Comparative Efficacy,Safety,and Acceptability of Pimavanserin and Other Atypical Antipsychotics for Parkinson’s Disease Psychosis: Systematic Review and Network Meta-Analysis
Restricted accessResearch articleFirst published online September, 2023
Comparative Efficacy,Safety,and Acceptability of Pimavanserin and Other Atypical Antipsychotics for Parkinson’s Disease Psychosis: Systematic Review and Network Meta-Analysis
The current comparative efficacy, safety, and acceptability of atypical antipsychotics (AAPs) in treating Parkinson's Disease Psychosis (PDP) are not entirely understood.
Objective
To evaluate comparative efficacy, safety, and acceptability of AAPs in patients with PDP.
Methods
We conducted a systematic review and a network meta-analysis to compare the efficacy, safety, and acceptability of pimavanserin, quetiapine, olanzapine, clozapine, ziprasidone, and risperidone. We estimated relative standardized mean differences (SMDs) for continuous outcomes and odds ratios (OR) for binary outcomes, with their respective 95% confidence intervals (CIs).
Results
We included 19 unique studies evaluating AAPs in a total of 1,242 persons with PDP. Based on Clinical Global Impression Scale for Severity, pimavanserin (SMD, −4.81; 95% CI, −5.39, −4.24) and clozapine (SMD, −4.25; 95% CI, −5.24, −3.26) significantly improved symptoms compared with placebo. Also, compared to placebo, pimavanserin (OR, 1.16; 95% CI, 1.07, 1.24) significantly improved psychotic symptoms based on Scale for Assessment of Positive Symptoms for Parkinson's Disease Psychosis/Hallucinations and Delusions scores. In comparison to placebo, clozapine (SMD, −0.69; 95% CI, −1.35, −0.02), pimavanserin (SMD, −0.01; 95% CI, −0.56, 0.53), and quetiapine (SMD, 0.00; 95% CI, −0.68, 0.69) did not impair motor function per Unified Parkinson's Disease Rating scale. Based on Mini-Mental State Examination scale, quetiapine (SMD, 0.60; 95% CI, 0.07, 1.14) significantly impaired cognition compared to placebo.
Conclusions
In patients with PDP, pimavanserin and clozapine demonstrated significant improvement in psychosis without affecting motor function. With quetiapine being associated with a significant decline in cognition and despite not impairing motor function, our findings suggest that it should be avoided in patients with PDP and reduced cognitive abilities.
SuranM. How prolonged isolation affects people with parkinson disease during the COVID-19 pandemic. JAMA. 2022;327(9):801-803.
2.
MarrasCBeckJCBowerJH, et al.Prevalence of Parkinson’s disease across North America. npj Parkinson's Disease. 2018;4(1):21.
3.
WeissHDMarshL. Impulse control disorders and compulsive behaviors associated with dopaminergic therapies in Parkinson disease. Neurol Clin Pract. 2012;2(4):267-274.
4.
WeintraubDBurnDJ. Parkinson's disease: The quintessential neuropsychiatric disorder. Mov Disord. 2011;26(6):1022-1031.
5.
ForsaaEBLarsenJPWentzel-LarsenT, et al.A 12-year population-based study of psychosis in Parkinson disease. Archives of Neurology. 2010;67(8):996-1001.
6.
ChenJJ. Treatment of psychotic symptoms in patients with Parkinson disease. Ment Health Clin. 2018;7(6):262-270.
7.
AarslandDBallardCLarsenJPMcKeithI. A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinson's disease with and without dementia. Int J Geriatr Psychiatry. 2001;16(5):528-536.
8.
ChouKLMessingSOakesDFeldmanPDBreierAFriedmanJH. Drug-induced psychosis in Parkinson disease: phenomenology and correlations among psychosis rating instruments. Clin Neuropharmacol. 2005;28(5):215-219.
9.
WetmoreJBLiSYanH, et al.Increases in institutionalization, healthcare resource utilization, and mortality risk associated with Parkinson disease psychosis: Retrospective cohort study. Parkinsonism Relat Disord. 2019;68:95-101.
10.
AarslandDLarsenJPTandbergELaakeK. Predictors of nursing home placement in Parkinson's disease: a population-based, prospective study. J Am Geriatr Soc. 2000;48(8):938-942.
11.
FredericksDNortonJCAtchisonCSchoenhausRPillMW. Parkinson's disease and Parkinson's disease psychosis: a perspective on the challenges, treatments, and economic burden. Am J Manag Care. 2017;23(5 Suppl):S83-S92.
12.
AarslandDAndersenKLarsenJPLolkA. Prevalence and characteristics of dementia in Parkinson Disease: An 8-Year Prospective Study. Archives of Neurology. 2003;60(3):387-392.
ZhangHWangLFanY, et al.Atypical antipsychotics for Parkinson's disease psychosis: A systematic review and meta-analysis. Neuropsychiatr Dis Treat. 2019;15:2137-2149.
15.
AndrewDMYongMSandiaA, et al.Mortality among parkinson’s disease patients treated with pimavanserin or atypical antipsychotics: An observational study in medicare beneficiaries. American Journal of Psychiatry.0(0):appi.ajp.21090876.
16.
SeppiKRay ChaudhuriKCoelhoM, et al.Update on treatments for nonmotor symptoms of Parkinson's disease-an evidence-based medicine review. Mov Disord. 2019;34(2):180-198.
17.
JethwaKDOnalajaOA. Antipsychotics for the management of psychosis in Parkinson's disease: Systematic review and meta-analysis. BJPsych Open. 2015;1(1):27-33.
18.
El-SaifiNMoyleWJonesCTuffahaH. Quetiapine safety in older adults: A systematic literature review. Journal of Clinical Pharmacy and Therapeutics. 2016;41(1):7-18.
19.
IketaniRFurushimaDImaiSYamadaH. Efficacy and safety of atypical antipsychotics for psychosis in Parkinson's disease: A systematic review and Bayesian network meta-analysis. Parkinsonism Relat Disord. 2020;78:82-90.
20.
AlvirJMLiebermanJASaffermanAZSchwimmerJLSchaafJA. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med. 1993;329(3):162-167.
21.
MilanoVRKayhartBMMorganRJDeSimoneDCMaraKCLeungJG. Second-generation antipsychotics and pneumonia-related hospitalizations. Prim Care Companion CNS Disord. 2020;22(4).
22.
HigginsJMSanCLagnadoGChuaDMihicT. Incidence and management of clozapine-induced myocarditis in a large tertiary hospital. Can J Psychiatry. 2019;64(8):561-567.
23.
TiihonenJTanskanenABellJSDawsonJLKatajaVTaipaleH. Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland. Lancet Psychiatry. 2022;9(5):353-362.
MansuriZReddyAVadukapuramRTrivediCAmaraA. Pimavanserin in the treatment of Parkinson's Disease Psychosis: Meta-analysis and meta-regression of randomized clinical trials. Innov Clin Neurosci. 2022;19(1-3):46-51.
26.
HigginsJPTThomasJChandlerJCumpstonMLiTPageMJWelchVA (editors). Cochrane Handbook for Systematic Reviews of Interventionsversion 6.3 (updated February 2022). Cochrane, 2022. www.training.cochrane.org/handbook.
27.
PageMJMcKenzieJEBossuytPM, et al.The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Systematic Reviews. 2021;10(1):89.
28.
Diagnostic and statistical manual of mental disorders: DSM-5.Arlington, VA: American Psychiatric Association; 2013.
29.
BusnerJTargumSD. The clinical global impressions scale: Applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37.
30.
FernandezHHAarslandDFénelonG, et al.Scales to assess psychosis in Parkinson's disease: Critique and recommendations. Mov Disord. 2008;23(4):484-500.
31.
GoetzCG. Unified Parkinson’s Disease Rating Scale (UPDRS) and the movement-disorder society sponsored-unified Parkinson’s Disease rating scale (MDS-UPDRS). In: KompolitiKMetmanLV, eds. Encyclopedia of Movement Disorders.Oxford: Academic Press; 2010:307-309.
32.
HigginsJPTAltmanDGGøtzschePC, et al.The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
33.
SterneJAHernánMAReevesBC, et al.ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ (Clinical research ed). 2016;355:i4919-i4919.
34.
HuttonBSalantiGCaldwellDM, et al.The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777-784.
35.
SalantiG. Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool. Research Synthesis Methods. 2012;3(2):80-97.
36.
BucherHCGuyattGHGriffithLEWalterSD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol. 1997;50(6):683-691.
37.
ChaimaniASalantiG. Visualizing assumptions and results in network meta-analysis: The network graphs package. The Stata Journal. 2015;15(4):905-950.
38.
DiasSWeltonNJCaldwellDMAdesAE. Checking consistency in mixed treatment comparison meta-analysis. Stat Med. 2010;29(7-8):932-944.
39.
van ValkenhoefGDiasSAdesAEWeltonNJ. Automated generation of node-splitting models for assessment of inconsistency in network meta-analysis. Research synthesis methods. 2016;7(1):80-93.
40.
ToninFSRottaIMendesAMPontaroloR. Network meta-analysis: A technique to gather evidence from direct and indirect comparisons. Pharm Pract (Granada)2017;15(1):943.
41.
JacksonDBarrettJKRiceSWhiteIRHigginsJPT. A design-by-treatment interaction model for network meta-analysis with random inconsistency effects. Statistics in medicine. 2014;33(21):3639-3654.
42.
FaraoneSV. Interpreting estimates of treatment effects: implications for managed care. P T. 2008;33(12):700-711.
43.
AlbertSM. MMSE 2.0: A new approach to an old measure. Neuroepidemiology. 2014;43(1):26-27.
44.
WhiteIRBarrettJKJacksonDHigginsJPT. Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression. Research synthesis methods. 2012;3(2):111-125.
45.
SweetingMJSuttonAJLambertPC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004;23(9):1351-1375.
46.
SalantiGAdesAEIoannidisJP. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol. 2011;64(2):163-171.
47.
VeronikiAAStrausSERuckerGTriccoAC. Is providing uncertainty intervals in treatment ranking helpful in a network meta-analysis?J Clin Epidemiol. 2018;100:122-129.
48.
ChaimaniAHigginsJPTMavridisDSpyridonosPSalantiG. Graphical tools for network meta-analysis in STATA. PLoS One. 2013;8(10):e76654-e76654.
49.
SignorovitchJESikiricaVErderMH, et al.Matching-adjusted indirect comparisons: A new tool for timely comparative effectiveness research. Value in Health. 2012;15(6):940-947.
50.
CitromeLNortonJCChi-BurrisKDemosG. Pimavanserin for the treatment of Parkinson’s disease psychosis: number needed to treat, number needed to harm, and likelihood to be helped or harmed. CNS Spectrums. 2018;23(3):228-238.
51.
BallardCCummingsJTariotPNPathakSCoateBStankovicS. Pimavanserin for the treatment of Alzheimer’s Disease Psychosis: An evaluation of the clinical importance of efficacy results. medRxiv. 2022:2022.2008.2011.22278482.
52.
CummingsJIsaacsonSMillsR, et al.Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533-540.
53.
BreierASuttonVKFeldmanPD, et al.Olanzapine in the treatment of dopamimetic-induced psychosis in patients with Parkinson's disease. Biol Psychiatry. 2002;52(5):438-445.
54.
EllisTCudkowiczMESextonPMGrowdonJH. Clozapine and risperidone treatment of psychosis in Parkinson's disease. J Neuropsychiatry Clin Neurosci. 2000;12(3):364-369.
55.
FernandezHHOkunMSRodriguezRL, et al.Quetiapine improves visual hallucinations in Parkinson disease but not through normalization of sleep architecture: results from a double-blind clinical-polysomnography study. Int J Neurosci. 2009;119(12):2196-2205.
56.
Giménez-RoldánSMateoDNavarroEGinésMM. Efficacy and safety of clozapine and olanzapine: an open-label study comparing two groups of Parkinson's disease patients with dopaminergic-induced psychosis. Parkinsonism Relat Disord. 2001;7(2):121-127.
57.
GoetzCGBlasucciLMLeurgansSPappertEJ. Olanzapine and clozapine: Comparative effects on motor function in hallucinating PD patients. Neurology. 2000;55(6):789-794.
58.
MeltzerHYMillsRRevellS, et al.Pimavanserin, a serotonin(2A) receptor inverse agonist, for the treatment of parkinson's disease psychosis. Neuropsychopharmacology. 2010;35(4):881-892.
59.
MerimsDBalasMPeretzCShabtaiHGiladiN. Rater-blinded, prospective comparison: Quetiapine versus clozapine for Parkinson's Disease Psychosis. Clinical Neuropharmacology. 2006;29(6):331-337.
60.
MorganteLEpifanioASpinaE, et al.Quetiapine and clozapine in parkinsonian patients with dopaminergic psychosis. Clin Neuropharmacol. 2004;27(4):153-156.
61.
IncAP. A Study of the Safety and Efficacy of Pimavanserin (ACP-103) in Patients With Parkinson's Disease Psychosis. https://ClinicalTrials.gov/show/NCT00477672. Published 2009. Updated June. Accessed.
62.
IncAP. A Study of Safety and Efficacy of Pimavanserin (ACP-103) in Patients With Parkinson's Disease Psychosis. https://ClinicalTrials.gov/show/NCT00658567. Published 2009. Updated December. Accessed.
63.
NicholsMJHartleinJMEickenMGRacetteBABlackKJ. A fixed-dose randomized controlled trial of olanzapine for psychosis in Parkinson disease. F1000Res. 2013;2:150.
64.
OndoWGLevyJKVuongKDHunterCJankovicJ. Olanzapine treatment for dopaminergic-induced hallucinations. Mov Disord. 2002;17(5):1031-1035.
65.
OndoWGTintnerRVoungKDLaiDRingholzG. Double-blind, placebo-controlled, unforced titration parallel trial of quetiapine for dopaminergic-induced hallucinations in Parkinson's disease. Mov Disord. 2005;20(8):958-963.
66.
PintorLValldeoriolaFBaillésEMartíMJMuñizATolosaE. Ziprasidone versus clozapine in the treatment of psychotic symptoms in Parkinson disease: a randomized open clinical trial. Clin Neuropharmacol. 2012;35(2):61-66.
67.
PollakPTisonFRascolO, et al.Clozapine in drug induced psychosis in Parkinson's disease: A randomised, placebo controlled study with open follow up. J Neurol Neurosurg Psychiatry. 2004;75(5):689-695.
68.
RabeyJMProkhorovTMiniovitzADobronevskyEKleinC. Effect of quetiapine in psychotic Parkinson's disease patients: A double-blind labeled study of 3 months' duration. Mov Disord. 2007;22(3):313-318.
69.
ShotboltPSamuelMFoxCDavidAS. A randomized controlled trial of quetiapine for psychosis in Parkinson's disease. Neuropsychiatr Dis Treat. 2009;5:327-332.
70.
Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease. N Engl J Med. 1999;340(10):757-763.
71.
EspayAJGuskeyMTNortonJC, 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.
72.
YunusaIEl HelouMLPimavanserinAlsahali S.A novel antipsychotic with potentials to address an unmet need of older adults with dementia-related psychosis. Front Pharmacol. 2020;11:87-87.
RogersGDaviesDPinkJCooperP. Parkinson’s disease: Summary of updated NICE guidance. BMJ. 2017;358:j1951.
77.
GoldmanJGVernaleoBACamicioliR, et al.Cognitive impairment in Parkinson’s disease: A report from a multidisciplinary symposium on unmet needs and future directions to maintain cognitive health. npj Parkinson's Disease. 2018;4(1):19.
78.
WojtalaJHeberIANeuserP, et al.Cognitive decline in Parkinson’s disease: The impact of the motor phenotype on cognition. Journal of Neurology, Neurosurgery & Psychiatry. 2019;90(2):171.
79.
BaianoCBaronePTrojanoLSantangeloG. Prevalence and clinical aspects of mild cognitive impairment in Parkinson's Disease: A meta-analysis. Movement Disorders. 2020;35(1):45-54.
80.
EspayAJGuskeyMTNortonJC, et al.Pimavanserin for Parkinson's Disease psychosis: Effects stratified by baseline cognition and use of cognitive-enhancing medications. Movement disorders : official journal of the Movement Disorder Society. 2018;33(11):1769-1776.
Torres-YaghiYCarwinACarolanJNakanoSAmjadFPaganF. QTc Interval prolongation with therapies used to treat patients with Parkinson's Disease Psychosis: A narrative review. Neuropsychiatr Dis Treat. 2021;17:3791-3818.
85.
American Geriatrics Society 2019 Updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019;67(4):674-694.
86.
O'MahonyDO'SullivanDByrneSO'ConnorMNRyanCGallagherP. STOPP/START criteria for potentially inappropriate prescribing in older people: version 2. Age Ageing. 2015;44(2):213-218.
87.
SinghSLokeYK. Drug safety assessment in clinical trials: Methodological challenges and opportunities. Trials. 2012;13:138-138.
88.
RissardoJPDuranteÍSharonIFornari CapraraAL. Pimavanserin and Parkinson’s Disease Psychosis: A narrative review. Brain Sciences. 2022;12(10):1286.
89.
BrozekJFalavignaM. What determines the width of the confidence interval. Users’ guides to the medical literature: a manual for evidence-based clinical practiceNew York: McGraw-Hill. 2008:225-231.
90.
MbuagbawLRochwergBJaeschkeR, et al.Approaches to interpreting and choosing the best treatments in network meta-analyses. Systematic reviews. 2017;6(1):79-79.
91.
RückerGSchwarzerG. Ranking treatments in frequentist network meta-analysis works without resampling methods. BMC Medical Research Methodology. 2015;15(1):58.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
