0.058) and most patients in both groups were 70–79 years of age (PD patients vs. controls: 18 [46%] vs. 15 [46%], P = 0.078). Only three (4%) participants were living alone. In 39 PD patients, 17 (43%) had a disease duration of 5 years or more, 27 (69%) were classified into HY stage 3 or more, and the median MDS-UPDRS part 2 score was 17 (interquartile range: 10.0 to 20.5). The rates of cognitive impairment, hallucinations, and RBD were 6 (15%), 4 (10%), and 6 (15%), respectively. There were 9 (23%) patients who were prescribed 600 mg or more of L-DOPA, and dopamine agonists were taken by 15 (38%) patients. Psychiatric and sleeping medicines were used in 8 (20%) and 13 (33%) patients, respectively (Table 1). Among PD patients, there was no difference between female and male participants in disease duration, HY stage, non-motor symptoms, therapeutic medications, or MDS-UPDRS part 2 scores (S1 Table).

Table 1. Demographic characteristics of responders.

No. (%)
Characteristics Total PD Control P-value
Overall 71 (100) 39 (54.9) 32 (45.0)
Sex
Male 30 (42.2) 25 (64.1) 5 (15.6) < 0.001
Female 41 (57.7) 14 (35.8) 27 (84.3)
Age, y
<70 25 (35.2) 11 (15.4) 14 (19.7) 0.078
70–79 33 (46.4) 18 (46.1) 15 (46.8)
>80 13 (18.3) 10 (25.6) 3 (9.3)
Living alone 3 (4.2) 3 (7.6) - 0.109
Disease duration, years
< 5 22 (56.4) - -
≥ 5 17 (43.5) - -
HY stage
stage 0–2 12 (30.7) - -
stage 3, 4 27 (69.2) - -
Non-motor symptoms
Cognitive impairment 6 (15.3) - -
Hallucinations 4 (10.2) - -
RBD 6 (15.3) - -
L-DOPA, mg
< 600 30 (76.9) - -
≥ 600 9 (23.0) - -
Other medications
Dopamine agonist 15 (38.4) - -
Psychiatric medicines 8 (20.5) - -
Sleeping medicines 13 (33.3) - -
MDS-UPDRS part 2, 17 (10–20.5) - -
median (IQR), n = 36*
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Abbreviations: HY, Hoehn & Yahr; RBD, REM sleep behavior disorder; MDS-UPDRS, Movement Disorder Society Unified Parkinson's Disease Rating Scale; IQR, interquartile range.

*Of the 39 participants, 36 responded to the question about MDS-UPDRS part 2.

Severity and scores of measurements

Compared with controls, significantly more PD patients presented with clinical depression using PHQ-9 (PD patients vs. controls: 15 [39%] vs. 2 [6%], P = 0.002). Assessment of anxiety using GAD-7 and insomnia using ISI showed that PD patients tended to be more likely to present with clinical anxiety and insomnia, but neither reached significance (clinical anxiety among PD patients vs. controls: 19 (48%) vs. 11 (34%), P = 0.223; clinical insomnia among PD patients vs. controls: 13 (33%) vs. 7 (21%), P = 0.286) (Table 2). When analyzed by sex, significantly more female PD patients presented with clinical depression (PD patients vs. controls: 7 [50%] vs. 1 [3.8%], P = 0.001), whereas no significant difference was observed in male PD patients and controls (PD patients vs. controls: 8 [33%] vs. 1 [20%], P = 0.558) (S2A and S2B Table).

Table 2. Severity categories of depression, anxiety, and insomnia measurements in PD patients and controls.

No. (%)
Severity category Total PD Control P-value*
PHQ-9, depression symptoms n = 69 n = 38 n = 31
Normal 32 (46.3) 14 (36.8) 18 (58.0) 0.002
Mild 20 (28.9) 9 (23.6) 11 (0.35)
Moderate 9 (13.0) 8 (21.0) 1 (3.2)
Severe 8 (11.5) 7 (18.4) 1 (3.2)
GAD-7, anxiety symptoms n = 71 n = 39 n = 32
Normal 35 (49.2) 18 (46.1) 17 (53.1) 0.223
Mild 20 (28.1) 9 (23.0) 11 (34.3)
Moderate 10 (14.0) 7 (17.9) 3 (9.3)
Severe 6 (8.4) 5 (12.8) 1 (3.1)
ISI, insomnia symptoms n = 71 n = 39 n = 32
Absence 31 (43.6) 15 (38.4) 16 (50.0) 0.286
Subthreshold 20 (28.1) 11 (28.2) 9 (28.1)
Moderate 18 (25.3) 11 (28.2) 7 (21.8)
Severe 2 (2.8) 2 (5.1) 0 (0.0)
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Abbreviations: PHQ-9, 9-item Patient Health Questionnaire; GAD-7, 7-item Generalized Anxiety Disorder; ISI, 7-item Insomnia Severity Index.

* Cutoff scores for PHQ-9, GAD-7, and ISI were 10, 7, and 15, respectively. Participants who had scores greater than the cutoff threshold were characterized as showing clinical symptoms. Chi-squared test was applied to compare the rate of participants with clinical symptoms in PD patients and controls.

The median (IQR) score of PHQ-9 for depression in PD patients was significantly higher than in controls (PD patients vs. controls: 7.0 [2.0–13.0] vs. 2.0 [0.0–7.0], P = 0.010). Scores of GAD-7 for anxiety and ISI for insomnia tended to be higher in PD patients, but neither reached significance (median [IQR] GAD-7 scores among PD patients vs. controls: 6.0 [1.5–10.5] vs. 4.0 [1.0–7.0], P = 0.130; median [IQR] ISI scores among PD patients vs. controls: 10.0 [5.0–16.0] vs. 7.5 [2.0–13.25], P = 0.170) (Table 3). When analyzed by sex, no significant differences between PD patients and controls in depression, anxiety, and insomnia were observed for either sex (S3A and S3B Table).

Table 3. Scores of depression, anxiety, and insomnia measurements in PD patients and controls.

Median (IQR)
Scale Total score PD Control P-value*
PHQ-9, depression symptoms 5.0 7.0 2.0 0.010
(1.0–8.0) (2.0–13.0) (0.0–7.0)
GAD-7, anxiety symptoms 5.0 6.0 4.0 0.130
(1.0–9.0) (1.5–10.5) (1.0–7.0)
ISI, Insomnia symptoms 8.0 10.0 7.5 0.170
(2.5–15.0) (5.0–16.0) (2.0–13.25)
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Abbreviations: PD, Parkinson's disease; IQR, interquartile range; PHQ-9, 9-item Patient Health Questionnaire; GAD-7, 7-item Generalized Anxiety Disorder; ISI, 7-item Insomnia Severity Index.

* Mann-Whitney U test was adapted to compare each questionnaire score between PD patients and controls on.

Among both PD patients and controls, 30–40% of participants complained of subjective worsening of motor performance and anxiety, but there were no significant differences (subjective worsening of motor performance among PD patients vs. controls: 16 [41%] vs. 12 [37%], P = 0.84; subjective worsening of anxiety among PD patients vs. controls: 12 [30%] vs. 14 [43%], P = 0.25). Interestingly, the control group was more likely to report subjective worsening of anxiety than PD patients. Fewer PD patients and controls complained of subjective worsening of insomnia (PD patients vs. controls: 5 [12%] vs. 3 [9%], P = 0.64) (Table 4). When analyzed by sex, more than 40% of female participants in both PD and control groups complained of subjective worsening of motor function and anxiety, whereas less than 20% of male participants in PD and control groups showed subjective worsening of motor function and 20–40% of them showed subjective anxiety (S4A and S4B Table).

Table 4. Rate of responders with worsening of motor performance, anxiety, and insomnia.

No. (%)
Values Total PD Control P-value
Overall 71 (100) 39 (54.9) 32 (45.0)
Worsening of motor performance 28 (39.4) 16 (41.0) 12 (37.5) 0.84
Worsening of anxiety 26 (36.6) 12 (30.7) 14 (43.7) 0.25
Worsening of insomnia 8 (11.2) 5 (12.8) 3 (9.3) 0.64
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Abbreviation: PD, Parkinson's disease.

Risk factors

Multivariate logistic regression analysis demonstrated that an MDS-UPDRS part 2 score was correlated with the presence of clinical depression (PHQ-9 score ≥ 10) and clinical anxiety (GAD-7 score ≥ 7) in PD patients (clinical depression: OR, 1.31; 95% CI, 1.04–1.66; P = 0.025; clinical anxiety: OR, 1.36; 95% CI, 1.07–1.72; P = 0.013). A male sex was also a significant risk factor for PD patients’ clinical anxiety in the multivariate model (OR, 17.12; 95% CI, 1.13–257.27; P = 0.040). Univariate logistic regression analysis showed that an MDS-UPDRS part 2 score was correlated with clinical insomnia (clinical insomnia: OR, 1.13; 95% CI, 1.01–1.26; P = 0.038), but it did not reach significance in the multivariate model (Table 5). The univariate model also showed the following results: the L-DOPA dose was not associated with clinical depression, anxiety, or insomnia, and the use of dopamine agonists was significantly correlated with clinical depression (clinical depression: OR, 5.40; 95% CI, 1.29–22.60; P = 0.021), but not with clinical insomnia or anxiety. In the multivariate model, the use of dopamine agonists did not reached significance (Table 6). Neither uni- nor multivariate logistic regression analyses were able to demonstrate significant risk factors for subjective worsening of motor performance, anxiety, and insomnia (Table 7).

Table 5. Risk factors for neuropsychiatric symptoms identified by uni- and multivariate logistic regression analyses.

Univariate model Multivariate model
No. of clinical cases/No. of total cases (%) Unadjusted OR P-value Adjusted OR P-value
Variable 95%CI Category Overall 95%CI Category Overall
PHQ-9, depression symptoms
Sex
Female 7/14 (50.0) 1 [reference] - 1 [reference] -
Male 8/24 (33.3) 0.5 (0.13 - 1.93) 0.314 5.66 (0.51 - 62.47) 0.157
Age
<70 7/11 (63.6) 1 [reference] - 0.123 1 [reference] - 0.530
70–79 4/17 (23.5) 0.18 (0.03 - 0.93) 0.084 0.61 (0.05 - 8.08) 0.750
≥80 4/10 (40.0) 0.38 (0.07 - 2.22) 0.901 0.19 (0.01 - 3.93) 0.264
Disease duration
< 5 5/22 (22.7) 1 [reference] - 1 [reference] -
≥ 5 10/16 (62.5) 5.67 (1.37 - 23.46) 0.017 1.01 (0.13 - 7.78) 0.995
HY stage
0–2 4/12 (33.3) 1 [reference] - 1 [reference] -
3, 4 11/26 (42.3) 1.47 (0.35 - 6.13) 0.600 10.17 (0.57 - 182.91) 0.116
MDS-UPDRS part 2* 1.24 (1.06 - 1.45) 0.008 1.31 (1.04 - 1.66) 0.025
GAD-7, anxiety symptoms
Sex
Female 7/14 (50.0) 1 [reference] - 1 [reference] -
Male 12/25 (48.0) 0.92 (0.25 - 3.42) 0.905 17.12 (1.13 - 257.27) 0.040
Age
<70 8/11 (72.7) 1 [reference] - 0.137 1 [reference] - 0.458
70–79 6/18 (33.3) 0.19 (0.04 - 0.98) 0.083 0.55 (0.04 - 7.69) 0.774
≥80 5/10 (50.0) 0.38 (0.06 - 2.31) 0.850 0.16 (0.01 - 3.08) 0.221
Disease duration
< 5 9/22 (40.9) 1 [reference] - 1 [reference] -
≥ 5 10/17 (58.8) 2.06 (0.57 - 7.47) 0.270 0.35 (0.04 - 3.08) 0.359
HY stage
0–2 6/12 (50.0) 1 [reference] - 1 [reference] -
3, 4 13/27 (48.1) 0.93 (0.24 - 3.62) 0.915 8.19 (0.52 - 128.74) 0.135
MDS-UPDRS part 2* 1.17 (1.03 - 1.32) 0.014 1.36 (1.07 - 1.72) 0.013
ISI, insomnia symptoms
Sex
Female 5/14 (35.7) 1 [reference] - 1 [reference] -
Male 8/25 (32.0) 0.85 (0.21 - 3.36) 0.814 1.68 (0.25 - 11.2) 0.595
Age
<70 6/11 (54.6) 1 [reference] - 0.116 1 [reference] - 0.310
70–79 3/18 (16.7) 0.17 (0.03 - 0.93) 0.052 0.21 (0.03 - 1.63) 0.158
≥80 4/10 (40.0) 0.56 (0.1 - 3.15) 0.693 0.53 (0.05 - 5.7) 0.884
Disease duration
< 5 6/22 (27.3) 1 [reference] - 1 [reference] -
≥ 5 7/17 (41.2) 1.87 (0.49 - 7.18) 0.364 1.55 (0.27 - 8.78) 0.620
HY stage
0–2 5/12 (41.7) 1 [reference] - 1 [reference] -
3, 4 8/27 (29.6) 0.59 (0.14 - 2.42) 0.464 0.87 (0.11 - 7.09) 0.900
MDS-UPDRS part 2* 1.13 (1.01 - 1.26) 0.038 1.11 (0.98 - 1.25) 0.113
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Abbreviations: Unadjusted OR, Unadjusted odds ratio; 95%CI, 95% confidence interval; PHQ-9, 9-item Patient Health Questionnaire; HY, Hoehn & Yahr; MDS-UPDRS, Movement Disorder Society-Unified Parkinson's Disease Rating Scale; GAD-7, 7-item Generalized Anxiety Disorder; ISI, 7-item Insomnia Severity Index.

* Continuous quantity was analyzed.

Table 6. Association with neuropsychiatric symptoms and PD drugs in uni- and multivariate logistic regression analyses.

Univariate model Multivariate model*
No. of clinical cases/No. of total cases (%) Unadjusted OR Adjusted OR
Variable 95%CI P-value 95%CI P-value
PHQ-9, depression symptoms
L-DOPA, mg
< 600 10/30 (33.3) 1 [reference] - 1 [reference] -
≥ 600 5/8 (62.5) 3.33 (0.66 - 16.85) 0.145 1.39 (0.13 - 15.26) 0.787
Dopamine agonist
without 6/24 (25.0) 1 [reference] - 1 [reference] -
with 9/14 (64.3) 5.40 (1.29 - 22.6) 0.021 9.33 (0.85 - 102.72) 0.068
GAD-7, anxiety symptoms
L-DOPA, mg
< 600 15/30 (50.0) 1 [reference] -
≥ 600 4/9 (44.4) 0.8 (0.18 - 3.57) 0.77
Dopamine agonist
without 9/24 (72.7) 1 [reference] - 1 [reference] -
with 10/15 (66.7) 3.33 (0.86 - 12.92) 0.082 13.07 (0.81 - 210.16) 0.070
ISI, insomnia symptoms
L-DOPA, mg
< 600 9/30 (30.0) 1 [reference] -
≥ 600 4/9 (44.4) 1.87 (0.41 - 8.61) 0.424
Dopamine agonist
without 8/24 (33.3) 1 [reference] -
with 5/15 (33.3) 1.00 (0.25 - 3.93) 1.000
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Abbreviations: Unadjusted OR, Unadjusted odds ratio; 95%CI, 95% confidence interval; PHQ-9, 9-item Patient Health Questionnaire; GAD-7, 7-item Generalized Anxiety Disorder; ISI, 7-item Insomnia Severity Index.

Table 7. Risk factors for subjective worsening of motor performance, anxiety, and insomnia identified by uni- and multivariate logistic regression analyses.

　 　 　 Univariate model Multivariate model
No. of clinical cases/No. of total cases (%) Unadjusted OR P-value Adjusted OR P-value
Variable 　 95%CI Category Overall 95%CI Category Overall
Subjective worsening of motor performance 　 　 　 　 　 　 　 　 　 　 　
Sex 　 　 　 　 　 　 　 　 　 　 　 　 　 　
Female 8/14 (57.1) 1 [reference] 　 　 　 - 　 1 [reference] 　 　 　 - 　
　 Male 8/25 (32.0) 0.35 (0.09 - 1.36) 0.131 　 0.60 (0.11 - 3.20) 0.547 　
Age 　 　
<70 6/11 (54.6) 1 [reference] 　 　 　 - 0.301 1 [reference] 　 　 　 - 0.582
70–79 5/18 (27.8) 0.32 (0.07 - 1.54) 0.126 0.39 (0.05 - 2.80) 0.307
　 ≥80 5/10 (50.0) 0.83 (0.15 - 4.63) 0.606 0.75 (0.07 - 7.65) 0.845
Disease duration 　 　
< 5 7/22 (31.8) 1 [reference] 　 　 　 - 　 1 [reference] 　 　 　 - 　
　 ≥ 5 9/17 (52.9) 2.41 (0.65 - 8.92) 0.188 1.90 (0.38 - 9.61) 0.437
HY stage 　 　 　 　 　 　 　 　 　 　 　 　 　 　
0–2 4/12 (33.3) 1 [reference] 　 　 　 - 　 1 [reference] 　 　 　 - 　
　 3, 4 12/27 (44.4) 1.60 (0.39 - 6.62) 0.517 3.68 (0.39 - 34.3) 0.253
MDS-UPDRS part 2* 　 1.06 (0.97 - 1.15) 0.217 　 1.02 (0.93 - 1.12) 0.694 　
Subjective worsening of anxiety 　 　 　 　 　 　 　 　 　 　 　 　
Sex 　 　 　 　 　 　 　 　 　 　 　 　 　 　
Female 7/14 (50.0) 1 [reference] 　 　 　 - 　 1 [reference] 　 　 　 - 　
　 Male 5/25 (20.0) 0.25 (0.06 - 1.05) 0.058 　 0.34 (0.06 - 2.15) 0.253 　
Age 　 　
<70 4/11 (36.4) 1 [reference] 　 　 　 - 0.561 1 [reference] 　 　 　 - 0.721
70–79 4/18 (22.2) 0.50 (0.09 - 2.62) 0.287 1.18 (0.12 - 12.04) 0.719
　 ≥80 4/10 (40.0) 1.17 (0.20 - 6.80) 0.516 2.61 (0.16 - 42.16) 0.427
Disease duration 　 　
< 5 5/22 (22.7) 1 [reference] 　 　 　 - 　 1 [reference] 　 　 　 - 　
　 ≥ 5 7/17 (41.2) 2.38 (0.59 - 9.53) 0.221 1.71 (0.29 - 9.91) 0.551
HY stage 　 　 　 　 　 　 　 　 　 　 　 　 　 　
0–2 3/12 (25.0) 1 [reference] 　 　 　 - 　 1 [reference] 　 　 　 - 　
　 3, 4 9/27 (33.3) 1.50 (0.32 - 6.94) 0.604 2.12 (0.17 - 26.69) 0.561
MDS-UPDRS part 2* 　 　 1.06 (0.97 - 1.16) 0.218 　 1.03 (0.93 - 1.15) 0.552 　
Subjective worsening of insomnia 　 　 　 　 　 　 　 　 　 　 　 　
Sex 　 　 　 　 　 　 　 　 　 　 　 　 　 　
Female 3/14 (21.4) 1 [reference] 　 　 　 - 　 1 [reference] 　 　 　 - 　
　 Male 2/25 (8.0) 0.32 (0.05 - 2.19) 0.245 　 0.705 (0.07 - 7.52) 0.772 　
Age 　 　
<70 3/11 (27.3) 1 [reference] 　 　 　 - 0.278 1 [reference] 　 　 　 - 0.569
70–79 1/18 (5.6) 0.16 (0.01 - 1.75) 0.302 0.19 (0.01 - 4.16) 0.412
　 ≥80 1/10 (10.0) 0.30 (0.02 - 3.45) 0.812 0.35 (0.01 - 8.82) 0.874
Disease duration 　 　
< 5 3/22 (13.6) 1 [reference] 　 　 　 - 　 1 [reference] 　 　 　 - 　
　 ≥ 5 2/17 (11.8) 0.84 (0.12 - 5.72) 0.863 0.66 (0.05 - 8.36) 0.745
HY stage 　 　 　 　 　 　 　 　 　 　 　 　 　 　
0–2 2/12 (16.7) 1 [reference] 　 　 　 - 　 1 [reference] 　 　 　 - 　
　 3, 4 3/27 (11.1) 0.63 (0.09 - 4.32) 0.634 1.90 (0.08 - 38.5) 0.676
MDS-UPDRS part 2* 　 　 1.09 (0.97 - 1.23) 0.131 　 1.11 (0.96 - 1.28) 0.172 　
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Abbreviations: Unadjusted OR, Unadjusted odds ratio; 95%CI, 95% confidence interval; HY, Hoehn & Yahr; MDS-UPDRS, Movement Disorder Society-Unified Parkinson's Disease Rating Scale.

* Continuous quantity was analyzed.

Discussion

This cross-sectional study in Japan involved 39 PD patients and 32 controls and revealed that PD patients were significantly more likely to have clinical depression than controls under the social restrictions imposed due to the COVID-19 pandemic. An MDS-UPDRS part 2 score was correlated with the presence of clinical depression and anxiety in PD patients. A male sex was a significant risk factor only for clinical anxiety in PD patients. Subjective worsening of motor performance was noted in about 40% of both PD patients and controls. Subjective worsening of anxiety was more common in controls, though it did not reach statistical significance.

It is becoming clear that the COVID-19 pandemic has a negative impact on the PD symptoms [8, 9, 20]. Van der Heide et al. showed that COVID-19-related stress load was positively correlated with psychological distress, resulting in more severe PD symptoms [14]. Shalash et al. showed that more than 52% of PD patients reported stress, anxiety, and disrupted contact with their physicians due to COVID-19 related social restrictions [9]. Basically, depression, anxiety, and sleep disturbance are common non-motor features from the prodromal to late stage of PD [4–6]. A previous systematic review of prevalence for depression in PD patients concluded that clinically significant depressive symptoms were observed in 35% of them [21]. Other studies using PHQ-9, like our study, for the assessment of depression reported the prevalence of clinical depression as 14–34% [22, 23]. Because we did not have data on the neuropsychiatric status of PD patients before the COVID-19 pandemic, we could not directly show that the COVID-19 pandemic in Japan worsened the neuropsychiatric status of our PD patients. However, the prevalence of clinical depression in PD patients of this study (39%) was as high as or higher than that of previous reviews. Considering this fact, the impact of the COVID-19 pandemic should not be ignored on the neuropsychiatric status of PD patients even in Japan, where no legal penalties were imposed for going out during the state of emergency.

PD patients with specific characteristics such as low optimism and high neuroticism were reported to show higher levels of psychological distress due to COVID-19 pandemic [14]. Previous reports described that PD patients with a maladaptive metacognitive style showed an increased vulnerability to psychological distress. In other words, uncontrolled anxiety in PD patients is likely to amplify the anxiety itself [24, 25]. In our study, clinical depression and anxiety were more common in PD patients, even though the prevalence of subjective worsening of anxiety was comparable between PD patients and controls. Overall, we may indicate that PD patients, especially who have pre-existing psychological problems, are more likely to develop clinical depression in response to social distress.

In this study, a high MDS-UPDRS part 2 score was shown to be a risk factor for clinical depression and anxiety. This is consistent with previous studies suggesting that reduced exercise time was associated with worsening of both motor and non-motor symptoms under COVID-19 pandemic [12–14] and that motor fluctuation and impairment of activities of daily life were significant risk factors for the development of depression [26]. In addition, we showed that a male sex was associated with clinical anxiety, while a female sex was reported to be a potential risk factor for anxiety both in general population and in PD patients [26, 27]. In the previous report, Xia et al. showed lower scores of depression and anxiety in male PD patient than female, though it was not multivariate analysis [10]. In addition, we are currently under the distinct stress due to COVID-19 pandemic that did not exist in the past, so we need more cases to determine the impact of sex on the neuropsychiatric symptoms under COVID-19 pandemic. Other potential risk factors for non-motor symptoms such as age, disease duration, and HY stage did not show statistical significance in this study [4–6]. A larger sample size may be needed to examine the correlation between neuropsychiatric symptoms and these potential risk factors because they presented statistical significance in the univariate model (Table 5).

Reasons for the high prevalence of subjective worsening of anxiety in controls may be related to the fact that they were caregivers, in addition to the fact that 84% of them are female. Oppo et al. also reported that caregivers complained similar or higher levels of worsened mental stress than PD patients during home confinement due to COVID-19 pandemic (PD patients vs. caregivers, 43% vs 54%, respectively) [12]. It has been reported that caregivers of PD patients have a marked mental burden [28, 29]. Research based on interviews revealed that caregivers of PD patients complained of increased responsibility and insufficient time to take care of themselves [30, 31]. Regarding COVID-19, Lara et al. showed that 30% of patients with Alzheimer’s disease and 40% of their caregivers reported worsening mental health conditions due to the COVID-19 lockdown [32]. Oppo et al. also indicated that some non-motor symptoms such as mood, cognition, and urinary problems in PD patients caused additional mental burden on the caregivers [12]. In addition to caregivers’ own health concerns, feeling responsible for PD patients’ health status may have led to the high prevalence of subjective worsening of anxiety in controls in this study.

Limitations of this study include the absence of information about depression, anxiety, and insomnia of participants before COVID-19 pandemic and a female bias in sex ratio in control group. We can review patients’ chart and find information about psychiatric or sleeping medicines to estimate pre-COVID-19 neuropsychiatric status of PD patients, though these are not perfect and would not be available for controls. As we mentioned above, several papers are now proving the negative impact of the COVID-19 pandemic on symptoms of PD patients, so we need to continue to monitor the impact of the COVID-19 pandemic on PD patients in Japan. Although we calculated the required number of samples to compare the prevalence of neuropsychiatric symptoms during COVID-19 pandemic in PD and control groups based on previous papers, we had a larger number of female participants in controls. We found more clinical depression among female PD patients, while there were no significant differences between male PD patients and controls. This result may be influenced by the small number of male controls. We may need to adjust the sex ratio of participants in future and need more participants to estimate risk factors which potentially influence neuropsychiatric symptoms of PD patients.

Conclusions

PD patients may be more likely to develop clinical depression than those without PD in the presence of social stresses, such as a pandemic, even in Japan where no legal penalties were imposed during the state of emergency. Considering the significant correlation between high MDS-UPDRS part 2 scores and the complication of severe depression and anxiety in PD patients, such patients may require special attention regarding the development of neuropsychiatric symptoms not only during COVID-19 pandemic but also in the event of another major disaster in the future.

Supporting information

S1 Table. Demographic characteristics of responders stratified by sex.

(DOCX)

Click here for additional data file. (22.7KB, docx)
S2 Table

a. Severity categories of depression, anxiety, and insomnia measurements in female PD patients and controls. b. Severity categories of depression, anxiety, and insomnia measurements in male PD patients and controls.

(DOCX)

Click here for additional data file. (15.8KB, docx)
S3 Table

a. Scores of depression, anxiety, and insomnia measurements in female PD patients and controls. b. Scores of depression, anxiety, and insomnia measurements in male PD patients and controls.

(DOCX)

Click here for additional data file. (13.9KB, docx)
S4 Table

a. Rate of female responders with worsening of motor performance, anxiety, and insomnia. b. Rate of male responders with worsening of motor performance, anxiety, and insomnia.

(DOCX)

Click here for additional data file. (12.9KB, docx)
S1 Data. Questions that ask for subjective change in participants and original data of all participants.

(XLSX)

Click here for additional data file. (17KB, xlsx)

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

This work was supported by Grants-in-Aid (18K07506 to T.K.; 20K16605 to T.O.) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.

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Decision Letter 0

Kensaku Kasuga

3 Dec 2020

PONE-D-20-34679

Risk factors for neuropsychiatric symptoms in patients with Parkinson’s disease during COVID-19 pandemic in Japan

PLOS ONE

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Additional Editor Comments (if provided):

This manuscript describes that PD patients were more likely to have depression than control, and showed an association between psychiatric symptoms, especially depression and anxiety, and ADL assessed with UPDRS part 2 in PD patients under the COVID-19 pandemic. Furthermore, this study showed caregiver’s stress as assessed by subjective worsening of anxiety.

This study would contribute to considerations for care of PD patients under stressful conditions such as the COVID-19 pandemic. As reviewer 1 mentioned, this paper should be published as soon as possible.

However, I think that a revision is needed to improve this manuscript.

As the authors noted in a limitation, PD patients were not compared to before the COVID-19 pandemic. Reviewer 2 has also pointed out this point (see reviewer’s comment). The prevalence of depression in PD patients in this study (39%) was actually comparable to a previous report (reference 19: 34%, 95%CI 27.9-40.6). It suggests that PD patients are likely to have depression even not under the COVID-19 pandemic. Alternatively, some PD patients could have less depression despite under stressful conditions. The authors should consider these points more with additional data or the previous reports.

Please respond to the reviewer’s and my comments to make the manuscript better.

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: No

**********

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: this study was well conducted.

this study was aimed to clarify the impact of social restrictions imposed due to the COVID-19 pandemic on neuropsychiatric symptoms in PD patients and to identify risk factors.

and they concluded, In the presence of social restrictions, more attention needs to be paid to the neuropsychiatric complications of PD patients, especially those with more severe motor symptoms.

this paper must be published urgently.

Reviewer #2: Although the authors performed statistical analyses rigorously, I think there is a critical flaw in the method of this research. If the authors wanted to assess impact of the COVID-19 pandemic on symptoms of PD, they should have compared those of pre- with those of post-COVID-19 pandemic, or at least tried to measure changes between pre- and post-COVID-19 pandemic in more detailed items and also in multipoint scale. It seems that only self-reported dichotomy data about changes in three symptoms (motor performance, anxiety and insomnia) were collected in this article. Thus, this study mainly assessed only association between the severity of motor symptoms and that of non-motor symptoms in PD patients regardless of the COVID-19 restrictions. It is important itself but it does not answer the research question which the authors raised. Also, questionnaire survey could be rather easily conducted in a multi-site study setting to collect more patients.

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PLoS One. 2021 Jan 22;16(1):e0245864. doi: 10.1371/journal.pone.0245864.r002

Author response to Decision Letter 0

10 Dec 2020

Dear Editors and Reviewers,

We deeply appreciate your informative suggestions. Here, we submit following documents: Manuscript (without track change), Revised manuscript with track changes, Response to reviewers, and revised Supporting information data. Thank you very much for your consideration.

Journal Requirements:

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

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(Answer) We appreciate the editor’s suggestion. We have corrected the manuscript as these PDF indicating.

2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

(Answer) We appreciate the editor’s comment. We have added the additional information about informed consent as follows (P1, Line 69-70): Written informed consent was provided by all survey participants. No minors were among the participants.

3. Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information, or include a citation if it has been published previously.

(Answer) We appreciate the editor’s comment. Validated Japanese questionnaires were introduced in ref. 15-18. We have added information about questions that ask for subjective mental/physical changes in participants to Supporting information data file as follows (P18, Line371 and Supporting information data file): Has the COVID-19 pandemic made your anxiety worse? Has the COVID-19 pandemic made your insomnia worse? Has the COVID-19 pandemic made your motor performance worse? (originally in Japanese)

4. Please provide further details on sample size and power calculations.

(Answer) We appreciate the editor’s comment. We have added the sentence as follows (P3, Line71-74): According to a priori power analysis (with 95% power and 5% type I error rate) of the results of previous studies, the minimum number for the sample was found to be 41 patients for the comparative study of the prevalence of psychiatric symptoms in PD and control groups.

-Additional Editor Comments (if provided):

-This manuscript describes that PD patients were more likely to have depression than control, and showed an association between psychiatric symptoms, especially depression and anxiety, and ADL assessed with UPDRS part 2 in PD patients under the COVID-19 pandemic. Furthermore, this study showed caregiver’s stress as assessed by subjective worsening of anxiety.

This study would contribute to considerations for care of PD patients under stressful conditions such as the COVID-19 pandemic. As reviewer 1 mentioned, this paper should be published as soon as possible.

However, I think that a revision is needed to improve this manuscript.

As the authors noted in a limitation, PD patients were not compared to before the COVID-19 pandemic. Reviewer 2 has also pointed out this point (see reviewer’s comment). The prevalence of depression in PD patients in this study (39%) was actually comparable to a previous report (reference 19: 34%, 95%CI 27.9-40.6). It suggests that PD patients are likely to have depression even not under the COVID-19 pandemic.

(Answer) We deeply appreciate the editor’s informative suggestion. As the editor and reviewer pointed out, we did not show the information about pre-COVID-19 status. However, recent accumulating articles are proving that the COVID-19 pandemic had a negative impact on the PD symptoms (Van der Heide et al. J Parkinson Dis. 2020, Subramanian et al. npj Parkinsons Dis. 2020, Song et al. Parkinsonism Relat Disord. 2020). Even though Japanese state of emergency impose no legal penalties unlike in European countries, we cannot ignore the impact of COVID-19 pandemic on neuropsychiatric symptoms in Japanese PD patients. Based on the editor and reviewer’s comment, we have corrected the manuscript as follows (P13, Line196-210): It is becoming clear that the COVID-19 pandemic has a negative impact on the PD symptoms (8, 9, 20). Van der Heide et al. showed that COVID-19-related stress load was positively correlated with psychological distress, resulting in more severe PD symptoms (14). Shalash et al. showed that more than 52% of PD patients reported stress, anxiety, and disrupted contact with their physicians due to COVID-19 related social restrictions (9). Basically, depression, anxiety, and sleep disturbance are common non-motor features from the prodromal to late stage of PD (4-6). A previous systematic review of prevalence for depression in PD patients concluded that clinically significant depressive symptoms were observed in 35% of them (21). Other studies using PHQ-9, like our study, for the assessment of depression reported the prevalence of clinical depression as 14-34% (22, 23). Because we did not have data on the neuropsychiatric status of PD patients before the COVID-19 pandemic, we could not directly show that the COVID-19 pandemic in Japan worsened the neuropsychiatric status of our PD patients. However, the prevalence of clinical depression in PD patients of this study (39%) was as high as or higher than that of previous reviews. Considering this fact, the impact of the COVID-19 pandemic should not be ignored on the neuropsychiatric status of PD patients even in Japan, where no legal penalties were imposed for going out during the state of emergency.

-Alternatively, some PD patients could have less depression despite under stressful conditions. The authors should consider these points more with additional data or the previous reports.

Please respond to the reviewer’s and my comments to make the manuscript better.

(Answer) We appreciate the editor’s comment. As the editor mentioned, pre-existing specific characteristics (such as high neuroticism and low optimism) may be potential risk factors for worsening of psychological problems. We mentioned this point in Line211-212.

-Comments to the Author

-Reviewer #1: this study was well conducted.

-this study was aimed to clarify the impact of social restrictions imposed due to the COVID-19 pandemic on neuropsychiatric symptoms in PD patients and to identify risk factors.

and they concluded, In the presence of social restrictions, more attention needs to be paid to the neuropsychiatric complications of PD patients, especially those with more severe motor symptoms.

this paper must be published urgently.

-Reviewer #2: Although the authors performed statistical analyses rigorously, I think there is a critical flaw in the method of this research. If the authors wanted to assess impact of the COVID-19 pandemic on symptoms of PD, they should have compared those of pre- with those of post-COVID-19 pandemic, or at least tried to measure changes between pre- and post-COVID-19 pandemic in more detailed items and also in multipoint scale. It seems that only self-reported dichotomy data about changes in three symptoms (motor performance, anxiety and insomnia) were collected in this article. Thus, this study mainly assessed only association between the severity of motor symptoms and that of non-motor symptoms in PD patients regardless of the COVID-19 restrictions. It is important itself but it does not answer the research question which the authors raised.

(Answer) We greatly appreciate the reviewer’s informative comments. As the editor and reviewer pointed out, we did not show the information about pre-COVID-19 status. However, recent accumulating articles are proving that the COVID-19 pandemic had a negative impact on the PD symptoms (Van der Heide et al. J Parkinson Dis. 2020, Subramanian et al. npj Parkinsons Dis. 2020, Song et al. Parkinsonism Relat Disord. 2020). Even though Japanese state of emergency impose no legal penalties unlike in European countries, we cannot ignore the impact of COVID-19 pandemic on neuropsychiatric symptoms in Japanese PD patients. Based on the editor and reviewer’s comment, we have corrected the manuscript as follows (P13, Line196-210): It is becoming clear that the COVID-19 pandemic has a negative impact on the PD symptoms (8, 9, 20). Van der Heide et al. showed that COVID-19-related stress load was positively correlated with psychological distress, resulting in more severe PD symptoms (14). Shalash et al. showed that more than 52% of PD patients reported stress, anxiety, and disrupted contact with their physicians due to COVID-19 related social restrictions (9). Basically, depression, anxiety, and sleep disturbance are common non-motor features from the prodromal to late stage of PD (4-6). A previous systematic review of prevalence for depression in PD patients concluded that clinically significant depressive symptoms were observed in 35% of them (21). Other studies using PHQ-9, like our study, for the assessment of depression reported the prevalence of clinical depression as 14-34% (22, 23). Because we did not have data on the neuropsychiatric status of PD patients before the COVID-19 pandemic, we could not directly show that the COVID-19 pandemic in Japan worsened the neuropsychiatric status of our PD patients. However, the prevalence of clinical depression in PD patients of this study (39%) was as high as or higher than that of previous reviews. Considering this fact, the impact of the COVID-19 pandemic should not be ignored on the neuropsychiatric status of PD patients even in Japan, where no legal penalties were imposed for going out during the state of emergency.

-As the reviewer pointed out, we need more detailed items and multipoint scale to assess subtle changes in symptoms in PD patients due to COVID-19 pandemic. The important previous paper (Van der Heide et al. J Parkinsons Dis. 2020) used 9-point scale to assess PD symptoms, however, they eventually analyzed the data into three groups: worse, no change, and improved. In addition, they showed that non-responders had a higher severity of PD symptoms. Given that our response rates was as high as 88% in PD patients, we believe that the simplified assessment method had some effect in avoiding respondent bias.

Also, questionnaire survey could be rather easily conducted in a multi-site study setting to collect more patients.

(Answer) We appreciate the reviewer’s important suggestion. Sample size calculation based on previous papers indicated that the number of participants needed to compare the prevalence of neuropsychiatric symptoms in PD and control group was 41 for each group, but we need more participants to assess risk factors by multivariate analysis. However, changes in work schedules of physicians at each facility due to stay-at-home order made multi-site study difficult. Based on the above, we have corrected the manuscript as follows (P14, Line 252-269): Although we calculated the required number of samples to compare the prevalence of neuropsychiatric symptoms during COVID-19 pandemic in PD and control groups based on previous papers, we had a larger number of female participants in controls. We found more clinical depression among female PD patients, while there were no significant differences between male PD patients and controls. This result may be influenced by the small number of male controls. We may need to adjust the sex ratio of participants in future and need more participants to estimate risk factors which potentially influence neuropsychiatric symptoms of PD patients.

Attachment

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Decision Letter 1

Kensaku Kasuga

11 Jan 2021

Risk factors for neuropsychiatric symptoms in patients with Parkinson’s disease during COVID-19 pandemic in Japan

PONE-D-20-34679R1

Dear Dr. Kasai,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Reviewers' comments:

Reviewer's Responses to Questions

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: This is well conducted study.

Reviewer #2: I still think the study design the authors employed is not the best for answering the research question they raised, however, they tried to cover this defect with reviewing recent literature in the article. Given that there are country/region -specific characteristics of patients with PD, a similar study from a different country/region is worth publishing and it should occur timely during the pandemic as the other reviewer wrote.

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Reviewer #1: No

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Acceptance letter

Kensaku Kasuga

13 Jan 2021

PONE-D-20-34679R1

Risk factors for neuropsychiatric symptoms in patients with Parkinson’s disease during COVID-19 pandemic in Japan

Dear Dr. Kasai:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Demographic characteristics of responders stratified by sex.

    (DOCX)

    Click here for additional data file. (22.7KB, docx)
    S2 Table

    a. Severity categories of depression, anxiety, and insomnia measurements in female PD patients and controls. b. Severity categories of depression, anxiety, and insomnia measurements in male PD patients and controls.

    (DOCX)

    Click here for additional data file. (15.8KB, docx)
    S3 Table

    a. Scores of depression, anxiety, and insomnia measurements in female PD patients and controls. b. Scores of depression, anxiety, and insomnia measurements in male PD patients and controls.

    (DOCX)

    Click here for additional data file. (13.9KB, docx)
    S4 Table

    a. Rate of female responders with worsening of motor performance, anxiety, and insomnia. b. Rate of male responders with worsening of motor performance, anxiety, and insomnia.

    (DOCX)

    Click here for additional data file. (12.9KB, docx)
    S1 Data. Questions that ask for subjective change in participants and original data of all participants.

    (XLSX)

    Click here for additional data file. (17KB, xlsx)
    Attachment

    Submitted filename: Response to reviewers_202012 (1).docx

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    Data Availability Statement

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