Article title: Management of Parkinson’s Disease Psychosis: an overview diagnosis and

pharmacological options
Short title: Management of Parkinson’s Disease Psychosis
Authors: Gina Costandache1*, Bianca Oroian1
1
Adult Psychiatry Department, Institute of Psychiatry Socola, Iasi, Romania
* Corresponding author : Gina Costandache, email: ginacostandache@gmail.com, ZIP code:
700282, Iasi, Romania Phone number: +040743981077;
No financial support;
The authors have no conflict of interest to declare;
Word count: 3901;
Tables :1;
Figures: 0;
Last literature review: December 2023
Abstract
Parkinson's disease frequently encompasses a diverse array of non-motor symptoms, with
psychosis emerging as a prominent psychiatric manifestation. Parkinson's disease psychosis
(PDP) is linked to adverse outcomes, significantly impacting the patient's quality of life and
imposing a considerable burden on caregivers. The spectrum of psychotic symptoms in
Parkinson's disease spans from minor perceptual disturbances to delusions and profound
hallucinations. Timely recognition, diagnosis, and intervention by clinicians are paramount.
Antipsychotics constitute the cornerstone of PDP treatment, with atypical antipsychotics being
the most commonly employed. Quetiapine stands as the primary off-label therapeutic option.
Nevertheless, the existing data on the efficacy of quetiapine manifests inconsistencies.
Clozapine, approved for Parkinson's disease psychosis treatment in specific European countries,
demonstrates efficacy without exacerbating motor function, showcasing anti-tremor effects, yet
requires regular monitoring. Pimavanserin is the only FDA-approved medication that proved a
significant reduction in the frequency and severity of hallucinations and delusions in PDP
without worsening PD motor symptoms. The primary objective of this article is to undertake a
comprehensive review of contemporary literature pertaining to Parkinson's Disease Psychosis
(PDP), with a specific emphasis on pharmacological interventions.
Keywords: Parkinson’s disease, psychosis, treatment, antipsychotics, quetiapine, clozapine,
pimavanserine;

1. Introduction

Parkinson’s disease (PD) is a complex neurological disorder, which represents the most common
movement disorder, [1] and the second most common neurodegenerative disorder, after
Alzheimer’s disease [2]. Neuropathologically, PD is characterized by the loss of dopaminergic
neurons in the pars compacta of the substantia nigra (SNpc), basal nucleus of Meynert, and the
dorsal motor nucleus of the vagus nerve. Moreover, at a histological level, the degeneration of
striatal dopaminergic neurons in the SNpc is associated with the accumulation of cytoplasmic
inclusion bodies, called Lewy’s bodies that contain abnormal aggregates of a-synuclein, making
Parkinson’s disease be classified as a synucleinopathy [3]. The most significant risk factor for
Parkinson’s disease is advancing age, with a median age of onset of 60 years. The prevalence in
the general population of industrialized countries is 3% in those aged 80 years or older. There is
a gender difference in the incidence and prevalence of PD, as men are more prone to develop the
disorder, with a likelihood 1.5 to 2.0 fold higher than women [4]. The clinical hallmark of
Parkinson’s disease is motor symptomatology, defined by the presence of bradykinesia, and
either a resting tremor, or rigidity, usually manifesting unilaterally, or at least asymmetrically,
along with modification in posture and gait [5]. In addition to the major motor features, non-
motor symptoms (NMS) are very frequent, and involve a wide array of dysfunctions, such as
sensory deficits, neuropsychiatric features, autonomic dysfunction, pain, and fatigue [6]. In most
cases, during the course of illness, patients will experience varying neuropsychiatric symptoms,
making them almost as common, and as disabling as the motor features [7]. The neuropsychiatric
symptoms (NPS) include a broad spectrum of disorders ranging from anxiety, apathy, sleep
disturbances, and impulse control disorders (e.g compulsive gambling, shopping, sexual
behaviors, and eating behavior), to depression, cognitive decline (both mild cognitive
impairment (MCI) and dementia), and psychosis [6]. Psychosis in Parkinson’s disease (PDP) is a
common psychiatric symptom, that is associated with negative outcomes, as it can severely
impair the quality of life of the patient, and place a substantial burden on the caregivers. The
psychotic symptoms of Parkinson’s disease encompass different types of misperception
symptoms ranging from minor psychotic experiences to delusion, and major hallucinations. The
minor phenomena spectrum is associated with the early stages of PD, but as the illness evolves,
hallucinations, loss of insight and delusions tend to represent the principal manifestations of
PD’s psychosis [8]. As PDP is the principal cause of admission to a nursing home, it is
imperative to identify patients with PD who are at risk of developing psychosis, at an early stage,
so that appropriate management can be implemented [9].

2. Epidemiology

The prevalence of PDP is slightly discrepant among studies, due to the use of different research
methods and objects. However, the risk of developing PDP is influenced by disease duration,
cognitive status, and Hoehn and Yahr stage [10]. In a cross-sectional analysis of 199 patients
with PD, the prevalence of psychotic features was 29%, with a rate of 14% for major
symptomatology, and isolated, minor phenomena in 15% of participants. Regarding the type of
major hallucinations, visual hallucinations were the most common, followed by olfactory, tactile,
auditory, and gustatory hallucinations [11]. Omoto et al., reported a 38% prevalence of minor
hallucinations in a cohort of 100 PD patients. [12], while Zhong et al., reported similar results
among 262 patients with PD, with a prevalence of 38,9%, and the most common type of minor
hallucinations being visual illusions [13]. Minor hallucinations seem to antedate the development
of motor symptomatology, as in one prospective study, one-third of participants experienced
presence or passage hallucinations starting 7 months to 8 years before the onset of Parkinson’s
disease primary characteristics [14]. The results from Parkinson's Progression Markers Initiative
showed an increasing prevalence of psychosis, from 3% at baseline to 5.3%, and 10.0% at 12
months, and respectively 24 months [15]. Moreover, in a prospective longitudinal cohort study,
after a 12-year disease duration, it was observed the development of hallucinations or delusions
in 60% of patients with PD [16]. A recent meta-analysis concluded that a fifth of patients with
Parkinson’s disease would experience psychosis at some point during the course of the disease.

3. Diagnosis and clinical presentation

There are no standardized diagnostic criteria for Parkinson’s disease psychosis. However, in
2007, the National Institutes of Neurological Disorders and Stroke (NINDS), and the National
Institute of Mental Health (NIMH) workgroup proposed a set of diagnostic criteria for PDP, that
includes the presence of one or more characteristic psychotic symptomatology, that persist either
continuously or recurrently for at least 1 month, a confirmed diagnosis of Parkison’s disease,
before the onset of psychotic features, along with the exclusion of other conditions, as detailed in
Tabel I [17]. Moreover, in the Diagnostic and Statistical Manual of Mental Disorders-Fifth
Edition (DSM-V), criteria for Parkison’s disease psychosis is under the umbrella of “psychosis
due to a medical condition”, and it is not completely in concordance with the diagnostic criteria
proposed by the NINDS-NIMH group. The main difference regards the emphasis on distress or
impairment of patients with psychosis, in social, occupational, or other important areas, which is
mentioned in DSM-V and omitted in the NINDS-NIMH diagnostic criteria [18].
To optimally screen the risk, diagnose, and rate the severity of psychotic features, a wide range
of scales are available, either as a part of a general PD scale or as a specifically tailored
assessment tool for neuropsychiatric symptoms. Scales focusing on NPS, such as the PD Non-
Motor Symptom Scale, the Scale for Assessment of Positive Symptoms for PD (SAPS-PD), the
Scale for Evaluation of Neuropsychiatric Disorders in Parkinson’s disease (SEND-PD), or the
Parkinson Psychosis Questionnaire (PPQ) can be used to assess the minor or major psychotic
symptoms. However, it is common in clinical practice to use the Movement Disorder Society
United PD Rating Scale (MDS-UPDRS), which includes psychiatric manifestations of PD as a
reliable method to assess the presence and severity of PD psychosis [9].

Table I. NINDS-NIMH Criteria for the diagnosis of Parkinson’s disease psychosis

Criteria
Psychotic symptomalogy
Diagnostic of PD
Exclusion of other causes
Description
At least of one of: illusions, false sense of presence, hallucination,
or delusions,with a duration of over 1-month time period
using the UK Brain Bank criteria, before the onset of psychotic
features
dementia with Lewy bodies, schizophrenia, schizoaffective
disorder, delusional disorder, mood disorder with psychotic
features, or a general medical condition, including delirium

As mentioned before, the clinical presentation of psychosis in Parkinson’s disease can be

separated into two main groups, delusion and major hallucinations (e.g. visual, auditory,
gustative, olfactory, tactile), and minor phenomena (MHs) including illusions, passage and
presence hallucinations.
Visual hallucinations (VH) can be either simple, with flashes of light or blurry colors, or
complex and commonly involve people. However, animals or objects can be also described by
patients. The content of complex visual hallucinations has a wide variation in terms of
familiarity, color scheme, and dimensions [19], [20]. VH are more frequent at nighttime, can last
for seconds or minutes, and have no apparent trigger [21]. Pareidolia is frequently observed in
PD patients and represents a specific type of visual illusion, in which faces and objects arise
from ambiguous forms embedded in formless visual stimuli. It can be experienced by patients
with PD without VH and can be used as a highly specific test for differentiating PD from
multiple system atrophy (MSA), another neurodegenerative parkinsonism disorder [22].
On the other side, nonvisual hallucinations are less frequent, usually appear concomitantly with
VH, and are especially associated with older patients. [19], [23] Patients experiencing delusion
tend to be younger than individuals with hallucinations, [23] and the themes vary from sin or
guilt, grandiosity, and reference, to religion, persecution, or jealousy [24].
Regarding MHs, PD patients can experience one or more minor symptoms (isolated MHs), or
they can concomitantly have another type of sensorial misperception (complex MHs) [25].
During presence hallucinations, the person experiences the feeling that someone is present,
which can either be a person or an animal. The passage hallucinations consist of fleeting, vague
images in the peripheral vision, while illusions are described as misperceptions of real stimuli
[20].
4. Pathophysiology
The pathophysiological mechanisms underlying Parkinson's disease psychosis are intricate and
remain incompletely understood. The emergence of PDP is likely influenced by a combination of
exogenous factors, related to treatment, and endogenous factors, specific to the disease, and the
patient.
4.1 Dopamine agonists
Some theories suggest that chronic use of dopaminergic medication could lead to the
hypersensitivity of mesolimbic dopamine receptors, which could contribute to the development
of psychosis. However, it is noteworthy that visual hallucinations have been reported in
Parkinson's disease patients who have not received dopaminergic treatment [26]. Additionally, in
individuals with PD who were already receiving dopaminergic medications, high-dose levodopa
infusions did not result in the occurrence of hallucinations [27]. Although certain investigations
have demonstrated a correlation between higher doses of levodopa or treatment with dopamine
agonists, it remains challenging to distinguish and understand the connection between psychotic
symptoms and medications prescribed for Parkinson's disease [20].
4.2 Genetic factors
Several studies have delved into the genetic etiology of psychosis in Parkinson's disease. The
foremost focus has been on the apolipoprotein (APO) E polymorphism, with subsequent
attention given to the polymorphisms present within the cholecystokinin (CCK) system,
dopamine receptors and transporters, the HOMER gene, serotonin, catechol-O-
methyltransferase, angiotensin-converting enzyme, and tau protein [28]. As studies have reported
the association of APO ε4 allele in Alzheimer’s disease patients with incidental hallucinations
and delusions, research was conducted to also find a connection between the development of
psychotic symptoms in patients with PD. Only in one study, the APO ε4 allele was associated
with VH, while several studies concluded that there is no association. However, they reported an
earlier onset of psychosis in PD patients carrying the ε4 allele [28]. Regarding the other genetic
polymorphisms that have been studied, the CCK polymorphism could be considered the most
promising target for future research, as it has been frequently associated with hallucinations, and
has shown more consistent results in previous studies.
4.3 Neurotransmitter involvement
Another hypothesis of PDP focuses on the neurotransmitter systems. Psychotic symptoms in
Parkinson's disease may not only be caused by the degeneration of dopaminergic neurons in the
ventral dopaminergic pathway and overstimulation of striatal/mesolimbic dopamine receptors
but also by the involvement of other neurotransmitter pathways, such as cholinergic and
serotonergic pathways. Cholinergic dysfunction has been proposed as a potential mechanism
underlying the development of visual hallucinations in Parkinson's disease, because of the
atrophy observed in the pedunculopontine nucleus, and nucleus basalis of Meyner [29], [20]. The
serotonin system may degenerate early in Parkinson's disease and could be involved in the
development of psychosis in some patients with Parkinson's disease. Studies have concluded that
the presence of anxiety and/or depressive disorders may be a predictor for the development of
psychotic symptoms in Parkinson's disease, particularly concerning the presence and severity of
hallucinations. The link between serotonin and psychosis in Parkinson's disease is supported by
several findings, including increased 5-HT2a binding in patients with Parkinson's disease
psychosis, the response of psychosis to 5-HT3 and 5-HT2 antagonists, and the response to
pimavanserin, a new antipsychotic for Parkinson's disease that is a 5-HT2a/c inverse agonist
[30].
4.4 Role of advanced neuroimaging
Advanced neuroimaging methods have been utilized to examine the structural, functional, and
metabolic dissimilarities between PD patients with and without visual hallucinations. The
majority of structural imaging studies have been associated with grey matter atrophy in various
regions of the brain, such as dorsal and ventral visual pathways, hippocampus, pedunculopontine
nucleus, and substantia innominata. The grey matter atrophy associated with the dorsal and
ventral visual pathways may be the cause of VH in PD, as these regions are implicated in spatial
location, motion perception, identification, and recognition of objects [31]. As the hippocampus
is highly interconnected with visuospatial memory, it has been hypothesized that alterations in
this area might contribute to visual hallucinations. The findings of Yao et al. support this theory,
as the results of the study concluded that microstructural deficits in the right hippocampus were
present in PD patients with hallucinations [32]. Moreover, white matter abnormalities were also
observed in a recent study by Lenka et al., located in the body of the corpus callosum, inferior
frontal-occipital fasciculus, inferior longitudinal fasciculus, right corticospinal tract, and
occipital-parietal lobes, in patients with PDP, when compared to non-psychotic PD individuals.
The inferior longitudinal fasciculus and inferior frontal-occipital fasciculus play a significant role
in relaying visual information from the occipital cortex to temporal regions, and subsequently to
the orbitofrontal cortex. These findings highlight and support the involvement of defective visual
pathways in the etiology of psychosis in Parkinson's disease [33], [34]. Functional neuroimaging
studies of Parkinson's disease patients with visual hallucinations have concluded that there is an
altered activation, blood flow, and hypometabolism in brain regions corresponding to visual
pathways. Additionally, abnormalities in the functions of frontal lobe structures and frontostriatal
circuits have been identified [31].
4.5 Other related risk factors
Other risk factors were also correlated with the development of PDP. Age, disease duration, and
severity proved to increase the risk of psychosis in a study analyzing 775 patients with PD [35].
With similar results, the retrospective study by Sawada et al., revealed that individuals with a
modified Hoehn-Yahr stage of ≥4, a longer duration of Parkinson's disease, and lower Mini-
Mental State Examination scores (≤24) were at a heightened risk of developing psychosis.
Notably, the use of anticholinergic medications was associated with a significantly increased risk
of psychosis, while the use of donepezil was found to be associated with a decreased risk of
psychosis, but only among patients aged 70 years or older [36]. The presence of hallucinations in
Parkinson's disease is frequently associated with global cognitive impairment (CI); however, the
pathogenic mechanism underlying delusions appears to be distinct, as they are not typically
correlated with cognitive domain deficits [37]. Studies have reported the association between
rapid eye movement sleep behavior disorder (RBD), visual hallucinations, and cognitive
impairment. The occurrence of vivid dreams and sleep disruption are clinical features preceding
the onset of RBD, while certain clinical subtypes of PD (e.g. akinetic-rigid), as well as the
freezing of gait, autonomic dysfunctions, and falls, are known risk factors for RBD, VH, and CI
[38]. PD psychosis onset was also correlated with olfactory impairment, depressive symptoms,
[39] female sex, a lower degree of education, and daytime sleepiness [40].

5. Treatment

The management of PDP begins with an assessment of the overall patient’s medication, with a
focus on the agents used to treat the motor symptomatology of PD. Appropriate measures that
may be taken include reducing anticholinergic medications for general medical conditions
(bladder conditions, sleep disorders, allergies, or cold medications), decreasing or eliminating
adjunct antiparkinsonian medications (monoamine oxidase inhibitors, amantadine,
trihexyphenidyl), or even reducing the dosage of dopaminergic agents [23]. Furthermore, the
exclusion of other factors that could lead to the development of a symptomatology similar to
PDP, such as delirium, infections, dehydration, imbalance of electrolytes, and other non-PD
medication factors is necessary [41]. However, in cases where the aforementioned measures are
insufficient to reduce the PDP symptoms, the administration of antipsychotic agents is
recommended.
5.1 Antipsychotics
While all current antipsychotics are expected to alleviate psychosis in Parkinson's disease, their
use is limited by the possible exacerbation of motor symptoms due to dopaminergic antagonism
[42]. The use of typical antipsychotics is discouraged owing to their negative impact on motor
function. Additionally, certain atypical antipsychotics may exacerbate underlying Parkinson's
disease. Numerous studies have indicated a decline in motor symptoms with risperidone, [43]
whereas olanzapine does not demonstrate improvement in psychotic symptoms and may lead to a
deterioration in motor function [44]. Recent findings indicate that, although aripiprazole may
effectively ameliorate hallucinations and delusions in specific patient groups, it has been
observed to exacerbate parkinsonism in other cases [45]. A systematic review determined that
ziprasidone, although occasionally can worsen motor symptomatology, is generally well-
tolerated. In specific instances, it could serve as a feasible alternative to quetiapine, clozapine,
and pimavanserin, especially in acute care settings [46]. In a randomized controlled trial (RCT),
melperone demonstrated no notable efficacy for PDP at any dosage. Nevertheless, there were no
significant adverse effects observed on motor functioning [43].
At the moment, antipsychotics with fast dissociation from dopamine receptors (e.g., quetiapine)
or preferential dopamine-4 receptor activity (e.g., clozapine) that may mitigate psychotic
symptoms without significant motor function compromise, are preferred [47]. Moreover,
pimavanserin, an antipsychotic with
partial inverse agonist and antagonist at serotonergic 5-HT2a receptors, but without any
dopamine D2 receptor antagonism, is effective and well tolerated in PDP [48].

5.1.1 Quetiapine
Quetiapine is the most commonly off-label prescribed medication among individuals with
Parkinson's disease experiencing psychosis, with several studies reporting that approximately
60–75% of patients have undergone treatment with this particular antipsychotic [49], [50].To
address Parkinson's disease psychosis, therapy with quetiapine typically commences at a low
dosage of 12.5 mg nightly, with subsequent increments of the same dosage until reaching a target
ranging from 50 to 150 mg nightly. Moreover, quetiapine is favored in clinical settings for its
simplicity of administration and the absence of a requirement for blood count monitoring [51].
However, the available data on the efficacy of quetiapine exhibits inconsistencies. Desmarais et
al. conducted a systematic review encompassing seven randomized controlled trials to evaluate
the efficacy of quetiapine in individuals with Parkinson's disease psychosis. The study revealed
an absence of a significant reduction in psychotic symptoms at daily doses of around 100 mg
quetiapine when compared to placebo, as objectively measured by the Brief Psychotic Rating
Scale. Notably, the administration of quetiapine did not result in discernible motor deterioration
[49]. Regarding side effects of quetiapine administration in this population, a series of mild
adverse effects were observed, including somnolence, dizziness, headache, weight gain, and
orthostasis [52]

5.1.2 Clozapine
Clozapine, a second-generation antipsychotic, was the first drug shown to be an effective
antipsychotic in PDP, that did not worsen motor function. It is approved by the European
Medicines Agency for treating Parkinson's disease psychosis in some European countries (e.g.,
France, Italy, UK), but lacks approval in the United States [53]. Clozapine's significant anti-
tremor effects in Parkinson's disease patients were demonstrated in both open and double-blind
trials. In two double-blind, placebo-controlled trials, the administration of low doses of clozapine
(6.25 mg/d to 50 mg/d) has been demonstrated to ameliorate drug-induced psychosis in
Parkinson's disease without causing notable deterioration in motor function [54], [55]. It is
important to acknowledge that clozapine is specifically linked to blood dyscrasias, necessitating
weekly blood monitoring for the initial 6 months, followed by biweekly evaluations for the
subsequent 6 months, and ultimately transitioning to monthly assessments. At the moment,
limited data are accessible regarding the incidence of neutropenia and agranulocytosis in patients
with Parkinson's disease, within the 6.25-50 mg dose range. However, in the general population,
the occurrence of these conditions is dose-independent within the schizophrenia dose range [56].

5.1.3 Pimavanserin
As mentioned before, pimavanserin is primarily recognized as a potent 5-HT2A receptor
antagonist/inverse agonist, which exhibits interactions with 5-HT2C receptor with approximately
40-fold less potency and has no dopaminergic, adrenergic, histaminergic, or muscarinic affinity
[52]. Pimavanserin was approved by the US Food and Drug Administration (FDA) in April 2016
for treating hallucinations and delusions in PDP. Its efficacy was established in a randomized,
placebo-controlled phase 3 trial, conducted on 199 patients with Parkinson’s disease who
experienced hallucinations and/or delusions, for a period of 6 weeks. The study demonstrated a
significant reduction in the frequency and severity of hallucinations and delusions in PDP,
without worsening of PD motor symptoms, with complete remission seen in 14% of
pimavanserin-treated patients [57]. Iketani et al. studied the efficacy and safety of pimavanserin
compared to atypical antipsychotics for PDP. The research findings indicated that clozapine is
successful in addressing psychotic aspects of Parkinson's disease. Additionally, while the
effectiveness of pimavanserin may be less than that of clozapine, it demonstrated a favorable
profile for treating PD psychosis [58]. In a 2022 meta-analysis conducted by Mansuri et al., the
effects of pimavanserin on the treatment of Parkinson's disease psychosis were reevaluated,
encompassing four randomized controlled trials comparing the antipsychotic with a placebo [59].
The findings indicated a notable decrease in hallucinations and delusions, accompanied by a
reduced incidence of orthostatic hypotension, with no significant safety concerns identified [59].
Pimavanserin is recommended at a total daily dosage of 34 mg (17 mg twice daily) for PDP, with
adjustments needed when co-administered with a CYP450 inhibitor or inducer. The use of
pimavanserin is contraindicated in Parkinson's disease patients with severe renal or hepatic
impairment, while individuals with mild to moderate renal impairment do not require dosage
modifications. Additionally, it is believed that pimavanserin does not contribute to somnolence,
as it does not interact with histamine receptors [42], [48]. However, like other antipsychotic
medications, pimavanserin can induce QT interval prolongation and is subject to a black box
warning regarding an elevated risk of death in elderly patients with dementia [59]. The most
prevalent side effects observed in patients on pimavanserin, in comparison to placebo groups,
included peripheral edema (7%) and confusion (6%) [48].

5.2 Other pharmacological options

5.2.1 Cholinesterase inhibitors

As structural neuroimaging studies have unveiled atrophy in vital cholinergic brain structures,
accompanied by functional abnormalities in cholinergic neurotransmission in patients with PDP,
researchers have postulated that these individuals may respond positively to cholinesterase
inhibitors [60].
In an RCT, the response to rivastigmine, an inhibitor of acetylcholinesterase and
butyrylcholinesterase, was compared to placebo in 188 patients with PD and visual
hallucinations and 348 patients with nonvisual hallucinations. The results indicated a significant
reduction in psychotic symptoms, along with benefits in other neuropsychiatric symptoms and
cognition for those taking rivastigmine [61]. Despite reports indicating that donepezil may
improve psychotic symptoms in dementia with Lewy bodies, a two-year randomized controlled
trial determined that donepezil did not exhibit a prophylactic effect on the development of
psychosis in Parkinson's disease [62]. Galantamine, an acetylcholinesterase inhibitor that
enhances cholinergic nicotinic neurotransmission, exhibited no significant difference in
neuropsychiatric symptoms, including hallucinations, when compared to a placebo in a 16-week
RCT [63].
5.2.2 Antidepressants
Concerning antidepressant agents, the literature lacks substantial evidence. The potential efficacy
of these agents may be attributed to their interaction with various receptors, including the 5-
HT2A receptor, that are well-established antipsychotic targets in Parkinson's disease. Various
studies have reported a reduction in hallucinations when utilizing medications such as
amoxapine, citalopram, clomipramine, escitalopram, mianserin, mirtazapine, and venlafaxine
[64]. Moreover, in a 2017 open-label study, thirteen individuals with Parkinson's disease and
hallucinations received treatment with 10mg/d-15mg/d escitalopram. By the finalization of the
4th week of treatment, 11 out of the 13 patients showed improvement, indicating good tolerance
to escitalopram [65].

6. Conclusions

PDP is a common neuropsychiatric disorder, with symptomatology varying from minor

phenomena to complex hallucinations and delusions. Pharmacological treatment involves the use
of atypical antipsychotics, supported by findings primarily derived from smaller randomized
controlled trials. This underscores the imperative for additional data from larger and more
extended studies. Moreover, treatment options are limited due to safety concerns associated with
antipsychotics. Pimavanserin stands as the only FDA-approved medication for addressing PDP.
The effectiveness of pimavanserin at a dosage of 34 mg/day for PDP was primarily established
through a randomized, placebo-controlled clinical study. Pimavanserin appears to effectively
treat psychotic features without affecting motor functionality and without causing any major side
effects. Clozapine has obtained approval in specific European countries as an efficacious
treatment for PDP; nevertheless, its impact on blood count, coupled with the imperative of
consistent patient monitoring, makes it a less prevalent option for addressing this disorder.
Quetiapine has been utilized as an off-label treatment owing to its mechanism of action, at low
dosages; however, studies reveal inconsistencies in its performance in treating psychosis.
Although various pharmacological agents have undergone scrutiny, the absence of replication
and comprehensive investigations designates them as alternative options rather than
recommended treatments.
References:

1. Tysnes OB, Storstein A. Epidemiology of Parkinson's disease. J Neural Transm (Vienna).

2017;124(8):901-905. doi:10.1007/s00702-017-1686-y
2. Reich SG, Savitt JM. Parkinson's Disease. Med Clin North Am. 2019;103(2):337-350.
doi:10.1016/j.mcna.2018.10.014
3. Hayes MT. Parkinson's Disease and Parkinsonism. Am J Med. 2019;132(7):802-807.
doi:10.1016/j.amjmed.2019.03.001
4. Lee A, Gilbert RM. Epidemiology of Parkinson Disease. Neurol Clin. 2016;34(4):955-
965. doi:10.1016/j.ncl.2016.06.012
5. Tolosa E, Garrido A, Scholz SW, Poewe W. Challenges in the diagnosis of Parkinson's
disease. Lancet Neurol. 2021;20(5):385-397. doi:10.1016/S1474-4422(21)00030-2
6. Schapira AHV, Chaudhuri KR, Jenner P. Non-motor features of Parkinson disease
[published correction appears in Nat Rev Neurosci. 2017 Aug;18(8):509]. Nat Rev
Neurosci. 2017;18(7):435-450. doi:10.1038/nrn.2017.62
7. Martinez-Martin P, Rodriguez-Blazquez C, Forjaz MJ, et al. Neuropsychiatric symptoms
and caregiver's burden in Parkinson's disease. Parkinsonism Relat Disord.
2015;21(6):629-634. doi:10.1016/j.parkreldis.2015.03.024
8. Taddei RN, Cankaya S, Dhaliwal S, Chaudhuri KR. Management of Psychosis in
Parkinson's Disease: Emphasizing Clinical Subtypes and Pathophysiological Mechanisms
of the Condition. Parkinsons Dis. 2017;2017:3256542. doi: 10.1155/2017/3256542. Epub
2017 Sep 12. PMID: 29104810; PMCID: PMC5613459.
9. Levin J, Hasan A, Höglinger GU. Psychosis in Parkinson's disease: identification,
prevention and treatment. J Neural Transm (Vienna). 2016;123(1):45-50.
doi:10.1007/s00702-015-1400-x
10. Chendo I, Silva C, Duarte GS, Prada L, Voon V, Ferreira JJ. Frequency and
Characteristics of Psychosis in Parkinson's Disease: A Systematic Review and Meta-
Analysis. J Parkinsons Dis. 2022;12(1):85-94. doi:10.3233/JPD-212930
11. Kulick CV, Montgomery KM, Nirenberg MJ. Comprehensive identification of delusions
and olfactory, tactile, gustatory, and minor hallucinations in Parkinson's disease
psychosis. Parkinsonism Relat Disord. 2018;54:40-45.
doi:10.1016/j.parkreldis.2018.04.008
12. Omoto S, Murakami H, Shiraishi T, Bono K, Umehara T, Iguchi Y. Risk factors for
minor hallucinations in Parkinson's disease. Acta Neurol Scand. 2021;143(5):538-544.
doi:10.1111/ane.13380
13. Zhong M, Gu R, Zhu S, Bai Y, Wu Z, Jiang X, Shen B, Zhu J, Pan Y, Yan J, Zhang L.
Prevalence and Risk Factors for Minor Hallucinations in Patients with Parkinson's
Disease. Behav Neurol. 2021 Oct 4;2021:3469706. doi: 10.1155/2021/3469706. PMID:
34646400; PMCID: PMC8505047.
14. Pagonabarraga J, Martinez-Horta S, Fernández de Bobadilla R, et al. Minor
hallucinations occur in drug-naive Parkinson's disease patients, even from the premotor
phase [published correction appears in Mov Disord. 2016 Mar;31(3):433]. Mov Disord.
2016;31(1):45-52. doi:10.1002/mds.26432
15. de la Riva P, Smith K, Xie SX, Weintraub D. Course of psychiatric symptoms and global
cognition in early Parkinson disease. Neurology. 2014 Sep 16;83(12):1096-103. doi:
10.1212/WNL.0000000000000801. Epub 2014 Aug 15. PMID: 25128183; PMCID:
PMC4166362.
16. Forsaa EB, Larsen JP, Wentzel-Larsen T, et al. A 12-year population-based study of
psychosis in Parkinson disease. Arch Neurol. 2010;67(8):996-1001.
doi:10.1001/archneurol.2010.166
17. Ravina B, Marder K, Fernandez HH, et al. Diagnostic criteria for psychosis in
Parkinson's disease: report of an NINDS, NIMH work group. Mov Disord.
18. Zhang S, Ma Y. Emerging role of psychosis in Parkinson's disease: From clinical
relevance to molecular mechanisms. World J Psychiatry. 2022 Sep 19;12(9):1127-1140.
doi: 10.5498/wjp.v12.i9.1127. PMID: 36186499; PMCID: PMC9521528.
19. Segal GS, Xie SJ, Paracha SU, Grossberg GT. Psychosis in Parkinson's Disease: Current
Treatment Options and Impact on Patients and Caregivers. J Geriatr Psychiatry Neurol.
2021;34(4):274-279. doi:10.1177/08919887211018280
20. Schneider RB, Iourinets J, Richard IH. Parkinson's disease psychosis: presentation,
diagnosis and management. Neurodegener Dis Manag. 2017;7(6):365-376.
doi:10.2217/nmt-2017-0028
21. Hejazi NS. Visual Hallucinations and Impulse Control Disorder in Parkinson's Disease.
Int J Neuropsychopharmacol. 2020 Dec 10;23(10):639-641. doi: 10.1093/ijnp/pyaa045.
PMID: 32658290; PMCID: PMC7727485.
22. Kurumada K, Sugiyama A, Hirano S, Yamamoto T, Yamanaka Y, Araki N, Yakiyama
M, Yoshitake M, Kuwabara S. Pareidolia in Parkinson's Disease and Multiple System
Atrophy. Parkinsons Dis. 2021 Oct 31;2021:2704755. doi: 10.1155/2021/2704755.
PMID: 34754412; PMCID: PMC8572613.
23. Jakel R, Stacy M. Parkinson’s disease psychosis. Journal of Parkinsonism and Restless
Legs Syndrome.March 2014. 10.2147/JPRLS.S40946
24. Ffytche DH, Creese B, Politis M, Chaudhuri KR, Weintraub D, Ballard C, Aarsland D.
The psychosis spectrum in Parkinson disease. Nat Rev Neurol. 2017 Feb;13(2):81-95.
doi: 10.1038/nrneurol.2016.200. Epub 2017 Jan 20. PMID: 28106066; PMCID:
PMC5656278.
25. Zhang Y, Zhang GY, Zhu XB, Zhang ZE, Gan J, Liu ZG. Clinical Characteristics of
Minor Hallucinations in Chinese Parkinson's Disease Patients. Front Aging Neurosci.
2022;13:723405. Published 2022 Jan 20. doi:10.3389/fnagi.2021.723405
26. Dotchin CL, Jusabani A, Walker RW. Non-motor symptoms in a prevalent population
with Parkinson's disease in Tanzania. Parkinsonism Relat Disord. 2009;15(6):457-460.
doi:10.1016/j.parkreldis.2008.11.013
27. Goetz CG, Pappert EJ, Blasucci LM, et al. Intravenous levodopa in hallucinating
Parkinson's disease patients: high-dose challenge does not precipitate hallucinations.
Neurology. 1998;50(2):515-517. doi:10.1212/wnl.50.2.515
28. Lenka A, Arumugham SS, Christopher R, Pal PK. Genetic substrates of psychosis in
patients with Parkinson's disease: A critical review. J Neurol Sci. 2016;364:33-41.
doi:10.1016/j.jns.2016.03.005
29. Samudra N, Patel N, Womack KB, Khemani P, Chitnis S. Psychosis in Parkinson
Disease: A Review of Etiology, Phenomenology, and Management. Drugs Aging. 2016
Dec;33(12):855-863. doi: 10.1007/s40266-016-0416-8. PMID: 27830568; PMCID:
PMC6760850.
30. Factor SA, McDonald WM, Goldstein FC. The role of neurotransmitters in the
development of Parkinson's disease-related psychosis. Eur J Neurol. 2017;24(10):1244-
1254. doi:10.1111/ene.13376
31. Lenka A, Jhunjhunwala KR, Saini J, Pal PK. Structural and functional neuroimaging in
patients with Parkinson's disease and visual hallucinations: A critical review.
Parkinsonism Relat Disord. 2015;21(7):683-691. doi:10.1016/j.parkreldis.2015.04.005
32. Yao N, Cheung C, Pang S, et al. Multimodal MRI of the hippocampus in Parkinson's
disease with visual hallucinations. Brain Struct Funct. 2016;221(1):287-300.
doi:10.1007/s00429-014-0907-5
33. Lenka A, Ingalhalikar M, Shah A, Saini J, Arumugham SS, Hegde S, George L, Yadav
R, Pal PK. Abnormalities in the white matter tracts in patients with Parkinson disease and
psychosis. Neurology. 2020 May 5;94(18):e1876-e1884. doi:
10.1212/WNL.0000000000009363. Epub 2020 Apr 21. PMID: 32317347; PMCID:
PMC7613151.
34. Huang X, Gilbert GJ. Psychosis in Parkinson disease: White matter matters. Neurology.
2020;94(18):767-768. doi:10.1212/WNL.0000000000009368
35. Munhoz RP, Teive HA, Eleftherohorinou H, Coin LJ, Lees AJ, Silveira-Moriyama L.
Demographic and motor features associated with the occurrence of neuropsychiatric and
sleep complications of Parkinson's disease. J Neurol Neurosurg Psychiatry.
2013;84(8):883-887. doi:10.1136/jnnp-2012-304440
36. Sawada H, Oeda T, Yamamoto K, et al. Trigger medications and patient-related risk
factors for Parkinson disease psychosis requiring anti-psychotic drugs: a retrospective
cohort study. BMC Neurol. 2013;13:145. Published 2013 Oct 12. doi:10.1186/1471-
2377-13-145
37. Factor SA, Scullin MK, Sollinger AB, et al. Cognitive correlates of hallucinations and
delusions in Parkinson's disease. J Neurol Sci. 2014;347(1-2):316-321. doi:
38. Lenka A, Hegde S, Jhunjhunwala KR, Pal PK. Interactions of visual hallucinations, rapid
eye movement sleep behavior disorder and cognitive impairment in Parkinson's disease:
A review. Parkinsonism Relat Disord. 2016;22:1-8. doi:10.1016/j.parkreldis.2015.11.018
39. Ffytche DH, Pereira JB, Ballard C, Chaudhuri KR, Weintraub D, Aarsland D. Risk
factors for early psychosis in PD: insights from the Parkinson's Progression Markers
 Initiative. J Neurol Neurosurg Psychiatry. 2017;88(4):325-331. doi:10.1136/jnnp-2016-
314832
40. Zhu K, Kangdi, et al. "Risk factors for hallucinations in Parkinson's disease: results from
a large prospective cohort study." Movement Disorders 28.6 (2013): 755-762.
41. Weintraub D, Aarsland D, Biundo R, Dobkin R, Goldman J, Lewis S. Management of
psychiatric and cognitive complications in Parkinson's disease. BMJ. 2022;379:e068718.
Published 2022 Oct 24. doi:10.1136/bmj-2021-068718
42. Isaacson SH, Citrome L. Hallucinations and delusions associated with Parkinson's
disease psychosis: safety of current treatments and future directions. Expert Opin Drug
Saf. 2022;21(7):873-879. doi:10.1080/14740338.2022.2069240
43. Broadstock M, Ballard C, Corbett A. Novel pharmaceuticals in the treatment of psychosis
in Parkinson's disease. Expert Rev Clin Pharmacol. 2014;7(6):779-786.
doi:10.1586/17512433.2014.966814
44. Jethwa KD, Onalaja OA. Antipsychotics for the management of psychosis in Parkinson's
disease: systematic review and meta-analysis. BJPsych Open. 2015;1(1):27-33. Published
2015 Jul 24. doi:10.1192/bjpo.bp.115.000927
45. Kashihara K, Maeda T, Yoshida K. Safety and tolerability of aripiprazole in patients with
psychosis associated with Parkinson's disease-Results of a multicenter open trial.
Neuropsychopharmacol Rep. 2022 Jun;42(2):135-141. doi: 10.1002/npr2.12235. Epub
2022 Feb 28. PMID: 35226404; PMCID: PMC9216359.
46. Younce JR, Davis AA, Black KJ. A Systematic Review and Case Series of Ziprasidone
for Psychosis in Parkinson's Disease. J Parkinsons Dis. 2019;9(1):63-71. doi:
10.3233/JPD-181448. PMID: 30475775; PMCID: PMC6398550.
47. Jethwa KD, Onalaja OA. Antipsychotics for the management of psychosis in Parkinson's
disease: systematic review and meta-analysis. BJPsych Open. 2015;1(1):27-33. Published
2015 Jul 24. doi:10.1192/bjpo.bp.115.000927
48. Patel RS, Bhela J, Tahir M, Pisati SR, Hossain S. Pimavanserin in Parkinson's Disease-
induced Psychosis: A Literature Review. Cureus. 2019 Jul 28;11(7):e5257. doi:
10.7759/cureus.5257. PMID: 31572642; PMCID: PMC6760879.
49. Desmarais P, Massoud F, Filion J, Nguyen QD, Bajsarowicz P. Quetiapine for Psychosis
in Parkinson Disease and Neurodegenerative Parkinsonian Disorders: A Systematic
 Review. J Geriatr Psychiatry Neurol. 2016;29(4):227-236.
doi:10.1177/0891988716640378
50. Rajagopalan K, Rashid N, Doshi D. Patients treated with pimavanserin or quetiapine for
Parkinson's disease psychosis: analysis of health resource utilization patterns among
Medicare beneficiaries. J Med Econ. 2023;26(1):769-776.
doi:10.1080/13696998.2023.2220597
51. Goldman JG, Holden S. Treatment of psychosis and dementia in Parkinson's disease.
Curr Treat Options Neurol. 2014 Mar;16(3):281. doi: 10.1007/s11940-013-0281-2.
PMID: 24464490; PMCID: PMC3994190.
52. Zhang H, Wang L, Fan Y, et al. Atypical antipsychotics for Parkinson's disease
psychosis: a systematic review and meta-analysis. Neuropsychiatr Dis Treat.
2019;15:2137-2149. Published 2019 Jul 29. doi:10.2147/NDT.S201029
53. Friedman JH. Clozapine Is Severely Underused in Parkinson's Disease Patients. Mov
Disord Clin Pract. 2022 Oct 23;9(8):1021-1024. doi: 10.1002/mdc3.13582. PMID:
36339313; PMCID: PMC9631840.
54. Parkinson Study Group. Low-dose clozapine for the treatment of drug-induced psychosis
in Parkinson's disease. N Engl J Med. 1999 Mar 11;340(10):757-63. doi:
10.1056/NEJM199903113401003. PMID: 10072410.
55. Pollak P, Tison F, Rascol O, et al. Clozapine in drug induced psychosis in Parkinson's
disease: a randomised placebo controlled study with open follow up. J Neurol Neurosurg
Psychiatr 2004;75:689–695.
56. Friedman JH. Pharmacological interventions for psychosis in Parkinson's disease
patients. Expert Opin Pharmacother. 2018;19(5):499-505.
doi:10.1080/14656566.2018.1445721
57. Heim B, Peball M, Krismer F, Djamshidian A, Seppi K. Pimavanserin: A Truly Effective
Treatment for Parkinson's Disease Psychosis? A Review of Interventions. Neuropsychiatr
Dis Treat. 2023 May 30;19:1303-1312. doi: 10.2147/NDT.S371641. PMID: 37274140;
PMCID: PMC10239266.
58. Iketani R, Furushima D, Imai S, Yamada H. Efficacy and safety of atypical
antipsychotics for psychosis in Parkinson's disease: A systematic review and Bayesian
 network meta-analysis. Parkinsonism Relat Disord. 2020;78:82-90.
doi:10.1016/j.parkreld
59. Mansuri Z, Reddy A, Vadukapuram R, Trivedi C, Amara A. Pimavanserin in the
Treatment of Parkinson's Disease Psychosis: Meta-analysis and Meta-regression of
Randomized Clinical Trials. Innov Clin Neurosci. 2022;19(1-3):46-51.
60. Powell A, Matar E, Lewis SJG. Treating hallucinations in Parkinson's disease. Expert
Rev Neurother. 2022;22(6):455-468. doi:10.1080/14737175.2021.1851198
61. Burn D, Emre M, McKeith I, et al. Effects of rivastigmine in patients with and without
visual hallucinations in dementia associated with Parkinson's disease. Mov Disord.
2006;21(11):1899-1907. doi:10.1002/mds.21077
62. Sawada H, Oeda T, Kohsaka M, et al. Early use of donepezil against psychosis and
cognitive decline in Parkinson's disease: a randomised controlled trial for 2 years. J
Neurol Neurosurg Psychiatry. 2018;89(12):1332-1340. doi:10.1136/jnnp-2018-318107
63. Grace J, Amick MM, Friedman JH. A double-blind comparison of galantamine
hydrobromide ER and placebo in Parkinson disease. J Neurol Neurosurg Psychiatry.
2009;80(1):18-23. doi:10.1136/jnnp.2008.144048
64. Sid-Otmane L, Huot P, Panisset M. Effect of Antidepressants on Psychotic Symptoms in
Parkinson Disease: A Review of Case Reports and Case Series. Clin Neuropharmacol.
2020;43(3):61-65. doi:10.1097/WNF.0000000000000384
65. Bergman. "Successful Use of Escitalopram for the Treatment of Visual Hallucinations in
Patients With Parkinson Disease," 2017.