[email protected]

Impulse-compulsive Behaviors and Depression in PD.
Journal Pre-proof
Depression is Associated with Impulse-compulsive Behaviors in
Parkinson´s disease.
D Santos Garcı́a , T de Deus Fonticoba , C Cores ,
E Suárez Castro , S Jesús , P Mir , B Pascual-Sedano ,
J Pagonabarraga , J Kulisevsky , J Hernández Vara ,
LL Planellas , I Cabo-López , M Seijo-Martı́nez , I Legarda ,
F Carrillo Padilla , N Caballol , E Cubo , V Nogueira ,
MG Alonso Losada , N López Ariztegui , I González Aramburu ,
J Garcı́a Caldentey , C Borrue , C Valero , P Sánchez Alonso , on
behalf of the COPPADIS Study Group
PII:
DOI:
Reference:
S0165-0327(20)33005-6
https://doi.org/10.1016/j.jad.2020.11.075
JAD 12696
To appear in:
Journal of Affective Disorders
Received date:
Revised date:
Accepted date:
18 April 2020
26 September 2020
8 November 2020
Please cite this article as: D Santos Garcı́a , T de Deus Fonticoba , C Cores , E Suárez Castro ,
S Jesús , P Mir , B Pascual-Sedano , J Pagonabarraga , J Kulisevsky , J Hernández Vara ,
LL Planellas , I Cabo-López , M Seijo-Martı́nez , I Legarda , F Carrillo Padilla , N Caballol ,
E Cubo ,
V Nogueira ,
MG Alonso Losada ,
N López Ariztegui ,
I González Aramburu ,
J Garcı́a Caldentey , C Borrue , C Valero , P Sánchez Alonso , on behalf of the COPPADIS Study
Group, Depression is Associated with Impulse-compulsive Behaviors in Parkinson´s disease., Journal
of Affective Disorders (2020), doi: https://doi.org/10.1016/j.jad.2020.11.075
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Highlights

Depression is associated with impulse-compulsive behaviors in Parkinson´s disease.

Pathological gambling, eating behavior, and hobbyism-punding were related to depression.

Quality of life is worse in patients who have impulse-compulsive behaviors to add to
depression.
Full-Length Research Paper
Depression is Associated with Impulse-compulsive Behaviors in Parkinson´s
disease.
Running title: Impulse-compulsive Behaviors and Depression in PD.
Santos García D1, de Deus Fonticoba T2, Cores C1, Suárez Castro E2, Jesús S3,4, Mir P3,4,
Pascual-Sedano B4,5,6, Pagonabarraga J4,5, Kulisevsky J4,5,6, Hernández Vara J7, Planellas LL8,
Cabo-López I9, Seijo-Martínez M9, Legarda I10, Carrillo Padilla F11, Caballol N12, Cubo E13,
Nogueira V14, Alonso Losada MG15, López Ariztegui N16, González Aramburu I4,17,
García
Caldentey J18, Borrue C19, Valero C20, Sánchez Alonso P21; on behalf of the COPPADIS Study
Group.
1
Complejo Hospitalario Universitario de A Coruña (CHUAC), A Coruña, Spain; 2Hospital Arquitecto
Marcide y Hospital Naval, Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña,
Spain; 3Hospital Universitario Virgen del Rocío, Sevilla, Spain; 4Centro de Investigación en RedEnfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; 5Hospital de la Santa Creu i Sant
Pau, Barcelona; 6Faculty of Health Sciences, Universitat Oberta de Catalunya (UOC), Barcelona,
Spain; 7Hospital Universitario Vall d´Hebron and Neurodegenerative Diseases Research Group,
Vall D Hebron Research Institute (VHIR), Barcelona, Spain;
Barcelona, Spain;
Spain;
8
Hospital Clínic de Barcelona,
9
Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra,
10
Hospital Universitario Son Espases, Palma de Mallorca, Spain; 11Hospital Universitario de
Canarias, San Cristóbal de la Laguna, Santa Cruz de Tenerife, Spain;
Hospital Moisés Broggi, Sant Joan Despí, Barcelona, Spain;
de Burgos, Burgos, Spain;
12
Consorci Sanitari Integral,
13
Complejo Asistencial Universitario
14
Hospital Da Costa de Burela, Lugo, Spain;
15
Hospital Álvaro
Cunqueiro, Complejo Hospitalario Universitario de Vigo (CHUVI), Vigo, Spain;
Hospitalario de Toledo, Toledo, Spain;
Spain;
18
16
Complejo
17
Hospital Universitario Marqués de Valdecilla, Santander,
Centro Neurológico Oms 42, Palma de Mallorca, Spain;
19
Hospital Infanta Sofía, Madrid,
Spain;
20
Hospital Arnau de Vilanova, Valencia, Spain;
21
Hospital Universitario Puerta de Hierro,
Madrid, Spain; 21CIBERNED, Instituto de Salud Carlos III, Madrid.
*Corresponding author:
Dr. Diego Santos García, Department of Neurology, Hospital Universitario de A Coruña (HUAC),
Complejo Hospitalario Universitario de A Coruña (CHUAC), C/ As Xubias 84, 15006, A Coruña,
Spain
e-mail: [email protected] Tel: 646173341.
Conflicts of interest: None.
Funding sources: None.
ABSTRACT
Background: Depression and impulse control disorders (ICDs) are both common in Parkinson´s
disease (PD) patients and their coexistence is frequent. Our aim was to determine the relationship
between depression and impulsive-compulsive behaviors (ICBs) in a large cohort of PD patients.
Methods: PD patients recruited from 35 centers of Spain from the COPPADIS cohort from January
2016 to November 2017 were included in the study. The QUIP-RS (Questionnaire for ImpulsiveCompulsive Disorders in Parkinson's Disease-Rating Scale) was used for screening ICDs (cutoff
points: gambling ≥6, buying ≥8, sex≥8, eating≥7) and compulsive behaviors (CBs) (cutoff points:
hobbyism-punding ≥7). Mood was assessed with the BDI-II (Beck Depression Inventory – II) and
major, minor, and subthreshold depression were defined.
Results: Depression was more frequent in PD patients with ICBs than in those without: 66.3%
(69/104) vs 47.5% (242/509); p<0.0001. Major depression was more frequent in this group as well:
22.1% [23/104] vs 14.5% [74/509]; p=0.041. Considering types of ICBs individually, depression
was more frequent in patients with pathological gambling (88.9% [8/9] vs 50.2% [303/603];
p=0.021), compulsive eating behavior (65.9% [27/41] vs 49.7% [284/572]; p=0.032), and
hobbyism-punding (69% [29/42] vs 49.4% [282/571]; p=0.010) than in those without, respectively.
The presence of ICBs was also associated with depression (OR=1.831; 95%CI 1.048-3.201;
p=0.034) after adjusting for age, sex, civil status, disease duration, equivalent daily levodopa dose,
antidepressant treatment, Hoehn&Yahr stage, non-motor symptoms burden, autonomy for
activities of daily living, and global perception of QoL.
Limitations: Cross-sectional design.
Conclusions: Depression is associated with ICBs in PD. Specifically, with pathological gambling,
compulsive eating behavior, and hobbyism-punding.
Keywords: Depression; Gambling; Hobbism-puding; Impulse control disorders; Parkinson’s
disease.
Abbreviations:
ADLS, Schwab & England Activities of Daily Living Scale; BDI-II, Beck Depression Inventory-II;
CBs, compulsive behaviors; EUROHIS-QOL8, European Health Interview Survey-Quality of Life 8
Item-Index; FOG, freezing of gait; FOGQ, Freezing Of Gait Questionnaire, GQoL, global quality of
life; HRQoL, health-related quality of life; H&Y, Hoenh & Yahr; ICBs, impulsive-compulsive
behaviors; ICDs, impulse control disorders; NMS, non-motor symptoms; NMSS, Non-Motor
Symptoms Scale; NPI, Neuropsychiatric Inventory; PD, Parkinson´s disease; PD-CRS, Parkinson's
Disease Cognitive Rating Scale; PDQ-39SI, 39-item Parkinson's Disease Quality of Life
Questionnaire Summary Index; PDSS, Parkinson's Disease Sleep Scale; QoL, Quality of life;
QUIP-RS, Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale;
UPDRS, Unified Parkinson's Disease Rating Scale; VAFS, Visual Analog Fatigue Scale; VASPain, Visual Analog Scale-Pain.
INTRODUCTION
Depression and impulse-compulsive behaviors (ICBs) are common in Parkinson´s disease
(PD) patients, and frequently coexist. A systematic review in PD patients found that the weighted
prevalence of major depressive disorder, minor depression, and dysthymia was 17%, 22%, and
13%, respectively [1]. ICBs include impulse control disorders (ICDs) and compulsive behaviors
(CBs). Their frequencies are estimated to range from approximately 14-60% in the case of ICDs
and 1.4-16.8% for CBs [2,3]. Some studies have addressed the cross-sectional relationship of
depression and ICDs in PD, providing some evidence of an association between these conditions
[4-7]. However, although depression scale scores have been observed to be higher among
patients with ICDs, a higher prevalence or severity of ICDs among depressed patients has not
been reported. Moreover, the directionality between ICDs and affective disorders is not still clear
[8]. Very recently, in the longitudinal follow-up of the PPMI cohort it has been observed that
depression could predispose a patient to the development of ICDs in PD [9]. However, depression
could also be a consequence of personal problems generated by ICDs. This relationship between
mood disorders and ICBs is important since both negatively impact quality of life (QoL) of the PD
patient [10].
From a large Spanish PD cohort, depression, ICDs, and CBs were recently detected in
50.2%, 12.7%, and 7.2% of patients, respectively [11]. Our aim was to determine the relationship
between depression and ICBs in the COPPADIS cohort. Specifically, we analyzed the frequency of
depression in PD patients with vs without ICBs and vice versa. Also, we tried to find what specific
types of ICBs were associated with depression. Moreover, we compared QoL in different groups:
PD patients with depression but without ICBs, PD patients with ICBs but without depression, and
PD patients with both depression and ICBs.
METHODS
Patients with PD recruited from 35 centers of Spain from the COPPADIS cohort [11] were
included in this study. Methodology about COPPADIS-2015 study can be consulted in
https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-016-0548-9 [12]. This is a multicenter, observational, longitudinal-prospective, 5-year follow-up study designed to analyze disease
progression in a Spanish population of PD patients. The data for the present study (cross-sectional
study) was obtained from the baseline evaluation of PD patients from the COPPADIS cohort
between January 2016 and October 2017. All patients included were diagnosed according to UK
PD Brain Bank criteria. Exclusion criteria were: non-PD parkinsonism, dementia (Mini Mental State
Examination [MMSE] < 26), age < 18 or > 75 years, inability to read or understand the
questionnaires, to be receiving any advanced therapy (continuous infusion of levodopa or
apomorphine, and/or with deep brain stimulation), and the presence of comorbidity, sequelae, or
any disorder that could interfere with the assessment.
Information on sociodemographic aspects, factors related to PD, comorbidity, and treatment
was collected. Patient baseline evaluation included motor assessment (H&Y, Unified Parkinson’s
Disease Rating Scale [UPDRS] part III and part IV, Freezing of Gait Questionnaire [FOGQ]), nonmotor symptoms (Non-Motor Symptoms Scale [NMSS], Parkinson's Disease Sleep Scale [PDSS],
Visual Analog Scale-Pain [VAS-Pain], Visual Analog Fatigue Scale [VAFS]), cognition (MMSE,
Parkinson's Disease Cognitive Rating Scale [PD-CRS], completing a simple 16-piece puzzle),
mood and neuropsychiatric symptoms (Beck Depression Inventory-II [BDI-II], Neuropsychiatric
Inventory [NPI], Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating
Scale [QUIP-RS]), disability (Schwab & England Activities of Daily Living Scale [ADLS]), health
related QoL (the 39-item Parkinson's disease Questionnaire [PDQ-39SI]), and global QoL (PQ-10,
EUROHIS-QOL 8-item index [EUROHIS-QOL8]). In patients with motor fluctuations, the motor
assessment was conducted during the OFF state (without medication in the last 12 hours) and
during the ON state. However, in patients without motor fluctuations, the assessment was only
performed without medication (first thing in the morning without taking medication in the previous
12 hours).
With regard to mood (assessed by BDI-II [13]), participants from the COPPADIS-2015
study were classified as with major depression, minor depression, subthreshold depression, or
non-depression [12]. Specifically, regarding to items 1, 4, 5, 9, 13, 15, 16, 17, and 18 of the BDI-II,
depression was defined: major depression, ≥ 5 symptoms with the presence of item 1 (feeling of
sadness) and/or item 4 (anhedonia) (DSM-IV criteria); minor depression, from 2 to 4 symptoms
with the presence of item 1 and/or item 4 (DSM-IV criteria); subthreshold depression, from 2 to 4
symptoms without the presence of item 1 and item 4 (Judd criteria) [14,15] (Table 1.SM). Nondepression was considered when no criteria for major, minor, or subthreshold depression were
observed. With regard to ICBs, ICDs (pathological gambling, compulsive shopping, hypersexuality,
and compulsive eating behavior) and CBs (punding, hobbyism, and dysregulation dopaminergic
syndrome) were considered. We applied previously published cutoff points of the QUIP-RS:
gambling ≥ 6, buying ≥ 8, sex ≥ 8, eating ≥ 7, hobbyism-punding ≥ 7 [16]. For dopaminergic
dysregulation syndrome, we accounted for the investigator´s criterion since an established cutoff
does not exist [17]. Patients suffering from at least one ICD and/or CB were considered as patients
presenting ICB.
Three different instruments were used to assess QoL: 1) the 39-item Parkinson's disease
Questionnaire (PDQ-39) [18], 2) a rating of global perceived QoL (PQ-10) on a scale from 0 (worst)
to 10 (best) [19], and 3) the EUROHIS-QOL 8-item index (EUROHIS-QOL8) [20]. The PDQ-39 is a
PD-specific questionnaire that assesses the patients’ health-related QoL. There are 39 items
grouped into 8 domains: (1) Mobility (items 1 to 10); (2) Activities of daily living (items 11 to 16); (3)
Emotional well-being (items 17 to 22); (4) Stigma (items 23 to 26); (5) Social support (items 27 to
29); (6) Cognition (items 30 to 33); (7) Communication (items 34 to 36); (8) Pain and discomfort
(items 37 to 39). For each item, the score may range from 0 (never) to 4 (always). The symptoms
refer to the 4 weeks prior to assessment. Domain total scores are expressed as a percentage of
the corresponding maximum possible score and a Summary Index is obtained as average of the
domain scores (PDQ-39SI). The EUROHIS-QOL8 is an 8-item global QoL questionnaire (quality of
life, health status, energy, autonomy for activities of daily living, self-esteem, social relationships,
economic capacity, and habitat) derived from the WHOQOL-BREF. For each item, the score
ranges from 0 (not at all) to 5 (completely). The total score is expressed as the mean of the
individual scores. A higher score indicates a better QoL.
Data analysis
Data were processed using SPSS 20.0 for Windows. Only patients with all data correctly
collected about both BDI-II and QUIP-RS were considered valid for the analysis. For determining
the frequency of ICBs in PD patients with depression vs without depression, the Fisher test was
used due to the fact that marginal sums of the data set (sums per row or column) were very
unequal. When the sign of the potential difference was known, a test of a tail was applied before
running the experiment and the test. With regard to QoL and other variables comparison between
groups, the Student’s t-test, Mann-Whitney U test, Chi-square test, Fisher test, or ANOVA, as
appropriate, were used (distribution for variables was verified by one-sample Kolmogorov-Smirnov
test). Spearman’s or Pearson’s correlation coefficient, as appropriate, were used for analyzing the
relationship between continuous variables. Correlations were considered weak for coefficient
values ≤ 0.29, moderate for values between 0.30 and 0.59, and strong for values ≥ 0.60. Binary
regression model was used for determining in what grade ICBs were associated with depression
(depression as dependent variable). The p-value was considered significant when it was < 0.05.
Standard protocol approvals, registrations, and patient consents
For this study, we received approval from the appropriate local and national ethical
standards committees. Written informed consents from all participants participating in this study
were obtained before the start of the study. COPPADIS-2015 was classified by the AEMPS
(Agencia Española del Medicamento y Productos Sanitarios) as a Post-authorization Prospective
Follow-Up study with the code COH-PAK-2014-01.
Data availability
The protocol and the statistical analysis plan are available on request. Deidentified
participant data are not available for legal and ethical reasons.
RESULTS
Six hundred and thirteen PD patients (62.5 ± 9.1 years old, 59.9% males) from the
COPPADIS cohort were included in this study. Mean BDI-II score was 8.8 ± 7.3 and 50.7% of the
patients presented depression: 15.8% major depression (N=97), 17% minor depression (N=104),
and 17.9% subthreshold depression (N=110) (Figure 1A). Mean QUIP-RS was 4.4 ± 8.4 and 17%
(N=104) of the patients presented ICB (ICD and/or CB): 12.2% (N=75) at least one ICD and 9.3%
at least one CB (N=57) (Figure 1B). The individual frequency of each ICB was: compulsive
gambling 1.5% (N=9); hipersexuality 4.7% (N=29); compulsive shopping 2.4% (N=15); compulsive
eating 6.7% (N=41); hobbysm-punding 6.9% (N=42); compulsive medication use 3.8% (N=23)
(Figure 1B). BDI-II score was higher (12 ± 8.4 vs 8.1 ± 6.9; p<0.0001) in patients with ICB vs
those without (Table 1).
Depression was more frequent in PD patients with ICBs compared to those without: 66.3%
(69/104) vs 47.5% (242/509); p<0.0001 (Figure 2). Specifically, major (22.1% [23/104] vs 14.5%
[74/509]; p=0.041) and subthreshold (26% [27/104] vs 16.3% [83/509]; p=0.016) depression were
more frequent in this group but not minor depression (18.3% [19/104] vs 16.7% [85/509]; p=0.396).
When it was compared to patients without the disorder, depression was significantly more frequent
in patients with at least one ICD (64% [48/75] vs 48.9% [263/538]; p=0.010) but not with at least
one ICB (trend to significant; 61.4% [35/57] vs 49.6% [276/556]; p=0.060). Considering types of
ICBs individually, depression was more frequent in patients with pathological gambling (88.9%
[8/9] vs 50.2% [303/603]; p=0.021), compulsive eating behavior (65.9% [27/41] vs 49.7%
[284/572]; p=0.032), and hobbyism-punding behavior (69% [29/42] vs 49.4% [282/571]; p=0.010)
than in those without, respectively (Figure 2).
Frequency of ICBs was twice in patients with depression compared to patients without
(22% [69/311] vs 11.6% [35/302]; p<0.0001) (Figure 3). In order of frequency, suffering from
hobbysm-punding behavior (9.2% [29/311] vs 4.3% [13/302]; p=0.010), compulsive eating behavior
(8.7% [27/311] vs 4.6% [14/302]; p=0.032), and pathological gambling (2.6% [8/311] vs 0.3%
[1/302]; p=0.021) was more frequent in patients with depression. When the analysis was
performed considering the three groups of the depression type defined, significant differences
between them were not observed (Table.2.SM). A weak positive correlation was observed
between BDI-II and QUIP-RS scores (r=0.197; p<0.0001; n=613). When only PD patients with any
ICD or CB were considered (n=104), the correlation was significant but weak as well (r=0.225;
p=0.022). However, when the analysis was conducted differentiating between ICDs and CBs, it
was observed a significant correlation between both variables in the group of patients with at least
one ICD (N=75; r=0.259; p=0.025) but not in those patients with at least on CB (N=57; r=0.157;
p=0.244).
With regard to the number of ICBs presenting simultaneously, the results were: 509
patients presented 0 (83%); 30 patients presented only one (4.9%); 44 patients presented 2 types
(7.9%); 19 patients presented 3 types (3.1%); 6 patients presented 4 types (1%); 4 patients
presented 5 types (0.7%); and 1 patient presented 6 types (0.2%). BDI-II score was higher (Figure
4A; p<0.0001) and major depression was more frequent (Figure 4B; p=0.040) in patients suffering
from a greater number of ICBs. Mean score on each item of the BDI-II scale was significantly
higher in all scores in PD patients with depression vs those without depression except on items 1
(sadness), 4 (loss of pleasure), 9 (suicidal thoughts or whishes), 10 (crying), 12 (loss of interest),
17 (irritability), and 21 (loss of interest in sex) (Table 3.SM).
With respect to QoL, both health-related (PDQ-39SI) and global (EUROHIS-QOL8) QoL
were worse in those patients with depression and ICBs (at least one ICD and/or CB) compared to
those patients with only depression without ICB and with only ICB without depression (Figure 5).
In this cohort (n=613), the presence of ICBs multiplies by two the probability of presenting
depression (OR=2.175; 95%CI 1.398-3.385; p=0.001). Suffering from ICBs was also associated
with depression (OR=1.831; 95%CI 1.048-3.201; p=0.034) after adjusting for age, gender, civil
status, disease duration, equivalent daily levodopa dose, antidepressant treatment, H&Y stage,
non-motor symptoms burden, autonomy for activities of daily living, and global perception of QoL
(Table 2).
DISCUSION
The present study finds a positive relationship between depression and ICBs in PD. In this
cross-sectional study, depression is reported to be significantly higher in PD patients with ICBs
compared to those without them. Moreover, in depressed PD patients, suffering from ICBs could
negatively impact QoL.
In the COPPADIS cohort, the frequency of depression and ICBs is in the line with previous
reports [1,16,17,21-23]. An important aspect in this study is that we considered depressed patients
as patients with major, minor, or subthreshold depression. Individually, some ICBs are not very
frequent (e.g., pathological gambling in our cohort, n=9) although as a whole, the prevalence of
any ICB symptom is higher than 15%. This point, along with the intention to be very sensitive in the
detection of depressive symptoms, explains why subthreshold depression was included in our
criterion definition of depression. Some reports have already described the importance of
subthreshold depression in PD [24,25]. In our study group, we recently observed that suffering
from subthreshold depression, compared to not suffering depressive symptoms at all, related to a
greater non-motor symptoms burden, a worse QoL, and a lesser autonomy for activities of daily
living [26]. In any case, not only was depression as a whole more frequent in PD patients with ICBs
but so was major depression (DSM criteria). At least 4 studies have addressed the cross-sectional
relationship of depression and ICBs in PD providing some evidence of an association between
these conditions [4-7]. Joutsa et al. [4] reported a higher BDI score was associated with ICDs in
575 PD patients from Finnish Parkinson Association, but they did not define depression with regard
to any specific criteria. Similarly, Callesen et al. [5] reported a higher score on the Geriatric
Depression Scale (short version of 15 items) in patients with ICBs (n=145) vs those without ICBs
(n=212). However, the difference was of only 1 point (4.3 vs 3.2), depression was again not
defined, and the frequency of ICBs was surprisingly high. A third study [6], designed to evaluate
the role of alexithymia in ICBs (n=91), found a significant correlation (r=348) between the BDI-II
total score and the QUIP-RS total score. The fourth study, aimed at evaluating the psychiatric
comorbidities of punding (but not ICDs), found no relationship between depression and punding
[7]. However, our study is the largest (n=613) and unique cross-sectional study designed
specifically (the aim of the study) for the analysis of the relationship between depression (with
specific criteria of depression defined) and ICBs. We defined the criterion of depression and used
the previously published cutoff points of the QUIP-RS for defining ICDs and CBs [16].
Individually, depressive symptoms were more frequent in patients suffering from all types of
ICDs and CBs, specifically for hobbyism-punding behavior, compulsive eating behavior, and
especially for pathological gambling behavior (89% vs 50%). Although depressive symptoms
represent an important adjustment problem that seems to co-occur frequently with gamblingassociated problems, as nearly half of problematic gamblers also present with a major depressive
disorder [27], this association has not been previously reported in PD. Pettorruso et al. [7] found a
relationship between punding and psychiatric comorbidity, particularly with psychosis and bipolar
disorder, but as previously mentioned, not depression (n=25). However, we observed in the
COPPADIS cohort that 69% of 42 patients suffering from hobbyism-punding behavior presented
depression, being both depressive symptoms and specifically subthreshold depression significantly
more frequent than in patients without hobbyism-punding. Moreover, suffering from any ICD and/or
CB doubles the probability of having depressive symptoms after adjustment to other variables
related to depression, such as quality of life perception or taking an antidepressive agent. This
applies not only to the type but also to the number of ICBs associated with depressive symptoms,
as previously reported [4]. The correlation between the BDI-II and the QUIP-RS total scores was
weak and ICBs were not more frequent in patients with major depression compared to those ones
with minor or subthreshold depression, but major depression frequency was higher in PD patients
with ≥ 4 ICBs simultaneously. More studies are necessary to know properly how the type, severity
and number of ICBs influence mood in patients with PD.
As mentioned, the present study has a cross-sectional design. It is not possible to analyze
the assessment of causality. Depression could be regarded as a consequence of ICBs, either as a
purely psychological reaction (reactive depression) [28] or as secondary to the reward mechanism
associated with ICBs [29]. Using longitudinal data from the PPMI (median follow-up of 4.1 years),
Marín-Lahoz et al. [9] recently observed that depression acts as a risk factor for the development
of ICDs in PD patients treated with a similar dose of dopamine agonists, the main known risk
factor. Although there are some limitations in this study, such as the fact that all patients who
changed from 0 to ≥ 1 in the QUIP total score were considered as patients developing an ICD and
that all patients taking antidepressants at baseline regardless of GDS-15 score were considered
depressed patients, it has relevant clinical implications: dopamine agonists should be used with
caution in PD patients with depression. Our results support this idea and suggest the importance of
asking for impulsive-compulsive symptoms in a patient with depression before deciding on
treatment. This is even more relevant if we take into account that QoL seems to be worse in these
patients.
The present study has some further limitations. As we commented, although COPPADIS is
a large cohort, the sample for some sub-groups of patients with some ICBs is small and a trend of
significance is observed in many analyses. Depression was considered for patients with major,
minor, or subthreshold depression and it was conducted using screening instruments by a
neurologist but not was based on an extensive complete psychiatric evaluation performed by a
specialized psychiatrist. For some variables, the information was not collected in all of the cases.
All scales or questionnaires used to assess motor and NMS are validated except PQ-10. Our
sample is not fully representative of the PD population due to inclusion and exclusion criteria (i.e.,
age limit, no dementia, no severe comorbidities, no second line therapies, etc.) which subsequently
entails a bias toward early PD. Finally, this is a cross-sectional study, but the aim of the
COPPADIS-2015 study [12] is to follow-up the cohort for 5 years, so the role of depression as
predictor of ICBs could be analyzed.
In conclusion, in this cross-sectional study it was observed that depression is associated
with ICBs, specifically with pathological gambling, compulsive eating, and hobbyism-punding. In
PD patients with depression and before deciding a treatment like a dopamine agonist, it is
necessary to ask for ICBs. Application of a screening validated tool, such as a QUIP-RS, should be
advised. Moreover, QoL is worse in patients who have ICBs to add to depression.
Contributors:
Santos García D: conception, organization, and execution of the project; statistical analysis; writing
of the first draft of the manuscript; recruitment and/or evaluation of participants.
de Deus Fonticoba T: review and critique; recruitment and/or evaluation of participants.
Cores C: review and critique.
Suárez Castro E: review and critique; recruitment and/or evaluation of participants.
Jesús S: review and critique; recruitment and/or evaluation of participants.
Mir P: review and critique; recruitment and/or evaluation of participants.
Pascual-Sedano B: review and critique; recruitment and/or evaluation of participants.
Pagonabarraga J: review and critique; recruitment and/or evaluation of participants.
Kulisevsky J: review and critique; recruitment and/or evaluation of participants.
Hernández Vara J: review and critique; recruitment and/or evaluation of participants.
Planellas LL: review and critique; recruitment and/or evaluation of participants.
Cabo-López I: review and critique; recruitment and/or evaluation of participants.
Seijo M: review and critique; recruitment and/or evaluation of participants.
Legarda I: review and critique; recruitment and/or evaluation of participants.
Carrillo Padilla F: review and critique; recruitment and/or evaluation of participants.
Caballol N: review and critique; recruitment and/or evaluation of participants.
Cubo E: review and critique; recruitment and/or evaluation of participants.
Nogueira V: review and critique; recruitment and/or evaluation of participants.
Alonso Losada MG: review and critique; recruitment and/or evaluation of participants.
López Ariztegui N: review and critique; recruitment and/or evaluation of participants.
González Aramburu I: review and critique; recruitment and/or evaluation of participants.
García Caldentey J: review and critique; recruitment and/or evaluation of participants.
Borrue C: review and critique; recruitment and/or evaluation of participants.
Valero C: review and critique; recruitment and/or evaluation of participants.
Sánchez Alonso P: review and critique; recruitment and/or evaluation of participants.
Financial Disclosures:
Santos-García D. has received honoraria for educational presentations and/or advice service by
Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva.
de Deus Fonticoba T. has received honoraria for educational presentations and advice service by
Abbvie.
Cores C: None.
Suárez Castro E.: None.
Jesús S. has received honoraria from AbbVie, Bial, Merz, UCB, and Zambon. She holds the
competitive contract "Juan Rodés" supported by the Instituto de Salud Carlos III. Also, she has
received grants from the Spanish Ministry of Economy and Competitiveness (PI18/01898) as well
as the Consejería de Salud de la Junta de Andalucía (PI-0459-2018).
Mir P. has received honoraria from AbbVie, Abbott, Allergan, Bial, Merz, UCB, and Zambon. He
has received grants from the Spanish Ministry of Economy and Competitiveness [ PI16/01575] cofounded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación). He also
received grants from Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de
Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the
Consejería de Salud y Bienestar Social de la Junta de Andalucía [ PI-0437-2012, PI-0471-2013],
the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the
Fundación Alicia Koplowitz, and the Fundación Mutua Madrileña.
Pascual-Sedano B. has received honoraria for educational services from Abbvie and UCB Pharma
and travel grants from Medtronic for attending conferences.
Pagonabarraga J. was supported by PERIS, Expedient Number SLT008/18/00088 (Generalitat de
Catalunya) and FIS grant PI18/01717, Instituto de Salud Carlos III (ISCIII), Spain.
Kulisevsky J.: (1) Consulting fees: Roche, Zambon; (2) Stock / allotment: No; (3) Patent royalties /
licensing fees: No; (4) Honoraria (e.g. lecture fees): Zambon, Teva, Bial, UCB; (5) Fees for
promotional materials: No; (6) Research funding: Roche; Zambon; Ciberned; PERIS, Expedient
Number SLT008/18/00088 (Generalitat de Catalunya); FIS grant PI18/01717, Instituto de Salud
Carlos III (ISCIII); FundacióLa Maratóde TV3; (7) Scholarship from corporation: No; (8) Corporate
laboratory funding: No; (9) Others (e.g. trips, travel, or gifts): No.
Hernández Vara J. has received travel bursaries and educational grants from Abbvie and has
received honoraria for educational presentations and or advisory honoraria from Abbvie, Teva,
Bial, Zambon, Britannia, Italfarmaco, and Sanofi-Genzyme.
Planellas LL. has received travel bursaries grant from Abbvie.
Cabo López I. has received honoraria for educational presentations and advice service by Abbvie,
Zambon, and Bial.
Seijo M. has received honoraria for educational services from KRKA, UCB, Zambon, and Bial as
well as travel grants from Daiichi and Roche.
Legarda I. has received honoraria for educational presentations and advice service by Abbvie,
UCB Pharma, Zambon, Bial, and Teva.
Carrillo Padilla F. has received honoraria from Zambon (SEN Congress assistance).
Caballol N. has received honoraria from Bial, Italfármaco, Qualigen, Zambon, UCB, Teva, and
KRKA as well as sponsorship from Zambon, TEVA, and Abbvie for attending medical conferences.
Cubo E.: Travel grants: Abbvie, Allergan, Boston; Lecturing honoraria: Abbvie, International
Parkinson´s disease Movement Disorder Society.
Nogueira V.: None.
Alonso Losada M. G. has received honoraria for educational presentations and advice service by
Zambon and Bial.
López Ariztegui N. has received honoraria for educational presentations and advice service by
Abbvie, Italfarmaco, Zambon, and Bial.
González Aramburu I.: None.
García Caldentey J. has received honoraria for educational presentations and advice service by
Qualigen, Nutricia, Abbvie, Italfarmaco, UCB Pharma, Lundbeck, Zambon, Bial, and Teva.
Borrue C.: None.
Valero C. has received honoraria for educational services from Zambon, Abbvie, and UCB.
Sánchez Alonso P. has received honoraria for educational presentations and advice service by
Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva.
Authors’ Roles:
Santos García D: conception, organization, and execution of the project; statistical analysis; writing
of the first draft of the manuscript; recruitment and/or evaluation of participants.
de Deus Fonticoba T: review and critique; recruitment and/or evaluation of participants.
Cores C: review and critique.
Suárez Castro E: review and critique; recruitment and/or evaluation of participants.
Jesús S: review and critique; recruitment and/or evaluation of participants.
Mir P: review and critique; recruitment and/or evaluation of participants.
Pascual-Sedano B: review and critique; recruitment and/or evaluation of participants.
Pagonabarraga J: review and critique; recruitment and/or evaluation of participants.
Kulisevsky J: review and critique; recruitment and/or evaluation of participants.
Hernández Vara J: review and critique; recruitment and/or evaluation of participants.
Planellas LL: review and critique; recruitment and/or evaluation of participants.
Cabo-López I: review and critique; recruitment and/or evaluation of participants.
Seijo M: review and critique; recruitment and/or evaluation of participants.
Legarda I: review and critique; recruitment and/or evaluation of participants.
Carrillo Padilla F: review and critique; recruitment and/or evaluation of participants.
Caballol N: review and critique; recruitment and/or evaluation of participants.
Cubo E: review and critique; recruitment and/or evaluation of participants.
Nogueira V: review and critique; recruitment and/or evaluation of participants.
Alonso Losada MG: review and critique; recruitment and/or evaluation of participants.
López Ariztegui N: review and critique; recruitment and/or evaluation of participants.
González Aramburu I: review and critique; recruitment and/or evaluation of participants.
García Caldentey J: review and critique; recruitment and/or evaluation of participants.
Borrue C: review and critique; recruitment and/or evaluation of participants.
Valero C: review and critique; recruitment and/or evaluation of participants.
Sánchez Alonso P: review and critique; recruitment and/or evaluation of participants.
Collaborators (COPPADIS STYDY GROUP).
Adarmes AD, Almeria M, Alonso Cánovas A, Alonso Frech F, Álvarez I, Álvarez Sauco M, Aneiros
Díaz A, Arnáiz S, Arribas S, Ascunce Vidondo A, Aguilar M, Ávila MA, Bernardo Lambrich N, BejrKasem H, Blázquez Estrada M, Botí M, Buongiorno MT, Cabello González C, Cámara Lorenzo A,
Carrillo F, Casas E, Catalán MJ, Clavero P, Cortina Fernández A, Cosgaya M, Cots Foraster A,
Crespo Cuevas A, de Fábregues-Boixar O, Díez-Fairen M, Erro E, Escalante S, Estelrich Peyret E,
Fernández Guillán N, Gámez P, Gallego M, García Campos C, García Moreno JM, Gastón I,
Guillén Fopiani D, Gómez Garre MP, Gómez Mayordomo V, González Aloy J, González Ardura J,
González García B, González Palmás MJ, González Toledo GR, Golpe Díaz A, Grau Solá M,
Guardia G, Horta-Barba A, Idoate Calderón D, Infante J, Kurtis M, Labandeira C, Labrador MA,
Lacruz F, Lage Castro M, López Díaz LM, López Manzanares L, López Seoane B, Lucas del Pozo
S, Macías Y, Mata M, Martí Andres G, Martí MJ, Martínez Castrillo JC, Martinez-Martin P, McAfee
D, Meitín MT, Menéndez González M, Méndez del Barrio C, Miranda Santiago J, Morales Casado
MI, Moreno Diéguez A, Novo Amado A, Novo Ponte S, Ordás C, Pareés I, Pastor P, Pérez Fuertes
A, Pérez Noguera R, Planas-Ballvé A, Prats MA, Prieto Jurczynska C, Puente V, Pueyo Morlans
M, Redondo Rafales N, Rodríguez Méndez L, Rodríguez Pérez AB, Roldán F, Ruíz De Arcos M,
Ruíz Martínez J, Sánchez-Carpintero M, Sánchez Díez G, Sánchez Rodríguez A, Santacruz P,
Segundo Rodríguez JC, Sierra Peña M, Solano Vila B, Tartari JP, Vargas L, Vela L, Villanueva C,
Vives B, Villar MD.
COPPADIS STYDY GROUP.
Adarmes AD, Almeria M, Alonso Losada MG, Alonso Cánovas A, Alonso Frech F, Álvarez I,
Álvarez Sauco M, Aneiros Díaz A, Arnáiz S, Arribas S, Ascunce Vidondo A, Aguilar M, Ávila MA,
Bernardo Lambrich N, Bejr-Kasem H, Blázquez Estrada M, Botí M, Borrue C, Buongiorno MT,
Cabello González C, Cabo López I, Caballol N, Cámara Lorenzo A, Carrillo F, Carrillo Padilla FJ,
Casas E, Catalán MJ, Clavero P, Cortina Fernández A, Cosgaya M, Cots Foraster A, Crespo
Cuevas A, Cubo E, de Deus Fonticoba T, de Fábregues-Boixar O, Díez-Fairen M, Erro E,
Escalante S, Estelrich Peyret E, Fernández Guillán N, Gámez P, Gallego M, García Caldentey J,
García Campos C, García Moreno JM, Gastón I, Guillén Fopiani D, Gómez Garre MP, Gómez
Mayordomo V, González Aloy J, González-Aramburu I, González Ardura J, González García B,
González Palmás MJ, González Toledo GR, Golpe Díaz A, Grau Solá M, Guardia G, Hernández
Vara J, Horta-Barba A, Idoate Calderón D, Infante J, Jesús S, Kulisevsky J, Kurtis M, Labandeira
C, Labrador MA, Lacruz F, Lage Castro M, Legarda I, López Ariztegui N, López Díaz LM, López
Manzanares L, López Seoane B, Lucas del Pozo S, Macías Y, Mata M, Martí Andres G, Martí MJ,
Martínez Castrillo JC, Martinez-Martin P, McAfee D, Meitín MT, Menéndez González M, Méndez
del Barrio C, Mir P, Miranda Santiago J, Morales Casado MI, Moreno Diéguez A, Nogueira V,
Novo Amado A, Novo Ponte S, Ordás C, Pagonabarraga J, Pareés I, Pascual-Sedano B, Pastor P,
Pérez Fuertes A, Pérez Noguera R, Planas-Ballvé A, Planellas L, Prats MA, Prieto Jurczynska C,
Puente V, Pueyo Morlans M, Redondo Rafales N, Rodríguez Méndez L, Rodríguez Pérez AB,
Roldán F, Ruíz De Arcos M, Ruíz Martínez J, Sánchez Alonso P, Sánchez-Carpintero M, Sánchez
Díez G, Sánchez Rodríguez A, Santacruz P, Santos García D, Segundo Rodríguez JC, Seijo M,
Sierra Peña M, Solano Vila B, Suárez Castro E, Tartari JP, Valero C, Vargas L, Vela L, Villanueva
C, Vives B, Villar MD.
Name (Last Name, First Name)
Astrid Adarmes, Daniela
Location
Hospital Universitario Virgen del
Rocío, Sevilla, Spain
Hospital Universitari Mutua de
Terrassa, Terrassa, Barcelona,
Spain
Hospital
Álvaro
Cunqueiro,
Complejo Hospitalario Universitario
de Vigo (CHUVI), Vigo, Spain
Hospital Universitario Ramón y
Cajal, Madrid, Spain
Role
Site investigator
Hospital Universitario Clínico San
Carlos, Madrid, Spain
Complejo Hospitalario Universitario
de Ferrol (CHUF), Ferrol, A
Coruña, Spain
Hospital Universitari Mutua de
Terrassa, Terrassa, Barcelona,
Spain
Hospital General Universitario de
Elche, Elche, Spain
Site investigator
Complejo Asistencial Universitario
de Burgos, Burgos, Spain
Hospital Universitari Mutua de
Terrassa, Terrassa, Barcelona,
Spain
Complejo Hospitalario de Navarra,
Pamplona, Spain
Hospital Universitari Mutua de
Terrassa, Terrassa, Barcelona,
Spain
Consorci Sanitari Integral, Hospital
General
de
L´Hospitalet,
L´Hospitalet
de
Llobregat,
Barcelona, Spain
Site investigator
Site investigator / PI
Coordination at the center
Evaluation of participants and/or
data management
Hospital de Tortosa Verge de la
Cinta (HTVC), Tortosa, Tarragona,
Spain
Hospital de Sant Pau, Barcelona,
Spain
Hospital Universitario Central de
Asturias, Oviedo, Spain
Hospital Universitari Mutua de
Terrassa, Terrassa, Barcelona,
Spain
Hospital Infanta Sofía, Madrid,
Spain
Site investigator
Evaluation of participants and/or
data management
Site investigator
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Neuropsychologist; evaluation of
participants
Hospital Universitari Mutua de
Terrassa, Terrassa, Barcelona,
Spain
Complejo Hospitalario de Navarra,
Pamplona, Spain
Complejo Hospitalario Universitario
de
Pontevedra
(CHOP),
Pontevedra, Spain
Site investigator
Coordination at the center
Evaluation of participants and/or
data management
Nurse study coordinator
Site investigator
Scheduling of evaluations
Site investigator / PI
Coordination at the center
Evaluation of participants and/or
data management
Consorci Sanitari Integral, Hospital
Moisés Broggi, Sant Joan Despí,
Barcelona, Spain.
Hospital Clínic de Barcelona,
Barcelona, Spain
Hospital Universitario Virgen del
Rocío, Sevilla, Spain
Hospital Universitario de Canarias,
San Cristóbal de la Laguna, Santa
Cruz de Tenerife, Spain
Complejo Asistencial Universitario
de Burgos, Burgos, Spain
Hospital Universitario Clínico San
Carlos, Madrid, Spain
Site investigator / PI
Coordination at the center
Evaluation of participants and/or
data management
Nurse study coordinator
Site investigator
Crespo Cuevas, Ane
Complejo Hospitalario de Navarra,
Pamplona, Spain
Complejo Hospitalario Universitario
de Ferrol (CHUF), Ferrol, A
Coruña, Spain
Hospital Clínic de Barcelona,
Barcelona, Spain
Institut d'Assistència Sanitària
(IAS) - Instituí Cátala de la Salud.
Girona, Spain
Hospital del Mar, Barcelona, Spain.
Cubo, Esther
Complejo Asistencial Universitario
Site investigator / PI
Almeria, Marta
Alonso Losada, Maria Gema
Alonso Cánovas, Araceli
Alonso Frech, Fernando
Aneiros Díaz, Ángel
Álvarez, Ignacio
Álvarez Sauco, María
Arnáiz, Sandra
Arribas, Sonia
Ascunce Vidondo, Arancha
Aguilar, Miquel
Ávila Rivera, Maria Asunción
Bernardo Lambrich, Noemí
Bejr-Kasem, Helena
Blázquez Estrada, Marta
Botí González, Maria Ángeles
Borrué, Carmen
Buongiorno, Maria Teresa
Cabello González, Carolina
Cabo López, Iria
Caballol, Nuria
Cámara Lorenzo, Ana
Carrillo, Fátima
Carrillo Padilla, Francisco José
Casas, Elena
Catalán, Maria José
Clavero, Pedro
Cortina Fernández, A
Cosgaya, Marina
Cots Foraster, Anna
Site investigator
Site investigator / PI
Site investigator
Site investigator / PI
Site investigator
Site investigator / PI
Site investigator
Site investigator
Site investigator
Site investigator
Site investigator
Site investigator / PI
Site investigator
Site investigator
Site investigator / PI
Site investigator
Site investigator / PI
Site investigator
Site investigator
Site investigator
Site investigator
Contribution
Evaluation of participants and/or
data management
Neuropsychologist; evaluation of
participants
Coordination at the center
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Neuropsychologist; evaluation of
participants
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Coordination of blood extractions
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Coordination at the center
de Burgos, Burgos, Spain
Complejo Hospitalario Universitario
de Ferrol (CHUF), Ferrol, A
Coruña, Spain
Hospital
Universitario
Vall
d´Hebron, Barcelona, Spain
Site investigator
Hospital Universitari Mutua de
Terrassa, Terrassa, Barcelona,
Spain
Complejo Hospitalario de Navarra,
Pamplona, Spain
Hospital de Tortosa Verge de la
Cinta (HTVC), Tortosa, Tarragona,
Spain
Institut d'Assistència Sanitària
(IAS) - Instituí Cátala de la Salud.
Girona, Spain
Complejo Hospitalario Universitario
de Ferrol (CHUF), Ferrol, A
Coruña, Spain
Complejo Asistencial Universitario
de Burgos, Burgos, Spain
Hospital La Princesa, Madrid,
Spain
Site investigator
García Caldentey, Juan
Centro Neurológico Oms
Palma de Mallorca, Spain
Site investigator / PI
García Campos, Cristina
Hospital
Universitario
Macarena, Sevilla, Spain
Hospital
Universitario
Macarena, Sevilla, Spain
De Deus Fonticoba, Teresa
De Fábregues-Boixar, Oriol
Díez Fairen, M
Erro, Elena
Escalante, Sonia
Estelrich Peyret, Elena
Fernández Guillán, Noelia
Gámez, Pedro
Gallego, Mercedes
42,
Site investigator / PI
Site investigator
Site investigator / PI
Site investigator
Evaluation of participants
data management
Nurse study coordinator
Evaluation of participants
data management
Coordination at the center
Evaluation of participants
data management
Evaluation of participants
data management
and/or
and/or
and/or
and/or
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Site investigator
Neuroimaging studies
Site investigator
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Site investigator
Coordination at the center
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Neuropsychologist; evaluation of
participants
Virgen
Site investigator
Virgen
Site investigator / PI
Gastón, Itziar
Complejo Hospitalario de Navarra,
Pamplona, Spain
Site investigator / PI
Guillén Fopiani, Desiré
Complejo Hospitalario Universitario
de
Pontevedra
(CHOP),
Pontevedra, Spain
Hospital Universitario Virgen del
Rocío, Sevilla, Spain
Hospital Clínico San Carlos,
Madrid, Spain
Institut d'Assistència Sanitària
(IAS) - Instituí Cátala de la Salud.
Girona, Spain
Hospital Universitario Marqués de
Valdecilla, Santander, Spain
Hospital
Universitario
Lucus
Augusti (HULA), Lugo, Spain
Site investigator
González García, Beatriz
Hospital
Spain
Madrid,
Site investigator
González Palmás, Maria Josefa
Complejo Hospitalario Universitario
de
Pontevedra
(CHOP),
Pontevedra, Spain
Hospital Universitario de Canarias,
San Cristóbal de la Laguna, Santa
Cruz de Tenerife, Spain
Complejo Hospitalario Universitario
de Ferrol (CHUF), Ferrol, A
Coruña, Spain
Consorci Sanitari Integral, Hospital
Moisés Broggi, Sant Joan Despí,
Barcelona, Spain
Hospital Universitari Mutua de
Terrassa, Terrassa, Barcelona,
Spain
Hospital
Universitario
Vall
d´Hebron, Barcelona, Spain
Site investigator
Evaluation of participants and/or
data management
Site investigator
Evaluation of participants and/or
data management
Site investigator
Laboratory analysis coordination
Site investigator
Evaluation of participants and/or
data management
Site investigator
Evaluation of participants and/or
data management
Site investigator / PI
Hospital de Sant Pau, Barcelona,
Spain
Complejo Hospitalario Universitario
de
Pontevedra
(CHOP),
Pontevedra, Spain
Hospital Universitario Marqués de
Valdecilla, Santander, Spain
Site investigator
Coordination at the center
Evaluation of participants and/or
data management
Neuropsychologist; evaluation of
participants
neuropsychologist; evaluation of
participants
Hospital Universitario Virgen del
Rocío, Sevilla, Spain
Hospital de Sant Pau, Barcelona,
Spain
Site investigator
Hospital
Site investigator / PI
García Moreno, Jose Manuel
Gómez Garre, María del Pilar
Gómez Mayordomo, Víctor
González Aloy, Javier
González Aramburu, Isabel
González Ardura, Jessica
González Toledo, Gabriel Ricardo
Golpe Díaz, Ana
Grau Solá, Mireia
Guardia, Gemma
Hernández Vara, Jorge
Horta Barba, Andrea
Idoate Calderón, Daniel
Infante, Jon
Jesús, Silvia
Kulisevsky, Jaime
Kurtis, Mónica
La
Princesa,
Ruber
Internacional,
Site investigator
Genetic studies coordination
Site investigator
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Site investigator
Site investigator
Site investigator / PI
Site investigaor
Site investigator / PI
Site investigator / PI
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Nurse study coordinator
Coordination at the center
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Coordination at the center
Madrid, Spain
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Hospital
Álvaro
Cunqueiro,
Complejo Hospitalario Universitario
de Vigo (CHUVI), Vigo, Spain
Hospital Universitario Virgen del
Rocío, Sevilla, Spain
Complejo Hospitalario de Navarra,
Pamplona, Spain
Complejo Hospitalario Universitario
de
Pontevedra
(CHOP),
Pontevedra, Spain
Hospital
Universitario
Son
Espases, Palma de Mallorca,
Spain
Site investigator
Site investigator / PI
Coordination at the center
Evaluation of participants and/or
data management
Complejo Hospitalario de Toledo,
Toledo, Spain
Hospital Da Costa de Burela,
Lugo, Spain
Hospital La Princesa, Madrid,
Spain
Site investigator / PI
Complejo Hospitalario Universitario
de Ferrol (CHUF), Ferrol, A
Coruña, Spain
Hospital
Universitario
Vall
d´Hebron, Barcelona, Spain
Fundación Hospital de Alcorcón,
Madrid, Spain
Hospital Infanta Sofía, Madrid,
Spain
Hospital
Universitario
Vall
d´Hebron, Barcelona, Spain
Hospital Clínic de Barcelona,
Barcelona, Spain
Site investigator
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Neuroimaging studies
Martínez Castrillo, Juan Carlos
Hospital Universitario Ramón y
Cajal, Madrid, Spain
Site investigator /PI
Martinez-Martin, Pablo
Centro Nacional de Epidemiología
y CIBERNED, Instituto de Salud
Carlos III. Madrid
University
of
Pennsylvania,
Philadelphia
Hospital Da Costa de Burela,
Lugo, Spain
Hospital Universitario Central de
Asturias, Oviedo, Spain
Collaborator in statistical
methods analysis
Hospital Universitario Virgen del
Rocío, Sevilla, Spain
Hospital Universitario Virgen del
Rocío, Sevilla, Spain
Site investigator
Complejo Asistencial Universitario
de Burgos, Burgos, Spain
Complejo Hospitalario de Toledo,
Toledo, Spain.
Complejo Hospitalario Universitario
de Ferrol (CHUF), Ferrol, A
Coruña, Spain
Hospital Da Costa de Burela,
Lugo, Spain
Site investigator
Complejo Hospitalario Universitario
de Ferrol (CHUF), Ferrol, A
Coruña, Spain
Hospital Universitario Puerta de
Hierro, Madrid, Spain.
Hospital Rey Juan Carlos, Madrid,
Spain, Madrid, Spain.
Hospital de Sant Pau, Barcelona,
Spain
Hospital
Ruber
Internacional,
Madrid, Spain
Hospital de Sant Pau, Barcelona,
Spain
Hospital Universitari Mutua de
Terrassa, Terrassa, Barcelona,
Spain
Complejo Hospitalario Universitario
de Ferrol (CHUF), Ferrol, A
Coruña, Spain
Hospital
Universitario
Virgen
Macarena, Sevilla, Spain
Consorci Sanitari Integral, Hospital
Moisés Broggi, Sant Joan Despí,
Site investigator
Labandeira, Carmen
Labrador Espinosa, Miguel Ángel
Lacruz, Francisco
Lage Castro, Melva
Legarda, Inés
López Ariztegui, Nuria
López Díaz, Luis Manuel
López Manzanares, Lydia
López Seoane, Balbino
Lucas del Pozo, Sara
Macías, Yolanda
Mata, Marina
Martí Andres, Gloria
Martí, Maria José
McAfee, Darrian
Meitín, Maria Teresa
Menéndez González, Manuel
Méndez del Barrio, Carlota
Mir, Pablo
Miranda Santiago, Javier
Morales Casado, Maria Isabel
Moreno Diéguez, Antonio
Nogueira, Víctor
Novo Amado, Alba
Novo Ponte, Sabela
Ordás, Carlos
Pagonabarraga, Javier
Isabel Pareés
Pascual-Sedano, Berta
Pastor, Pau
Pérez Fuertes, Aída
Pérez Noguera, Rafael
Planas-Ballvé, Ana
Site investigator
Neuroimaging data analysis
Site investigator
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Site investigator
Site investigator
Site investigator / PI
Site investigator
Site investigator
Site investigator
Site investigator
Site investigator / PI
and
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Methods and statistical reviewer
Collaborator in english style
English style reviewer
Site investigator
Evaluation of participants
data management
Coordination at the center
Evaluation of participants
data management
Evaluation of participants
data management
Coordination at the center
Evaluation of participants
data management
Evaluation of participants
data management
Evaluation of participants
data management
Neuroimaging studies
Site investigator / PI
Site investigator / PI
Site investigator
Site investigator
Site investigator / PI
Site investigator
Site Investigator
Site investigator
Site investigator
Site Investigator
Site investigator
and/or
and/or
and/or
and/or
and/or
and/or
Coordination at the center
Evaluation of participants and/or
data management
Neuroimaging studies
Evaluation of participants
data management
Evaluation of participants
data management
Evaluation of participants
data management
Evaluation of participants
data management
Evaluation of participants
data management
Evaluation of participants
data management
and/or
and/or
and/or
and/or
and/or
and/or
Site investigator
Blood analysis
Site investigator
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Site investigator
Barcelona, Spain
Hospital Clínic de Barcelona,
Barcelona, Spain
Institut d'Assistència Sanitària
(IAS) - Instituí Cátala de la Salud.
Girona, Spain
Hospital Rey Juan Carlos, Madrid,
Spain, Madrid, Spain
Planellas, Lluís
Prats, Marian Ángeles
Prieto Jurczynska, Cristina
Site investigator
Site investigator
Site investigator / PI
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Puente, Víctor
Hospital del Mar, Barcelona, Spain
Site investigator / PI
Pueyo Morlans, Mercedes
Hospital Universitario de Canarias,
San Cristóbal de la Laguna, Santa
Cruz de Tenerife, Spain
Hospital La Princesa, Madrid,
Spain
Site investigator
Site Investigator
Evaluation of participants and/or
data management
Complejo Hospitalario Universitario
de Ferrol (CHUF), Ferrol, A
Coruña, Spain
Hospital General Universitario de
Elche, Elche, Spain
Hospital Universitario Virgen del
Rocío, Sevilla, Spain
Hospital
Universitario
Virgen
Macarena, Sevilla, Spain.
Hospital Universitario Donostia,
San Sebastián, Spain
Hospital Universitario Puerta de
Hierro, Madrid, Spain
Complejo Hospitalario Universitario
de Ferrol (CHUF), Ferrol, A
Coruña, Spain
Hospital Universitario Ramón y
Cajal, Madrid, Spain
Hospital Universitario Marqués de
Valdecilla, Santander, Spain
Hospital Clínic de Barcelona,
Barcelona, Spain
CHUAC, Complejo Hospitalario
Universitario de A Coruña
Complejo Hospitalario de Toledo,
Toledo, Spain
Complejo Hospitalario Universitario
de
Pontevedra
(CHOP),
Pontevedra, Spain
Hospital Universitario Marqués de
Valdecilla, Santander, Spain
Institut d'Assistència Sanitària
(IAS) - Instituí Cátala de la Salud.
Girona, Spain
Complejo Hospitalario Universitario
de Ferrol (CHUF), Ferrol, A
Coruña, Spain
Hospital Universitari Mutua de
Terrassa, Terrassa, Barcelona,
Spain
Hospital Arnau de Vilanova,
Valencia, Spain
Site investigator
Blood analysis
Site investigator
Evaluation of participants and/or
data management
Neuroimaging studies
Hospital Universitario Virgen del
Redondo, Nuria
Rodríguez Méndez, Luisa
Rodríguez Pérez, Amparo Belén
Roldán, Florinda
Ruíz de Arcos, María
Ruíz Martínez, Javier
Sánchez Alonso, Pilar
Sánchez-Carpintero, Macarena
Sánchez Díez, Gema
Sánchez Rodríguez, Antonio
Santacruz, Pilar
Santos García, Diego
Segundo
Rodríguez,
Clemente
Seijo, Manuel
Sierra, María
Solano, Berta
Suárez Castro, Ester
Tartari, Juan Pablo
Valero, Caridad
Vargas, Laura
José
Site investigator
Site investigator
Site investigator
Site investigator
Site investigator
Site investigator
Site investigator
Site investigator
Coordinator of the Project
Site investigator
Site investigator / PI
Site investigator
Site investigator / PI
Site investigator
Evaluation of participants and/or
data management
Site investigator
Evaluation of participants and/or
data management
Site investigator
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Vela, Lydia
Fundación Hospital de Alcorcón,
Madrid, Spain
Site investigator / PI
Villanueva, Clara
Hospital Universitario Clínico San
Carlos, Madrid, Spain
Hospital
Universitario
Son
Espases, Palma de Mallorca,
Spain
Hospital Universitario de Canarias,
San Cristóbal de la Laguna, Santa
Cruz de Tenerife, Spain
Site investigator
Villar, Maria Dolores
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Coordination of the COPPADIS2015
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Coordination at the center
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Site investigator
Rocío, Sevilla, Spain
Vives, Bárbara
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Evaluation of participants and/or
data management
Neuroimaging studies
Site investigator
Site investigator
Evaluation of participants and/or
data management
Acknowledgements
We would like to thank all patients, caregivers and all persons, companies or institutions
collaborating in this project. Thanks also to Fundación Española de Ayuda a la Investigación en
Parkinson (Curemos el Parkinson) (www.curemoselparkinson.org) and Alphabioresearch.com
(www.alphabioresesearch.com). Thanks to Darrian McAfee foe reviewing English style.
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Legend of figures
Figure 1. A. Frequency of different type of depressive disorders. B. Frequency of patients who
presented any ICB (at least one ICB), at least one ICD (any ICD) and at least one CB (any CB)
and specifically, different types of ICDs and CBs. CBs, compulsive behaviors; ICBs, impulsivecompulsive behaviors; ICDs, impulse control disorders.
Figure 2. Comparison of PD patients presenting depression (%, axis Y) in relation to ICBs (axis X;
for each variable, patients with symptoms in bright color on the left and patients without symptoms
in slight color on the right). The bar represents depression but in color type of depression is shown:
orange, major depression; blue, minor depression; green, subthreshold depression. * significant
results (p<0.05) regarding to depression as a whole. When type of depression was considered
individually for the analysis (**), only hobbysm-punding behavior and any CB were significantly
associated with subthreshold depression (12.7% vs 5.6% [p=0.010] and 14.5% vs 8.2% [p=0.032],
respectively), as well as any ICB (ICD or CD) with major depression and subthreshold depression
(23.7% vs 15.7% [p=0.041] and 24.5% vs 15.3% [p=0.016], respectively). Fisher test was applied.
CBs, compulsive behaviors; ICBs, impulsive-compulsive behaviors; ICDs, impulse control
disorders.
Figure 3. Percentage of PD patients with vs without depression (in dark) suffering (in light) from
impulse and/or compulsive symptoms. *, p<0.05. Fisher test was applied. CBs, compulsive
behaviors; ICBs, impulsive-compulsive behaviors; ICDs, impulse control disorders.
Figure 4. A. BDI-II score in patients according to the number of ICBs (from 0, 509 patients, to ≥ 4,
11 patients; p<0.0001). B. Percentage of patients with major depression according to the number
of ICBs (p=0.040). ANOVA (A) and Chi-square (B) test were applied. Mild outliers (O) are data
points that are more extreme than Q1 - 1.5 * IQR or Q3 + 1.5 * IQR. BDI-II, Beck Depression
Inventory-II; ICBs, impulsive-compulsive behaviors; ICDs, impulse control disorders.
Figure 5. Scores on PDQ-39, PQ-10 and EUROHIS-QOL8 according to mood and impulsecompulsive symptoms: patients without depression or ICBs (n=267) vs patients with depression
but not ICBs (n=242) vs patients with ICBs but not depression (n=35) vs patients with both
depression and ICBs (n=69); p<0.0001 for all analysis. A, comparison between all groups (ANOVA
test was applied); B, comparison between patients with depression and ICBs vs those with only
depression (Mann-Whitney test was applied); C, comparison between patients with depression and
ICBs vs those with ICBs but not depression (Mann-Whitney test was applied); D, comparison
between patients with depression but not ICBs vs those with ICBs but not depression (MannWhitney test was applied). Mild outliers (O) are data points that are more extreme than Q1 - 1.5 * IQR or
Q3 + 1.5 * IQR. ICBs, impulsive-compulsive behaviors.
Table 1. PD related variables in patients with and without ICBs (at least one ICD and/or CB)
(n=613).
ICBs
N=104
59.7 ± 9.4
6.5 ± 4.2
61.5
Non ICBs
N=509
63 ± 8.9
5.3 ± 4.5
59.5
0.001
0.001
0.395
Smoke
Alcohol intake
Cultural level
Lifestyle
Habitat
Historical ICB
Premorbid impulsive persornality
Family history of ICB
Antidepressants treatment
10.6/27.9/61.5
22.1/0/79.9
39.4/30.8/29.8
82.7/2.9/9.6/4.8
10.6/21.2/68.3
26
14.4
8.8
30.8
9.3/28.5/62.2
20/0.4/79.4
43/30.7/26.3
80/5.5/11/4.5
12.6/17.5/69.9
13
7.5
8.7
24
0.943
0.845
0.835
0.699
0.736
0.003
0.059
0.813
0.317
Daily dose L-dopa (mg)
Eq. daily dose L-dopa (mg)
Taking a dopamine agonist
Eq. daily dose of dopamin agonist
Time under L-dopa (months)
Number of anti-PD drugs
Number of non-anti PD drugs
401.4 ± 300.3
655.2 ± 436.4
86.5
238.1 ± 181.5
39.6 ± 44.7
3 ± 1.1
2.3 ± 2.2
332.9 ± 309.2
530 ± 405.3
65.2
171.2 ± 165.6
32.2 ± 43.8
2.3 ± 1.1
2.7 ± 2.6
0.011
0.004
<0.0001
<0.0001
0.032
<0.0001
0.159
Hoehn & Yahr
UPDRS-III
UPDRS-IV
FOGQ
2 ± 0.6
24.5 ± 12.5
2.7 ± 2.4
5.6 ± 5.5
1.9 ± 0.5
22.3 ± 11
1.8 ± 2.3
3.3 ± 4.3
0.488
0.142
<0.0001
<0.0001
MMSE
PD-CRS
NMSS
BDI-II
NPI – subject
QUIP-RS
PDSS
VAS-PAIN
VASF − physical
VASF − mental
29.1 ± 1.1
92.2 ± 16.5
59.6 ± 42.5
12 ± 8.4
8.5 ± 9.9
18.5 ± 11.2
104 ± 25.4
2.8 ± 3
3.7 ± 2.8
3 ± 2.7
29.2 ± 1
91.6 ± 15.9
40.4 ± 33.3
8.1 ± 6.9
5.3 ± 7.2
1.5 ± 3.1
117.1 ± 25.7
2.6 ± 2.9
2.8 ± 2.8
1.9 ± 2.5
0.535
0.708
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
0.671
0.002
<0.0001
ADLSL ≥ 80%
PDQ-39SI
PQ-10
EUROHIS-QOL8
22.8 ± 14.8
7 ± 1.6
3.6 ± 0.6
15.4 ± 12.3
7.4 ± 1.6
3.8 ± 0.5
<0.0001
0.089
<0.0001
Age
Disease duration (years)
Sex (male)
p
Chi-squared and Mann-Whitney-Wilcoxon test were applied. The results represent percentages or mean ±
SD. Data about H&Y and UPDRS-III are during the OFF state (first thing in the morning without taking
1
2
medication in the previous 12 hours). Smoke (active/ex-exmoker/non exmoker). Alcohol intake (non
3
4
excesive/excesive/any). Culture level (Elementary/Hihg School/Universitary); Life style (Living with the
5
partner/with a son and/or daughter/Alone/Others); Habitat (Rural/Semiurban/Urban).
ADLS, Schwab & England Activities of Daily Living Scale; BDI, Beck Depression Inventory-II; FOGQ,
Freezing Of Gait Questionnaire; ICBs, impulse control behaviors; NMSS, Non-Motor Symptoms Scale; NPI,
Neuropsychiatric Inventory; PD, Parkinson´s disease; PD-CRS, Parkinson’s Disease Cognitive Rating Scale;
PDQ-39SI, 39-item Parkinson’s Disease Quality of Life Questionnaire Summary Index; PDSS, Parkinson’s
Disease Sleep Scale; QUIP-RS, Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-
Rating Scale; UPDRS, Unified Parkinson’s Disease Rating Scale; VAFS, Visual Analog Fatigue Scale; VASPain, Visual Analog Scale-Pain.
Table 2. Binary logistic regression model showing that ICBs (at least one ICD and/or CB) related to
depression (dependent variable) after adjustment to other covariates (n=613).
OR
95% IC
p
Age
1.023
0.997 – 1.049
0.079
Gender (male)
0.749
0.479 – 1.170
0.204
Civil status (alone)
1.556
0.642 – 3.770
0.327
Disease duration
0.922
0.869 – 0.978
0.007
To be taking an antidepressive agent
0.543
0.319 – 0.926
0.025
To suffer from any ICB
1.831
1.048 – 3.201
0.034
L-dopa eq. daily dose (mg)
1.000
0.999-1.001
0.782
Hoehn & Yahr
1.240
0.794 – 1.937
0.344
Very severe NMS burden (NMSS > 70)
3.027
1.536 – 5.967
0.001
EUROHIS-QOL8
0.163
0.096 – 0.275
<0.0001
ADLS
1.050
0.798 – 1.381
0.728
2
ADLS, Schwab & England Activities of Daily Living Scale. R =0.361.