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Received: 9 January 2020    Revised: 28 February 2020    Accepted: 13 March 2020

DOI: 10.1111/jsr.13040

REG UL AR RE SE ARCH PAPER

Prevalence and predictors of mood disturbances in idiopathic

REM sleep behaviour disorder

Nicholas K. H. Chiu1,2  | Kaylena A. Ehgoetz Martens1,3 | Vincent C.T. Mok2 |

Simon J.G. Lewis1 | Elie Matar1,4

1
Forefront Parkinson's Disease Research
Clinic, Brain and Mind Centre, University of Abstract
Sydney, Sydney, NSW, Australia Depression and anxiety are commonly associated with synucleinopathies. Mood dis-
2
Department of Medicine and Therapeutics,
turbances have also been reported in patients with idiopathic REM sleep behaviour
Faculty of Medicine, Margaret K.L. Cheung
Research Centre for Management of disorder (iRBD) and are difficult to treat due to exacerbation of sleep symptoms with
Parkinsonism, The Chinese University of
standard antidepressants. Despite this, detailed prevalence studies of mood symp-
Hong Kong, Hong Kong SAR, China
3
Department of Kinesiology, University of
tomatology and contributors to mood disturbances in iRBD are limited. Mood, sleep,
Waterloo, Waterloo, ON, Canada autonomic, cognitive and motor symptoms were assessed in 49 well-characterized
4
Central Clinical School, Faculty of Medicine patients with iRBD using a variety of clinical scales. Spearman correlations, factor
and Health, University of Sydney, Sydney,
NSW, Australia analysis and multiple linear regression were used to uncover associations between
mood and non-motor and motor symptoms. The prevalence of significant depression
Correspondence
Elie Matar, Parkinson's Disease Research was 17.0% and that of anxiety was 14.6% in the iRBD cohort. Age and disease dura-
Clinic, L2 Brain and Mind Centre, 100 tion were not correlated with these affective symptoms in iRBD patients. We found
Mallett Street, Camperdown, Sydney, NSW
2050, Australia. depression was significantly predicted by the presence and severity of motor, sleep
Email: elie.matar@sydney.edu.au and cognitive symptoms. Anxiety was predicted by the severity of nocturnal and day-
Funding information time sleep-related symptoms, cognitive symptoms and autonomic symptoms, with a
This work is supported by the Sydney differential effect depending on the questionnaire used. Depression and anxiety are
Research Excellence Initiative 2020 grant.
ForeFront is a collaborative research group common in iRBD patients and can be significantly explained by specific sets of non-
at the Brain and Mind Centre University of motor and motor symptoms. These associations provide insight into the underlying
Sydney supported by a NHMRC Dementia
Team Grant (#1095127). NKHC is supported pathophysiology and emphasize the importance of a holistic approach to mood dis-
by the Margaret K.L. Cheung Research turbance in this population, which may circumvent the reliance on pharmacotherapy
Centre for Management of Parkinsonism and
the Innovation and Technology Scholarship that can exacerbate dream enactment behaviour.
2019 of the HKSAR government. EM is
supported by an ANZAN ECR scholarship KEYWORDS
and an NHMRC Postgraduate scholarship
(#1151722). KEM is supported by a Sydney
parasomnia, Parkinson's, prodromal, psychiatric symptoms
University Fellowship. SJGL is supported by
a NHMRC-Australian Research Dementia
Research Development Fellowship
(#1110414). GMH is a NHMRC Senior
Principal Research Fellow (#1079679)

1 |  I NTRO D U C TI O N phase of sleep (Iranzo, Santamaria, & Tolosa, 2016). The phenom-
enon of RBD most often occurs in the context of synuclein-based
Rapid eye movement (REM) sleep behaviour disorder (RBD) is a neurodegenerative diseases, including Parkinson's disease (PD), de-
parasomnia in which patients act out their dreams during the REM mentia with Lewy bodies (DLB) and multiple system atrophy (MSA)

J Sleep Res. 2021;30:e13040. wileyonlinelibrary.com/journal/jsr © 2020 European Sleep Research Society |

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https://doi.org/10.1111/jsr.13040
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(Iranzo et al., 2016). In addition, there is growing acceptance that
RBD occurring in the absence of another primary disease, termed
‘‘idiopathic’’ (or ‘‘isolated’’) RBD (iRBD), is the strongest predictive
biomarker for the development of these disorders and can precede
their onset by many years (Berg et al., 2015).
Psychiatric comorbidities are common and important in PD and
DLB (Chaudhuri, Healy, Schapira, & National Institute for Clinical
Excellence, 2006). Studies have shown an association between the
presence of RBD and depression (Rolinski et al., 2014). Moreover, psy-
chiatric symptoms have also been shown to be prodromal markers for
the development of synucleinopathies (Berg et al., 2015; Bourgouin
et al., 2019; Chaudhuri et al., 2006). Therefore, it follows that psychi-
atric symptoms would also be expected to co-occur in iRBD. Indeed,
a recent multicentre study has reported the prevalence of depression
as ranging from 25.6% to 28.8% and anxiety from 17.7% to 22.6% in
the iRBD population (Postuma et al., 2019). Furthermore, one study
has shown mood symptoms are more severe in those with iRBD than
in those with early, untreated PD or healthy older adults (Barber et al.,
2017). This may contribute to the finding in the same study that iRBD
patients have a similarly impaired quality of life to early PD patients
(Barber et al., 2017). It should also be appreciated that treatment of
mood disturbances in patients with RBD can be difficult, as antidepres-
sants can exacerbate symptoms; thus there is a need to find alternate
means to treat these mood disturbances (Iranzo et al., 2016).
Although mood disturbances in iRBD have been recognized, de-
tailed studies of mood symptomatology (especially anxiety) and its
contributors to iRBD remain limited in the literature. In general, ex-
isting studies have focused on reporting mood symptoms as just one
of the several standard prodromal non-motor symptoms in iRBD but
the relationship between mood and other early symptoms manifest-
ing in iRBD has yet to be studied (Aguirre-Mardones et al., 2015;
Rolinski et al., 2014). Other work has focused on mood in cohorts of
young-onset RBD or probable RBD based on questionnaires, which
may not reflect underlying synucleinopathy (Mahlknecht et al., 2015;
Teman, Tippmann-Peikert, Silber, Slocumb, & Auger, 2009). Moreover,
although some mood questionnaires have been shown to have supe-
rior neuropsychometric properties in synuclein populations (Leentjens
et al., 2014), they have not been tested in iRBD patients.
In this study, we aimed to characterize in detail the prevalence
and severity of anxiety and depression in a cohort of older patients
with iRBD that would be representative of most prodromal synucle-
inopathy populations. We then set out to determine the interactions
between mood and other prodromal symptoms that may represent
alternative targets for addressing mood and improving overall qual-
ity of life in iRBD patients.
2 |  M ATE R I A L S A N D M E TH O DS
2.1 | Participants
Forty-nine patients with iRBD (42 men, seven women; median
age, 68  years [range 52–82]; median disease duration, 6  years
[range 1–22]) were recruited to our research programme at the
Brain and Mind Centre, University of Sydney. All patients under-
went video-polysomnography and were diagnosed with iRBD ac-
cording to the International Classification of Sleep Disorders (III)
and following assessment by a neurologist (S.J.G.L.), excluding
the presence of PD, MSA, DLB or any other neurological disor-
der. Patients with severe and untreated obstructive sleep apnea
were excluded. Patients meeting criteria for a major neurocogni-
tive disorder (dementia) according to the Diagnostic and Statistical
Manual of Mental Disorders-V were also excluded from this study.
Antidepressant use was noted in just two of the included patients.
Ethical approval was obtained by the Sydney University Human
Research Ethics Committee, and written informed consent was
obtained from participants.
2.2 | Assessments
2.2.1 | Mood
The Hospital Anxiety and Depression Scale (HADS) was used to
assess both anxiety (-A) and depression (-D), with a cut-off at >7
for significant anxiety or depression. The HADS-A has been shown
to underestimate severity of anxiety in PD patients (Ehgoetz
Martens et al., 2016); thus the Parkinson's Anxiety Scale (PAS)
was also used in our cohort as a complementary measure of anxi-
ety, which asks more targeted questions and would presumably
be more sensitive in a prodromal synuclein population. The PAS
also has a better factorial structure than the HADS-A and offers
insight into subtypes of anxiety symptoms, including persistent
(-P), episodic (-E) and avoidant (-A) anxiety (Leentjens et al., 2014).
To assess state and trait anxiety, the State-Trait Anxiety Inventory
(STAI) was employed. The Movement Disorders Society Unified
Parkinson's Disease Rating Scale (UPDRS) Section 1 screening
questions for depression (1.3), anxiety (1.4) and apathy (1.5) were
also extracted. Original citations for all instruments are provided
in Appendix S1.
2.2.2 | Sleep
The REM Sleep Behaviour Disorder Screening Questionnaire
(RBDSQ) was utilized to screen for RBD symptoms. The Epworth
Sleepiness Scale (ESS) was used to assess daytime sleepiness. The
Scale for Outcomes in Parkinson's Disease–Sleep (SCOPA-S) was
also used to assess the range of daytime sleepiness (DS) and night-
time sleep disturbances (NS) that would potentially occur in iRBD.
2.2.3 | Autonomic
The Scale for Outcomes in Parkinson's disease–Autonomic (SCOPA-
AUT) was used to assess the range and severity of autonomic
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symptoms that have been reported to occur in iRBD (Postuma, TA B L E 1   Patient demographics (n = 49) and results of non-
Gagnon, Vendette, & Montplaisir, 2009), with higher scores indicat- motor and motor assessments

ing increasing severity; the Movement Disorders Society UPDRS Median

Section 1 screening questions for urinary problems (1.10), constipa-   (range)/ % (n)
tion problems (1.11) and light headedness on standing (1.12) were Demographics
also extracted for analysis. Age, years 68 (52–82)
Male, % 85.7% (42)
Disease duration, years 6 (1–22)
2.2.4 | Cognitive
Mood
HADS-total (/42) 4.5 (0–28)
The Montreal Cognitive Assessment (MoCA) and Mini-Mental State
Anxiety
Examination (MMSE) were both used to assess general cognition.
HADS-A (/21) 3 (0–15)
HADS-A > 7 14.6% (7)
2.2.5 | Motor UPDRS item 1.4 (anxiety) > 0 39.6% (19)
STAI – State (20–80) 25 (20–45)
The Movement Disorders Society UPDRS Section III total score was STAI – Trait (20–80) 30.5 (21–60)
extracted based on assessment by a trained assessor, and a move- PAS (Persistent) (/20) 4 (0–10)
ment disorders neurologist (S.J.G.L) independently assessed the pa- PAS (Episodic) (/16) 1 (0–4)
tients to confirm that they did not meet the threshold for PD, DLB
PAS (Avoidant) (/12) 0 (0–6)
or MSA.
PAS-total (/48) 6 (0–18)
Depression
HADS-D (/21) 1 (0–14)
2.3 | Statistical analysis
HADS-D > 7, % 17.0% (8)

Descriptive statistics were reported using median, range and per- UPDRS Item 1.3 (depression) > 0 35.4% (17)

centages unless otherwise specified. Spearman's correlation was Apathy

employed to assess the relationship between mood and non- UPDRS Item 1.5 (apathy) > 0 27.1% (13)
motor/motor variables based on results of normality testing by Sleep
the Kolmogorov-Smirnov test. A p  ˂  .05 was considered signifi- ESS score (/24) 4 (0–23)
cant. Standard multiple regression was performed using HADS-D, SCOPA-S (DS) (/18) 2 (0–13)
HADS-A and PAS-Total scores as dependent variables. Based on cor- SCOPA-S (NS) (/15) 2 (0–10)
relation results, SCOPA-S (DS), SCOPA-S (NS), SCOPA-AUT, UPDRS RBDSQ score (/13) 9 (2–13)
Section III and MMSE scores were selected as the independent vari-
Autonomic
ables. Age and disease duration were also included as a confounder
SCOPA-AUT total 6.5 (2–19)
in all regression analyses, due to the high frequency of mood dis-
UPDRS item 1.10 (Urinary problems) >0 43.7% (21)
orders in older adults (Whyte & Rovner, 2006) and the increased
UPDRS item 1.11 (Constipation problems) >0 27.1% (13)
prevalence of other physical and medical comorbidities with older
UPDRS item 1.12 (Light headedness on 39.6% (19)
age and longer disease duration that may contribute to mood impair-
standing) >0
ments. Any variable with p ˂ .1 was retained in the model. MoCA was
Motor
not used in the regression analysis as it did not correlate significantly
UPDRS section III total score 9 (0–29)
with any variables. An auxiliary factor analysis was also conducted
using Varimax rotation (selecting factors with eigenvalues > 1) to also Cognitive

support selection of variables of the regression model above, aiming MoCA score (/30) 27 (20–30)

to minimize variables with multi-collinearity (refer to Supplementary
Table S3). All analyses were performed with the Statistical Package
for the Social Sciences version 25 for Windows (IBM Corp, 2017).
3 | R E S U LT S
The demographic characteristics of our cohort are presented in
Table 1. In our cohort, 35.4% reported depressive symptoms on
MMSE score (/30) 29 (20–30)
Abbreviations: ESS, Epworth Sleepiness Scale; HADS, Hospital Anxiety
and Depression Scale – Depression (-D) and Anxiety (-A); MMSE, Mini-
Mental State Examination; MoCA, Montreal Cognitive Assessment;
PAS, Parkinson's Anxiety Scale; RPDSQ, REM Sleep Behaviour
Disorder Screening Questionnaire; SCOPA-AUT, Scales for Outcomes
in Parkinson's Disease – Autonomic; SCOPA-S, Scales for Outcomes in
Parkinson's Disease – Sleep - daytime sleepiness (DS) and night-time
sleep disturbances (NS); STAI, State-Trait Anxiety Inventory; UPDRS,
Unified Parkinson's Disease Rating Scale.
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UPDRS Item 1.3, and 17.0% of patients had significant depres- including age, disease duration and autonomic scores, did not cor-
sion (HADS-D>7). In terms of anxiety, 39.6% reported anxiety relate significantly with the HADS-D. A multiple linear regression
symptoms on UPDRS Item 1.4, and 14.6% had significant anxiety analysis (Table 3) was carried out with the HADS-D as the depend-
(HADS-A>7). Trait anxiety was more frequent in our respondents ent variable and age, disease duration, SCOPA-S (DS), SCOPA-S (NS),
(25%; STAI-T>40) than state anxiety (STAI-S>40), which was only MMSE, UPDRS Section III scores as independent variables. In the
reported in 5% of respondents. Using the PAS, presence of any per- final model, the SCOPA-S (DS) (β = 0.328), SCOPA-S (NS) (β = 0.353),
sistent anxiety symptoms (PAS-P) was more frequent than episodic MMSE (β  =  −0.311) and UPDRS Section III (β  =  0.288) accounted
(PAS-E) and avoidant (PAS-A) anxiety (90%, 65% and 42% of pa- for most of the variance in the correlation with HADS-D scores
tients, respectively). Over a quarter (27.1%) of participants reported (R 2 = .488, p < .001). Other variables could not significantly account
some apathy-related symptoms (UPDRS 1.5>1), although overall the for mood scores in the model.
scores were mild (range, 0–2). In agreement with previous studies,
sleep and autonomic symptoms were reported with high frequency
(UPDRS 1.7 > 0 = 87.5%, 1.8 Daytime sleepiness > 0 = 52.1%, 1.10 3.2 | Predictors of anxiety
Urinary problems > 0 = 43.7%, Constipation problems > 0 = 27.1%,
Light headedness on standing > 0 = 39.6%) across a wide range of The HADS-A was significantly correlated with the SCOPA-S (DS)
scores, thus facilitating the subsequent correlational analyses. As (r = .516) and SCOPA-S (NS) (r = .615) (Table 2). Other variables
expected, early motor deficits were seen in a significant proportion tested, including age, disease duration, and autonomic, motor and
of patients, albeit mild (UPDRS-III median score, 9). cognitive scores, did not correlate significantly with the HADS-A.
A linear regression analysis was carried out with the HADS-A as
the dependent variable and age, disease duration and the SCOPA-S
3.1 | Predictors of depression (DS), SCOPA-S (NS) and MMSE as independent variables (Table 3).
In the final model, the SCOPA-S (DS) (β = 0.315) and SCOPA (NS)
The correlational analysis between mood scores of interest and (β = 0.425) accounted for most of the variance in the correlation with
the motor and non-motor features detected is shown in Table 2. the HADS-A (R 2 = .429, p < .001). Other variables could not signifi-
The HADS-D was significantly correlated with the ESS (r  =  .408), cantly account for mood scores in the model.
SCOPA-S (DS) (r = .503), SCOPA-S (NS) (r = .484), MMSE (r = −0.251) The PAS-total significantly correlated with the SCOPA-S (NS)
and UPDRS Section III (r = .277) (Table 2). Other variables tested, (r = .485), SCOPA-AUT (r = .602) and MMSE (r = −.488). Age was only
correlated with PAS-A (r = .497). Other variables tested, including
TA B L E 2   Correlations between mood and other motor and non- disease duration and motor examination, did not correlate signifi-
motor symptoms cantly with the PAS-total. A linear regression analysis was carried
out with the PAS-Total as the dependent variable and age, disease
Variable HADS-D HADS-A PAS-Total
duration and the SCOPA-S (DS), SCOPA-S (NS), SCOPA-AUT, MMSE
Sleep
and UPDRS Section III as independent variables. In the final model,
ESS 0.408** n.s. n.s.
the SCOPA-AUT (β = 0.618) and MMSE (β = −0.430) accounted for
SCOPA-S (DS) 0.503*** 0.516*** n.s. most of the variance in the correlation with the PAS-Total (R 2 = .663;
SCOPA-S (NS) 0.484*** 0.615*** 0.485* p < .05). Other variables could not significantly account for mood
Autonomic scores in the model.
SCOPA-AUT n.s. n.s. 0.602**
Cognitive
MMSE −0.251*^ n.s. −0.488* 4 | D I S CU S S I O N
MoCA n.s. n.s. n.s.
In this study, the prevalence and characteristics of mood symp-
Motor      
toms, alongside motor and non-motor symptoms, were character-
UPDRS Section III 0.277*^ n.s. n.s.
ized in an iRBD cohort. The precise rates of depressive and anxiety
Note: Spearman correlation coefficients between mood symptoms and
symptoms in iRBD differ between studies (Postuma et al., 2019),
motor/non-motor scores. Only variables with significant correlations
which may be due to different types of assessment scales utilized
have been reported in the table. ^ one-tailed. Variables with significant
correlations (and p < .1) used in subsequent predictive models below. and heterogeneity between populations, including culture, age and
* = significant p < .05; ** = significant p < .01; *** = significant p < .001. disease durations. In spite of this, all studies, including this one,
Abbreviations: ESS, Epworth Sleepiness Scale; MMSE, Mini-Mental tend to support mood disturbances as an important comorbidity af-
State Examination; MoCA, Montreal Cognitive Assessment; n.s., not
fecting a significant proportion of iRBD patients. Furthermore, we
significant; SCOPA-AUT, Scales for Outcomes in Parkinson's Disease
– Autonomic; SCOPA-S, Scales for Outcomes in Parkinson's Disease – demonstrate utility of more specific validated anxiety measures in
Sleep - daytime sleepiness (DS) and night-time sleep disturbances (NS); iRBD, such as the STAI and PAS, which highlights the novel find-
UPDRS, Unified Parkinson's Disease Rating Scale. ing that trait or persistent anxiety affects iRBD patients more than
CHIU et al. |
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TA B L E 3   Predictors of mood
Standardized
symptoms in iRBD
Mood R2 value Significant predictors coefficients β

HADS-D R2 = .488, F = 5.88, df = 6, SCOPA-S (DS) β = 0.328, t = 2.44;

37; p < .001 p < .05
SCOPA-S (NS) β = 0.353, t = 2.81;
p < .01
MMSE β = −0.311, t = −2.42;
p < .05
UPDRS- III β = 0.288, t = 2.05;
p < .05
HADS-A R2 = .429, F = 6.01, df = 5, SCOPA (DS) β = 0.315, t = 2.58;
40; p < .001 p < .05
SCOPA (NS) β = 0.425, t = 3.33;
p < .01
PAS-total R2 = .663, F = 3.097, df = 7, SCOPA-AUT β = 0.618, t = 2.44;
11; p < .05 p < .05
MMSE β = −0.430, t = −1.96;
p < .1

Note: Multiple linear regression model using mood variables as dependent variables and non-motor
and motor variables as independent variables. Only variables with significant correlations have
been reported in the table.
Abbreviations: HADS, Hospital Anxiety and Depression Scale – Depression (-D) and Anxiety (-A);
MMSE, Mini-Mental State Examination; PAS, Parkinson's Anxiety Scale; SCOPA-AUT, Scales for
Outcomes in Parkinson's Disease – Autonomic; SCOPA-S, Scales for Outcomes in Parkinson's
Disease – Sleep - daytime sleepiness (DS) and night-time sleep disturbances (NS); UPDRS, Unified
Parkinson's Disease Rating Scale.

state or episodic anxiety. We also found a discrepancy between self-
reported depression and anxiety in the UPDRS and the HADS, with
the former having a higher sensitivity for detecting depression and
anxiety symptoms in our cohort. Studies in PD patients have shown
that patients tend to develop milder or subclinical, but subjectively
important, forms of depression that do not meet diagnostic criteria
(Marsh, 2013). Our findings support the use of more targeted scales
that may be more sensitive in synuclein-based disorders (such as the
PAS, which addresses ‘‘trait’’-based anxiety) in prodromal popula-
tions such as those with iRBD.
Depression and anxiety are multifactorial and complex syn-
dromes, which can often be circumstantial and arise as a result of,
or be augmented by, the presence of other physical and mental
comorbidities (Niles et al., 2015). The optimal treatment of mood
disturbances relies on the appreciation and treatment of these
other interacting factors. Motivated by this, our study explicitly ex-
plores associations of depression and anxiety with other motor and
non-motor symptoms that frequently co-occur in iRBD. We found
relationships between depression and sleep, cognitive and motor
symptoms. We also found sleep symptoms correlated well with anx-
iety symptoms according to both the HADS-A and PAS. Using anx-
iety measures derived from the PAS also highlighted contributions
of cognitive and autonomic symptoms. This latter finding could be
explained by the additional subtypes of anxiety symptomatology ex-
plored by the PAS when compared to the HADS-A.
Nocturnal sleep problems and daytime sleepiness were found
to be strong and consistent predictors of both depression and
anxiety scores in our iRBD cohort. With respect to the charac-
ter of the nocturnal symptoms, the domains of the SCOPA-S for
which participants scored positively included: insufficient sleep
during the night, sleep fragmentation and early morning waken-
ing. Chronic sleep fragmentation and poor sleep quality increase
sleep debt and may contribute to excessive daytime sleepiness.
This has been observed to be a significant factor in excessive day-
time somnolence in PD patients (Swick, 2012). Sleep disturbances
have been shown to exacerbate psychopathological symptoms in
various age groups, with insomnia associated with greater severity
of anxiety and depression (Tkachenko et al., 2014). Mood symp-
toms may arise from the direct effects of sleep disruption, such as
fatigue or the indirect effect of an anticipatory anxiety response
to further sleep loss (Irwin et al., 2012). The role of the prefron-
tal cortex has been implicated in emotional regulation and studies
have shown reduced metabolic activity and functional connec-
tivity in subjects with worsened sleep quality (Taylor, Lichstein,
Durrence, Reidel, & Bush, 2005). It has been proposed that REM
sleep is important in processing affective information, with mod-
els implicating REM sleep in emotional memory resolution and re-
calibration (Goldstein & Walker, 2014). Interestingly, REM stability
and REM-NREM transitions are shown to be disrupted in iRBD
(Christensen et al., 2016). This disruption in sleep, and in particular
REM sleep stability, may possibly lead to maladaptive emotional
responses by the above mechanisms. It is also important to con-
sider that sleep disturbances may themselves arise as a result of
anxiety and depression (Oh, Kim, Na, Cho, & Chu, 2019). However,
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in our cohort, we were unable to achieve a good regression model
explaining sleep disturbances (nocturnal or daytime) and other
motor and non-motor variables when treating depression and anx-
iety as independent variables (refer to Appendix S2). In these, the
strength of the models (R 2) in the reverse direction is significantly
reduced, indicating that mood alone contributes a much smaller
proportion of the variance to the variables examined in the study.
This further supports our treatment of mood as a dependent vari-
able, at least in our cohort. Furthermore, mood symptoms in our
cohort are mostly in the mild range and thus unlikely alone to gen-
erate profound physical manifestations, as would be seen in more
severe depression and anxiety states. Thus, although a bidirec-
tional relationship is likely to be present to some degree, our find-
ings, together with the fact that iRBD is primarily a parasomnia,
support the view of sleep disturbances in the context of iRBD as
a driver behind mood disturbances. Clinicians should therefore be
prepared to identify and address sleep disturbances in any iRBD
patient with concomitant mood symptoms, as they may be sec-
ondary to, or at least exacerbated by, the sleep problems.
Poor cognitive performance on the MMSE was also found to be
a predictor for depression and anxiety in our regression analysis.
Although psychiatric conditions are known to cause cognitive im-
pairments, a recent longitudinal study in PD patients supports our
results that poor cognitive performance may explain an increase
in severity of anxiety and depression (Petkus, Filoteo, Schiehser,
Gomez, & Petzinger, 2019). Another study among old Hispanic
non-demented healthy adults revealed the same trend (Perrino,
Mason, Brown, Spokane, & Szapocznik, 2008). Possible explanations
for cognitive impairment contributing to anxiety and depression may
include psychological distress arising from awareness of cognitive
deficits, or impaired cognitive functioning affecting one's ability to
regulate mood or improve mood through engagement in social activ-
ities or exercise (Perrino et al., 2008).
Dysautonomia was revealed in our study to be a strong pre-
dictor of anxiety in iRBD, as reported by the PAS. Interestingly,
studies in PD patients have previously demonstrated a significant
association between autonomic impairment and anxiety (Berrios,
Campbell, & Politynska, 1995). One such study has suggested a
pathophysiological predisposition and stronger response towards
physical symptoms of anxiety in patients with autonomic failure
in PD (Cui et al., 2017). Even when considering non-PD patients,
symptoms of urinary incontinence (Felde, Ebbesen, & Hunskaar,
2017) and orthostatic hypotension (Claassen, Adler, Hewitt, &
Gibbons, 2018) are all associated with higher levels of anxiety. The
dysfunctional neural circuitry involved in anxiety has been argued
to have potential links with the central autonomic network (Kim,
Lee, & Kim, 2016). Fortunately, there are many effective non-phar-
macological and pharmacological options for treating autonomic
symptoms. Thus, as with sleep symptoms, it would be incumbent
on the clinician to assess and treat these features as part of a mul-
tipronged approach for treating mood disturbance, especially anx-
iety, in their iRBD patients.
Motor impairment reflected by the Section III score of the
UPDRS was also shown to be a predictor of depression in our iRBD
cohort. Motor disability has been reported to explain symptoms of
depression in PD patients, with self-perception of disability being
more severe than actual disability (Cui et al., 2017). Although motor
impairments may be milder in iRBD, the psychological response to
irritating or even disabling motor symptoms may cause significant
mood disturbances, and such perception of and sensitivity to dis-
ability may be increased by knowledge about the risk of developing
synucleinopathies in the future (Iranzo et al., 2016).
Another explanation for the correlations between mood and
non-motor and motor symptoms may be that these symptoms are
a consequence of early neurodegeneration affecting key brainstem
regions, as suggested by the Braak hypothesis of PD progression
(Braak, Ghebremedhin, Rub, Bratzke, & Del Tredici, 2004). Indeed,
studies using positron emission tomography (Teman et al., 2009)
and transcranial sonography (Bourgouin et al., 2019) have shown
abnormalities in the locus coeruleus and dorsal raphe nucleus, re-
spectively, in depressed iRBD patients. Thus, the co-occurrence of
depression, especially, and other non-motor symptoms could be
thought to simply reflect concomitant neurodegeneration in multi-
ple regions giving rise to these symptoms. However, a recent, large
multicentre study aimed at identifying variables that predict the pro-
gression from iRBD to synucleinopathy found that depression and
anxiety, as well as the sleep and most autonomic symptoms assessed
here, were not significant predictors of neurodegeneration (Postuma
et al., 2019). In line with this, age, which has been shown to relate
to probability of phenoconversion, was not a significant predictor
of mood disturbance in our cohort. Furthermore, anxiety and de-
pression were predicted by a distinct set of motor/non-motor symp-
toms in our cohort, suggesting potentially separable mechanisms.
Thus, these findings argue for a more nuanced explanation of mood
symptoms in iRBD that considers the interplay and contribution of
comorbid motor/non-motor features to this symptom, rather than
being a co-occurring phenomenon explained by concomitant neuro-
degeneration. Importantly, such a perspective can help redirect clin-
ical management of depression and anxiety in iRBD patients through
optimization of non-pharmacological treatments such as exercise,
diet and sleep hygiene, instead of prescribing antidepressants and
anxiolytics, which may exacerbate dream-enactment behaviour.
Finally, limitations of this study relate to its cross-sectional na-
ture, which compared with longitudinal population-based studies is
unable to definitively disentangle the strength of bidirectional re-
lationships present between sleep or cognition, and mood. Careful
interpretation of the results is needed as predictors do not on their
own suggest causality. Additionally, other potential causes of mood
disturbances such as personal circumstances and personality traits
were not measured here. These could potentially be included in future
studies to explain the remaining variance in depression and anxiety
scores. Our findings support the value of further studies evaluating
mood in iRBD patients, particularly involving more detailed explora-
tion of symptoms such as apathy and the use of auxiliary measures
CHIU et al.
of neurodegeneration such as dopamine transporter imaging to un-
derstand its contribution to mood in iRBD patients.
AC K N OW L E D G E M E N T S
We would like to acknowledge the patients for their participation in
the research study. We would also like to acknowledge Dr N Khalil,
Dr A Powell, Dr YY Szeto, nurse specialists D Hammond and M
Pereira, Ms N Taylor and Ms D Quek for their assistance in the col-
lection of data.
C O N FL I C T O F I N T E R E S T
There are no conflicts of interest to declare.
AU T H O R C O N T R I B U T I O N S
NKHC was responsible for statistical analysis and writing of the man-
uscript. KEM was responsible for data collection, review and critique
of the manuscript. VCTM was responsible for review and critique of
the manuscript. SJGL was responsible for conception, organization,
review and critique of statistical analysis and the manuscript. EM
was responsible for conception, organization, data collection, review
and critique of statistical analysis and the manuscript.
E T H I C A L A P P R OVA L
This research study was approved by the University of Sydney
Human Research Ethics Committee (Project 2012/2517). Informed
consent was obtained from all participants and/or their appointed
next of kin where appropriate. We confirm that we have read the
Journal's position on issues involved in ethical publication and affirm
that this work is consistent with those guidelines.
ORCID
Nicholas K. H. Chiu  https://orcid.org/0000-0002-9012-8010
Elie Matar  https://orcid.org/0000-0002-4994-0488
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S U P P O R T I N G I N FO R M AT I O N
Additional supporting information may be found online in the
Supporting Information section.
How to cite this article: Chiu NKH, Ehgoetz Martens KA, Mok
VCT, Lewis SJG, Matar E. Prevalence and predictors of mood
disturbances in idiopathic REM sleep behaviour disorder. J
Sleep Res. 2021;30:e13040. https://doi.org/10.1111/jsr.13040