ARTICLE IN PRESS

Depression and Anxiety in

Parkinson’s Disease
Anette Schrag*,1, Raquel N. Taddei†
*UCL Institute of Neurology, London, United Kingdom
†
King’s College Hospital, London, United Kingdom
1
Corresponding author: e-mail address: a.schrag@ucl.ac.uk

Contents
1. Definition and Diagnosis 622
2. Subtypes of Depression and Anxiety in PD 622
3. Epidemiology 623
4. Impact on Quality of Life 630
5. Scales for Depression and Anxiety 631
5.1 Depression 631
5.2 Anxiety 635
6. Biomarkers in Depression and Anxiety in PD 635
7. Management 639
7.1 Depression 639
7.2 Anxiety 641
8. Conclusions 641
References 641

Abstract
Depression and anxiety are some of the most common comorbidities arising in patients
with Parkinson’s disease. However, their timely recognition and diagnosis are often hin-
dered by overlap with other somatic features and a low rate of self-report. There is a
need for greater awareness and for better assessment and treatment options are highly
required. Currently available scales can serve as tools to monitor change over time and
the effect of interventional strategies. Development of new therapeutic strategies,
including nonpharmacological approaches such as transcranial magnetic stimulation
and deep brain stimulation, may provide alternatives to currently available treatment
approaches. In this chapter we will give an overview of the most recent advances in
the diagnosis and treatment of these important nonmotor symptoms.

International Review of Neurobiology # 2017 Elsevier Inc. 621

ISSN 0074-7742 All rights reserved.
http://dx.doi.org/10.1016/bs.irn.2017.05.024
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622 Anette Schrag and Raquel N. Taddei

1. DEFINITION AND DIAGNOSIS

Anxiety and depressive disorders are common neuropsychiatric com-
plications of Parkinson’s disease (PD). Their assessment is complicated by
the overlap of features with other manifestations of PD and, whilst they
may have particular characteristics (Cleo et al., 2015), there is no clearly
defined difference to depressive or anxiety disorders in non-PD patients.
Therefore, diagnosis of anxiety and depressive disorders is based on standard
criteria, including ICD-10 diagnostic criteria and the definitions of anxiety
and depressive disorders in the DSM Diagnostic and Statistical Manual of
Mental Disorders (DSM) V criteria by the American Psychiatric Association.
The types of depressive disorders seen in PD include major depression,
minor depression, and dysthymia. Patients with minor depressive disorder
patients do not formally satisfy DSM V criteria but suffer from significant
depressive symptoms interfering in their lives (Fils et al., 2010). Dysthymia,
now called persistent depressive disorder in DSM V, is major depressive
disorder lasting for at least 2 years (http://psychcentral.com/disorders/
dysthymic-disorder-symptoms/). However, subsyndromal depression not
fulfilling full diagnostic criteria for depression is also common and should
be included in the assessment of depressive symptoms of PD (Marsh,
McDonald, Cummings, & Ravina, 2006). Anxiety can present with panic
attacks, phobias, or generalized anxiety disorder (Pellicano et al., 2007).
Both disorders in PD can be episodic or nonepisodic and may be associated
with off periods, with or without motor features (Sagna, Gallo, &
Pontone, 2014).

2. SUBTYPES OF DEPRESSION AND ANXIETY IN PD

Within the definitions of anxiety and depressive disorders, the symp-
toms of depression and anxiety in patients with PD vary. The PROMS-PD
study subclassified patients according to their neuropsychiatric phenotype
(Brown et al., 2011; Burn et al., 2012) into four clinical phenotypes:
anxious-depressed, predominantly depressed, predominantly anxious, and
healthy subgroup. The investigators reported that depression was more
strongly related to axial motor symptoms, whereas anxiety was more com-
monly found among patients with motor fluctuations as well as younger age
of onset (below the age of 55 years). Patients with the postural instability and
gait disorder (PIGD) or nontremor-dominant motor subtypes were more
likely to be represented in any of the mood subgroups when compared with
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Depression and Anxiety in Parkinson’s Disease 623

non-PIGD and tremor-dominant patients. Furthermore, cognition was

found to be a predictor of depression but not anxiety scores.

3. EPIDEMIOLOGY
Assessment of prevalence of depression and anxiety in PD is often
complicated by overlap of somatic features of depression with other features
of PD, coexisting cognitive problems and side effects of dopaminergic med-
ication (Gallagher & Schrag, 2012). However, depressive symptoms in PD
are reported to be present in approximately 20%–30% of patients with PD
(Schrag, Ben-Shlomo, & Quinn, 2002), with wide variation between stud-
ies, ranging from 2.7% to up to 90% in the literature (Reijnders, Ehrt,
Weber, Aarsland, & Leentjens, 2008). In a review by Reijnders et al.
(2008), the weighted prevalence of major depressive disorder was 17% that
of minor depressive symptoms 22% and dysthymia 13%. The authors con-
cluded an increased prevalence of depression in PD, but lower than generally
assumed. While depressive symptoms are also common in the general pop-
ulation, they have clearly been shown to be more frequent in PD patients
than age-matched populations, and they are also more common in this neu-
rological condition than in other comorbid health problems such as diabetes
or osteoarthritis (Nilsson, Kessing, Sorensen, Andersen, & Bolwig, 2002). In
Table 1, a summary of the reported prevalence rates of the different types of
depressive disorders are shown.
Although anxiety is often assessed together with depression and is fre-
quently comorbid with depression (Menza, Golbe, Cody, & Forman,
1993; Starkstein, Robinson, Leiguardia, & Preziosi, 1993), it can occurr
independently and has been reported to exert a higher impact on quality
of life among PD patients than depression itself (Qureshi, Amspoker,
Calleo, Kunik, & Marsh, 2012; Yamanishi et al., 2013). Studies on the prev-
alence of anxiety are scarce and complicated by symptom overlap and
comorbid disorders. Report prevalence rates range from 25% to 52%
(Broen, Narayen, Kuijf, Dissanayaka, & Leentjens, 2016; Chen, 2004;
Schrag, 2004; Walsh & Bennett, 2001). Table 2 summarizes the prevalence
of anxiety in PD among different studies.
Overall, depression and anxiety are both inadequately recognized as
complications of PD in daily clinical practice and are not diagnosed in up
to 50% of PD patients. However, they are more frequently recognized than
some other nonmotor features, such as those possibly considered more
embarrassing (Chaudhuri et al., 2010; Gallagher, Lees, & Schrag, 2010;
Kano et al., 2011).
Table 1 Rate (%) of Depression in PD in Different Studies
Clinically
Major Relevant
Sample Quality Depressive Minor Depressive
Study Sample Size Score Disorder Depression Dysthymia Symptoms
Structured clinical interview
Starkstein, Preziosi, Bolduc, and Robinson (1990) Outpatient clinic 105 5 21 20 41
Starkstein, Mayberg, Leiguarda, Preziosi, Outpatient clinic 92 5 20 21 41
and Robinson (1992)

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Hantz, Caradoc-Davies, Caradoc-Davies, Weatherall, Population 73 7 2.7 2.7
and Dixon (1994)
Starkstein, Sabe, Petracca, et al. (1996) Outpatient clinic/ 33 6 30 27 57
dementia
Liu et al. (1997) Outpatient clinic 109 5 16.5 25.7 42.2
de Rijk and Bijl (1998) Population 384 5 2.3 4.7 7
Starkstein, Petracca, Chemerinski, et al. (1998) Outpatient clinic 112 6 22 31.3 53.3
Leentjens, Verhey, Lousberg, et al. (2000) Outpatient clinic 63 6 25 25
Leentjens, Verhey, Luijckx, et al. (2000) Outpatient clinic 53 6 23 23
Anguenot, Loll, Neau, Ingrand, and Gil (2002) Outpatient clinic 135 6 55.6 2.2 57.8
Naarding, Leentjens, van Kooten, and Verhey (2002) Outpatient clinic 85 6 23.5 23.5
Weintraub, Moberg, Duda, Katz, and Stern (2003) Outpatient clinic 77 6 20.8 13 33.8
Lauterbach, Freeman, and Vogel (2004) Outpatient clinic 28 5 14.3 3.6 17.9
Nuti, Ceravolo, Piccinni, et al. (2004) Outpatient clinic 90 6 21.1 18.8 39.9
Ertan, Ertan, Kiziltan, and Uygucgil (2005) Outpatient clinic 109 6 22.9 28.4 51.4
Papapetropoulos, Gonzalez, Lieberman, Villar, Brain bank data 67 7 43.3
and Mash (2005)
Costa, Peppe, Carlesimo, Pasqualetti, and Caltagirone Inpatient clinic 58 5 20.7 34.5 55.2

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(2006a)
Costa, Peppe, Carlesimo, Pasqualetti, and Caltagirone Inpatient clinic 83 6 21.7 25.3 47
(2006b)
Visser, Leentjens, Marinus, Stiggelbout, Outpatient clinic 92 6 19 19
and van Hilten (2006)
Wichowicz, Slawek, Derejko, and Cubala (2006) Population 100 6 35 35
Clinical interview
Santamaria, Tolosa, and Valles (1986) Outpatient clinic/ 34 4 2.9 29.4 32.3
recent onset
Mayeux, Stern, Rosenstein, et al. (1988) Outpatient and 339 4 47
inpatient clinic
Brown and MacCarthy (1990) Outpatient clinic 40 6 25
Aarsland, Tandberg, Larsen, and Cummings (1996) Population 235 6 7.7 7.7
Tandberg, Larsen, Aarsland, and Cummings (1996) Population 245 6 7.7 7.7
Continued
Table 1 Rate (%) of Depression in PD in Different Studies—cont’d
Clinically
Major Relevant
Sample Quality Depressive Minor Depressive
Study Sample Size Score Disorder Depression Dysthymia Symptoms
Tandberg, Larsen, Aarsland, Laake, and Cummings Population 245 6 7.7 7.7
(1997)
Tandberg, Larsen, and Karlsen (1998) Population 239 6 7.8 7.8
Aarsland, Larsen, Cummins, and Laake (1999) Population 235 5 7.2 7.2

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Karlsen, Larsen, Tandberg, and Maeland (1999) Population 233 6 7.7 7.7
Cubo, Bernard, Leurgans, and Raman (2000) Outpatient clinic 88 5 7.3 7.3
Giladi, Treves, Paleacu, et al. (2000) Outpatient clinic 172 5 33
Larsen, Karlsen, and Tandberg (2000) Population 240 6 7.6 7.6
Krishnan, Bhatia, and Behari (2003) Outpatient clinic 126 5 12.7
Rating scale
Mindham (1970) Inpatient 89 3 89
psychiatric
hospital
Tison et al. (1995) Outpatient clinic 60 6 32.7
and nursing home
Meara, Mitchelmore, and Hobson (1999) General practice 132 5 64
Schrag, Jahanshahi, and Quinn (2000) General practice 92 5 19.6
Happe et al. (2001) Outpatient clinic 56 4 76.4
Schrag, Jahanshahi, and Quinn (2001) General practice 97 5 19.6
Shulman, Taback, Bean, and Weiner (2001) Outpatient clinic 99 3 36
Happe, Ludemann, and Berger (2002) Outpatient clinic 116 4 37.1
Marinus, Leentjens, Visser, Stiggelbout, Outpatient clinic 177 4 38.4
and van Hilten (2002)

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Schrag et al. (2002) General practice 128 5 20
Shulman, Taback, Rabinstein, and Weiner (2002) Outpatient clinic 101 3 44
Rojo et al. (2003) Outpatient clinic 353 4 56.9
Hely, Morris, Reid, and Trafficante (2005) Outpatient clinic 52 4 53.6
Holroyd, Currie, and Wooten (2005) Outpatient clinic 100 4 15
Kang et al. (2005) Population 193 5 13
Prado and Barbosa (2005) Outpatient clinic 60 4 38.3
Kirsch-Darrow, Fernandez, Marsiske, Okun, and Outpatient clinic 80 3 26.3
Bowers (2006)
Weintraub, Morales, Duda, Moberg, and Stern (2006) Outpatient clinic 130 4 36.2
Weighted mean 5.1 17 22 13 35
From Reijnders, J. S., Ehrt, U., Weber, W. E., Aarsland, D., & Leentjens, A. F. (2008). A systematic review of prevalence studies of depression in Parkinson’s disease. Movement Disorders,
23, 183–189.
Table 2 Overview of Studies Reporting Clinically Relevant Anxiety Symptoms in PD According to Validated Rating Scales
Sample Quality Cutoff Clinically Relevant
Study Sample Size Score Scale Used Score Used Anxiety Symptoms (%)
Marinu et al. (2002) Outpatient clinic 177 16 HADS 11 19.8
Carod-Artal, Ziomkowski, Outpatient clinic 144 14 HADS 11 23.6
Mourão Mesquita, and
Martı́nez-Martin (2008)
Mondolo et al. (2007) Outpatient clinic 46 14 HADS 8 10.8
Carod-Artal et al. (2008) Outpatient clinic 115 14 HADS 11 30.4

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McKinlay et al. (2008) Outpatient clinic 42 15 HADS 8 16
Havlikova et al. (2008) Outpatient clinic 150 14 HADS 11 30.6
Kulisevsky et al. (2008) Outpatient clinic 1351 19 HADS 11 20.8
Rodriguez-Blazquez Outpatient clinic 387 14 HADS 11 22
et al. (2009)
Nègre-Pagès et al. (2010) Population 422 17 HADS 11 (8) 27 (51)
Hu et al. (2011) Population 197 14 HADS 11 32
Brown et al. (2011) Outpatient clinic 513 16 HADS 11 22
Ozdilek and Gunal (2012) Outpatient clinic 50 14 HADS 10 18
Quelhas and Costa (2009) Outpatient clinic 33 14 HADS 11 (8) 18.2 (54.5)
Fereshtehnejad et al. (2015) Outpatient clinic 140 14 HADS 8 38.9
Borek, Kohn, and Outpatient clinic 120 16 HARS 14 23.2
Friedman (2006)
Stefanova, Ziropadja, Outpatient clinic 360 19 HARS 11 37.8
Petrovi
c, Stojkovi
c, and
Kosti
c (2013)
Jiang et al. (2015) Outpatient clinic 99 14 HARS >11 25.3
Wu, Liao, Chen, Chang, Outpatient clinic 301 15 HARS >14 10.6
and Lin (2015)
Schulman et al. (2001) Outpatient clinic 101 16 BAI 10 39
Rutten et al. (2015) Outpatient clinic 294 16 BAI >12 45

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Yamanishi et al. (2013) Outpatient clinic 117 15 STAI 41 (men) 42 55
(women)
Weintraub et al. (2015) Outpatient clinic 423 15 STAI >39 24.6
Siri et al. (2010) Population 486 15 SCL-90 >1 46
Bugalho, da Silva, Outpatient clinic 36 15 SCL-90-R >1 28
Cargaleiro, Serra, and Neto
(2012)
Henderson, Kurlan, Outpatient clinic 164 16 Zung >49 15
Kersun, and Como (1992)
Baig et al. (2015) Outpatient clinic 769 17 Leeds anxiety score >7 17.3
Aarsland, Marsh, and Population 175 16 NPI 4 6.9
Schrag (2009)a
a
Drug naı̈ve.
Glossary: BAI, Beck Anxiety Inventory; HADS, Hospital Anxiety and Depression Scale; HARS, Hamilton Anxiety Rating Scale; NPI, neuropsychiatric inventory; SCL-
90, Symptom Checklist-90; STAI, State-Trait Anxiety Inventory.
Taken from Broen, M. P., Narayen, N. E., Kuijf, M. L., Dissanayaka, N. N., & Leentjens, A. F. (2016). Prevalence of anxiety in Parkinson’s disease: A systematic review
and meta-analysis. Movement Disorders, 31(8), 1125–1133.
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630 Anette Schrag and Raquel N. Taddei

In the prediagnostic phase of PD, depression and initiation of an antide-

pressant treatment are associated with an increase of risk of PD with an OR
of 1.8–2.4 (Alonso, Rodriguez, Logroscino, & Hernan, 2009; Fang et al.,
2010; Leentjens, Van den Akker, Metsemakers, Lousberg, & Verhey,
2003; Weisskopf, Chen, Schwarzschild, Kawachi, & Ascherio, 2003). Studies
have also shown a link between existence of anxiety and the development of
PD with a relative risk of 1.5–1.6 (Bower et al., 2010; Weisskopf et al., 2003;
Zhu, van Hilten, & Marinus, 2017). A premorbid Parkinsonian personality
with anxious traits has also been suggested, with lower novelty-seeking
behavior and higher harm avoidance (Ishihara & Brayne, 2006; Menza
et al., 1993; O’Sullivan et al., 2008).
Risk factors for the development of depression in PD patients have been
examined in large-scale studies, reporting an increased risk among women,
in the advanced stages of PD and in patients with cognitive impairment
(Aarsland, Pahlhagen, Ballard, Ehrt, & Svenningsson, 2011).
Genetic risk factors for the development of depression or anxiety in PD
have so far shown inconsistent results (Burn, Tiangyou, Allcock, Davison, &
Chinnery, 2006; Dissanayaka, Silburn, O’Sullivan, & Mellick, 2009; Menza,
Palermo, DiPaola, Sage, & Ricketts, 1999; Mossner et al., 2001), although
one study has suggested that depression is more common among carriers of
the Gly2019Ser mutation in the LRRK2 gen, when compared with non-
carriers (Belarbi et al., 2010). A longitudinally followed GBA mutation-
positive cohort was found to have increased scores of depression (Beavan
et al., 2015). The relationship between PARK2, PINK1, PARK7, and
DJ1mutations and depression/anxiety has also been studied, but no clear
correlation could be found between the mutation carriers and the noncar-
riers for these genes (Abbas et al., 2016; Caccappolo et al., 2011; Hanagasi
et al., 2016; Hedrich et al., 2006; Kumazawa et al., 2008; Srivastava et al.,
2011; Tan et al., 2006).
Risk factors associated with anxiety were examined in a longitudinal
study by Zhu et al. who reported that depressive symptoms, insomnia,
dysautonomia, and cognitive impairment were risk factors associated with
higher Hospital Anxiety and Depression Scale-Anxiety (HADS-A) scores
(Zhu et al., 2017).

4. IMPACT ON QUALITY OF LIFE

Anxiety and depression have also been shown to be determinants of
poorer quality of life in PD patients (Bach et al., 2012; Balestrino &
Martinez-Martin, 2017; Duncan et al., 2014; Fan, Chang, & Wu, 2016;
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Depression and Anxiety in Parkinson’s Disease 631

Fereshtehnejad et al., 2015; Gallagher et al., 2010; Lawson et al., 2014; Leroi
et al., 2011; M€ uller, Assmus, Herlofson, Larsen, & Tysnes, 2013; Rahman,
Griffin, Quinn, & Jahanshahi, 2008; Santos-Garcı́a & de la Fuente-
Fernández, 2013). They result in a reduced quality of life, worse functional
status, and worse cognitive function (Weintraub, Moberg, Duda, Katz, &
Stern, 2004), and have been linked with an increased mortality (Hughes,
Ross, Mindham, & Spokes, 2004). While greater evidence exists for the
impact of depressive disorders on quality of life, some studies found anxiety
to be the main related neuropsychiatric disorder contributing to impaired
quality of life (Fan et al., 2016; Hanna & Cronin-Golomb, 2012; Jones
et al., 2015; Quelhas & Costa, 2009). One study reported two distinct pat-
terns, distinguishing the impact of depression mainly on the “mental
component” from the impact on anxiety mainly based on the “physical
component” of quality of life measured by the SF-36 scale (Dubayova
et al., 2013). In Table 3, the effect of neuropsychiatric comorbidity on qual-
ity of life among PD patients in different studies is shown.

5. SCALES FOR DEPRESSION AND ANXIETY

As depression and anxiety cause considerable burden on patients’ and
carers’ quality of life and effective treatment has the potential to improve
these symptoms and thereby outcome and prognosis of PD patients, early
detection and diagnosis are important. Although common and relevant to
quality of life, they remain undetected in up to 50% of PD patients
(Gallagher & Schrag, 2012; Kano et al., 2011; Martinez-Martin et al.,
2016), and screening tools such as scales and questionnaires have an impor-
tant role in clinical practice and research.

5.1 Depression
Several reviews for screening and rating scales for depression have been pub-
lished. An evaluation of screening methods for depression by the American
Academy of Neurology (AAN) in 2006 concluded that the Beck Depression
Inventory (BDI), Hamilton Depression Rating Scale (HAMD-17), and
Montgomery–Asberg Depression Rating (MADRS) Scale had the highest
diagnostic accuracy and were adequate to screen PD patients (evidence
level B) and highlighted the need for specific validation (Miyasaki et al.,
2006). Similarly, in 2007 a review by the MDS Task Force on Depression
rating scales was published, concluding that the HAM-D, BDI, HADS,
MADRS, and GDS are appropriate as screening scales for depression in
PD with the CES-D and CSDD as alternative requiring further validation
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632 Anette Schrag and Raquel N. Taddei

Table 3 Determinants of Health-Related Quality of Life in PD

Specific NPS Considered in the NPS Determinants
References No. for NPS Regression Analysis of HRQoL
1. Cross-sectional studies
Greene and Camicioli 51 Yes Depression Depression
(2007)
Carod-Artal et al. 115 No Depression, anxiety Depression,
(2008) anxiety
Klepac, Trkulja, Relja, 124 Yes Depression Depression
and Babi
c (2008)
McKinlay et al. (2008) 49 No Depression, apathy, Anxiety,
anxiety, depression,
hallucinations hallucinations
Muslimovic et al. 190 No Depression, anxiety Depression,
(2008) anxiety
Rahman et al. (2008) 130 No Depression, anxiety Depression,
anxiety
Qin et al. (2009) 391 No Depression Depression
Quelhas and Costa 46 No Depression, anxiety Anxiety
(2009)
Žiropađa, Stefanova, 102 No Depression Depression
Potrebi
c, and Kosti
c
(2009)
Gallagher et al. (2010) 89 No Apathy, psychosis, Depression
depression, anxiety,
mood/apathy,
perception problem/
hallucinations
Naismith, Hickie, and 35 No Depression Depression
Lewis (2010)
Winter et al. (2010) 81 No Depression Depression
Benito-León, Cubo, 557 Yes Apathy Apathy
Coronell, ANIMO
Study Group (2012)
Gómez-Esteban et al. 99 Yes NPS NPS
(2011)
Martinez-Martin et al. 411 No Mood/apathy, Mood/apathy
(2016) perception problem/
hallucinations
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Depression and Anxiety in Parkinson’s Disease 633

Table 3 Determinants of Health-Related Quality of Life in PD—cont’d

Specific NPS Considered in the NPS Determinants
References No. for NPS Regression Analysis of HRQoL
Leroi et al. (2011) 99 No Depression, anxiety, Depression,
impulsiveness impulsiveness
Winter et al. (2010) 70 No Depression Depression
Bach et al. (2012) 1449 No Depression, Depression,
psychosis/ psychosis
hallucinations
Hanna and Cronin- 38 Yes Anxiety, depression Anxiety,
Golomb (2012) depression
Dubayova et al. (2013) 153 No Depression, anxiety Depression,
anxiety
Rodrı́guez-Violante 177 No Mood/apathy, Mood/apathy
et al. (2013) perception problem/
hallucinations
Santos-Garcı́a and de 150 No Depression Depression
la Fuente-Fernández
(2013)
Duncan et al. (2014) 158 No Mood/apathy, Depression,
perception problem/ anxiety
hallucinations,
depression
Lawson et al. (2014) 219 Yes Depression, NPS Depression, NPS
Phu et al. (2014) 100 Yes ICDs and related Depression, ICDs
behaviors, depression and related
behaviors
Alvarado-Bolaños 492 Yes Psychotic symptoms, Mood/apathy,
et al. (2015) mood/apathy, ICDs ICDs
Fereshtehnejad et al. 157 No Depression, anxiety, Anxiety,
(2015) psychosis, apathy depression
Jones et al. (2015) 107 Yes Depression, anxiety, Anxiety
apathy
Kadastik-Eerme, 268 No Depression Depression
Rosenthal, Paju,
Muldmaa, and Taba
(2015)
Skorvanek et al. (2015) 291 No Depression, anxiety, DDS
psychosis, DDS
Continued
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634 Anette Schrag and Raquel N. Taddei

Table 3 Determinants of Health-Related Quality of Life in PD—cont’d

Specific NPS Considered in the NPS Determinants
References No. for NPS Regression Analysis of HRQoL
Diaz et al. (2016) 59 No Depression, anxiety Anxiety,
depression
Fan et al. (2016) 134 No Depression, anxiety Depression,
anxiety
Rieu et al. (2016) 136 Yes Depressive mood, Hyperemotionality
hypomanic mood,
anxiety, irritability
and aggressiveness,
hyperemotionality,
psychotic symptoms,
nocturnal
hyperactivity, eating
behavior, creativity,
hobbyism, punding,
risk-taking behavior,
compulsive
shopping,
pathological
gambling,
hypersexuality,
dopaminergic
addiction, excess in
motivation
Vela et al. (2016) 87 Yes Depression, ICDs Depression
2. Longitudinal studies
Forsaa, Larsen, 82 No Depression, psychosis Depression
Wentzel-Larsen,
Herlofson, and Alves
(2008)
Marras et al. (2008) 362 No Depression Depression
M€
uller et al. (2013) 166 No Depression, apathy Depression
Prakash, Nadkarni, 227 No Apathy, attention, Mood/apathy
Lye, Yong, and Tan memory,
(2016) hallucinations,
delusions, depression,
anxiety, anhedonia
Glossary: DDS, dopamine dysregulation syndrome; ICDs, impulse control disorders; NPS, neuropsychi-
atric symptoms.
From Balestrino, R., & Martinez-Martin, P. (2017). Reprint of neuropsychiatric symptoms, behavioural
disorders, and quality of life in Parkinson’s disease. Journal of the Neurological Sciences, 374, 3–8.
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Depression and Anxiety in Parkinson’s Disease 635

(Goetz et al., 2007). Williams et al. (2012) compared nine scales for the
assessment of depression in PD of which the GDS-30 was judged the most
efficient screening tool for depression in PD. A more recent review by
Torbey, Pachana, and Dissanayaka (2015) concluded that the HAM-D
and the self-report GDS scales are recommended for screening and measur-
ing severity of depression in PD, with the HADS-D, HDI, and the BDI, and
MADRS being valid in PD and the CSDD for screening for PD in patients
with and without dementia. Table 4 shows the cutoff scores for the different
validated scales for depression in PD (Martinez-Martin et al., 2016).

5.2 Anxiety
The use of validated scales for assessment of anxiety in PD was also reviewed
by an MDS Task Force in 2008 (Leentjens et al., 2008), assessing the follow-
ing scales: Beck Anxiety Inventory (BAI), HADS-A, Zung’s Self-Rating
Anxiety Scale (Zung’s SAS), Anxiety Sensitivity Index (ASI), State-Trait
Anxiety Inventory (STAI), Hamilton Anxiety Rating Scale (HARS), and
section 5 of Neuropsychiatric Inventory (NPI). Since there were no scales
fulfilling criteria for a recommended scale for the assessment of anxiety in
PD at that point of time, further validation studies were recommended. Since
then, the three most commonly applied scales, BAI, HADS, and HARS, have
been validated for use in PD. Due to limitations of all existing scales for assess-
ment of anxiety in PD, the Parkinson Anxiety Scale (PAS), a PD-specific
anxiety scale, was developed and reported to have higher specificity and sen-
sitivity for its use as a screening tool than other scales (Forjaz et al., 2015).
Another anxiety scale for PD patients, the Geriatric Anxiety Inventory
(GAI), was developed and validated (Matheson et al., 2012), but further
large-scale studies to validate these scales in other populations are required.

6. BIOMARKERS IN DEPRESSION AND ANXIETY IN PD

It has been suggested that in depression there is dysfunction of both
dopamine and serotonin systems and their interaction in the brain, contrib-
uting to the development of depressive disorders. To date, only a few studies
have assessed this interconnection, with important results coming from PET
imaging models (Lee et al., 2015). In rat models, Lee et al. found a corre-
lation between a decrement of 5HT-1A receptor-binding sites and a depres-
sion severity. In studies on depression in humans, Drevets et al. (2007) found
reduced 5HT-1A receptor-binding sites and reduced serotonin mRNA
expression in postmortem analysis of the brainstem of suicide victims.
A recent review on PET imaging and depression by Savitz and Drevets
Table 4 Recommended Cutoff Scores and Performance of Screening Instruments for Depression in PD
Cutoff Score Sensitivity (%) Specificity (%) PPV (%) NPV (%) References
BDI-I 8/9 92 59 39 96 Leentjens, Verhey, Luijckx,
et al. (2000)
BDI-II 6/7 95 60 62 94 Williams et al. (2012)
CESD-R 11/12 72 70 62 79 Williams et al. (2012)
CSDD 5/6 83 73 54 92 Williams and Marsh (2009)
GDS-15 4/5 88 85 61 96 Weintraub et al. (2006)
5/6 84 89 59 97 Baillon, Dennis, Lo, and

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Lindesay (2014)
7/8 78 88 67 93 Chagas et al. (2010)
6/7 79 88 66 93 Chagas et al. (2013)
GDS-20 10/11 100 76 33 100 Mondolo et al. (2006)
GDS-30 9/10 81 84 58 94 McDonald et al. (2006)
9/10 89 62 71 84 Ertan et al. (2005)
HADS
Total score 10/11 92 51 34 96 Leentjens, Verhey, Lousberg,
et al. (2000)
HADS-D 10/11 100 95 71 100 Mondolo et al. (2006)
HAMD-17 13/14 88 89 74 96 Leentjens, Verhey, Luijckx,
et al. (2000)
IDS-C 11/12 81 79 73 86 Williams et al. (2012)
Table 4 Recommended Cutoff Scores and Performance of Screening Instruments for Depression in PD—cont’d
Cutoff Score Sensitivity (%) Specificity (%) PPV (%) NPV (%) References
IDS-SR 13/14 90 60 61 90 Williams et al. (2012)
MADRS 14/15 88 89 74 96 Leentjens, Verhey, Luijckx,
et al. (2000)
7/8 72 82 72 82 Silberman et al. (2006)
NICE screening 100 84 54 100 Baillon et al. (2014)
questions

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PHQ-9 5/6 66 80 69 77 Williams et al. (2012)
8/9 100 83 63 100 Chagas et al. (2013)
PHQ-2 2/3 75 89 70 91 Chagas, Sanches, Tumas,
Marchi, and Tirapelli (2011)
UPDRS-D 1/2 66 81 81 66 Starkstein and Merello (2007)
WHO-5 12/13 88 74 37 97 Schneider and Obeso (2015)
Zung’s SDS 54/55 89 83 61 96 Chagas et al. (2010)
54/55 90 82 59 96 Chagas et al. (2013)
Glossary: BDI, Beck Depression Inventory; CESD-R, Center for Epidemiologic Studies Depression Rating Scale-Revised; CSDD, Cornell Scale for Depression in
Dementia; GDS, Geriatric Depression Scale; HADS, Hospital Anxiety and Depression Scale; HADS-D, depression subscale; HAMD-17, Hamilton Depression Rating
Scale; IDS-C, Inventory of Depressive Symptoms-Clinician; IDS-SR, Inventory of Depressive Symptoms-Patient; MADRS, Montgomery–Asberg Depression Rating
Scale; NICE, UK National Institute for Health and Clinical Excellence; PHQ, Patient Health Questionnaire; PNV, predictive negative value; PPV, predictive positive
value; UPDRS-D, Unified Parkinson’s Disease Rating Scale-Depression; WHO-5, WHO-Five Well-Being Index; Zung’s SDS, Zung’s Self-rating Depression Scale.
From Martinez-Martin, P., Leentjens, A. F., de Pedro-Cuesta, J., Chaudhuri, K. R., Schrag, A. E., Weintraub, D. (2016). Accuracy of screening instruments for detec-
tion of neuropsychiatric syndromes in Parkinson’s disease. Movement Disorders, 31(3), 270–279.
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638 Anette Schrag and Raquel N. Taddei

(2013), however, highlighted mixed results in the literature, some groups

reporting a decrease in 5HT-1A receptor-binding sites and others hypoth-
esizing an elevation in pre- and postsynaptic binding sites (Shrestha et al.,
2012). They further hypothesized reduced 5HT-2A, 5HT-1B, Dopamine
D1, MAO-A, and muscarinic M2 receptor binding in patients with mood
disorders and concluded that the role of D2/D3 receptor-binding sites is
currently unclear, suggesting the current need for further studies.
In PD, there is evidence from imaging studies for both serotonergic
(Maillet et al., 2016) and dopaminergic dysfunction. Structural imaging sug-
gests increased frontal atrophy in depressed patients with PD as the most
strongly associated neural correlate of neuropsychiatric symptomatology
in PD (Alzahrani & Venneri, 2015). In addition, hyperperfusion in occipital
areas and hypoperfusion in fronto-temporo-limbic areas was reported as a
potential biomarker for depression in PD (Kim et al., 2016), and a significant
increase in amygdala metabolism in depressed PD patients and decreased
caudate metabolism in anxious PD patients (Huang et al., 2013). In another
neuroimaging study of depression, anxiety and apathy in PD increased neu-
ral activity in prefrontal regions and decreased functional connectivity
between prefrontal and limbic structures were found in depressed PD
patients with an inverse correlation between the dopaminergic density in
the caudate and putamen and the severity of anxiety in PD patients
(Wen, Chan, Tan, & Tan, 2016). However, further studies to assess poten-
tially involved pathways of neuropsychiatric symptoms in PD are needed.
Blood-based biomarkers are of increasing interest in PD with one study
reporting that lower plasma levels of peripheral levels of 5HT and its metab-
olite 5HIAA in PD patients correlate with more severe depression and with
pain (Tong, Zhang, et al., 2015). The same group also studied correlations
between plasma levels of amino acids and nonmotor symptoms and found a
correlation between lower levels of ASP and glutamate and depression as
well as sleep disturbances (Tong, Xu, et al., 2015). Some other recent studies
found a relation between anxiety/depression and lower uric acid levels in
serum (Moccia et al., 2015, 2014). Studies on inflammatory markers in
the cerebrospinal fluid of PD patients have indicated higher levels of inflam-
matory parameters such as interleukin-1 beta, interleukin-6, and tumor
necrosis factor alpha in PD patients (Blum-Degen et al., 1995; Mogi
et al., 1994) and have more recently also been linked with nonmotor symp-
toms in PD (Barnum & Tansey, 2012). A recent study on inflammatory bio-
markers in depression in PD by Lindqvist et al. (2013) specifically correlated
HADS depression score with higher CRP levels and HADS anxiety score
with IP-10 positivity.
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Depression and Anxiety in Parkinson’s Disease 639

7. MANAGEMENT
7.1 Depression
7.1.1 Pharmacological Treatment
Although the prevalence of depression and anxiety among PD patients is
high and both neuropsychiatric features have a significant impact on quality
of life, evidence to guide their treatment is insufficient. Efficacy has been
reported for the tricyclic antidepressants (TCAs) desipramine and nortripty-
line, the serotonin–noradrenaline reuptake inhibitor (SNRIs) venlafaxine,
and the selective serotonin reuptake inhibitors (SSRIs) citalopram, sertra-
line, and paroxetine in randomized, double-blind, placebo-controlled clin-
ical trials (Leentjens, 2011; Marsh, 2013; Richard et al., 2012). However,
sample sizes of these studies were small and there is currently still inconclu-
sive evidence on the effectiveness of individual antidepressants compared to
each other and even against placebo. Nonetheless, in a recent systematic
review on systematic treatments for depression in PD comparing 13 inter-
ventional trials, only SSRIs showed a statistically significant improvement of
depression (Bomasang-Layno, Fadlon, Murray, & Himelhoch, 2015;
Cooney & Stacy, 2016). In contrast, other studies concluded TCAs to be
at a similar level of efficacy as SSRIs (Antonini et al., 2006; Devos et al.,
2008; Menza et al., 2009). There is also evidence that dopamine agonists
improve depression when compared with placebo, with most evidence
available for pramipexole (Barone et al., 2010) and transdermal Rotigotine
(Ray Chaudhuri et al., 2013). An MDS evidence-based review concludes
that pramipexole is efficacious for the treatment of depression in PD
(Seppi et al., 2011). The importance of dopaminergic agents in the occur-
rence of mood disorders of PD is also reflected in the development of
depression in the context of dopamine withdrawal syndrome and increased
rates of apathy and depression following rapid medication reduction after
deep brain stimulation (DBS) surgery (Williams & Okun, 2013).
The results of pharmacological trials for depression in PD are summa-
rized in Table 2.
Current guideline by the AAN state that the TCA amitriptyline (level C)
may be considered for treatment of depression in PD, with currently insuf-
ficient evidence to make recommendations on other pharmacological treat-
ments. A more recent meta-analysis with slightly different methodology by
Liu et al. comparing the efficacy and acceptability of different medications
for depression in PD concluded that TCAs might be the best choice when
starting antidepressant treatment in PD due to its favorable balance between
 ARTICLE IN PRESS

640 Anette Schrag and Raquel N. Taddei

benefit and acceptability, followed by pramipexole, SNRIs, and SSRIs (Liu

et al., 2013). Other meta-analyses, however, concluded that while both
SSRI and TCA are effective, SSRIs have been tolerability in PD (Qiu,
Qiao, & Yong, 2014) or that the antidepressant effect is only significant
for SSRIs and not TCA.

7.1.2 Nonpharmacological Treatment

A multidisciplinary approach improves depression scores in PD (Wade et al.,
2003) and can include education about the mood disturbances and its rela-
tion to PD, use of skills to cope with these symptoms and emotional support
(Taylor, Anderson, Brandt, Mari, & Pontone, 2016), as well as more specific
pharmacological and nonpharmacological approaches. Increasingly evi-
dence is emerging on the role of the nonpharmacological options. The best
evidence exists for cognitive behavioral therapy (CBT) and there is some
evidence for other nonpharmacological interventional strategies including
transcranial magnetic stimulation (TMS) and DBS, but this needs further
evaluation.
A systematic review of CBT therapy for depression in PD found two
randomized controlled trials, where significant reductions in depression
scores could be seen, with a maintenance of the effect over the follow-up
periods of 1 and 6 months. Although the authors concluded that CBT shows
promising evidence of efficacy in the treatment of depression and anxiety in
PD, they recommend further large-scale studies with longer follow-up
periods (Egan, Laidlaw, & Starkstein, 2015).
TMS for the treatment of mood symptoms in PD has also been assessed in
a number of small studies with some encouraging results in some. While
there was no clear evidence of an improvement of mood symptoms when
compared to sham-TMS (Brys et al., 2016; Shin, Youn, Chung, & Sohn,
2016), others concluded some beneficial effect of TMS on depression
(Pal, Nagy, Aschermann, Balazs, & Kovacs, 2010). Further large-scale stud-
ies are needed.
DBS has been associated with worsening mood as well as apathy scores
(Kirsch-Darrow et al., 2011). However, a review of the effect of DBS on
depression in PD (G€ okbayrak, Piryatinsky, Gavett, & Ahmed, 2014) con-
cluded that the results on depression were inconsistent, likely due to the var-
iation in anatomical targets (Ashkan, Samuel, Reddy, & Ray Chaudhuri,
2013; Bronstein et al., 2009; Okun et al., 2003), although a comparison
of differential outcomes depending on target selection did not identify
any significant differences (Elgebaly, Elfil, Attia, Magdy, & Negida, 2017).
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Depression and Anxiety in Parkinson’s Disease 641

Importantly, the risk of suicide following DBS surgery has been reported to
be significantly increased and needs particular attention (Voon et al., 2008).

7.2 Anxiety
Anxiety has been given less attention than depression, although its pre-
valence is similar to that of depression in PD and overlap between both is
commonly observed. Treatment of anxiety in PD has not been assessed sys-
tematically and in large-scale studies. There are currently no randomized,
controlled trials for treatment guidelines on anxiety in PD. The movement
disorders society task force based review on the treatment of anxiety in
PD found insufficient evidence as to make recommendations (Seppi
et al., 2011).

8. CONCLUSIONS
Understanding of the features, pathophysiology, and management of
depression and anxiety in PD is increasing, but appropriate management of
these neuropsychiatric features still poses an important unmet need in PD
patients. Their high prevalence and impact on quality of life highlight the
importance of an early detection and identification of biomarkers and risk
factors, and better evidence on treatment approaches. Early detection, thor-
ough assessment and adequate treatment, can provide substantial improve-
ment in the overall management of patients with PD. Validation of clinical
scales especially for anxiety, development of biomarkers, and large-scale tri-
als to guide management of depression with pharmacological and non-
pharmacological options are urgently needed.

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