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The psychosis spectrum in


Parkinson disease
Dominic H. ffytche1,2, Byron Creese1,3, Marios Politis1,4, K. Ray Chaudhuri1,5,
Daniel Weintraub1,6,7, Clive Ballard1,3 and Dag Aarsland1,2
Abstract | In 2007, the clinical and research profile of illusions, hallucinations, delusions and
related symptoms in Parkinson disease (PD) was raised with the publication of a consensus
definition of PD psychosis. Symptoms that were previously deemed benign and clinically
insignificant were incorporated into a continuum of severity, leading to the rapid expansion of
literature focusing on clinical aspects, mechanisms and treatment. Here, we review this literature
and the evolving view of PD psychosis. Key topics include the prospective risk of dementia in
individuals with PD psychosis, and the causal and modifying effects of PD medication. We discuss
recent developments, including recognition of an increase in the prevalence of psychosis with
disease duration, addition of new visual symptoms to the psychosis continuum, and identification
of frontal executive, visual perceptual and memory dysfunction at different disease stages. In
addition, we highlight novel risk factors for example, autonomic dysfunction that have
emerged from prospective studies, structural MRI evidence of frontal, parietal, occipital and
hippocampal involvement, and approval of pimavanserin for the treatment of PD psychosis.
The accumulating evidence raises novel questions and directions for future research to explore the
clinical management and biomarker potential of PD psychosis.

In 2007, consensus recommendations from an interna- of representing distinct symptom classes, the various
tional work group redefined the landscape of psychosis phenomena formed a continuum progressing over the
in Parkinson disease (PD)1. Symptoms of psychosis, such course of PD. The typical clinical scenario was of minor
as illusions, hallucinations and delusions, are collectively phenomena evolving to formed visual hallucinations,
referred to as positive, carrying the implication of an with insight initially preserved but lost in later stages,
excess of function or brain activity, in contrast with neg- and with delusions and non-visual for example, audi-
ative symptoms of deficit. Though all long recognized as tory, tactile and olfactory hallucinations also devel-
nonmotor manifestations of PD, positive symptoms such oping (BOX1). This spectrum of positive symptoms was
as illusions, hallucinations and delusions were tradition- termed PD psychosis, and the proposed diagnostic cri-
ally considered to be distinct from one another, with dif- teria included the chronology of symptoms (occurrence
ferent clinical implications. In particular, hallucinations after the onset of PD) and symptom duration (recur-
of a person, animal or indefinite object passing through rent or continuous for 1month). The NINDSNIMH
the peripheral visual field (passage hallucinations), recommendations led to a paradigmatic shift in focus
misperception of actual stimuli (illusions) and a distinct from individual positive symptoms to a symptom con-
class of perceptual experiences without visual content but tinuum, which was further characterized in a series of
a feeling of someone present (presence hallucinations) landmark reviews published in the years that followed28.
1
KCL-PARCOG group, were not thought to carry the same clinical significance These reviews benchmarked knowledge of PD psycho-
Institute of Psychiatry, as formed visual hallucinations of animals, objects or fig- sis in terms of its phenomenology, prevalence, clinical
Psychology & Neuroscience,
ures. This distinction was reflected in the terminology, implications, mechanisms, treatment and future research
Kings College London,
De Crespigny Park, whereby illusions and passage and presence hallucina- directions, and led to a rapidly expanding literature. In
London SE5 8AF, UK. tions were described as benign or minor hallucinations. this Review, we reflect on the advances that have been
Correspondence to D.H.f. After reviewing the available evidence, the com- made in the 10years since the publication of the con-
dominic.ffytche@kcl.ac.uk bined National Institute of Neurological Disorders sensus work group criteria, highlighting key research
doi:10.1038/nrneurol.2016.200 and Stroke (NINDS) and National Institute of Mental findings and directions in PD psychosis, and their impli-
Published online 20 Jan 2017 Health (NIMH) work group concluded that instead cations for clinical practice and the neuroscience of PD.

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Key points seen as an unformed visual shadow or mist in up to one-


third of cases, may or may not be recognizable, and can
Parkinson disease (PD) psychosis refers to a spectrum of illusions, hallucinations and be a persistent or recurrent experience of someone who
delusions that occur throughout the disease course has just left the room (palinparousia)11. An online ques-
Evolving literature highlights the importance of recognizing and treating PD tionnaire administered to individuals with PD suggested
psychosis, and understanding its role as a clinical biomarker of disease stage, an overall prevalence of 50% for presence and passage
distribution and future progression hallucinations (extracampine hallucinations was used as
Current evidence points to PD psychosis as a set of symptoms with distinct a collective term for both experiences, although this dif-
pathophysiological mechanisms, as opposed to a single pathophysiological symptom fers from its classic usage), with individual prevalences
with a spectrum of severity
of 25% for presence hallucinations and 46% for passage
The relationship between neuropathology in PD psychosis and invivo measures of hallucinations12. Studies of formed hallucinations in PD
reduced metabolism, functional MRI alterations and cortical volume loss remains
have found an association between the cognitive pro-
unclear
file and the type of hallucination experienced13: patients
Further studies are needed to explore the role of PD medication in unmasking
with PD whose typical hallucinations are of unfamiliar
psychosis symptoms, why psychosis symptoms predict worse cognitive outcome,
comparisons of psychosis symptoms and mechanisms in different clinical conditions,
content (for example, unidentified figures) have more-
and development of novel treatments profound deficits of inhibitory executive function than
do patients with hallucinations that are recognized (for
example, family members). Additional visual symptoms
Phenomenology and diagnosis that are observed in the early stages of PD and might
As described by the NINDSNIMH consensus work be considered to belong to the psychosis spectrum are
group1, symptoms of the psychosis spectrum in early listed in TABLE1.
stages of PD include minor experiences, such as passage
and presence hallucinations, illusions, and formed hal- Later PD psychosis symptoms
lucinations most commonly, recurring visual halluci- As PD progresses, hallucinations in non-visual (audi-
nations of people, animals or inanimate objects with tory, tactile and olfactory) modalities occur alongside
insight preserved (BOX1). In later PD stages, delusions visual hallucinations. In one cohort of PD patients with-
and hallucinations occur in other modalities, for exam- out hallucinations at baseline, 60% were experiencing
ple, auditory hallucinations consisting of a voice that hallucinations in multiple sensory modalities by 10years
may not be comprehensible9, or non-verbal sounds, such of follow-up14,15. These non-visual hallucinations are
as steps or music10. The hallucinations tend to occur in not confined to end-stage PD dementia; they are also
conditions of low ambient stimulation, typically when found in patients whose cognition is relatively intact
the individual is alone in a quiet environment, are expe- (Mini-Mental State Examination (MMSE) score 24 or
rienced several times a day, and last for seconds to min- 25)16,17.
utes in the early stages of PD psychosis. Evidence that One study has estimated the prevalence of delusions
has emerged since the publication of the consensus work in a PD clinical setting at 16%18, rising to 47% in the
group recommendations has helped to further charac- subset of patients with PD psychosis18. Of note, an earlier
terize the phenomenology of different PD psychosis study of patients with PD psychosis taking part in a
stages, and their relationship with the progression of clinical trial indicated an even higher prevalence of
Lewy body pathology (BOX2). delusions (76%)16. The delusional themes that are iden-
tified depend on the assessment instruments used, but
Early PD psychosis symptoms they typically encompass sin or guilt, grandiosity, refer-
According to a report on the largest series of PD patients ence, religion, persecution, jealousy, and theft, without
with presence hallucinations to date, the presence is prominence of any specific theme16. Delusional mis
identification syndromes, a specific subset of delusions
characterized by pathological familiarity, include the
Author addresses Capgras delusion (the belief that someone familiar has
been replaced by an imposter), reduplicative paramnesia
2
Department of Old Age Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, (the belief that a room or place has been duplicated and
Kings College London, UK. De Crespigny Park, London SE5 8AF, UK. is present at two locations simultaneously) and the mir-
3
University of Exeter Medical School, University of Exeter, EX1 2LU, UK. ror sign (failure to recognize oneself in the mirror)19,20.
4
Neurodegeneration Imaging Group, Maurice Wohl Clinical Neuroscience Institute,
In patients who have dementia with Lewy bodies (DLB),
Institute of Psychiatry, Psychology & Neuroscience, Kings College London,
125 Coldharbour Lane, London SE5 9NU, UK. the prevalence of misidentification syndromes was
5
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience found to increase with greater cognitive decline (40% for
Institute, National Parkinson Foundation Centre of Excellence, Kings College London/ MMSE score >20 compared with 60% for MMSE score
Kings College Hospital, 5 Cutcombe Road, London SE5 9RT, UK. <10)21. A similar trend was observed in individuals with
6
Departments of Psychiatry and Neurology, Perelman School of Medicine at the AD, although the prevalence was lower overall (18%
University of Pennsylvania 3615 Chestnut Street, #330, Philadelphia, for MMSE score >20 and 28% for MMSE score <10). A
Pennsylvania 19104, USA. smaller-scale study of patients with PD dementia found
7
Parkinsons Disease and Mental Illness Research, Education and Clinical Centres a 16.7% prevalence of misidentification symptoms, and
(PADRECC and MIRECC), Philadelphia Veterans Affairs Medical Centre 3900 Woodland also noted an association between these symptoms and a
Avenue, Philadelphia, Pennsylvania 19104, USA.
specific profile of memory and language deficits20.

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Box 1 | The psychosis spectrum in Parkinson disease Frequency and clinical consequences
As concluded by the NINDSNIMH psychosis work
Positive symptoms in Parkinson disease (PD) vary across its course. Early in the disease, group and related reviews, psychosis spectrum symp-
symptoms experienced include passage hallucinations (where a person, animal or toms are common in PD and have important clinical
indefinite object is seen briefly passing in the peripheral visual field), illusions (for consequences, in particular, an increased risk of demen-
example, seeing the branch of a tree as a cat), and presence hallucinations (a feeling that
tia, nursing home placement and mortality. Quality
someone is nearby). Pareidolia refers to a specific class of illusion where faces and objects
are seen in formless visual stimuli, such as clouds, flames or tree bark, or in geometric of life is also impaired, both overall and in subdomains of
visual patterns, such as carpets or wallpaper. This type of illusion can occur as a normal emotional well-being, daily living, cognition and bodily
perceptual experience, but is increased in frequency in PD159 and related disorders such discomfort26. Recent studies have provided revised prev-
as dementia with Lewy bodies. alence estimates for PD psychosis based on longitudinal
Later in PD, formed visual hallucinations, typically of animals or people, occur. Insight study data, and have better characterized the link to poor
that is, recognition that the experiences are hallucinations is preserved at this cognitive outcome.
stage, but becomes lost as PD progresses, with the onset of false beliefs (delusions) and
hallucinations in other sensory modalities (multimodality hallucinations). Cognitive Prevalence
decline and loss of insight parallel symptom progression, as illustrated by the transition In early cross-sectional studies, the prevalence of the
in the arrow on the left from dark shading (cognition/insight intact) to light shading
psychosis spectrum varied depending on which symp-
(cognition/insight impaired).
Approximate ratings of the Movement Disorder Society United PD Rating Scale toms were included, and which PD population was
(MDS-UPDRS) hallucination/psychosis item are shown on the right of the figure, marking studied. For example, estimates of complex visual hallu-
progression through different categories of experience on the continuum. The terms cinations ranged from 2238%, compared with 022%
pseudohallucination and hallucinosis are used as synonyms for hallucinations with for auditory hallucinations 3. Prevalence estimates
insight in some psychiatric and neurological traditions, but also have other meanings and from older studies that excluded minor hallucinations
were not adopted by the NINDSNIMH work group1. required revision after the publication of the consen-
sus guidelines27. According to the latest figures, minor
MDS- phenomena are reported in 42% of patients with very
UPDRS
early disease28, although this high estimate could reflect
Diplopia
Minor recall bias29. In a large-scale study (n=250) that excluded
illusions Passage 1 patients with MMSE scores 23, the prevalence of PD
Illusions psychosis was 26%30.
Presence Longitudinal studies conducted in the wake of the
consensus guidelines have established that the prev-
Insight/cognition

alence of the psychosis spectrum is time dependent,


increasing with the duration of PD3,3133. In a study that
Hallucinations 2
with insight used detailed phenomenological interviews31, 82.7% of
patients experienced psychosis spectrum symptoms over
a period of 36months. In another study, which excluded
minor hallucinations, 60% of patients had experienced
Hallucinations psychosis spectrum symptoms by the end of a 12year
3
without insight followup period33. The Parkinsons Progression Markers
Initiative (PPMI) reported an increase in the prevalence
of psychosis from 3% around the time of PD diagnosis
to 10% at 2years follow-up32.
Delusions 4
Risk of cognitive decline
An association between visual hallucinations and the
Nature Reviews | Neurology subsequent emergence of dementia was first reported
Assessment scales in 2003 (REF.34). Patients who reported previous visual
Several scales to measure positive symptoms were hallucinations at study entry had an increased risk of
available in 2007 (REF.22), but none were specifically dementia at 8years (OR3.1, 95%CI 1.66.2). This
designed for use in PD. As a result, many of the studies association has been replicated in several recent studies
reviewed here used a definition of psychosis spectrum of shorter followup duration. One study35 found that
status that was based on a single question item within visual hallucinations and visual illusions at baseline had
the Movement Disorder Society United PD Rating Scale separate predictive effects for dementia at ~4years, and
(MDS-UPDRS), with a range of 04 (BOX1). New scales another study36 found that the longitudinal emergence
have emerged to better capture the diversity of symp- of visual hallucinations that is, emergence across the
toms and for use in clinical trials, including the North- duration of the study increased the risk of dementia at
East Visual Hallucinations Interview (NEVHI)23 and a ~6years. The PRIAMO study of early PD found a decline
shortened version of the Scale for Assessment of Positive in cognitive function at 2years in patients with psychosis
Symptoms adapted for PD (SAPSPD)24. A test to meas- spectrum symptoms37. The detailed profile of cognitive
ure susceptibility to pareidolia has been developed for decline over 12years has been reported in prospective
DLB25, and might also have a role in the assessment of cohorts defined at baseline by the presence or absence
early symptoms of PD psychosis. of visual hallucinations38,39. A significant grouptime

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Box 2 | Psychosis spectrum progression and Braak stage Psychosis spectrum symptoms are not the sole predic-
tors of future cognitive decline in PD: a range of factors
The fact that illusions, passage and presence hallucinations progress to formed visual have been identified, the interrelationship of which has
hallucinations in Parkinson disease (PD) need not imply that they all have the same yet to be clarified. According to multivariate analyses34,36,
underlying mechanism. Evidence has emerged that minor hallucinations and formed visual hallucinations are independent of other factors,
visual hallucinations are associated with different sets of risk factors. For example,
but their predicitive statistical significance is reduced
presence hallucinations have been linked to sleep regulation and somnolence scores,
illusions are related to somnolence and motor severity scores160, and neurobiological when cognitive measures are included36, suggesting that
explanations of passage hallucinations implicate dysfunctional brainstem eye movement cognition and visual hallucinations are closely related.
control mechanisms and subcortical and cortical motion pathways, including dorsal
stream areas in the visual parietal lobe105,161. Previous studies of visual hallucinations have Association with motor subtypes
linked visual parietal areas to hallucinations in the peripheral visual field162 (as described Exploratory and confirmatory cluster analysis of a large
for passage hallucinations) and palinopsia (helping to account for palinparousia PD data set revealed associations between non-tremor-
recently decribed palinopsia-like presence hallucinations11), and subregions of the dominant PD and psychopathology, including hallu-
intraparietal sulcus are linked to eye movement control163. By contrast, formed visual cinations and cognitive impairment41. The association
hallucinations are associated with changes in cognition, visual function and affect160, between clinically defined non-tremor subtypes and
probably reflecting cortical involvement in ventral occipitotemporal lobe regions162. The
dementia, but not the association with hallucinations,
onset of minor hallucinations might even precede the development of motor symptoms28.
The difference in timing of and risk factors for minor hallucinations and formed visual was replicated in a subsequent study42. This discrepancy
hallucinations mirrors the Braak progression of Lewy body pathology from brainstem to between studies might be attributable to differences in
forebrain systems systems164. This observation suggests that symptom progression along methodology.
the PD psychosis continuum begins with isolated minor experiences, indicating
brainstem pathology (pink shading in figure) and its wider impact on subcortical and Mechanisms and risk factors
cortical motion and eye movement control networks, including the visual parietal lobe A range of possible mechanisms to explain the psychosis
(arrows note that dysfunction within these cortical networks does not necessarily spectrum, including changes in visual function, sleep,
imply cortical Lewy body pathology (BOX4)). Subsequent emergence of visual medication effects and cognition, were identified by
hallucinations with insight indicates basal forebrain involvement (orange shading) and its the NINDSNIMH work group and in related reviews,
wider impact on cortical cholinergic projections (arrows), in particular, projections to the
with unifying models being presented to summarize the
ventral occipitotemporal cortex. Finally, multimodality hallucinations, delusions and loss
of insight indicate widespread cortical Lewy body pathology. proposed interrelationship between these mechanisms13.

The eye and low-level vision


The predominantly visual nature of PD psychosis spec-
trum symptoms points to dysfunction in the visual
system, and early studies focused on low-level deficits in
colour vision, contrast sensitivity and acuity (reviewed
elsewhere2). More recently, evidence has emerged of
retinal changes in PD, as measured by techniques such
as ocular coherence tomography (OCT) and electro
retinography43; however, to date, only one study using
such techniques has investigated the retinal associations
of the PD psychosis spectrum. In patients with visual
hallucinations, OCT revealed thinning of the retinal
ganglion cell layer in the dominant eye at both nasal and
Diplopia temporal retinal locations44. Such thinning could be the
Illusions result of a primary process within the eye, or could be
secondary to retrograde trans-synaptic degeneration
caused by changes in the brain. Thinning was more
pronounced in PD psychosis patients without dementia
Passage (as measured by MMSE score), pointing to a primary
process within the eye.

Presence Visual perception and cognition


Early studies of the psychosis spectrum focused on
visual hallucinations, and included patients with a
range of severity of what might now be termed PDMCI.
Nature Reviews | Neurology More-recent studies have concentrated on differences in
interaction was found, with a steeper decline across a cognitive profiles for specific symptom subtypes, and the
range of cognitive domains and an increased risk of cognitive profile of the psychosis spectrum at different
dementia at followup in patients with visual hallucina- stages of global cognitive impairment. TABLE2 shows a
tions. A recent metabolic imaging study of PDassociated range of cognitive tests that have been repeated in dif-
mild cognitive impairment (PDMCI) has also found ferent studies, although the same version of a given test
elevated rates of dementia at 30month followup in is rarely used by different groups. Most studies inves-
patients with visual hallucinations40. tigating visual perception, irrespective of the selection

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Table 1 | Symptoms related to the PD psychosis spectrum


Symptom Phenomenology Association with psychosis spectrum
Isolated diplopia 179
Image doubling related to an isolated object or May precede the onset of visual
figure as opposed to the whole scene in hallucinations by 23years
the visual environment
Freezing180 Walking cessation when passing through Associated with passage hallucinations in
narrow spaces PD without cognitive impairment
Spatial misjudgement180 Difficulty estimating distance of objects when Associated with presence and passage
walking hallucinations
PD, Parkinson disease.

criteria (for example, unselected PDMCI cohorts ver- significant differences46,49 (although see Katzen etal.50
sus participants selected for higher cognitive function) for evidence of deficits on the Benton test). The lack of
have shown deficits in the perception of objects, includ- consistent findings could be a test sensitivity issue, as
ing faces. Similarly, most studies investigating executive other measures of visuospatial function for example,
function, as measured by the Stroop task, response inhi- the Visual Object and Space Perception (VOSP) number
bition and verbal fluency, have found deficits in patients location subtest47,51 have been shown to differ between
with visual hallucinations. patients with and without visual hallucinations. Tests
Deficits in memory and related hippocampal func- examining motion, spatiotemporal aspects of visual per-
tion tests are found in PD patients with visual hallucina- ception, and eye movements in the PD psychosis spec-
tions, in both unselected PDMCI and higher-function trum have not been reported to date, but are of particular
groups. These deficits withstand correction for MMSE relevance given the hypothesized role of dysfunctional
score, depression and PD stage45. Some studies have motion perception and eye movement control in passage
reported deficits that are specific to visual as opposed and presence hallucinations.
to verbal memory46. Greater memory deficits have
also been found for black-and-white visual stimuli Minor hallucinations. Only one study has focused on
than for coloured visual stimuli, perhaps reflecting the cognitive profile associated with minor hallucina-
more-limited encoding of visually impoverished stimuli tions in PD52. Compared with patients without psychosis
in patients with visual hallucinations47. A transitive infer- spectrum symptoms, patients with minor hallucinations
ence test thought to measure hippocampal function has had no significant differences in verbal memory, verbal
uncovered impairments in patients with PD psychosis48. fluency or sustained attention. Progressive decreases in
TABLE2 helps to illustrate agreement between studies cognitive performance were seen across the spectrum
regarding cognitive functions that are deficient, but it from no hallucinations, through minor hallucinations
does not reveal whether some cognitive functions show and hallucinations with insight, to hallucinations with-
relative sparing. Tests purporting to measure visuospa- out insight. The lack of cognitive deficits in patients
tial function, such as the Benton judgement of line orien- with minor hallucinations raises the issue of whether
tation and the Rey complex figure test, are often included the onset of psychosis spectrum symptoms predates
in test batteries for PD psychosis, but tend not to show measurable cognitive decline.

Table 2 | Visual and cognitive deficits in the PD psychosis spectrum


Domain Subdomain or task Significant deficit associated with PD Minor hallucinations
psychosis spectrum
Unselected PDMCI MMSE score >25
Visual perception Object Yes 51,55,181
Yes47,55
Face Yes 45

Spatial Yes47,51
Executive function Stroop Yes 46,49,182,183
Yes 13

Gonogo Yes46,182 Yes13
Verbal fluency Yes45,49,182184; No50 Yes13 No52
Attention Yes 51,181
No52
Memory Visual Yes45,46,49 Yes47
Verbal Yes 45,49,184
; No 50
No52
Yes and No refer to presence and absence, respectively, of significant deficit reported in studies cited; indicates test not
performed. In most studies, PD psychosis spectrum was defined by the presence of visual hallucinations. Studies that pooled
ztransformed scores from a range of tests into a single domain summary (for example, Goldman etal.101) are not included, as
individual test scores were lost. Studies using evidence from items within global assessment scales such as MOCA (for example,
Chung etal.185) or SCOPA-COG (for example, Gallagher etal.55) are also excluded. MCI, mild cognitive impairment; MMSE,
Mini-Mental State Examination; PD, Parkinson disease.

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Multimodal hallucinations. One might expect patients involvement, a recent study has found no association
with non-visual hallucinations in the later stages of PD between Lewy body, tau or amyloid pathology in fron-
to exhibit greater cognitive deficits or a different cogni- tal, parietal and temporal regions and visual hallucina-
tive profile compared with PD patients with visual hal- tions after controlling for dementia, but found strong
lucinations alone. However, one study that compared associations with dementia after controlling for visual
patients with visual only and visual plus non-visual hallucinations58. Such findings suggest that the neuro-
hallucinations50 found no evidence of significant addi- pathological changes underlying visual hallucinations
tional decline in the latter group for any of the cognitive are distinct from those underlying dementia.
domains tested (including verbal memory and verbal Involvement of the cholinergic system in visual
fluency). The number of patients with hallucinations hallucinations is suggested by brainstem atrophy in the
in multiple modalities was small (n=12), so the study pedunculopontine nucleus60 and atrophy of the sub-
might have been underpowered to detect such changes. stantia innominata, which contains the nucleus basalis
of Meynert46. The cause of the atrophy is unclear, as no
Delusions. Only one study has compared cognitive pro- association has been found between visual hallucina-
files between PD psychosis spectrum patients with hal- tions and Lewy body, tau or amyloid load in the nucleus
lucinations but not delusions and those with delusions basalis of Meynert58.
but not hallucinations18. Cognitive profiles did not differ
significantly between the two groups. Cognitive scores Non-cognitive risk factors
in a range of domains were found to correlate with the Patients with visual hallucinations exhibit abnor-
severity and number of hallucination modalities (for malities on a range of autonomic tests, including the
example, auditory, olfactory somatic and/or visual), but tilt-table test, the Valsalva manouevre and cardiac
not with the severity and number of delusion modali- 123
I-metaiodobenzylguanidine imaging, indicating
ties (for example, jealousy, grandiosity and/or religious sympathetic dysfunction61. In addition, autonomic dys-
delusions). These findings suggest that cognitive risk fac- function was found to be an independent risk factor for
tors for hallucinations and delusions might differ. This hallucinations (all modalities included) in PROPARK,
view is supported by evidence from a study investigating a large-scale 5year prospective study 62. The same
risk factors for a specific delusion (delusional jealousy), study also reported female sex as an independent risk
where an association was found with dopamine agonist factor62. REM sleep behaviour disorder (RBD) is also
treatment but not dementia, in contrast to hallucina- associated with visual hallucinations (recently reviewed
tions, where an association was found with dementia elsewhere63), although the association is weak64, and the
but not dopamine agonist treatment53. proportions of patients with visual hallucinations who
do and do not have RBD are similar. Vivid dreams are
Neuropathology associated with visual hallucinations after controlling
Neuropathological studies provide important insights for factors including PD duration, depression, anxiety
into the distribution of Lewy body pathology at differ- and UPDRS scores65. Depression has been associated
ent stages of the PD psychosis spectrum (BOX2). The first with hallucinations in PD2. The urinary concentration
study to report on this issue found significantly higher of the oxidative stress marker 8hydroxydeoxyguano-
Lewy body load in the amygdala and parahippocam- sine was found to correlate with the hallucination score
pal gyrus in patients with visual hallucinations, half of (modality unspecified) after controlling for MMSE
whom met the clinicopathological criteria for PD and score, age, duration and UPDRS part 3 score66.
half of whom met the criteria for DLB54. Subsequent
studies have replicated the finding of limbic pathology Dopamine agonists
associated with visual hallucinations55,56, with increased The role of medication in PD psychosis was noted to
pathology also found in other regions, including the be the most controversial aspect of these criteria in
superior and lateral frontal cortex (Brodmann area 8/9), the 2007 consensus recommendations1. Clinical expe-
inferior and lateral temporal cortex (Brodmann areas 20 rience suggested that the onset of PD psychosis could
and 21), inferior parietal cortex (Brodmann areas 39 and be linked to medication onset and improved with dose
40), and cingulate cortex (Brodmann area 24). Visual reduction, but there was no evidence of a direct causal
hallucinations are also linked to higher levels of amyloid relationship between pharmacological treatments or
and tau pathology in frontal, parietal and hippocampal medication dose and PD psychosis (for example, levo
areas57. Only one study has investigated the occipital lobe dopa infusion did not induce hallucinations67), and PD
in patients with visual hallucinations: Lewy body and psychosis was recognized to occur in unmedicated
tau pathologies were found to be absent, and amyloid patients.
burden was rated as mild58. In the intervening years, the role of medication has
Unlike patients with PD psychosis who have demen- received relatively little research attention. The lack of
tia, those without dementia do not have cortical Lewy a direct causal role for medication is supported by a
body involvement. An early study of PD patients with high prevalence of minor symptoms28 or visual hallu-
visual hallucinations and MMSE scores >25 found cinations68 in drug-naive patients, and the finding that
increased Lewy body load in the basolateral nucleus of levodopa dose equivalence did not increase the risk of
the amygdala, but only sparse Lewy bodies in the cortex psychosis in some prospective studies14,31, including
and hippocampus59. Consistent with the lack of cortical the PPMI cohort32. However, though failing to reach

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Box 3 | Genetic risk factors for psychosis in Parkinson disease Genetics


A recent review of the genetics of psychotic symptoms
GBA in PD identified 26 published articles on this topic69.
Associated with an increased risk of psychosis in three studies7880. One study including The most commonly studied genetic factor is the apoli
only two cases with hallucinations found no association165. poprotein E 4 (APOE*4) allele, although dopamin-
MAPT ergic pathway genes have been the focus of a number
Mixed findings: one positive association and one negative71,72. of studies.
APOE With regard to APOE*4, little evidence is available to
No association (in six of seven studies). The APOE*4 allele was associated with suggest an association with psychotic symptoms in PD
hallucinations within 5years of diagnosis in one study7076. (only one of seven studies reported an association with
COMT visual hallucinations)7076, a finding that is mirrored in
No association74,166. the AD literature77. The extended microtubule-associated
protein tau (MAPT) haplotype is less well studied in
SLC6A3 (also known as DAT1)
Mixed findings: two of three studies reported an association, one with the variable PD psychosis: an initial study reporting an association
number tandem repeat and one with the 839C>T polymorphism167169. between visual hallucinations and the H1 haplotype was
not replicated by a second larger study70,71. By contrast,
DRD2
an increasing body of evidence suggests that glucosylce-
Mixed findings: one of four studies reported an association73,167,168,170.
ramidase (GBA) mutations are associated with psychosis
DRD3 in PD7880. Of note, the influence of GBA is not limited to
No association73,167,168,170. psychosis: GBA, like APOE and MAPT, has been asso-
DRD4 ciated with cognition in PD, as well as faster progres-
No association73,167. sion to dementia and more-severe motor stages79,81. Any
CCK associations between psychosis and these three genes are
Mixed findings: two of four studies show evidence of an association with CCK 45C>T, perhaps most likely to be driven by fundamental dis-
and one reported a combined effect with the CCKAR CC genotype171174. ease processes, such as tau or Lewy body accumulation.
HTR2A Therefore, considering any associations with a particular
No association83. symptom in isolation would be too narrow an approach.
Specifically, it will be important to establish whether any
SLC6A4
One study reported an increased risk associated with the LL genotype in a mixed Lewy
subtypes of PD have a pattern of cognitive impairment
body dementia sample82. that is more similar to AD and carries a relatively low
risk of psychosis (which might be predicted by APOE),
ACE compared with an early dysexecutive syndrome and
Mixed findings: one study reported a significant association with levodopa-induced
greater risk of hallucinations (as indicated by the pattern
psychosis, whereas another reported no association175,176.
of association with GBA).
HOMER1 Consistent evidence links GBA, but not APOE, with
Mixed findings: one study reported an association with the A allele, and a second psychosis in PD; however, findings related to other genes
reported an association with the G allele and a reduced risk of adverse effects of
have been equivocal. Polymorphisms in dopaminer-
levodopa treatment177,178.
gic pathway genes have been examined in 15 studies
(BOX3). Although there is some evidence of a relationship
between polymorphisms in dopamine transporter and
statistical significance, a link to medication is implied cholecystokinin genes and psychosis, the overall number
in the threefold increase in psychosis onset for patients of studies examining these associations is small, making
starting dopamine replacement therapy in the PPMI it difficult to draw reliable conclusions. Research in sero
study. Similarly, a large-scale prospective study iden- tonin (5hydroxytryptamine, or 5HT) pathway genes
tified elevated baseline levodopa dose as a risk factor is limited to two studies82,83, but with the recent demon-
for PD psychosis, with an odds ratio of 1.26 per 100mg stration of efficacy of pimavanserin for the treatment of
of dose equivalence increase33, and a prospective study of PD psychosis (see below), serotonergic genes or other
early PD (PRIAMO) found increased rates of dopamine genes in serotonergic signalling pathways may provide
agonist treatment in patients who went on to develop promising avenues for future research.
PD psychosis37. The PROPARK study also identified The genetic aetiology of psychosis in PD will be
dyskinesia and levodopa equivalence measures as complex, and is likely to involve many genes each
independent risk factors for PD psychosis62. with a small effect size. As such, the most promising
The NINDSNIMH work group1 suggested anti- genetic approaches will probably be those that lever-
parkinsons medication as a modifier rather than a age genome-wide data, which has the advantage of
necessary feature for the diagnosis of PD psychosis to full genome coverage and is not constrained by biases
help reconcile the medication-related and medication- resulting from apriori hypotheses. In the broader liter-
independent viewpoints. Evidence that has since ature, recent advances in the analysis of genome-wide
emerged supports this modifier account, but highlights data sets have uncovered genetic pleiotropy between
the need for further work in this area to clarify the rela- clinically distinct diseases 84,85. Moreover, analyses
tionship between dopamine replacement therapy and whereby biological pathways (for example, molecular,
PD psychosis. cellular, organ/system or disease) are constructed on

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the basis of genomic data and tested for enrichment of Imaging and electrophysiology
single nucleotide polymorphisms in cases versus con- The raised profile of PD psychosis, combined with
trols have shown promise in late-life depression86. These developments in imaging methodology, has resulted in
types of emerging techniques have clear applications in a rapidly advancing evidence base that helps to inform
heterogeneous conditions such as PD, where questions the risk factor and mechanistic accounts of the symptom
surrounding the overlapping aetiology between psycho- spectrum.
sis across neurodegenerative diseases and psychiatric
disorders remain unanswered. The increasing availabil- Structural MRI
ity of larger, better-characterized data sets will provide Despite methodological differences, structural imaging
greater potential to conduct these more-sophisticated studies of visual hallucinations have yielded a number
genetic analyses. of consistent findings98100. Several studies have reported
atrophy in the visual cortex101103 broadly defined as
Explanatory models extending into lateral and ventral occipitotemporal
Explanatory models of PD psychosis attempt to inte- regions including the fusiform gyrus and visual pari-
grate risk factors into unifying accounts (reviewed etal cortex (corresponding to dorsal and ventral visual
elsewhere87). The ActivationInputModulation (AIM) streams) although this finding is not univeral104. One
model88 takes a dimensional approach to PD psychosis, study of PD patients with and without visual hallucina-
with contributions from an activation factor (the level tions (some patients had hallucinations in both visual
of arousal), an input factor (the spectrum of externally and other modalities), matched for cognitive status, only
and internally driven visual percepts), and a modulation detected atrophy in posterior cortical regions101, whereas
factor (neurotransmitter and medication effects). The another study of visual hallucinations, in which global
activation factor may help to explain why hallucina- cognition (MMSE score) was included as a covariate,
tions typically occur with low ambient stimulation. The found atrophy in frontal, hippocampal and thalamic
Perception and Attention Deficit (PAD) model89 argues regions46. A study focusing on minor hallucinations
that the core mechanism of complex hallucinations found atrophy in the midbrain, cerebellar vermis and
is dysfunctional integration of perceptual and atten- visual parietal cortex, as well as areas of increased cor-
tional processing, leading to the intrusion of generic tical volume in the limbic cortex and the posterior lobe
representations (proto-objects) into perceptual con- of the cerebellum, which might be linked to compensa-
sciousness. In the attentional control model90, the core tory mechanisms105. Studies that did not control specif-
pathology of PD psychosis is dysfunctional integration ically for cognition found atrophy of the hippocampal
between three networks (dorsal attention network, ven- head106, frontal regions (particularly the lateral frontal
tral attention network and default mode network), with cortex)103,107,108, cerebellum103 and lateral parietal cortex103
a failure to engage the dorsal attention network in the in patients with visual hallucinations.
context of ambiguous visual input and the intrusion The distribution of atrophy described in the various
of default mode contents into perceptual conscious- studies is consistent with the profile of cognitive deficits
ness9092. This account is supported by evidence from found in PD psychosis (FIG.1). At 30month followup,
PD patients with visual hallucinations or illusions of patients who report visual hallucinations at baseline
elevated strength of mental imagery 93, attentional have greater progression of cortical atrophy within lim-
set-shifting deficits94, altered resting state and task acti- bic, frontal and thalamic regions, and are more likely to
vation networks95, and increased functional connectiv- have developed dementia38. The greater rate of atrophy
ity in the default mode network96. A dopamine-based and hypothesized progression from hippocampal head
model of PD psychosis97 argues for abnormalities of involvement to diffuse hippocampal atrophy in patients
biasing and gating access to a global workspace that with visual hallucinations106 might account for the asso-
is thought, according to some accounts, to underlie ciation between visual hallucinations and poor cognitive
conscious experience. outcome.
These unifying models are informed by clinical Few studies have investigated white matter changes
associations for example, the combination of visual in PD psychosis. An early study found no differences
perceptual and frontal executive deficits that were with regard to a range of clinically defined white matter
recognized at the time that the models were formulated. lesion indices in patients with and without visual hallu-
As the range of risk factors increases, the question arises cinations109. A more recent volumetric study described
as to whether all risk factors are linked to the mecha- decreased white matter volume in occipital and para-
nisms underlying PD psychosis. Distinctions may need hippocampal regions103. Another study showed that the
to be drawn between associations that are integral to the microstructural integrity of deep white matter, as meas-
mechanisms of PD psychosis or its individual symptoms, ured by fractional anisotropy, was affected in PD psychosis
and syndromic associations caused by the spread of PD (defined as the presence of perceptual errors, hallucina-
pathology to neighbouring brain regions or to separate tions in any modality, or delusions). When fractional aniso
brain regions at a similar disease stage. Which associa- tropy was compared across groups as an absolute measure
tions and risk factors are integral to PD psychosis and or normalized to globus pallidus or substantia nigra val-
which are syndromic associations is unclear at present, ues, reduced fractional anisotropy was detected within
and such information will be pivotal to the development regions of interest in the occipital lobe, frontal lobe and
of novel treatment approaches. cingulate gyrus, and deep to the left hippocampal head110.

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Superior parietal101,102

Lateral parietal103 Lateral frontal46,101,103

Lateral and ventral


occipitotemporal101,103

Cerebellar103 Hippocampal46,106

Figure 1 | Regions of cortical atrophy in PD psychosis. The figure summarizes studies that have reported regions of
Nature Reviews
increased atrophy in patients with Parkinson disease (PD) psychosis (defined by visual hallucinations Neurology
in most |studies)
compared with PD controls. The results are superimposed on a lateral view of the right hemisphere. The approximate
locations of regions of atrophy identified in previous work are indicated by circles annotated by the relevant
references. The red regions indicate atrophy in our own study (ffytche, D. etal., unpublished work), in which PD patients
with visual hallucinations (n=8; mean Mini-Mental State Examination (MMSE) score 27.3) were compared with PD
controls (n=9; mean MMSE score 29.6). A lenient statistical threshold (P<0.01; 100 contiguous voxels) is used for
illustrative purposes. Lighter red shading indicates regions deep to the rendered cortical surface. These summary
findings indicate that visual hallucinations in PD are associated with widely distributed but specific regions of
cortical atrophy.

Neurotransmitter imaging the KMMSE cut-off score, the Korean version of the
Reduced dopamine transporter binding in the striatum MMSE), but were also present in patients with KMMSE
in early PD, as measured by the 123I-CIT tracer, is asso- scores above the threshold value119.
ciated with an increased prospective risk of PD psychosis In contrast to spared occipital metabolism in the
at 5years (assessed using the UPDRS thought disorder studies described above, a recent study of PDMCI has
item)111. It is unclear whether this binding reduction rep- found evidence of occipital hypometabolism in PD
resents the underlying mechanism of the psychosis spec- patients with visual hallucinations40. The hypometabo-
trum or is an indirect association, for example, reflecting lism did not differ between patients who did and did
more-extensive neurodegenerative involvement in PD not subsequently develop dementia40. Evidence also
psychosis. exists of decreased posterior perfusion in medication-
In a serotonergic imaging study that used the 5HT2A induced hallucinations (mostly visual) that would now
receptor ligand 18F-setoperone, increased binding in be termed PD psychosis, with significant reductions of
ventral occipitotemporal regions and bilateral frontal rCBF in the posterior temporo-occipital cortex but not
cortex was identified in patients with visual hallucina- in the occipital lobe120. Similarly, another study of visual
tions112. By contrast, a 5HT1A receptor binding study hallucinations in PD found trend-level posterior perfu-
in postmortem tissue found no association with visual sion deficits that spared occipital cortices121. A region
hallucinations, although 5HT1A binding was elevated of decreased perfusion outside the occipital lobe in the
in sublayers of the orbitofrontal, ventral temporal and ventral temporal cortex (fusiform gyrus) became signif-
motor cortex in patients with PD, irrespective of visual icant after controlling for confound covariates, as did a
hallucinations113. region of increased perfusion in the superior and middle
temporal gyrus121.
Metabolic and blood flow imaging In summary, consistent evidence points towards
Occipital hypometabolism and reduced regional cere- posterior changes in metabolism and perfusion in PD
bral blood flow (rCBF) are characteristics of DLB114,115, patients with visual hallucinations, but the presence or
and have been linked to visual hallucination severity116. absence of involvement of the occipital lobe remains
Whether the same regions exhibit reduced metabo- unclear.
lism and rCBF in PD psychosis is less clear. Metabolic
imaging studies of PD patients with and without visual Functional MRI
hallucinations have identified reductions in posterior There is a paucity of data on brain changes occurring in
metabolism that spare the occipital pole117 or primary PD at the time of a hallucination (capture studies). One
visual cortex (data from table in Nagano-Saito etal.118). functional MRI (fMRI) case study found a decrease in
In addition to posterior metabolic deficits, one study activity in visual areas coincident with visual halluci-
found increased frontal metabolism in PD psycho- nations122. This decrease in occipital activity contrasts
sis118. Another study found that posterior metabolic with evidence from eye disease, schizophrenia and
deficits were more pronounced in patients with visual induced visual hallucinations, which indicates that
hallucinations and cognitive impairment (defined by activity in visual areas increases at the time of visual

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hallucinations123. The PD case study also reported placebo controlled trials in patients with PD psychosis,
increased activity in the frontal lobe during the halluci- including trials of pimavanserin (a 5HT2A inverse ago-
nations122. Frontal activations are not found in eye dis- nist) and memantine that have been published since this
ease and schizophrenia during hallucinations; however, topic was last reviewed. For patients without prominent
another PD case report, in which a different technique was cognitive impairment, clozapine and pimavanserin have
used (single-photon emission CT with technetium99m the best evidence of efficacy in PD psychosis. In patients
ethyl cysteinate dimer), documented frontal and ante- with cognitive impairment and visual hallucinations,
rior temporal increases in rCBF during visual halluci- rivastigmine was found to reduce the Neuropsychiatric
nations124. Contrasting findings of occipital increases or Inventory score (predominantly the agitation compo-
decreases and the presence or absence of frontal activa- nent) in a secondary analysis, and unpublished evidence
tions across clinical contexts may suggest differences in suggests efficacy of pimavanserin in PD psychosis with
the underlying mechanisms of hallucinations. cognitive impairment. The clozapine and pimavanserin
Studies in which visual stimulation was used to probe trials have indicated a therapeutic effect specific to
cerebral activity have reported decreased activation in hallucinations as a whole but, to date, no studies have
the parietal lobe, lateral occipitotemporal cortex125 and reported a specific effect on visual hallucinations. No
occipital cortex126 in PD patients with a history of visual treatment trials targeting minor symptoms have yet been
hallucinations. An early fMRI study reported decreased reported.
activity in the primary visual cortex but increased activa-
tion in the visual association cortex127. In the frontal lobe, Atypical antipsychotics
both activation increases125 and activation decreases126,128 Evidence for the efficacy of clozapine in PD psychosis136138
have been reported in response to visual stimulation. sparked interest in the potential efficacy of quetiapine,
The contrasting findings might relate to differences in a structurally related compound. Although early studies
the stimuli and tasks used. suggested a beneficial effect of quetiapine, several subse-
Reduced occipital low frequency fluctuations have quent studies failed to replicate the findings in PD139,140
been found in the resting state in PD patients with a his- and across the spectrum of dementia with parkinsonian
tory of visual hallucinations129. These fluctuations are symptoms141. Similarly, open-label studies suggested
thought to be an indirect measure of cerebral glucose that olanzapine was efficacious for PD psychosis, but
metabolism and local field potentials, supporting the placebo-controlled142 and comparative143 trials found
idea of occipital hypometabolism in patients with PD a worsening of motor symptoms without significant
who are susceptible to visual hallucinations. Increased improvement of hallucinations. The 2011 Movement
connectivity between occipital and frontal regions, the Disorder Society evidence-based medicine review of
striatum and the thalamus129 and greater co-activation of treatments for nonmotor symptoms concluded that
default mode network nodes in the posterior cingulate/ there was insufficient evidence on the efficacy of quet-
precuneus and lateral frontal cortex are associated with iapine, and that olanzapine carried unacceptable risk135.
susceptibility to visual hallucinations in PD96. Despite the lack of an evidence base, atypical and
typical antipsychotics continue to be used in clinical
Electrophysiology practice144, but are associated with increased mortality
In PD patients with a history of visual hallucinations, the in the context of clinical trials145 and a retrospective
P100 component of visual evoked potentials in response database analysis, which ranked haloperidol as carrying
to reversing checkerboard stimulation was found to be the highest risk, followed by olanzapine, risperidone and
delayed130, as was the P300 component of a visual odd- quetiapine144. Such evidence cautions against the use of
ball task131. A delay in evoked potential latency has also antipsychotics in PD, and highlights the need for further
been found in association with illusions and visual hal- studies in this area, as well as the development of new
lucinations in an immersive virtual reality environment therapeutic approaches for PD psychosis.
following short-term PD medication deprivation132. The
evoked potential delays might fall within the distribu- Pimavanserin
tion of normal variation, however, as rates of retinal The therapeutic effect of clozapine in PD psychosis is
and cortical evoked measures categorized as normal or thought to relate, in part, to blockade at the 5HT2A recep-
abnormal on the basis of normal population standard tor146. A large double-blind, placebo-controlled study of
deviation cut-off values do not differ between patients pimavanserin found a significant improvement on the
with and without hallucinations 132,133. Changes in SAPS-PD147, with greater improvement in a subgroup
cholinergic-related electrophysiological measures (short- with more-pronounced cognitive impairment (Ballard, C.
latency afferent inhibition) associated with susceptibility etal., unpublished work, see TABLE3). In an earlier study, a
to visual hallucinations in PD are consistent with a loss global measure of hallucinations assessed as a secondary
of cortical cholinergic input134. end point improved in patients treated with pimavanserin,
but the reduction in visual hallucinations was not signif-
Treatment icant when considered separately146. The relative lack of
As outlined in previous reviews, treatment of PD psy- efficacy of pimavanserin for visual hallucinations suggests
chosis includes psychological therapies, dose reduction that the wider improvement in psychotic symptoms is
of PD medication, and medication to treat psycho- mediated by a different subset of 5HT receptors than
sis symptoms1,2,135. TABLE3 summarizes double-blind, those stimulated by lysergic acid diethylamide (LSD),

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Table 3 | Double-blind studies of psychosis spectrum treatments


Reference Drug Number of Mean MMSE Psychosis (improvement Effect Visual hallucinations
participants score over placebo) size (improvement over placebo)
Atypical antipsychotics
Pollak etal. (2014)136 Clozapine Drug: 32 26.1 CGI 1.2* (P=0.001) 0.90* PANNS 4.8 (P<0.0001)
(4weeks) Placebo: 28 24.1
The Parkinson Clozapine Drug: 30 23.8 CGI 1.1* (P<0.001) 4.40* SAPS 8* (P=0.01)
Study Group137 (4weeks) Placebo: 30 21.7
Kurlan etal. Quetiapine Drug: 20 19.2 BPRS 2.2 (not significant)
(2007)141 (10weeks) Placebo: 20 17.2
Ondo etal. (2005)139 Quetiapine Drug: 21 26.1 No significant change
(12weeks) Placebo: 10 27.0 on Baylor Hallucination
Questionnaire or BPRS
Shotbolt etal. Quetiapine Drug: 11 24.6 Secondary outcome: no No significant change
(2009)140 (12weeks) Placebo: 13 20.8 significant change on on Baylor Hallucination
BPRS Questionnnaire or NPI
Breier etal. (2002)186 Olanzapine Drug: 41 24.0 No significant change on No significant change on NPI
(4weeks) Placebo: 42 24.7 BPRS positive symptom hallucinations score
cluster subscore
Breier etal. (2002)186 Olanzapine Drug: 49 24.7 No significant change on No significant change on NPI
(4weeks) Placebo: 28 25.0 BPRS positive symptom hallucinations score
cluster subscore
Ondo etal. (2002)142 Olanzapine Drug: 16 26.8 No significant change on
(9weeks) Placebo: 11 UPDRS thought disorder
item
Cholinesterase inhibitor
Burn etal. (2006)187 Rivastigmine Drug: 118 18.9 Secondary outcome: 0.40* No significant change on
(24weeks): visual Placebo: 70 17.9 NPI10 4.19 (P=0.01) NPI10 visual hallucination
hallucination subscore
subgroup
NMDA receptor antagonist
Aarsland etal. Memantine Drug: 34 20.0 Secondary outcome:
(2009)188 (24weeks) Placebo: 38 20.0 NPI 0.1 (not significant)
Serotonin 2A receptor inverse agonist
Cummings etal. Pimavanserin Drug: 95 26.0 SAPSPD 3.06 (P=0.001) 0.50 SAPS hallucinations domain
(2014)147 (6weeks) Placebo: 95 26.6 score 2.08 (P=0.003)
Ballard, C etal., Pimavanserin Drug: 27 <25.0 SAPSPD 6.64 3.50*
unpublished work (6weeks) Placebo: 19 <25.0
Meltzer etal. Pimavanserin Drug: 29 Individuals SAPS total domain score 0.56 No significant change on SAPS
(2010)146 (4weeks) Placebo: 31 with dementia 4.6 (trend: P=0.09) visual hallucinations score
excluded
*Calculated from tabulated data: drug versus placebo difference divided by mean standard deviation of drug versus placebo change. MMSE scores for drug and
placebo groups combined. BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impression; MMSE, Mini-Mental State Examination; NPI, Neuropsychiatric
Inventory; PANNS, Positive and Negative Symptom Scale; SAPS, Scale for Assessment of Positive Symptoms; PD, Parkinson disease; UPDRS, Unified PD Rating Scale
(thought disorder item relates to illusions, hallucinations and delusions).

the use of which is associated with predominantly visual for case report and open-label study evidence that apo-
phenomena. Pimavanserin received FDA approval in morphine does not exacerbate psychosis symptoms and,
April 2016 for the treatment of PD psychosis. Its adverse in some studies, may ameliorate these symptoms149 or
event profile to date suggests advantages over other anti improve visual contrast sensitivity150. The mode of apo-
psychotics in terms of risk of stroke, falls, fatigue, blood morphine administration may influence its impact on
dyscrasia, neuroleptic malignant syndrome, orthostatic psychotic symptoms151. The open-label EUROINF study
hypotension, and worsening of motor symptoms. found improvements in perceptual and hallucination
symptoms in patients treated with either apomorphine
Apomorphine or intrajejunal levodopa152. The effect size for apomor-
The chemical structure of apomorphine includes a pip- phine (0.32) was larger than for intrajejunal levodopa
eridine moiety and, unlike other dopamine agonists, (0.29), although the difference was not significant152.
this drug exerts intrinsic antagonist effects at the 5HT2A Apomophine might have a place in the treatment of PD
receptor as well as agonist affects at both D1like and psychosis; however, a better evidence base is needed to
D2like receptors148. This unique profile might account guide future recommendations148,152,153.

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Box 4 | Relationship between brain structure, function and neuropathology in PD psychosis


The relationship between different imaging biomarkers of Parkinson disease (PD) psychosis remains unclear. Areas of
reduced posterior cortical metabolism40 overlap with areas of reduced activation in functional MRI (fMRI) studies125, so
might reflect similar underlying functional alterations or a causal link (for example, an area of reduced metabolism might
result in a reduced blood oxygen level-dependent (BOLD) signal). Likewise, regions of increased metabolic activity
in the frontal cortex118, as identified in some studies, may relate to regions of increased frontal fMRI activation125.
One question that arises is why specific subregions of frontal, parietal, limbic and occipital lobes are altered in PD
psychosis. Some regions with atrophic or metabolic change have shown increased Lewy body and/or amyloid and tau
pathology in postmortem studies5557. However, other regions, in particular the occipital cortex, have limited
neuropathological load even in end-stage disease58, contrasting with atrophy and possible hypometabolism in imaging
studies. Therefore, invivo imaging changes may not simply reflect localized neuropathology, but have other causes, for
example, loss of cholinergic or serotonergic cortical projections, leading to a specific distribution of receptor
upregulation, functional alterations and, in the longer term, atrophy.

Electroconvulsive therapy and the subsequent development of dementia. Another


No sham-controlled studies of electroconvulsive ther- unresolved issue is the relationship between individual
apy (ECT) for PD psychosis have been undertaken, but symptoms in the PD psychosis spectrum in terms of
two case series have reported improvements in PD psy- underlying pathophysiological mechanisms. Evidence
chosis spectrum symptoms. In one study (n=5), Brief from studies of minor hallucinations, formed hallucina-
Psychiatric Rating Scale scores improved after five to 12 tions and delusions, for example, suggest that the mecha-
ECT sessions, and the effects persisted for 530weeks154. nisms are not the same for all symptoms, with important
In another study (n=8), SAPS scores improved at 1week implications for the assessment of PD psychosis in
(longer-term data not reported) after a mean of six ECT research studies. A continuum assessment scale might
sessions155. be helpful in epidemiological and risk factor studies, but
may be less useful for studying specific symptoms and
Systemic illness their underlying mechanism.
Psychosis is part of a range of acute events in PD, and is Other areas identified as requiring further research
often seen in hospitalized patients with systemic infection, include the role of PD medication as a modifier or
dopamine agonist withdrawal syndrome or parkinsonism unmasker of psychosis symptoms, motion perception
hyperpyrexia syndrome, as well as in postsurgical states156. and eye movement control deficits associated with pas-
Management of the underlying precipitant, along with sage and presence hallucinations, and the transition from
rehydration, cautious use of antipsychotic agents and hallucinations with insight to those without insight and
in suitable cases gentle introduction of low-dose its impact on quality of life and the move to supervised
dopamine agonists, may be required. care. These negative outcomes are arguably the most
clinically relevant aspects of PD psychosis; however, the
Conclusions brain changes that underlie them are unclear.
The paradigmatic shift in perspective that followed Finally, visual hallucinations are not unique to synu-
the 2007 consensus definition of PD psychosis revital- cleinopathies, and patients with eye disease, serotonergic
ized research interest and led to a rapidly expanding dysfunction or AD also have visual symptoms that over-
literature. The impact of these studies is still evolving, lap with those of PD but are associated with different
but there have already been important clinical conse- cognitive profiles157,158. The progressive improvement of
quences, such as a change in our understanding of the visual hallucinations in eye disease contrasts with the
prevalence of PD psychosis, given that it increases with progressive deterioration in PD and AD psychosis157,158,
PD duration; expansion of the range of symptoms con- and comparative studies of brain changes associated with
sidered part of the psychosis spectrum; and recognition visual hallucination susceptibility across clinical contexts
of new prospective risk factors for PD psychosis. The might shed light on why these differences exist.
largest expansion of literature has been in the mecha- Overall, two major themes can be recognized in the
nism domain, particularly in studies of cognitive profile, literature that has emerged over the past decade. One
structural brain imaging and genetics. theme highlights the clinical challenges of PD psycho-
Despite substantial progress over the past decade, sis, with an urgent need for better characterization of its
our current state of knowledge leaves key questions symptoms and their impact, and for evidence on how
unanswered (BOX 4) . For example, the relationship to assess and treat these symptoms. The second theme
between PD psychosis, PDMCI and PD dementia highlights what the psychosis spectrum reveals about PD
is unclear. Most patients with PD dementia will have in terms of disease stage and distribution, and its role as
psychosis, but only a small proportion of those with a clinical biomarker for PD outcomes. Further research
PDMCI have such symptoms. Does this observation in this area will have implications that extend beyond
imply a difference in PDMCI cognitive profiles for the symptoms themselves to the wider issues of cogni-
patients with and without psychosis? If so, an under- tive decline in PD, patient and carer experience, and the
standing of these profile differences might help to development of novel treatments for positive symptoms
explain the link between early PD psychosis symptoms in PD and other clinical contexts.

12 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneurol



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