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Neuropsychology Review



Delusions in Parkinson’s Disease: A Systematic Review

of Published Cases
Nicola Warren 1,2 & Cullen O’Gorman 1,3 & Zena Hume 2 & Steve Kisely 1,2 & Dan Siskind 1,2

Received: 13 December 2017 / Accepted: 25 June 2018

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Delusions in Parkinson’s disease (PD) are thought to be associated with disease progression and cognitive impairment. However,
this symptom description is not consistent in the literature and there is a suggestion that different subgroups of psychotic patients
occur in PD, which we aimed to clarify. Case reports were identified through a systematic search of databases (PUBMED,
EMBASE, PsychInfo). Cases with isolated delusions were compared to those with both delusions and hallucinations. We
identified 184 cases of delusions in PD. Delusions were primarily paranoid in nature (83%) and isolated in 50%. Those with
isolated delusions had an earlier onset of PD (46 years vs 55 years), higher rates of impulse control disorders (40.2 vs 10.3%),
dopamine dysregulation (29.9 vs 11.3%) and lower rates of cognitive impairment (8.0 vs 26.8%). There is unexpected hetero-
geneity amongst cases of delusional psychosis, that cannot adequately be explained by existing models of PD psychosis.

Keywords Parkinson’s disease . Psychosis . Delusion . Dopamine . Systematic review

Introduction and the National Institute of Mental Health, is a continuum

where delusions occur through a progression of delusions and
Delusions in Parkinson’s disease (PD) are associated with a hallucinations rather than distinct symptom classes (Ffytche et
significant impact on quality of life and an increased risk of al. 2017a; Ravina et al. 2007; Moskovitz et al. 1978). This
carer burden, nursing home placement and hospitalisation progression occurs with cognitive decline and advancement of
(Aarsland et al. 1999). Although they are less common than PD (Ffytche et al. 2017a). Isolated delusions, those without
hallucinations in PD, with an estimated prevalence of between the co-occurrence of hallucinations, have been considered rare
5 and 16%, delusions almost always require antipsychotic treat- (Mack et al. 2012). However, this is not a consistent finding
ment (Kiziltan et al. 2007; Lee and Weintraub 2012; Factor et (Kiziltan et al. 2007; Stefanis et al. 2010). Additionally, spe-
al. 2014). This treatment necessitates the delicate and complex cific PD subpopulations, such as those with dopamine dysreg-
balance between control of psychosis with parkinsonian side ulation syndrome, have demonstrated elevated rates of isolat-
effects. ed delusions (Cilia et al. 2014; Warren et al. 2017).
The current conceptualisation of PD psychosis, as defined Identified risk factors for PD psychosis include severity
by the National Institute of Neurological Disorders and Stroke and duration of PD, increasing age, cognitive impairment,
REM sleep behaviour disorder, depression, and visual pro-
Electronic supplementary material The online version of this article cessing deficits (Aarsland et al. 1999; Ffytche et al. 2017b;
(https://doi.org/10.1007/s11065-018-9379-3) contains supplementary Forsaa et al. 2010; Holroyd et al. 2001; Lee and Weintraub
material, which is available to authorized users. 2012; Mack et al. 2012; Pacchetti et al. 2005). The above
model and risk factors are based upon research that focused
* Nicola Warren
solely on hallucinations or grouped delusions with hallucina-
tions. The risk factors for isolated delusions are unknown.
We propose that the model for PD psychosis is incomplete
School of Medicine, University of Queensland, Brisbane, Australia and it is our hypothesis that delusions can occur without hallu-
Metro South Addiction and Mental Health Service, cinations or cognitive impairment. Additionally, we speculate
Brisbane, Australia that the content of delusions and the presence of perceptual
Department of Neurology, Princess Alexandra Hospital, 199 Ipswich phenomena vary with age and in certain sub-populations of
Rd, Woolloongabba, Brisbane Qld, 4102, Australia
Neuropsychol Rev

PD, such as those with early onset PD. To further clarify the Cases were included if there was documentation of both a
nature of delusions in PD, we conducted a systematic review of delusion and idiopathic Parkinson’s disease. Cases with cog-
all published cases. We aimed to identify: 1) the spectrum of nitive impairment or Parkinson’s disease dementia were in-
clinical presentations, 2) evaluation of known PD psychosis risk cluded. However, with concern for potential diagnostic con-
factors, 3) co-morbidities, and 4) effective treatment strategies. fusion, cases with a primary diagnosis of Lewy Body
Dementia (DLB) or those with symptoms consistent with the
international consensus guidelines for DLB were excluded
(McKeith et al. 2005). Other exclusion criteria were: psycho-
Methods sis without delusions, presence of delirium, prior diagnoses of
schizophrenia or other psychotic disorders. Case selection was
The Preferred Reporting Items for Systematic Reviews and made independently by two authors (NW, CO) with discrep-
Meta-Analyses (PRISMA) statement recommendations were ancies discussed with all authors.
followed (see Fig. 1 Moher et al. 2009). The study was pre- Data collected included: Demographics (gender, age), fea-
registered with PROSPERO: CRD 42017076792. Cases were tures of PD (age of PD diagnosis, levodopa equivalent daily
identified by search of PubMed, Embase and PsychInfo dose (LEDD), dopamine agonists use, dyskinesia, visual pro-
(Inception to June 2017) with search terms: Parkinson’s, psycho- cessing deficits), features of psychosis (psychiatric history,
sis, delusions, paranoid or paranoia, Othello, jealousy, misidenti- age of delusion commencement, suspected trigger for delu-
fication, Capgras. Search and screening was conducted indepen- sion, type of delusion, hallucination presence and type, agita-
dently by two authors (NW, ZH). Cases were accepted from any tion), comorbid disorders (cognitive impairment, impulse con-
source including poster abstracts, case reports, cohort or case- trol disorders, dopamine dysregulation syndrome, REM sleep
control studies. However, if individual data for each case was behaviour disorder, anxiety, depression) as well as treatment
not available in the cohort or case-control studies those cases use and outcome of psychosis management. Levodopa equiv-
were not included. References of selected articles were checked alent daily dose, if not supplied, was calculated using a stan-
to identify other eligible studies. All languages were included. dard formula (Tomlinson et al. 2010). Any mention of

Fig. 1 PRISMA 2009 Flow

Neuropsychol Rev

Bdementia,^ Bsevere cognitive impairment,^ or a MMSE <24 (2 cases) and illusions (1 case) were noted rarely. The presence
was considered a ‘cognitive impairment’ (Folstein et al. or absence of hallucinations was not recorded in 21 cases.
1975). If there was no documentation as to whether the vari- When documented, anxiety (43/59 cases) and depression
ables were either present or not they were considered absent. (47/70 cases) were commonly comorbid, although in many
Data was analysed using descriptive statistics. Comparisons of these cases it was unclear if this disturbance was historical
were made by Student’s t-test and Fisher’s exact test for contin- or concurrent. Significant agitation or aggression was reported
uous and nominal variables respectively. Effect sizes were cal- in 61 cases. Impulse control disorders were noted in 45 cases
culated using Cohen’s d and effect-size correlation, rYl for the (24.5%), most frequently hyper-sexuality (29 cases), patho-
continuous variables, and odds ratios (OR) for the nominal var- logical gambling (11 cases) or compulsive shopping (8 cases),
iables (Cohen 1988). The Bonferroni correction was applied for less frequently punding (4 cases) and binge eating (3 cases).
multiple comparisons, giving p < 0.00217 for significance Dopamine dysregulation syndrome was noted in 37 cases
(Miller 1966). (20.1%). The presence of REM sleep behaviour was docu-
mented in only nine cases.
When comparing the group of isolated delusions (n = 87)
Results with those with both delusions and hallucinations (n = 97)
there were some statistically significant differences (see
A total of 633 non-duplicated articles were identified in the Table 1). The cases with isolated delusions were more likely
databases. Following full text screening, 119 studies with 184 to be younger, with earlier onset of PD. Impulse control
cases of delusions in PD were identified, with publication date disorders I (OR = 5.90) and dopamine dysregulation syn-
ranges from 1976 to 2017 (see Fig. 1 and online drome (OR = 3.35) were more common in those with isolated
supplementary material). There were 114 cases from individ- delusions. Cognitive impairment was seen less frequently in
ual case reports, 63 from case series, and 7 from case control the cases with isolated delusions (OR = 0.25) than in those
studies. with both delusions and hallucinations. There was no statisti-
There were 121 males (65.8%) and 63 females. The mean cally significant difference between groups for anxiety, agita-
age of onset of PD was 51 years (SD = 11.8) and duration of tion or depression.
PD was 9.9 years (SD 6.1), with 91 cases (49.5%) classified as Since there was a significant difference between groups for
early onset PD (onset before 50 years: Pagano et al. 2016). age of onset, and the average age of onset for all cases was
Dyskinesia or significant motor fluctuation was reported in 57 close to the defined limit for early-onset PD; a second com-
cases (31%). The Mean LEDD was 1116.7 mg (SD = 1022.3). parison was performed, comparing all early-onset cases with
Dopamine agonists were used in 115 cases (62.5%). Cognitive all others, using the same variables (see Table 2).
impairment was present in 33 cases (17.9%) but was not spe- In this comparison, the age of onset data were unavailable for
cifically excluded in 70 cases. 8 cases. Cases of early onset PD represented >50% of the sam-
Delusions were predominantly paranoid in nature (152 ple. The main findings of note were significantly higher fre-
cases, 82.6%) with themes of persecution (117 cases) and quency of impulse control disorders (OR = 7.07) and dopamine
delusional jealousy (44 cases). Misidentification syndromes dysregulation syndrome (OR = 3.99) in the early onset cases.
also occurred (21 cases, 11.4%), with Capgras (17 cases), There was a lower rate of cognitive impairment in the early
reduplication (3 cases) and Fregoli (1 case). Other delusional onset cases (9.1% compared to 26.7%, OR 0.27) but this result
themes included: grandiosity (7 cases), delusions of reference did not reach statistical significance (p = 0.0028).
(7 cases), infestation (6 cases), nihilism (3 cases), guilt (2 Most cases either improved (93 cases, 50.5%) or resolved
cases), somatic concerns (2 cases) and religion (1 case). (35 cases, 19%) with treatment, however, many (49.7%) re-
There was more than one delusional type in 28 cases, and quired more than one treatment strategy. Using anti-
unspecified in six. The onset of delusions was reported to be psychotics (124 cases) or reducing dopamine replacement
related to a change in dopaminergic treatment in 53 cases therapy (102 cases) were the primary treatment options. The
(28.8%) and secondary to deep brain stimulation in 10 most commonly used anti-psychotics were clozapine (61
(5.4%). With increasing age, the frequency of misidentifica- cases), quetiapine (59 cases), olanzapine (18 cases) and
tion syndromes increased, delusional jealousy decreased, and aripiprazole (7 cases). Associated anti-psychotic induced mo-
persecutory delusions remained stable (see Fig. 2). Of the 91 tor impairment was frequently noted and there was one death
cases with early onset PD, only one clearly had a misidentifi- related to quetiapine induced neuroleptic malignant syndrome
cation syndrome (Islam et al. 2015). (Schattner et al. 2016). Electro-convulsive therapy was used in
Hallucinations were reported in 92 cases (50%): visual (45 11 cases and cholinesterase inhibitors in three. Deep brain
cases), auditory (14 cases), both visual and auditory (24 stimulation was used successfully as a treatment in three
cases), tactile (3 cases), olfactory (1 case), and unspecified cases. In the majority of cases it was unclear which treatment
(7 cases). Minor hallucinations, such as presence phenomena strategy lead to improvement or resolution of psychosis.
Neuropsychol Rev

Fig. 2 Frequency of delusion type across age-range of cases

Discussion of early onset PD cases in this series (Pringsheim et al. 2014).

Excessive dopamine replacement therapy was not used in
The gender distribution in this study reflects published PD most cases, although psychosis often followed a change or
cohorts. The age of onset of PD is lower than would be ex- increase in dopaminergic medications. Delusions were pri-
pected in a clinical cohort of PD, reflecting the high proportion marily paranoid in nature with common themes such as delu-
sional jealousy perhaps reflecting stage of life and environ-
Table 1 Cases of delusions in Parkinson’s disease ment. Misidentification syndromes, which are uncommon in
primary psychiatric populations, occurred more frequently
Total Delusions Delusions &
with older age and cognitive impairment (Cummings 1985).
Hallucinations only occurred in around half of the cases and
N 184 87 97 were again more common with age and cognitive impairment.
Male (%) 121 59 (67.8) 62 (63.9)
(65.8) Table 2 Comparison of groups by age of onset
Mean age of onset, years (SD) 51 (11.8) 47.1 54.3 (11.3)*a
(11.2)* Early onset Typical onset
Mean disease duration, years 9.9 (6.1) 9.4 (6.0) 10.4 (6.2)
(SD) N 88 86
Cognitive impairment, % 17.9 8.0* 26.8*b
Male (%) 64 (72.7%) 52 (60.5)
Impulse control disorder, % 24.5 40.2* 10.3*c
Mean age of onset, years (SD) 41.6 (7.0) 60.4 (7.2)
Dopamine dysregulation 20.1 29.9* 11.3*d
Mean disease duration, years (SD) 10.4 (7.1) 9.0 (4.7)
syndrome, %
Agitation, % 33.2 26 39 Cognitive impairment, % 9.1 26.7
Anxiety, % 23.4 29.9 17.5 Impulse control disorder, % 42.0* 9.3*5
Depression, % 26.1 29.9 22.7 Dopamine dysregulation syndrome, % 31.8* 10.5*6
Agitation, % 31.8 33.7
[Reference group: Delusions] Anxiety, % 30.7 17.4
Cohen’s d, 0.72 (medium to large effect), effect-size correlation, rYl: Depression, % 31.8 19.8
OR = 0.25 [Reference group: Early onset]
c a
OR = 5.90 OR = 7.07
d b
OR = 3.35 OR = 3.99
*statistically significant at p = 0.00217 *statistically significant at p < 0.00217
Neuropsychol Rev

Interestingly, a similar picture of difference in perceptual phe- bias. Inevitably, potentially useful data are omitted from re-
nomena and type of delusions with increased age and cogni- ports, such as ethnicity, presence of REM sleep behaviour
tive impairment is seen in Alzheimer’s disease (Ismail et al. disorder and visual processing deficits, that were rarely men-
2011). tioned. Available data may be incomplete, such as details re-
Those with delusional PD psychosis appear more likely to garding perceptual phenomena or detailed assessment of cog-
have impulse control disorders, dopamine dysregulation syn- nitive function. For this analysis, continuous variables (e.g.,
drome and possibly mood and anxiety disturbance, compared cognitive impairment) were dichotomised to permit analysis
to published cohorts of PD (Barone et al. 2009; Vazquez et al. in the absence of more complete data. Similarly, omission of a
1993; Cilia et al. 2014; Weintraub et al. 2010). The association reported symptom (e.g., impulse control disorder, hallucina-
with co-morbid disorders was further increased when compar- tion) was taken as equivalent to definite absence for the pur-
ing cases of isolated delusions to those who had both delusions pose of analysis. These simplifications were necessary given
and hallucinations. The group with isolated delusions had lower the source material, but potentially limit clinically application
age of onset and was less likely to have cognitive impairment. of our findings. The aim of this study was primarily descrip-
These findings were similar when cases were compared by age tive, given the existing knowledge in this area is limited.
of onset, perhaps suggesting that the underlying differences be- This is the first systematic review of delusions in PD psy-
tween the groups may be influenced by age of onset. chosis and our findings suggest that the current conceptuali-
Cognitive impairment has been considered a necessary sation of PD psychosis does not account for all cases and
component in the development of PD psychosis (Ffytche et perhaps is an over simplification. There are possible implica-
al. 2017a). The rate of impairment was higher in cases with tions for screening, diagnosis and treatment. Prospective stud-
combined hallucinations and delusions than in cases with iso- ies, with careful examination of psychiatric phenomena, and
lated delusions. We speculate that cognitive impairment may assessment of other relevant risk factors, such as cognitive
be less important for delusion formation than for hallucina- impairment, REM sleep behaviour disturbance and processing
tions in PD psychosis. deficits may help guide clinicians in targeting treatment and
A hypothesis derived from schizophrenia research suggests other interventions. In particular, advanced imaging modali-
that delusion formation occurs through the aberrant signalling ties including functional MRI (fMRI), diffusion tensor imag-
of salience to environmental stimuli and their mental represen- ing (DTI) and single-photon emission computed tomography
tations, mediated by sensitised meso-limbic dopaminergic neu- (SPECT) have recently been applied to evaluation of the
rons (Kapur 2003). Chronic use of dopaminergic medication meso-limbic circuit affected in Parkinson’s disease (Sharman
has been shown to sensitise meso-limbic neurons (Moskovitz et al. 2013; Son et al. 2016). Combining these techniques with
et al. 1978). This sensitisation may be particularly important for specific examination of psychosis in early onset PD may allow
those with early onset PD, in whom disease progression is expansion and testing of hypotheses generated by this study.
slower with a greater subsequent sparing of the ventral tegmen-
tal area and the projections to the ventral striatum Funding This work was conducted without financial support. Dr. Siskind
is partially supported through a grant from NHMRC (ECF APP1111136).
(Wickremaratchi et al. 2009; Pagano et al. 2016; Kish et al.
1988). A relative and sensitised mesolimbic predominance of
dopaminergic neurons is also thought to be associated with the Compliance with Ethical Standards
development of impulse control disorders, dopamine dysregu-
Conflict of Interest The authors declare that they have no conflict of
lation syndrome and mood or anxiety fluctuations (Brewer and interest.
Potenza 2008; Eskow Jaunarajs et al. 2011; Linazasoro 2009).
Distorted ‘top down’ cognitive explanations of this aberrant Ethical Approval For this type of study formal consent is not required.
salience may also be required for delusion formation (Poletti and
Bonuccelli 2013). Mood and anxiety disturbance, as seen fre-
quently in cases of isolated delusions, may alter or impair the
cognitive explanation (Morgante et al. 2012). There is a sugges-
tion that those with PD, especially with impulse control disor-
ders, have an increased rate of ‘jumping to conclusions,’ a cog- Aarsland, D., Larsen, J. P., Cummins, J. L., & Laake, K. (1999). Prevalence
nitive characteristic that may lead to early acceptance of delu- and clinical correlates of psychotic symptoms in Parkinson disease: A
sional explanations (Djamshidian et al. 2012). community-based study. Archives of Neurology, 56(5), 595–601.
It is important to note that the above are hypotheses that https://doi.org/10.1001/archneur.56.5.595.
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