The Neuropsychiatry of Parkinson Disease: A Perfect Storm: Sciencedirect

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Am J of Geriatric Psychiatry &&:&& (2019) &&−&&
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journal homepage: www.ajgponline.org
Review
The Neuropsychiatry of Parkinson

Disease: A Perfect Storm
Daniel Weintraub, M.D., Eugenia Mamikonyan, M.S.
ARTICLE INFO ABSTRACT
Article history: Affective disorders, cognitive decline, and psychosis have long been recognized
Received January, 30 2019 as common in Parkinson disease (PD), and other psychiatric disorders
Revised March, 4 2019 include impulse control disorders, anxiety symptoms, disorders of sleep and
Accepted March, 4 2019 wakefulness, and apathy. Psychiatric aspects of PD are associated with
numerous adverse outcomes, yet in spite of this and their frequent occurrence,
Key Words: there is incomplete understanding of epidemiology, presentation, risk factors,
Anxiety neural substrate, and management strategies. Psychiatric features are typi-
cognition cally multimorbid, and there is great intra- and interindividual variability in
dementia presentation. The hallmark neuropathophysiological changes that occur in
depression PD, plus the association between exposure to dopaminergic medications and
impulse control disorder certain psychiatric disorders, suggest a neurobiological basis for many psychi-
Parkinson disease atric symptoms, although psychological factors are involved as well. There is
psychosis evidence that psychiatric disorders in PD are still under-recognized and
undertreated and although psychotropic medication use is common, con-
trolled studies demonstrating efficacy and tolerability are largely lacking.
Future research on neuropsychiatric complications in PD should be oriented
toward determining modifiable correlates or risk factors and establishing effi-
cacious and well-tolerated treatment strategies. (Am J Geriatr Psychiatry 2019;
&&:&&−&&)
“Perfect storm: an extremely bad situation in which INTRODUCTION

many bad things happen at the same time.”
—Cambridge English Dictionary James Parkinson may have described depression
as a feature of what eventually came to be called
Parkinson disease (PD), but careful study of his dis-
ease-defining essay finds that none of his six
From the Perelman School of Medicine (DW, EM), University of Pennsylvania, Philadelphia; and the Parkinson’s Disease Research, Education
and Clinical Center (PADRECC) (DW), Philadelphia Veterans Affairs Medical Center, Philadelphia. Send correspondence and reprint requests
to Daniel Weintraub, M.D., Perelman School of Medicine, University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104. e-mail:
[email protected]
© 2019 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jagp.2019.03.002
Am J Geriatr Psychiatry &&:&&, && 2019 1

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The Neuropsychiatry of Parkinson Disease
illustrative cases had any neuropsychiatric features. education/training, and clinical care. Given the now
In fact, he made a point to note that cognition was irrefutable evidence that PD is a neuropsychiatric dis-
not affected in his patients.1 It has only been in the order, there ensues a responsibility to respond
past 50 years, with the introduction of levodopa and accordingly to improve the lives of patients.
other PD medications and treatments to clinical prac-
tice, the increasing lifespan of patients, and increasing Cognitive Decline
awareness and research, that neuropsychiatric disor-
ders and cognitive complications (here combined Of all NPS that can occur in PD, significant cogni-
and called neuropsychiatric symptoms [NPS]), and tive impairment is the most problematic and dreaded.
non-motor symptoms more broadly,2 have gained The original assumption, based on early cross-sec-
recognition as being common, as disabling as motor tional studies, was that approximately 30% of
symptoms, associated with poor long-term outcomes patients with PD suffer from PD dementia (PDD),
and caregiver burden, and requiring special expertise and that the profile of cognitive impairment in PD
for optimal management.3 was distinct from that of Alzheimer disease (AD). Ini-
By 2020, close to 1 million persons living in the tial cognitive changes in PD were thought to be pri-
United States will have a diagnosis of PD.4 Although marily characterized by impairment in executive
PD is still considered a movement disorder and is abilities and attention, whereas in AD by memory
diagnosed based on motor signs and symptoms,5 the and language impairments. However, it is now recog-
high prevalence of numerous NPS suggests that it is nized that initial impairments in PD occur in a range
more accurately conceptualized as a neuropsychiatric of cognitive domains, including executive, memory,
disorder.3 In addition to the most commonly studied visuospatial, attentional, and even language func-
NPS, such as cognitive impairment (both mild cogni- tions, even in patients with milder cognitive deficits
tive impairment [MCI] and dementia), depression, or MCI.6−10
and psychosis, other relatively common and clinically Prospective, long-term studies have now found that
significant psychiatric complications include compul- dementia may actually occur in up to 80% of PD
sive behaviors diagnosed as impulse control disor- patients.11,12 In addition, approximately 25% of non-
ders (ICDs), various anxiety symptoms, disorders of demented patients have MCI,9 which has prognostic
sleep and wakefulness, apathy, and fatigue. significance for predicting more rapid conversion to
This relatively recent, dramatic shift in our under- dementia, both in early13 and well-established dis-
standing of the symptomatology of PD is in part ease,14 and MCI is also a risk factor for mortality in
because of the efforts of individual and collaborative early PD.15 A significant percentage (10%−20%) of
research efforts, as well as professional society-led newly-diagnosed PD patients have cognitive defi-
task forces and patient-caregiver organizations. Areas cits,16−18 or experience cognitive decline over several
of focus regarding the NPS of PD have included epi- years.19 More recently, changes in cognition have even
demiologic, neurobiological, assessment (diagnostic been reported prior to PD diagnosis20 in population-
criteria and assessment instruments) and treatment based studies.21,22 Additionally, prospective studies
research, educating patients and families, training have demonstrated cognitive worsening in individuals
treatment providers, and improving the delivery of with prodromal or at-risk PD (i.e., those having
treatment. impaired olfaction and dopamine transporter [DAT]
As summarized in the following text, the high deficits23 or rapid eye movement [REM] sleep behav-
cumulative prevalence of a large number of NPS in ior disorder [RBD]),24 and cognitive impairments in
PD does appear to be the result of a perfect storm, the latter population may predict conversion to
with contributing factors including demographic dementia with Lewy bodies (DLB) rather than PD.25
characteristics, diffuse and multiple neurodegenera- A point of controversy related to cognition in PD
tive disease pathologies, other neurobiological fac- pertains to the related disorder of DLB, and whether
tors, and PD treatments themselves. Weathering this differences between the two are categorically, or sim-
storm, including adapting to a rapidly changing PD ply dimensionally, different.26 DLB, which presents
treatment landscape, will require an ongoing, con- with dementia and some combination of parkinson-
certed effort with a tripartite focus on research, ism, psychosis, and RBD, is hard to distinguish
2 Am J Geriatr Psychiatry &&:&&, && 2019

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Weintraub and Mamikonyan
clinically and neuropathologically from PDD, with gray and white matter neurodegeneration, primarily in
the exception of increased AD pathology or bio- the medial temporal lobe, parietal lobe, and prefrontal
markers in DLB versus PDD,27−29 or perhaps alpha- cortex (PFC),63−67 some suggestion for increase white
synuclein genetic variability.30 There remains a con- matter hyperintensities,68−70 and metabolic deficits71,72
troversial “one-year rule” in place, with dementia with cognitive decline in PD, as well as electrophysio-
that precedes or occurs within one year of onset of logical changes measured with electroencephalogram,
parkinsonism being labeled as DLB and all other quantitative electroencephalogram, or magnetoence-
cases being diagnosed as PDD,31 although recently phalogram (i.e., overall diffuse slowing, with low peak
proposed clinical diagnostic criteria for PD allow for frequency, high theta power, low beta power and spe-
PDD to be diagnosed at disease onset.5,32 cific patterns of cortical neural synchronization).73−77
A range of demographic and clinical correlates and There is also an emerging interest in plasma-based bio-
potential risk factors for identifying PD patients at markers, with low epidermal growth factor as one
risk for more rapid cognitive decline have emerged, potential predictor of cognitive decline.78,79 Given the
including increasing age and duration of PD (often numerous and diverse changes reported earlier, it is
correlated), male sex (which differentiates PD from likely that pathological and neurochemical heterogene-
AD), “atypical” parkinsonian features (i.e., postural ity underpins cognitive decline in PD,80 with disrup-
instability gait disorder instead of tremor-dominant tions to multiple distinct neural networks occurring
features), psychiatric disorders (e.g., psychosis, apa- over time.81
thy, depression, and RBD),33−39 impaired olfaction,40 A major step forward was taken a decade ago with
autonomic changes (e.g., orthostatic hypotension the creation of an International Parkinson and Move-
[OH]),41 and comorbid vascular disease (e.g., diabetes ment Disorder Society (IPMDS) dementia task force.
mellitus, hypertension, and hyperlipidemia).42 Clinical criteria for the diagnosis of PDD82 and an
There have been significant strides made in our cur- algorithm for diagnosing PDD83 were proposed, lead-
rent understanding of the neural substrate of cognitive ing to significant improvements in the validity and
decline in PD. Neuropathological studies have demon- reliability of a PDD diagnosis. This was followed by
strated that diffuse, cortical, fibrillized alpha-synuclein the creation of an IPMDS task force for PD-MCI,
(i.e., Lewy bodies) appears to be the major contributing which produced both a review article84 and recom-
pathology to cognitive decline in PD.43−45 However, at mended diagnostic criteria and guidelines, including
least one-third of PDD patients also have AD-related recommended cognitive testing.85 This task force has
neuropathological changes at autopsy,46 with more also published research on the predictive validity of
beta amyloid plaque than tau tangle deposition,47 and PD-MCI criteria for conversion to PDD,86 and the rel-
the combination of PD and AD pathology is the best ative sensitivity of commonly used cognitive tests in
predictor of a lifetime dementia diagnosis.48 In addi- non-demented PD patients.87 In parallel work, sev-
tion to pathology, AD cerebrospinal fluid (CSF) bio- eral cognitive assessment instruments for different
markers (AB 1-42),49 genetic risk factors (APOE Ɛ4),50 purposes have now been validated for use in PD,
positron emission tomography amyloid scans,51 and a including the Parkinson Disease-Cognitive Rating
structural magnetic resonance imaging AD signature Scale,88 the Parkinson Neuropsychometric Dementia
of atrophy, weighted toward medial temporal lobe Assessment,89 the Scales for Outcomes of Parkinson
and hippocampal atrophy,52 are all associated with Disease-Cognition,90 the Mattis Dementia Rating
cognitive impairment and decline in PD. Scale-2,91,92 and the Montreal Cognitive Assess-
Beyond neuropathology, a range of neurotransmit- ment.93,94 In addition, two PD- and cognition-spe-
ter deficits are associated with cognitive impairment, cific daily function questionnaires have been
including acetylcholine,53 dopamine,54−56 and norepi- developed and validated,95,96 and performance-
nephrine.57,58 Besides APOE Ɛ4, other genes implicated based functional cognition measures have recently
include brain-derived neurotrophic factor (BDNF) val66 been validated in PD97 or have been shown to be
met,59 catechol-O-methyltransferase (COMT) val158met,60 sensitive to change in a PD-MCI clinical trial.98
microtubule-associated protein tau (MAPT) H1 poly- The management of cognitive impairment has
morphisms,38,61 and glucocerebrosidase (GBA).62 A benefitted from treatment strategies developed for
range of neuroimaging techniques have found diffuse AD. Despite this, only one large, positive controlled

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cholinesterase inhibitor randomized controlled trial that the frequency of major (i.e., more severe) depres-
(RCT) in PDD has been published,99 leading to the sion is 5%−20%, with non-major forms of depression
Food and Drug Administration (FDA) approval of (i.e., minor or subsyndromal depression) occurring in
rivastigmine as a treatment of PDD, but this was an additional 10%−30% of patients.115−118 Therefore,
15 years ago. Statistically significant, but clinically up to 50% of PD patients experience depression at
modest, effects for rivastigmine on a range of primary some point in the course of their illness. Yet there is
and secondary outcome measures were observed, evidence that dPD remains under-recognized and
and cholinesterase inhibitor treatment was associated undertreated,119 even in specialty care settings.120,121
with increased nausea, vomiting, tremor, and dizzi- Another advance is our understanding of the
ness. A similar clinical trial of donepezil for PDD pro- numerous correlates or possible risk factors for dPD,
duced similar numerical results for cognitive including female sex,116 a personal122 or familial123 his-
improvement, but because of an outlier site was a tory of depression, early-onset PD,124 “atypical” par-
negative study based on the primary outcome mea- kinsonism,117 and psychiatric comorbidity (e.g., worse
sure.100 In two RCTs that included both PDD and cognition, psychosis, anxiety, apathy, fatigue, and
DLB patients, memantine was found to be partially insomnia).116,125−128 There is inconsistent evidence that
beneficial for PDD in one101 but not the other,102 dPD is distinct from non-PD depression; some studies
although the latter study showed secondary psychiat- report higher rates of anxiety, pessimism, suicide idea-
ric benefit in patients with a DLB diagnosis. The treat- tion without suicide behavior, and less guilt and self-
ment landscape for PD-MCI has been no more reproach in dPD compared with their non-PD counter-
promising to date, with failed RCTs for both rasagi- parts.129 However, overall predictors of depression are
line103 and rivastigmine patch,98 although the latter similar in both populations.130 Not surprisingly, core
study showed a secondary, positive effect on a perfor- non-somatic symptoms of depression discriminate
mance-based measure of cognitive functioning. most highly between depressed and non-depressed
In terms of PD medications, there is no evidence patients (i.e., less likelihood of symptom overlap).131 It
that choice of the initial PD medication makes a dif- has almost become dogma that suicide is uncommon
ference in terms of long-term dementia rates,104,105 in PD,132,133 perhaps related to personality traits (e.g.,
but the association between anticholinergic medica- high neuroticism and harm avoidance, and low open-
tion use and long-term cognitive decline in PD106 is a ness, extraversion, and novelty) thought to characterize
concern given the common use of medications with PD patients overall,134,135 although the notion of a par-
anticholinergic properties in this population.107 For kinsonian personality remains controversial, largely
non-pharmacological approaches, there is prelimi- owing to concerns of recall bias in studies performed
nary evidence that cognitive108 and physical109,110 post-PD diagnosis. Yet more recent research challenges
training/activity may lead to at least short-term bene- this and suggests that both death ideation and suicide
fit in some cognitive abilities. Given the association ideation, if not completed suicide, may be relatively
between vascular risk factors42,111 and pathology112 common.136
and cognitive impairment in PD, and the association Depression in PD likely results from a complex
between both OH41 and obstructive sleep apnea interaction of psychological, physical/neurologic, and
(OSA)113,114 and cognitive performance in PD, treat- neurobiological factors. The strong association between
ing other common medical or non-motor symptoms frequency of depression and severity of PD under-
is important as well. scores the impact of disease-related functional impair-
ments.137,138 Similar rates of depression in PD and
equally disabled patients with other diseases indicates
Depression
that psychological factors are also important.139
Depression has been the most studied of all non- Finally, supporting the contribution of neurobiological
cognitive psychiatric disorders in PD,3 and there have factors are findings that depression may be a prodro-
been major advances in characterizing the frequency, mal syndrome in some PD patients.140−142 Biologically,
clinical phenotype, and diagnosis. Instead of consid- dPD may be related to dysfunction in: 1) subcortical
ering depressed PD (dPD) patients as a homogenous nuclei and the PFC; 2) striatal-thalamic-PFC circuits
group, recent epidemiologic research has reported and the basotemporal limbic circuit; and 3) brainstem

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monoamine and indolamine (i.e., dopamine, serotonin, Psychosis

and norepinephrine) systems.71,143−150 One study
Although PD psychosis (PD-P) (hallucinations or
found an association between the SLC6A15 and TPH2
delusions) was thought to occur in less than 10% of
genes and depression in PD,151 but multiple studies
untreated PD patients and was uncommon prior to
examining the serotonin transporter (SERT) and DAT
the introduction of dopamine replacement therapy
genes have been inconclusive.
(DRT),165 recent research using a detailed psychiatric
An IPMDS-commissioned task force reviewed and
interview suggested a high prevalence rate (42%) for
made recommendations for the use of depression rat-
minor hallucinations in newly diagnosed, untreated
ing scales in PD.152 Around the same time a National
patients,166 although these findings require replica-
Institute of Neurological Disorders and Stroke/
tion. In addition, a prospective study that encom-
National Institute of Mental Health work group sug-
passed currently available PD treatments reported a
gested provisional diagnostic criteria for dPD,153 pro-
long-term cumulative prevalence of 60%.167
posing modifications that are similar to those for
Psychosis is associated with reduced quality of
depression in AD.154
life168,169 and worse prognosis.170 Psychotic symp-
Approximately, 20%−25% of PD patients are on an
toms are an independent predictor of increased mor-
antidepressant at any given time, even de novo,
tality in PD,171 and are also the single greatest risk
untreated patients,155 most commonly a selective
factor for nursing home placement in patients with
serotonin reuptake inhibitor (SSRI).121,156 Relatively
PD.172−174 It is associated with increased caregiver
few controlled antidepressant studies for dPD have
burden; when compared with other symptoms in PD,
been published. However, there is now evidence
psychosis has been singled out as the most prominent
from several, relatively recent RCTs that a tricyclic
determinant of caregiver distress.175 The effects on
antidepressant (nortriptyline),157 an SSRI (paroxe-
caregivers include deterioration of physical health,
tine), and a serotonin and norepinephrine reuptake
increasing depression scores, and strained social
inhibitor (venlafaxine)158 are all relatively efficacious
life.176 Related to increased caregiver burden is the
in the treatment of dPD. However, it must be noted
finding that PD-P is also a major cause of hospitaliza-
that in the pivotal Study of Antidepressants in PD,158
tions and repeat hospitalizations,177 a significant
the differences between active (paroxetine and venla-
problem for PD patients as hospitalization often leads
faxine) and placebo treatments for dichotomous out-
to major disruptions in their PD medication regimen
comes (i.e., response and remission rates) were not
and neurologic decline.178
statistically significant. In another small RCT, atom-
Although visual hallucinations are most com-
oxetine (a selective norepinephrine reuptake inhibi-
monly reported in PD, it is now recognized that audi-
tor) was not efficacious for depression, but was
tory, tactile, and olfactory hallucinations are also
associated with improvement in global cognitive per-
relatively common.179 Correlates or risk factors
formance and daytime sleepiness.159 In terms of the
include exposure to PD medications,180 older age,126
effects of PD medications, a dopamine agonist (DA)
and greater cognitive impairment,127 including
(pramipexole) study for depressive symptoms in PD
dementia.181 In addition, the overwhelming majority
was positive,160 but an initial suggestion of an antide-
of PD-P patients also report disturbances of sleep and
pressant effect for an monoamine oxidase B (MAO-B)
wakefulness, including RBD,182 and it has been theo-
inhibitor (rasagiline) in PD155 was followed by a
rized that some hallucinations represent a narco-
failed RCT for depressive symptoms.161 Regarding
lepsy-like REM sleep disorder during daytime hours,
non-pharmacological approaches, cognitive-behav-
with these hallucinations having particular character-
ioral therapy (CBT) has been shown to be efficacious
istics (e.g., frequent vision of human figures, faces or
for dPD,162 a positive development given that many
animals, or scenery of great beauty).183
dPD patients may prefer psychotherapy, do not
Despite the association between medication expo-
respond to pharmacotherapy, or are reluctant to take
sure and PD-P, the dosage and duration of antiparkin-
another medication.163 Finally, for severe, treatment-
sonian treatment does not clearly correlate with
refractory dPD, electroconvulsive therapy has been
psychosis,126,184 and acute, intravenous, high-dose
shown to be effective, with the added benefit of tem-
levodopa challenge does not precipitate hallucinations
porary improvement in parkinsonism.164

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in PD with pre-existing hallucinations,185 indicating and physical morbidity208 in PD patients treated with
that the etiology of PD-P is complex. One proposed both typical and atypical APs, similar to what has
mechanism is that chronic DRT may lead to excessive been reported in AD patients. Among traditional
stimulation or hypersensitivity of mesocorticolimbic atypical APs, quetiapine is the most commonly used,
D2/D3 receptors.186 Cholinergic deficits and a seroto- despite the fact that all controlled clinical trials with
nergic/dopaminergic imbalance using a range of imag- reasonable sample sizes have been negative or unin-
ing modalities and other neural probes, have also been terpretable.209−211 Three randomized clinical trials
implicated,186−188 particularly in the primary visual showed that low-dose clozapine is efficacious for PD-
system and dorsal/ventral visual association path- P,212−214 yet the drug is rarely used in PD,215 likely
ways.189−193 Neurodegeneration of widespread limbic, due to required routine blood monitoring for poten-
paralimbic, and neocortical gray matter, including the tial agranulocytosis, as well as adverse events such as
PFC, is associated with PD-P.194−196 Although many sedation, OH, and sialorrhea.
genes have been examined for an association with There is now an FDA-approved treatment specifi-
PD-P, the results are negative or mixed for all except cally for PD-P, pimavanserin, which is a selective
for CCK.197,198 serotonin 2A (5-HT2A) receptor inverse agonist with-
An IPMDS task force reviewed psychosis rating out dopamine receptor-blocking properties. Pimavan-
scales used in PD, and listed four instruments as “rec- serin was granted breakthrough therapy designation
ommended” for use in PD as primary outcome meas- by the FDA because of the large unmet need in the
ures in clinical trials including the Neuropsychiatric treatment of PD-P, and was approved on the basis of
Inventory (when a caregiver/informed other is avail- a single, positive RCT,200 with a subsequent partially
able), the Schedule for Assessment of Positive Symp- positive (i.e., positive at week 6, but not at week 12)
toms (SAPS), the Positive and Negative Syndrome trial in patients with AD psychosis.216 Given recent
Scale and Brief Psychiatric Rating Scale, and the controversy concerning the validity and reliability of
Clinical Global Impression Scale as a secondary out- the primary outcome measure (the SAPS-PD), possi-
come measure.199 A recent pivotal trial200 used a dif- ble delayed response compared with clozapine
ferent instrument, a PD-modified SAPS called the (2−4 weeks versus 1 week), and unanswered ques-
SAPS-PD.201 tions about mortality risk, additional research is
Management of PD-P is complex. Observational needed to confirm the efficacy and more fully evalu-
research suggests that management of comorbid ate the safety and tolerability of pimavanserin in PD-
medical conditions and discontinuation or decreasing P patients, particularly in patients with comorbid
dosages of non-essential medications may be suffi- dementia,217,218 although a secondary analysis of the
cient for many patients, at least in the short-term.202 pivotal PD-P study data found that patients with
PD medications are usually discontinued sequentially lower Mini-Mental State Examination scores had a
and gradually (anticholinergics, MAO-B inhibitors, more robust response to pimavanserin.219
amantadine, DAs, catechol-O-methyltransferase
inhibitors, and finally, a reduction in levodopa dos-
ICDs and Related Behaviors
age), although this strategy is expert-recommended
as opposed to evidence-based, and the aforemen- This topic has been of increasing importance in PD
tioned ordering is contentious (e.g., discontinuing over the past 15 years, coinciding with the introduc-
MAO-B inhibitors before amantadine and DAs).203 tion of D2 receptor-selective DAs. ICDs were first
In PD-P, several theoretically promising atypical reported as a sporadic occurrence in case reports or
antipsychotic (AP) medications, such as risperi- series,220 and then characterized epidemiologically
done,204 olanzapine,205 and aripiprazole,206 either and phenomenologically in detail. Initial systematic
have not been assessed in RCTs or have been tried studies showed that ICDs (i.e., most commonly com-
clinically and found to be associated with adverse pulsive and idiosyncratic gambling, buying, sexual
events, primarily worsening parkinsonism presum- behavior, and eating behaviors) occur relatively com-
ably due to dopamine receptor blocking, have pre- monly in treated PD patients,221,222 and more recent
cluded their routine prescription. In addition, recent studies confirmed that ICD rates are not elevated in
research suggests an increased risk of mortality207 de novo, untreated patients.223 As patients may not

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report such behaviors to a treating physician, either also extrastriatal (e.g., anterior cingulate cortex) dopa-
because of embarrassment, not suspecting an associa- mine receptors,245 and decreased striatal DAT avail-
tion with PD treatment, or ambivalence regarding ability in ICD patients.246 Functional imaging studies
ceasing the behavior or treatment, ICDs still remain have reported altered striatal, cingulate and orbito-
generally under-recognized in clinical practice,222 frontal activation, and cortico-striatal connectivity, in
with patient reporting often discrepant from their ICD patients,247−249 particularly when ICD patients
informed others.224 are in an “on” PD medication state.250 More recent
In the largest, international, multisite, cross-sec- prospective studies have demonstrated that lower
tional study done to date, an ICD was identified in striatal DAT availability may be a risk factor for
14% of PD patients, and 29% of those with an ICD future ICD development,251 and certain single nucleo-
had more than one.225 A recent national multisite tide polymorphisms (e.g., serotonin 2A receptor,
study reported a 5-year cumulative ICD incidence kappa or mu opioid receptors, and dopamine decar-
rate of 46%, although the study recruited patients boxylase) previously linked with ICDs in the general
from 2009−2013, before significant changes were population or in PD may also predict incident ICD
made in PD medication prescribing,226 and another behaviors with initiation of DRT.252,253
study found clinically significant ICD symptoms in Several PD-specific questionnaires and rating
36% of PD patients with dyskinesias.227 DA treatment scales have been developed for detecting and moni-
is the strongest PD medication correlate,225,226 but toring ICDs and related behaviors in PD, including
ICDs may not have their onset until years after DA the Questionnaire for Impulsive-Compulsive Disor-
initiation.228 Additionally, higher-dose levodopa,225 ders in Parkinson Disease,254 the Questionnaire for
amantadine,229 and MAO-B inhibitor230 have all been Impulsive-Compulsive Disorders in Parkinson Dis-
associated with ICDs in PD, although to a lesser ease-Rating Scale,255 the Ardouin Scale of Behavior in
extent compared with DA treatment. The effects of Parkinson Disease,256 and the Parkinson Impulse-
DAs do not appear unique to PD patients, as a similar Control Scale for the Severity Rating of Impul-
association with ICDs has been reported in restless se Control Behaviors in Parkinson Disease.257
legs syndrome (RLS),231,232 fibromyalgia,233 and pro- In terms of clinical monitoring, as previously men-
lactinoma or pituitary adenoma234 patients treated tioned, ICDs may not have their onset until many
with a DA. years after initiation of DA or other PD medication
A personal or familial history of alcoholism or therapy,228,258 so ongoing, long-term vigilance is
gambling, impulsive or novelty-seeking characteris- required. ICD behaviors often resolve after discontin-
tics, young age, male sex, depression and anxiety, uing DA treatment.259 However, some patients do
and early PD onset have emerged as additional corre- not want to or tolerate DA discontinuation, and a DA
lates, or potential risk factors, associated with ICDs in withdrawal syndrome with significant physical and
PD.221,225,235 Dopamine dysregulation syndrome psychological symptoms has been described.260 The
(DDS) (or compulsive PD medication use) and other relationship between deep brain stimulation (DBS)
compulsive disorders in PD have also been recog- and ICDs is complex. Subthalamic nucleus (STN)
nized, particularly in the countries where high doses DBS has been associated with short- and long-term
of levodopa are used.236 Punding (i.e., repetitive non- improvement in ICD symptoms,261−263 most notably
goal directed activity) was reported in 14% of PD when significant decreases in DRT is made postsur-
patients on higher levodopa dosages in one study,237 gery.264 However, there is also anecdotal evidence
but another larger study of unselected PD patients that ICDs may begin or worsen transiently post-DBS
reported a frequency of less than 2%.238 surgery,265 possibly when DRT doses remain high
A range of cognitive impairments have been postsurgery.266 A range of psychiatric treatments
reported in PD ICD patients, most commonly execu- (e.g., antidepressants and APs) have been used to
tive deficits, including impulsive decision-making treat ICDs in PD, but there is no empirical evidence to
and impaired set shifting.239−242 The dopamine sys- support their use in PD patients. A small RCT
tem has been implicated, with both ICD and DDS reported benefit for amantadine as a treatment for
patients having sensitized D2/D3 receptors243,244 and pathological gambling in PD,267 but as previously
dysfunction not only in midbrain D2/D3 receptors by noted amantadine has been associated with ICDs in a

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large epidemiologic study.229 An RCT using naltrex- more recent research suggests they may actually be a
one, an opioid antagonist FDA-approved for alcohol manifestation of EDS.284
use disorder, was negative on the primary outcome Treatment of disorders of sleep and wakefulness
(Clinical Global Impression Scale−Investigator) but depends on the underlying etiology, and includes
positive for change on the Questionnaire for Impul- adjustment to PD medications (for PD motor symp-
sive-Compulsive Disorders in Parkinson Disease-Rat- tom-related sleep disturbances, RLS, and periodic leg
ing Scale,268 and there has been a positive CBT study movements in sleep) and clonazepam (for RBD),
for ICDs in PD.269 although there have been no RCTs for clonazepam in
PD RBD in spite of its common use clinically. Melato-
nin may improve subjective sleep disturbance and
Disorders of Sleep and Wakefulness
RBD in PD,285,286 and a controlled trial of eszopiclone
Remarkably, disorders of sleep and wakefulness (a non-benzodiazepine hypnotic) was partially posi-
have emerged as perhaps the most common non- tive.287 Evidence has been mixed for modafinil for
motor complications of PD, with up to 90% of daytime sleepiness,288−291 although a recent meta-
patients reporting insomnia (either initiating or main- analysis of three trials showed a significant reduction
taining sleep), hypersomnia, sleep fragmentation, in sleepiness, as assessed by the Epworth Sleepiness
sleep terrors, nightmares, nocturnal movements, Scale.292 An RCT of caffeine for EDS in PD was par-
reductions in non-REM or REM sleep, or RBD.270,271 tially positive.293 Psychostimulants (methylpheni-
RBD, along with impaired olfaction and affective dis- date)294 are also used clinically for EDS and fatigue in
orders (depression and anxiety), may be a key clinical PD. There has been a single, limited quality positive
feature of prodromal PD,272 with near universal con- study of continuous positive airway pressure therapy
version of idiopathic RBD to a Lewy body disorder in improving sleep and daytime sleepiness in patients
(PD, DLB, or multiple system atrophy) long with PD and OSA.295
term.273,274 Consistent with idiopathic RBD predict-
ing conversion to DLB in approximately 50% of cases,
Complications of DBS Surgery
RBD in the context of PD is also associated with long-
term cognitive decline.275 Other sleep cycle-related Over the past 15 years, DBS has been used increas-
disorders occurring in PD are RLS, periodic leg ingly as a treatment for PD, and in spite of many
movements in sleep, and OSA,270 with OSA associ- studies its impact on non-motor symptoms appears
ated with worse cognitive performance in PD.276 to be varied and complex.296,297 A recent meta-analy-
RBD and other sleep disturbances have been attrib- sis298 and two controlled studies of DBS versus best
uted both to progressive degeneration of the cholin- medical therapy299,300 identified significant declines
ergic pedunculopontine nucleus277 and reduced post-DBS in executive functions and verbal learning
striatal dopaminergic activity.278 Associated clinical and memory, not surprising given that DBS electro-
factors that can disrupt sleep in PD patients are par- des course through the PFC and subcortical white
kinsonism, autonomic symptoms, and psychiatric/ matter when implanted. Cortical point of entry dur-
cognitive disorders.33,270,279 ing surgery, passage through the caudate nucleus,
Excessive daytime sleepiness (EDS) (persistent and stimulation of particular STN subregions may
sleepiness) and physical/mental fatigue (tiredness or also increase risk of cognitive impairment post-
exhaustion) both are common in PD,280−282 but the DBS.301 Use of model-based stimulation parameters
difference and relationship between the two has not to minimize the spread of current to non-motor por-
been fully delineated. EDS has been attributed vari- tions of the STN reverses the cognitive decline that
ably to impairments in the striatal-thalamic-frontal occurred post-DBS,302 suggesting that post-DBS cog-
cortical system, exposure to DRT (especially DAs), nitive decline may be preventable. In addition, a
and nocturnal sleep disturbances.270,279 As with RBD, more recent study of DBS in younger patients with
psychiatric comorbidity280,283 is frequently associated shorter disease duration showed better cognitive
with EDS and fatigue. Daytime “sleep attacks” were tolerability.303
first reported toward the end of the last century and In addition to the relationship between DBS and
were initially attributed to DA treatment, although ICDs already discussed, other psychiatric findings

ARTICLE IN PRESS
post-DBS have included both overall improvement including generalized anxiety disorder, panic attacks,
and occasionally worsening of depression, anxiety, and social phobia,314−317 and anxiety and depression
psychosis, mania, apathy, and emotional lability.296 symptoms are highly comorbid.318 Increasing anxiety
In controlled DBS studies, there were no between- and discrete anxiety attacks have been associated
group differences in mood post-DBS surgery,300,304 with NMFs, particularly the onset of “off” peri-
and one study reported improvement in anxiety ods.316,317 Similar to depression, there is an increased
symptoms with DBS.299 Interestingly, in one con- frequency of anxiety disorders up to 20 years prior to
trolled study comparing STN with globus pallidus PD onset,319,320 but other than this clue little is known
interna DBS, patients who received STN DBS were about the etiology of anxiety in PD. There is now a
more likely to experience worsening in both depres- PD-specific, validated anxiety rating scale, the Parkin-
sive symptoms and processing speed,305 but meta- son Anxiety Scale.321 There have been no published
analyses of RCTs have come to mixed conclusions on RCTs focused on anxiety in PD, and some157 but not
this topic.306,307 Clinically, pre- and post-DBS psychi- all158 antidepressant treatment studies have reported
atric and cognitive monitoring are important, espe- secondary benefit for anxiety symptoms. For patients
cially given reports of postsurgical suicide ideation who experience anxiety as part of an “off” state, PD
and completed or attempted suicide,308 although medication adjustments, using FDA-approved medi-
analysis of data from one RCT found no increase in cations for MFs, can be made in an attempt to
suicide ideation or attempts in the 6-month period decrease the duration and severity of these episodes.
after patients were randomized to DBS versus best However, some patients require treatment with ben-
medical therapy.309 zodiazepines (e.g., lorazepam or alprazolam) owing
to the disabling nature of their anxiety symptoms,
although this medication class must be used cau-
Non-Motor Fluctuations tiously in PD patients because of their propensity to
Although motor fluctuations (MFs) (i.e., dyskine- increase sedation, gait imbalance, and cognitive
sias and “off” periods) have long been recognized as a impairment. For non-pharmacologic approaches,
complication of DRT, only recently has research dem- CBT techniques can be effective for treating situa-
onstrated that the majority of patients with MFs also tional anxiety and anxiety attacks.
experience non-motor fluctuations (NMFs), including
anxiety (e.g., anxiety attacks), slowness of thinking, Apathy
fatigue, and dysphoria.310 Furthermore, NMFs are
often the more disabling of these complications.310 Apathy occurs in approximately 40% of PD
The relationship between motor status and NMFs is patients322,323 and can occur independently of depres-
complex, as there is not always a correlation between sion and cognitive impairment, although overlap is
affect and motor state,311,312 and improvements in common.322,324 Studies of apathy in PD have reported
mood post-levodopa infusion in patients with MFs associations with executive deficits, verbal memory
can precede improvements in motor status.313 It impairment, and bradyphrenia,322,325 and with
remains to be seen if treatments approved on the basis decreased cingulate and inferior frontal gyri vol-
of reducing severity or time of MFs, including newly umes.326 There has been one RCT showing benefit for
available longer-acting levodopa or levodopa admin- reintroduction of a DA in patients experiencing apa-
istered via enteral or oral suspension, also lead to thy with DA discontinuation post-DBS surgery,327
improvements in severity or duration of NMFs. and stimulants (e.g., methylphenidate and amphet-
amines) are used clinically.
Other Disorders of Affect

Pseudobulbar affect
Anxiety
Pseudobulbar affect (PBA), also called affective or
Compared with depression, anxiety in PD has emotional lability, can occur in a variety of neurode-
received scant attention to date. Up to 40% of PD generative diseases and neurologic conditions, and
patients experience anxiety symptoms or disorders, prevalence rates of 5%−10% have been reported in

ARTICLE IN PRESS
PD.328 Similar to apathy, PBA and depression appear the Unified Parkinson’s Disease Rating Scale has an
to be overlapping but distinct disorders. Regarding expanded Part I that queries about cognitive
the neuropathophysiology of PBA, a final common impairment, psychosis, depression and anxious
pathway appears to be disinhibition of brainstem bul- mood, apathy, and impulse control disorder behav-
bar nuclei that control the expression of crying and iors, sleep problems, daytime sleepiness, and
laughing, possibly from impairment in neural path- fatigue.341 Finally, the IPMDS has commissioned
ways connecting the cortex and brainstem.329 Numer- development and validation of a new global, compre-
ous small-scale studies have found both tricyclic hensive non-motor rating scale, including NPS, called
antidepressants and SSRIs to be efficacious in the the Movement Disorder Society Non-Motor Scale,342
treatment of PBA, although none included PD with the primary validation study now completed.
patients,330 and studies in multiple sclerosis and
amyotrophic lateral sclerosis found benefit for the
Landmark Studies and Research Efforts
FDA-approved combination of dextromethorphan
and quinidine.331,332 In addition, it is important to There have been numerous longitudinal, observa-
educate patients and family members regarding the tional studies and other academic efforts, many ongo-
distinction between PBA and depression. ing, that have informed our understanding of
psychiatric and cognitive complications in PD,
including the Sydney Multicenter Study of PD,12 the
Global NPS
Norwegian ParkWest Study Group,11 the CamPaIGN
Recent neuropsychiatric research focuses on global Study of PD,38 the DeNoPa Study,42 the Fox Founda-
NPS and advanced statistical techniques to delineate tion-funded international PD-MCI Task Force,86,87 the
neuropsychiatric profiles in PD, to help account for PD Cognitive Genetics Consortium,343 the IPMDS
the substantial comorbidity and interindividual het- Non-Motor PD Study Group, and the Cognitive/Psy-
erogeneity.333 For instance, in one study that used chiatric (Behavior) Working Group of the Parkinson
latent class analysis in a cohort of mild-moderate PD Study Group.37,344
patients, three of the four delineated classes (psychiat- A landmark research study is the Parkinson Pro-
ric, psychiatric-cognitive, cognitive, and intact) expe- gression Markers Initiative (PPMI), conducted by the
rienced significant, but different, patterns of cognitive Michael J. Fox Foundation for Parkinson Research
and psychiatric symptoms and comprised over two- with numerous co-funders and supporting agencies.
thirds of patients.334 Another study using factor anal- PPMI is a biomarker-intensive study following a rela-
ysis found that the first and strongest of four factors tively large cohort of de novo PD patients, at-risk PD
included cognitive impairment, psychotic symptoms, patients (based on specific genes or having idiopathic
depression, and EDS.335 Finally, a study using cluster RBD), and healthy controls longitudinally. Cognitive
analysis and including both broad non-motor and findings to emerge from this study include: 1) the
motor symptoms identified four clusters: mild, non- prevalence of cognitive impairment in PD patients at
motor dominant, motor-dominant, and severe. In baseline varies based on assessment methods used,
addition, when including only non-motor symptom ranging from 10%−20%; 2) significant cognitive
data, six clusters were identified.336 This line of impairment (i.e., dementia) is uncommon in the first
research has also established that the burden of global 5 years of disease, in part related to the relatively
NPS has a significant, detrimental effect on health- young, highly educated and highly motivated cohort,
related quality of life even in early PD.337 but using internal (i.e., derived from healthy controls)
Recently, several global assessment instruments versus published normative data increases sensitivity
have been developed and tested for clinical use in to detecting initial cognitive decline; 3) there are mul-
PD, including the Non-Motor Symptoms Scale338 and tiple clinical (e.g., age, olfaction, and RBD symptoms)
the Scales for Outcomes in Parkinson Disease-Psychi- and biological (e.g., biofluids, CSF, AD biomarkers),
atric Complications.339 The Neuropsychiatric Inven- neuroimaging (DAT scan, structural magnetic reso-
tory340 is commonly used in PD to document the nance imaging, white matter hyperintensities, and
presence and severity of a range of NPS, and the genetics) predictors of cognitive decline in early PD;
Movement Disorder Society Sponsored Revision of 4) there is significant overlap between cognitive

ARTICLE IN PRESS
decline in PD and other non-motor symptoms (e.g., outcomes (including morbidity and mortality), and
olfactory impairment and RBD symptoms); 5) there greater caregiver burden; 3) there have been signifi-
are modifiable risk factors (e.g., vascular disease) that cant advances in the assessment (e.g., questionnaires
predict cognitive decline in early PD; and 6) cognitive and rating scales) and diagnosis (i.e., consensus diag-
changes can be detected in general population nostic criteria) of disorders, which has led to
patients at risk for PD, most notably idiopathic RBD improved clinical management and higher quality
patients.18,40,68,275,345−352 Psychiatric findings from research; 4) mounting evidence finds that the neural
PPMI include: 1) overall non-motor symptom burden substrate of non-motor complications in PD is a com-
increases significantly over time in early PD, and plex interaction of strategically placed PD and other
have clinical predictors (e.g., female sex, older age, (i.e., AD) neurodegenerative disease pathology,
and worse PD motor symptoms); 2) affective disorder changes in multiple neurotransmitter systems, impair-
symptoms (i.e., depression and anxiety) are common ments in neural circuitry subserving mental function-
in PD and increase slightly in prevalence over the first ing, and genetic influences; 5) core PD treatments,
5 years of disease; 3) symptoms associated with DRT, especially DRT and DBS, have a complex and varied
particularly chronic or higher-dose exposure (e.g., effect on psychiatric symptoms and cognitive abilities;
psychosis and ICDs), remain relatively uncommon in and 6) in spite of the advances highlighted earlier,
the first 5 years of PD; 4) symptoms of sleep and current treatment options for the range of disorders
wakefulness disorders (e.g., insomnia, RBD, and discussed, while growing, still remain quite limited,
fatigue) increase significantly in frequency over time; with nearly all efficacious drugs developed or first
5) there are biological predictors of NPS presence or used for similar conditions in non-PD patients.
development, including changes in DAT availability, Looking ahead, high priority areas for future
specific genetic single nucleotide polymorphisms, research in PD include continuing long-term, longitu-
and structural imaging changes; 6) both antidepres- dinal epidemiologic research focused on course and
sant and anxiolytic/sedative-hypnotic medication predictors of prevalent and incident psychiatric disor-
use are common in early PD (each medication class ders and cognitive decline; expanding use of sophisti-
taken by approximately 25% of patients), and antide- cated statistical techniques to re-conceptualize the
pressant use may have an impact on amyloid bio- classification of psychiatric and cognitive disorders,
markers and cognitive course; 7) patients diagnosed to account for the significant interindividual hetero-
with PD but without evidence of dopaminergic deficit geneity that occurs; improving recognition and diag-
have an increase in a range of non-motor symptoms nosis through continued development and validation
compared with healthy controls; and 8) there are sex of diagnostic criteria and clinically useful assessment
differences in several non-motor symptoms in de tools that are specific to PD; improving our under-
novo PD, with men predisposed to some and women standing of the neural substrate of cognitive and psy-
to others.18,223,251,252,350,353−359 chiatric complications, through examination of
neuropathology, disease-specific biomarkers (includ-
ing developing a positron emission tomography
tracer that binds to abnormal or misfolded alpha-syn-
CONCLUSION
uclein, or even a validated CSF or plasma alpha-synu-
Some overarching themes have emerged over the clein biomarker), neurotransmitters, brain structure,
past 20 years in our understanding of psychiatric and neural circuitry, and genetics; resolving the DLB ver-
cognitive complications in PD, including: 1) prospec- sus PDD debate, perhaps by using the umbrella clini-
tive, longitudinal studies have demonstrated that the cal diagnosis of Lewy body disorders with subtypes
cumulative prevalence of most psychiatric and cogni- to capture both disorders, or a diagnosis of synuclei-
tive complications are far higher than earlier cross- nopathies to also include multiple system atrophy;
sectional studies suggested, with many disorders hav- and conducting large-scale clinical trials to determine
ing a cumulative frequency over 50%, with dementia the efficacy of different interventions for different
and sleep disorders likely reaching 80% long term; 2) psychiatric and cognitive complications, including
non-motor complications are associated overall with use of disease-modifying agents (when available) to
excess disability, worse quality of life, poorer delay or prevent cognitive and psychiatric

ARTICLE IN PRESS
complications. Ultimately, reducing the impact of PD Research Initiative (ATRI), Alzheimer’s Disease Coopera-
on patients and families will require improved recog- tive Study (ADCS), the International Parkinson and
nition and development of better therapies for its Movement Disorder Society (IPMDS), and the Parkinson
numerous and clinically significant neuropsychiatric Study Group (PSG); honoraria for consultancy from Aca-
complications. dia, Alkahest, Cure Huntingdon’s Disease Initiative
(CHDI) Foundation, Clintrex, LLC, F. Hoffmann-La
E.M. receives consulting fees from the Michael J. Fox Roche Ltd., and Sunovion; license fee payments from the
Foundation. D.W. has received research funding or sup- University of Pennsylvania for the Questionnaire for
port from the Michael J. Fox Foundation for Parkinson’s Impulsive-Compulsive Disorders in Parkinson’s Disease
Research, National Institutes of Health (NINDS), Depart- (QUIP) and Questionnaire for Impulsive-Compulsive Dis-
ment of Veterans Affairs, Alzheimer’s Therapeutic orders in Parkinson’s Disease-Rating Scale (QUIP-RS).
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The Neuropsychiatry of Parkinson

ARTICLE INFO ABSTRACT

“Perfect storm: an extremely bad situation in which INTRODUCTION

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monoamine and indolamine (i.e., dopamine, serotonin, Psychosis

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Other Disorders of Affect

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