Psychiatric Annals

CME Article 

Psychosis in Parkinson's Disease

Matthew Remz, MD; Meagen Salinas, MD

Abstract

Clinically defined by consensus in 2007, Parkinson's disease psychosis (PDP) encompasses psychiatric symptoms of illusions, hallucinations, and delusions associated with Parkinson's disease. Since that time, an increase in research has yielded new insights into clinical features of PDP, how these symptoms evolve over time, and novel therapeutic targets. This article reviews the literature surrounding PDP, highlighting the spectrum of clinical manifestations, the pathophysiology, and treatment options. The article concludes with a treatment strategy incorporating the reviewed evidence. [Psychiatr Ann. 2020;50(3):113–120.]

Abstract

Clinically defined by consensus in 2007, Parkinson's disease psychosis (PDP) encompasses psychiatric symptoms of illusions, hallucinations, and delusions associated with Parkinson's disease. Since that time, an increase in research has yielded new insights into clinical features of PDP, how these symptoms evolve over time, and novel therapeutic targets. This article reviews the literature surrounding PDP, highlighting the spectrum of clinical manifestations, the pathophysiology, and treatment options. The article concludes with a treatment strategy incorporating the reviewed evidence. [Psychiatr Ann. 2020;50(3):113–120.]

Parkinson's disease (PD) is the second most prevalent, only to Alzheimer's disease, neurodegenerative disease worldwide.1,2 In the United States, its prevalence is approximately 1% to 2% of people older than age 65 years.1 A common non-motor complication of PD is psychosis. Patients who suffer from Parkinson's disease psychosis (PDP) are burdened by increased health care use and associated costs.3 PDP symptoms are underrecognized and often suboptimally treated, thus negatively impacting patient quality of life and caregiver burden. Since the creation of the National Institute of Neurological Disorders and Stroke (NINDS) PDP work group diagnostic criteria published in 2007, there has been extensive investigation into the manifestations of PDP and its potential etiologies.4 This article reviews the clinical features of PDP, risk factors, and evidence-based treatment strategies.

Definition

Although there is mention of psychotic symptoms in James Parkinson's Essay on the Shaking Palsy, hallucinations were not specifically addressed until much later.5 PDP was further confounded by the outbreak of von Economo encephalitis, which made it more difficult to attribute psychosis as a non-motor feature of PD.5 The first standardized diagnostic criteria for PDP was created by the 2007 NINDS.6

The NINDS PDP work group defines PDP as the clinical entity encompassing at least one of the following symptoms: illusions, false sense of presence, hallucinations, or delusions in a patient with a primary diagnosis of PD.6 The patient must have recurrent or continuous psychotic symptoms for 1 month. The psychosis must begin after the onset of motor symptoms of PD and not be accounted for by an alternative diagnosis. The importance of evaluating for potential alternative primary psychiatric etiologies highlights the vital role of psychiatrists. The diagnosis of PDP may be associated with or without insight, dementia, or treatment for PD.4

Epidemiology and Burden of Disease

There are limitations to the quantification of PDP prevalence, particularly given the relatively recent unifying diagnostic criteria. Regardless, the prevalence of PDP varies in the literature and ranges from 25% to 70% of the PD population with higher rates (89%) in PD dementia patients.7–9 Cognitive impairment is cited as the principal nonmodifiable risk factor.7 Other risk factors for PDP include older age, duration and severity of disease, rapid eye movement behavioral disorder, daytime somnolence, and depression.7

Despite the heterogeneity of available data, the epidemiological literature emphasizes the association between PDP and caregiver distress and patient quality of life.7 The presence of PDP is a predictor for early nursing home placement and increased systemic burdens.3,10 Falls were 3.4 times more frequent, fractures 2.3 times higher, and health resource use and total costs were 2.1 times higher in PDP as compared to PD controls.3

A Spectrum of Psychosis in PD

Early Phase

Classically, the symptoms of PDP begin with minor phenomena including hallucinations of presence or passage, illusions, and major (formed) visual hallucinations (VH) (Figure 1). Sense of presence is a feeling that a distinct entity is nearby but none is seen.11 Passage hallucinations are positive phenomena occurring in the peripheral vision.11 The prevalence of passage and presence hallucinations is estimated at 50% with patients with PD and approximately one-third of those patients also had unformed VH.11 In the early stages of PDP, symptoms are often associated with preserved insight.4 A case series by Fénelon et al.11 found that the majority of patients could identify the present entity and about 75% of patients were not distressed by the presence. There is some evidence to suggest a correlation between the cognitive status of the patient and the familiarity of the content in the hallucinations, with more unfamiliar content associated with more profound inhibition of executive function.4

The relationship of clinical progression of psychosis, cognitive impairment, and insight.

Figure 1.

The relationship of clinical progression of psychosis, cognitive impairment, and insight.

Other symptoms of early PDP include pareidolia, a specific type of illusion wherein formless objects with an inherent pattern, such as tree bark, are interpreted to contain faces or other meaningful objects to the patient.12

Late Phase

As PDP progresses, VH become well formed into people or animals, insight is gradually lost, and hallucinations of other sensory modalities develop. In one study, VH were about twice as common as auditory, 4 times as common as tactile and 6 times as common as olfactory hallucinations.13

PDP can also be accompanied by delusions that are often comorbid with significant cognitive decline.4 Delusions are commonly related to sin, guilt, grandiosity, reference, religion, persecution, jealousy, and theft.13 In one study that employed a neuropsychiatric inventory, hallucinations were twice as common as delusions in patients with PD.9

Assessment

There is no universally agreed upon scale for the assessment of PDP symptoms. Further, none of the scales commonly employed to assess psychosis were developed specifically for PDP. Studies cited in this review use wide-ranging metrics from a single question on the Movement Disorder Society United PD Rating Scale to more specific tools such as the Scale for the Assessment of Positive Symptoms adapted for PD.4 The lack of standardization makes accurate comparisons of therapeutic options even more challenging.

Pathophysiology

Despite the global burden of PD, there is unfortunately no clear mechanism for its pathogenesis. Whereas the obvious mechanisms of dopamine replacement therapy (DRT) as a cause of psychosis have resulted in theories relating the two, the evidence has not entirely borne out this connection. A study of the natural course of neuropsychiatric symptoms in PD did show an increase in overall neuropsychiatric symptoms in those started on DRT, but the presence of psychotic symptoms was not significantly different.4 The prevalence of early VH in patients who are untreated also argues against this theory from a causative perspective.4

Postmortem pathologic studies have revealed the progressive deposition of alpha-synuclein in characteristic Lewy bodies.4 Braak et al.14 described the progression of alpha-synuclein pathology in 2003, and additional evidence has correlated PDP progression with Braak's stages.4 Many theories on the neural circuitry involved in PDP stem from imaging studies. The underlying mechanism is thought to involve alterations in perception and visual processing, which is supported by functional magnetic resonance imaging (MRI) evidence of differing activation patterns of the visual associative areas with simple and complex hallucinations.15 Additionally, voxel-based morphology studies on MRI have shown atrophic changes in the ventral and dorsal neostriatal pathways that appear to correlate with minor hallucinations in early PDP.16,17

There are varying neurotransmitter-based theories for PDP, and perhaps the most intuitive is the hypothesis of dysregulation of the mesolimbic dopaminergic projections.18 This theory explains the rationale for reducing dopamine agonists and employing dopamine antagonism to treat PDP.18 Pre-motor phase and treatment-naïve PDP disproves dopamine agonism as the sole explanation for the dysregulation.5,7 Other neurotransmitters have been implicated, including acetylcholine and norepinephrine.18 Serotonergic dysregulation has been a target of recent pharmacological advancement, and there is some evidence that this is complementary to the theories surrounding dopamine.18

Treatment

Several medications have been previously employed for the treatment of PDP with varied results. Given the heterogeneity of treatment strategies, a systematic review of the literature was conducted to clarify the supporting evidence of available pharmacotherapies. The literature was searched using MEDLINE, MEDLINE InProcess, EPub, and Embase for drug trials on “Parkinson Disease” and “psychotic disorders” or “psychoses” or “hallucinations” or “illusions,” and the authors reviewed the available clinical trials, meta-analyses, systematic reviews, cohort studies, follow-up studies, prospective, and retrospective studies as well as very small comparative drug studies/trials. The search was limited to the English literature, human participants, and people age 19 years to older than age 65 years. The search resulted in approximately 70 articles and this review focuses on the therapeutic agents with higher-quality studies with additional therapies reviewed in Table 1.

Pharmacotherapy in Parkinson's Disease Psychosis: A Systematic ReviewPharmacotherapy in Parkinson's Disease Psychosis: A Systematic Review

Table 1.

Pharmacotherapy in Parkinson's Disease Psychosis: A Systematic Review

Attenuation of DRT as a therapeutic option for PDP symptoms remains a practiced strategy for patients that tolerate it. Expert opinion supports the efficacy of this strategy, although no randomized controlled trials (RCTs) are available and prospective data suggest those treated with DRT have greater incidence of psychosis.18,19

Quetiapine

Seventeen studies on quetiapine and additional comparison trials20,21 were reviewed with heterogeneous conclusions. Of the five RCTs reviewed, only one study (the smallest of the group) was able to demonstrate efficacy of quetiapine beyond that of placebo. Open label trials and some retrospective and long-term follow-up studies demonstrate superiority of quetiapine to placebo. However, multiple literature reviews conclude that quetiapine is not superior to placebo for the treatment of PDP.20,21

Clozapine

Twenty-one studies on clozapine, comparison studies to other antipsychotics, as well as meta-analysis and multidrug reviews have unanimously described clozapine as efficacious for the treatment of PDP.18,22–24 Unfortunately, the quality of studies comparing clozapine to other agents is largely limited by low sample size and open label methodology. Agranulocytosis is a known potential adverse reaction but upon review of literature is an infrequent occurrence.23–25

Pimavanserin

Pimavanserin is a novel therapeutic option that remains the only US Food and Drug Administration (FDA)-approved treatment for PDP not associated with dementia. The hypothesis that clozapine worked through inhibition of the 5HT-2A receptor was the basis for the development of pimavanserin, a 5HT-2A receptor inverse agonist.26 Avoidance of dopaminergic antagonism limits side effects of worsening motor symptoms.26 The preliminary retrospective review and the RCT performed for FDA approval demonstrate efficacy and safety27,28 albeit with a delayed effect of approximately 4 weeks after initiation. The efficacy of pimavanserin in those with cognitive impairment is less clear.29,30

Other Antipsychotics

Open label studies and retrospective reviews of risperidone seem to indicate efficacy31–33 and comparison trials with clozapine showed similar efficacy although with worsening of motor function.34 For ziprasidone, one open label study and another case series concluded it was efficacious, and intramuscular ziprasidone may have some promise as an agent for emergency situations.35,36 One small, open label comparison of ziprasidone and clozapine found them to be equally efficacious.37 RCTs, case series, and comparison trials have largely found olanzapine to be ineffective for the treatment of PDP and highly limited by motor side effects.38–41 Two small open label studies of aripiprazole failed to show any efficacy for PDP.42,43 Remoxipride and melperone have been examined in small open label trials with some promise but insufficient evidence to recommend use at this time.44–46

What remains an outstanding question is whether the effectiveness of an antipsychotic is related to its lower dopaminergic activity, higher serotonergic affinity, or, more likely, a combination of the two.

Other Pharmacologic Options

Rivastigmine has been shown to be more efficacious than placebo in the improvement of cognitive function and behavioral measures, especially in those with PDP.47,48 Donepezil and galantamine have shown mixed efficacy in small early trials.49–51 Escitalopram,52 ondansetron,53 cannabidiol,54 and apomorphine55 all have limited data in the treatment of PDP.

Conclusions

After its definition in 2007, understanding of the manifestations, treatment, and the pathophysiology of PDP has increased, but data remain limited. From the available studies, however, emerges sufficient evidence of strategies for intervention, including agents to avoid and others to keep in one's arsenal. These authors use a standardized approach to the management of PDP once symptoms are determined to be subacute or chronic and nondistressing (Figure 2). Moreover, these studies suggest that the pathophysiology of PDP likely involves a more complex network of neurotransmitters and neural circuits that can be exploited. Future studies are required to better characterize these, the role of DRT, and potential biomarkers to ascertain the risk of PDP. The need remains for reliable, generalizable, and objective measures of PDP symptoms and further randomized, controlled studies of the therapeutic effects on these measures.

The authors' stepwise approach to management of Parkinson's disease psychosis. COMT, catechol-O-methyltransferase; MAOI, monoamine oxidase inhibitors; MCI, mild cognitive impairment; NINDs, National Institute of Neurological Disorders and Stroke; PDP, Parkinson's disease psychosis; TDD, total daily dose.

Figure 2.

The authors' stepwise approach to management of Parkinson's disease psychosis. COMT, catechol-O-methyltransferase; MAOI, monoamine oxidase inhibitors; MCI, mild cognitive impairment; NINDs, National Institute of Neurological Disorders and Stroke; PDP, Parkinson's disease psychosis; TDD, total daily dose.

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Pharmacotherapy in Parkinson's Disease Psychosis: A Systematic Review

Medication Study Design Number of Studies Sample Size (Range) Study Outcome
Quetiapine20,21 Randomized, placebo controlled Open label/cohort study Retrospective study Meta-analysis 5 9 1 2 16–58 2–98 106 601 4 of 5 studies showed no difference over placebo Superiority of quetiapine over placebo Improvement in psychosis No difference over placebo
Clozapine18,22–24 Randomized, placebo controlled Open label/cohort study Case series Randomized vs quetiapine Randomized vs olanzapine Randomized vs ziprasidone Randomized vs risperidone 4 10 2 2 1 1 1 6–10 5–53 14–49 20–27 15 16 10 Improvement in symptoms over placebo Improvement in symptoms Improvement in symptoms Improvement in both groups, no agranulocytosis Improvement in clozapine grp, worsening of parkinsonism in olanzapine grp Improvement in both groups, no agranulocytosis Improvement in both groups, no agranulocytosis
Ziprasidone35–37 Open label/cohort study Randomized vs clozapine 2 1 5–12 16 Improvement in symptoms, no worsening of parkinsonism No difference over clozapine, no worsening of parkinsonism
Risperidone31–34 Open label/cohort study Case series Open label vs clozapine 2 1 1 17–39 9 10 Improvement in psychosis Improvement in psychosis No difference over clozapine, worsening of motor symptoms in risperidone grp
Olanzapine38–41 Randomized, placebo controlled Open label/cohort study Randomized vs clozapine 3 5 1 23–160 5–21 15 No difference over placebo Symptom reduction, worsening of parkinsonism in 3 of 5 studies Symptom reduction in clozapine grp only, worsening of parkinsonism in olanzapine grp
Aripiprazole42,43 Open label/cohort study 2 8–16 Improvement in psychosis, worsening of parkinsonism in large fraction of patients
Remoxipride44,45 Open label/cohort study 1 9 Improvement in symptoms, no worsening of parkinsonism
Melperone44,46 Open label/cohort study Randomized, placebo controlled 1 1 30 90 Improvement in symptoms, no worsening of parkinsonism No difference over placebo, no worsening of parkinsonism
Pimavanserin26–30 Randomized, placebo controlled Open label/cohort study 2 1 60–199 26 Improvement in symptoms seen in 1 of 2 studies, no worsening of parkinsonism Improvement in symptoms seen in 50% and required at least 4 weeks for effect
Rivastigmine47,48 Randomized, placebo controlled Open label/cohort study 1 1 536 12 Improvement in symptoms, greater resp in patients with visual halluciations Improvement in symptoms, no worsening of parkinsonism
Donepezil49,50 Randomized, placebo controlled Open label/cohort study 1 1 145 8 No benefit in preventing development of psychosis Improvement in symptoms, worsening of motor symptoms in 25%
Galantamine51 Open label/cohort study 1 16 Improvement in symptoms, worsening of motor symptoms in 23%
Escitalopram52 Open label/cohort study 1 13 Improvement in symptoms in all but one patient
Apomorphine55 Open label/cohort study Case series 1 1 10 12 Improvement in symptoms with concomitant titration of dopamine-agonists Improvement in symptoms, study patients were intolerant of oral dopamine agonists
Selegiline56 Open label/cohort study 1 15 Improvement in symptoms with concomitant titration of dopamine-agonists
Ondansetron53 Open label/cohort study 2 7–16 Significant improvement seen in 1 of 2 studies, no worsening of parkinsonism
Cannabidiol54 Open label/cohort study 1 6 Improvement in symptoms, no worsening of parkinsonism
Authors

Matthew Remz, MD, is a Resident Physician. Meagen Salinas, MD, is an Assistant Professor. Both authors are affiliated with the Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center.

Address correspondence to Meagen Salinas, MD, Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390; email: meagen.salinas@utsouthwestern.edu.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/00485713-20200210-02

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