Managing Nonmotor Symptoms: Psychosis in Parkinson Disease

PSYCHOSIS IS A debilitating nonmotor symptom of Parkinson disease (PD). A recent meta-analysis based on 15 published studies with 2919 patients showed that the pooled frequency of PD-associated psychosis (PD-P) is 20%.¹ However, in some individual longitudinal studies, the reported cumulative frequency was more than 80%, and the cross-sectional prevalence was approximately 50%.^1,2

PD-P leads to considerable financial and psychosocial burden because of its association with cognitive impairment, greater risk of nursing home placement, and high caregiver distress.^3-5 Moreover, several studies have reported higher mortality rates in patients with PD with psychosis than those without psychosis.⁶ Therefore, neurologists and psychiatrists must remain updated about the advances in the field of PD-P research to identify and manage this nonmotor symptom effectively and promptly. In this article, we provide an overview of the clinical features and diagnosis of PD-P and discuss some of the hot topics related to its pathogenesis and treatment.

Abhishek Lenka, MD, PhD

Phenomenology of Psychosis in PD

The spectrum of the phenomenology PD-P is broad. Hallucinations in the visual domain are the most common manifestation of PD-P, and this encompasses well-formed or complex visual hallucinations (VHs) and minor hallucinations (MHs).^7,8 The usual contents of VH are people (known or unknown to the patient), animals, or insects. MH comprises a false sense of presence or passage (also known as presence of passage hallucinations) and illusions. Although it is described as minor from the hallucination standpoint, because of its association with large-scale functional and structural changes in the brain and the future occurrence of well-formed VH and cognitive impairment, it seems to have major clinical and research implications.⁷ Contrary to the assumption that psychosis emerges late in the disease process, results of a study from Spain showed that MH might be present in de novo patients with PD, and in some it may predate the onset of motor symptoms.⁹ Therefore, neurologists treating patients with PD should be cognizant of MH and ask about MH during all patient encounters. Although relatively less common, patients with PD-P also experience nonvisual hallucinations, including auditory, tactile, olfactory, and gustatory hallucinations. It is common for a patient to have multiple types of hallucinations (FIGURE).¹⁰

Although a majority of the literature on PD-P is on hallucinations, there are several reports on delusions in patients with PD. A systematic review of 119 publications (184 cases) reported that the majority had paranoid delusions (83%), and in 50% of the cases, the delusion was an isolated psychotic symptom.¹¹ Compared with patients with delusion and hallucinations, those with isolated delusion were younger and had other comorbidities such as impulse control disorder and dopamine dysregulation syndrome. In addition, there are several publications on delusional jealousy (Othello syndrome) in PD, and in one series, it was associated with the presence of VH.¹² Other rare delusions reported in PD are delusional misidentification syndromes such as Capgras syndrome and Fregoli syndrome.

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In PD-P, insight is preserved early on but lost as the disease progresses, and cognitive decline parallels symptom progression. Therefore, in part 1 (question 1.2) of the International Parkinson and Movement Disorders Society’s Unified Parkinson Disease Rating Scale (MDS-UPDRS), hallucinations with insight get a lower score (score, 2) than those without insight (score, 3). Although MH gets a score of 1, the presence of delusions is deemed the most severe form of psychosis, with a score of 41.¹³

Diagnostic Criteria

PD-P is diagnosed as per the National Institutes of Neurological Disorders and Stroke and National Institute of Mental Health criteria proposed in 2007.¹⁴ For diagnosing PD-P, a patient must have at least 1 of the core symptoms, including illusions, a false sense of presence, hallucinations, or delusions. These core symptom(s) must be present for at least 1 month or be recurrent. Additionally, the core symptoms must have occurred after the patient’s diagnosis of PD. Although the criteria are straightforward, the biggest challenge is obtaining the history of these symptoms. Patients and caregivers may spontaneously report well-formed VH; however, other features such as MH, nonvisual hallucinations, and delusions may get overlooked if not explored in detail. Therefore, semistructured interviews and targeted questionnaires have immense value in exploring psychotic symptoms.¹⁵

Pathogenesis of PD-P: The Story So Far

Several risk factors for PD-P have been identified, including older age, greater disease stage/severity, presence of REM sleep behavior disorder, and depression.^16-18 Several medications—especially dopamine receptor agonists such as pramipexole (Mirapex) and ropinirole (Requip), amantadine, and trihexyphenidyl hydrochloride— are associated with an increased risk of developing PD-P. However, not every patient taking these medications or those with the above-mentioned demographic or clinical characteristics will develop psychosis. The pathogenesis of PD-P is multifactorial and is not fully understood. Results of many neuroimaging studies show that there could be large-scale structural and functional brain changes in dorsal and ventral visual pathways in patients with VH.^19-22 In addition, there is evidence suggesting an abnormal attentional network in PD-P.²³ Neurotransmitter imbalance, especially that involving the serotonergic system, is one of the widely accepted theories related to the pathogenesis of PD. Although the pathogenesis is not precisely understood, the aforementioned factors, along with certain genetic susceptibility, perhaps contribute to the emergence of psychosis in PD.²⁴ Although there are many studies of patients with VH, because of the scarcity of studies of patients with nonvisual hallucinations and delusions, pathogenesis of such symptoms is not well understood.

Arwa Bohra, MBBS

Management of Psychotic Symptoms in PD

It is important to determine whether psychosis in PD is caused by PD or other medical conditions. Neurologists should be vigilant about looking for common medical conditions such as systemic infections, dehydration, and metabolic derangements that often precipitate symptoms of psychosis. Similarly, given the high risk of falls, a history of head injury should be ruled out; intracranial bleeds such as subdural hematoma are commonly associated with acute or subacute neuropsychiatric changes. Patients’ medication lists should be carefully checked to see whether there was an introduction of any hallucinogenic medication or any increase in the dose of existing antiparkinsonian medications. For patients who have undergone deep brain stimulation, neurologists should check whether the onset of psychotic symptoms coincides with any recent augmentation of stimulation parameters.

If psychotic symptoms are persistent and bothersome and do not have any other apparent secondary cause, atypical antipsychotics should be considered.²⁵ The FDA has approved only 1 medication—pimavanserin (Nuplazid; Acadia Pharmaceuticals)—for treating patients with PD-P. Other antipsychotics that are relatively safe and do not have significant extrapyramidal adverse effects are clozapine and quetiapine (Seroquel; AstraZeneca). Pimavanserin is an inverse agonist of 5-HT 2A receptors and is prescribed at 34 mg/ day. It may take 4 to 6 weeks for pimavanserin to reduce the severity and frequency of hallucinations; however, some patients may not respond to this medication. It is reported that the effect of pimavanserin is robust in patients with cognitive impairment.²⁶ After its introduction to the market, there were concerns about its association with increased risk of mortality in PD, but results of recent studies have shown that it does not increase risk of mortality.^27,28

Pimavanserin is expensive (a 34-mg tablet costs $180 without insurance) and is available only in the United States. Therefore, a substantial majority of patients instead will take clozapine or quetiapine. Although clozapine has a potent antipsychotic effect, serious adverse effects such as agranulocytosis and the need to undergo frequent blood count monitoring are significant issues.²⁹ For those reasons, quetiapine is usually preferred as an initial medication for managing psychosis. Although its efficacy was not proved in double-blind, placebo-controlled studies, several off-label studies found it effective in managing PD-P.³⁰ Because cognitive impairment and VH are closely associated, patients with both should be prescribed cholinesterase inhibitors.

Conclusion

PD-P may affect more than half of patients with PD. Although PD-P commonly manifests with VH or MH, some patients may experience delusions and hallucinations of nonvisual domains. Because it substantially worsens quality of life, there should be efforts to develop biomarkers to predict the onset of PD-P. Medications such as pimavanserin, quetiapine, and clozapine are effective in managing hallucinations and should be prescribed for severe symptoms. However, because these medications are often limited by global unavailability or bothersome adverse effects, newer drugs need to be developed. Ongoing phase 2 trials of ulotaront (SEP-363856; NCT02969382) and ondansetron (TOPHAT; NCT04167813), if successful, may lead to additional therapeutic avenues.³¹

For correspondence:

Abhishek Lenka, MD, PhD
Parkinson’s Disease and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX 77030
Phone: 713-798-6576
Email: abhishek.lenka@bcm.edu

REFERENCES

1. 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

2. Gibson G, Mottram PG, Burn DJ, et al. Frequency, prevalence, incidence and risk factors associated with visual hallucinations in a sample of patients with Parkinson’s disease: a longitudinal 4-year study. Int J Geriatr Psychiatry. 2013;28(6):626-631. doi:10.1002/gps.3869

3. Fredericks D, Norton JC, Atchison C, Schoenhaus R, Pill MW. Parkinson’s disease and Parkinson’s disease psychosis: a perspective on the challenges, treatments, and economic burden. Am J Manag Care. 2017;23(suppl 5):S83-S92.

4. Santos-García D, de Deus Fonticoba T, Cores Bartolomé C, et al. Risk of cognitive impairment in patients with Parkinson’s disease with visual hallucinations and subjective cognitive complaints. J Clin Neurol. 2023;10.3988/ jcn.2022.0186.. doi:10.3988/jcn.2022.0186

5. Mantri S, Klawson E, Albert S, et al. The experience of care partners of patients with Parkinson’s disease psychosis. PLoS One. 2021;16(3):e0248968. doi:10.1371/journal.pone.0248968

6. Stang CD, Mullan AF, Camerucci E, et al. Incidence, prevalence, and mortality of psychosis associated with Parkinson’s disease (1991-2010). J Parkinsons Dis. 2022;12(4):1319-1327. doi:10.3233/JPD-213035

7. Lenka A, Pagonabarraga J, Pal PK, Bejr-Kasem H, Kulisvesky J. Minor hallucinations in Parkinson disease: a subtle symptom with major clinical implications. Neurology. 2019;93(6):259-266. doi:10.1212/WNL.0000000000007913

8. Ffytche DH, Creese B, Politis M, et al. The psychosis spectrum in Parkinson disease. Nat Rev Neurol. 2017;13(2):81- 95. doi:10.1038/nrneurol.2016.200

9. 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. Mov Disord. 2016;31(1):45-52. doi:10.1002/mds.26432

10. Toh WL, Yolland C, Gurvich C, Barnes J, Rossell SL. Non-visual hallucinations in Parkinson’s disease: a systematic review. J Neurol. Published online January 27, 2023. doi:10.1007/s00415-022-11545-6

11. Warren N, O’Gorman C, Hume Z, Kisely S, Siskind D. Delusions in Parkinson’s disease: a systematic review of published cases. Neuropsychol Rev. 2018; 28(3):310-316. doi:10.1007/s11065-018-9379-3

12. De Michele G, Palmieri GR, Pane C, et al. Othello syndrome in Parkinson’s disease: a systematic review and report of a case series. Neurol Sci. 2021(7);42:2721-2729. doi:10.1007/s10072-021-05249-4

13. Goetz CG, Tilley BC, Shaftman SR, et al; Movement Disorder Society UPDRS Revision Task Force. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23(15):2129-2170. doi:10.1002/mds.22340

14. 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. 2007;22(8):1061-1068. doi:10.1002/mds.21382

15. Greger J, Aladeen T, Rainka M, Kale A, Capote H. Evaluating rates of reporting symptoms of Parkinson’s disease psychosis: provider versus targeted questionnaire. Int J Neurosci. 2022;132(5):459-465. doi:10.1080/ 00207454.2020.1821678

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. Lenka A, George L, Arumugham SS, et al. Predictors of onset of psychosis in patients with Parkinson’s disease: who gets it early? Parkinsonism Relat Disord. 2017;44:91-94. doi:10.1016/j.parkreldis.2017.09.015

18. 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

19. Thomas GEC, Zeidman P, Sultana T, Zarkali A, Razi A, Weil RS. Changes in both top-down and bottom-up effective connectivity drive visual hallucinations in Parkinson’s disease. Brain Commun. 2022;5(1):fcac329. doi:10.1093/braincomms/fcac329

20. 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

21. Lenka A, Ingalhalikar M, Shah A, et al. Abnormalities in the white matter tracts in patients with Parkinson disease and psychosis. Neurology. 2020;94(18):e1876-e1884. doi:10.1212/WNL.0000000000009363

22. Li G, Zhu J, Wu X, et al. Baseline free water within the visual processing system predicts future psychosis in Parkinson disease. Eur J Neurol. 2023;30(4):892-90. doi:10.1111/ene.15668

23. Hall JM, O’Callaghan C, Shine JM, et al. Dysfunction in attentional processing in patients with Parkinson’s disease and visual hallucinations. J Neural Transm 2016;123(5):503-507. doi:10.1007/s00702-016-1528-3

24. 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

25. Lenka A, Gomathinayagam V, Bahroo L. Approach to the management of psychosis in Parkinson’s disease. Ann Mov Disord. 2019;2(3):83-90. doi:10.4103/AOMD.AOMD_27_19

26. Espay AJ, Guskey MT, Norton JC, et al. Pimavanserin for Parkinson’s disease psychosis: effects stratified by baseline cognition and use of cognitive-enhancing medications. Mov Disord. 2018;33(11):1769-1776. doi:10.1002/mds.27488

27. Mosholder AD, Ma Y, Akhtar S, et al. Mortality among Parkinson’s disease patients treated with pimavanserin or atypical antipsychotics: an observational study in Medicare beneficiaries. Am J Psychiatry. 2022;179(8):553-561. doi:10.1176/appi.ajp.21090876

28. Pham Nguyen TP, Thibault D, Hamedani AG, Weintraub D, Willis AW. Atypical antipsychotic use and mortality risk in Parkinson disease. Parkinsonism Relat Disord 2022;103:17-22. doi:10.1016/j. parkreldis.2022.08.013

29. Factor SA, Friedman JH, Lannon MC, et al. Clozapine for the treatment of drug-induced psychosis in Parkinson’s disease: results of the 12 week open label extension in the PSYCLOPS trial. Mov Disord. 2001;16(1):135-139. doi:10.1002/1531-8257(200101)16:1<135::aid-mds1006>3.0.co;2-q

30. Friedman JH. Quetiapine for Parkinson’s disease psychosis: evidence-based medicine versus expert belief: a case study. Mov Disord. 2018;33(7):1186-1187. doi:10.1002/mds.27378

31. 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:10.1080/147403 38.2022.2069240