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Incidence of antipsychotic use among community dwellers with and without Parkinson's disease

  • Satu Lilja
    Affiliations
    School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland

    Kuopio Research Centre of Geriatric Care, University of Eastern Finland, Kuopio, Finland
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  • Anna-Maija Tolppanen
    Affiliations
    School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland

    Kuopio Research Centre of Geriatric Care, University of Eastern Finland, Kuopio, Finland
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  • Marjaana Koponen
    Affiliations
    School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland

    Kuopio Research Centre of Geriatric Care, University of Eastern Finland, Kuopio, Finland

    Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia
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  • Sirpa Hartikainen
    Affiliations
    School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland

    Kuopio Research Centre of Geriatric Care, University of Eastern Finland, Kuopio, Finland
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  • Miia Tiihonen
    Correspondence
    Corresponding author. School of Pharmacy, University of Eastern Finland, PL1627, 70211, Kuopio, Finland.
    Affiliations
    School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland

    Kuopio Research Centre of Geriatric Care, University of Eastern Finland, Kuopio, Finland
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Open AccessPublished:August 23, 2022DOI:https://doi.org/10.1016/j.parkreldis.2022.08.024

      Highlights

      • The incidence of antipsychotic use starts to emerge before Parkinson's disease (PD).
      • The initiation of antipsychotic was nearly 3 times more common in people with PD than in the comparison cohort.
      • Quetiapine was the most commonly initiated antipsychotic among people with PD.

      Abstract

      Introduction

      Previous studies have assessed antipsychotic use after Parkinson's disease (PD) diagnosis, but incident antipsychotic use before PD diagnosis is unknown. The objective is to study the incidence of antipsychotic use among community-dwelling persons with and without PD 10 years before and after the PD diagnosis.

      Methods

      The study was based on the nationwide register-based FINPARK-study including 20,994 persons with PD (diagnosed 1996–2015) and 142,944 comparison persons who had not used antipsychotics during one-year washout before the follow-up. PD was diagnosed according to the United Kingdom's Parkinson's disease Society Brain Bank's criteria. Antipsychotic initiations in six-month time-windows was assessed.

      Results

      26.9% (n = 5,654) of people with PD initiated antipsychotics in comparison to 9.7% (n = 13,887) of people without PD during the entire follow-up. The incidence rate increased in people with PD approximately four years before the PD diagnosis. The most commonly initiated antipsychotic was quetiapine (n = 3,642, 64.4%) in persons with PD and risperidone (n = 5,232, 37.7%) in comparison persons. The initiation rates were higher in persons with PD before (6.5 and 3.0/1000 person-years for persons with and without PD, respectively, incidence rate ratio 2.18, 95%CI 2.03–2.33) and after the index date (43.3 and 11.7/1000 person-years for persons with and without PD, respectively, IRR 3.70, 95%CI 3.57–3.83).

      Conclusion

      Persons with PD have symptoms treated with antipsychotics both before and after diagnosis. Psychotic symptoms may be challenging to recognize as prodromal symptoms since they can occur years before the motor symptoms and thus, they cannot be clinically associated with the diagnosis of PD.

      Keywords

      1. Introduction

      Antipsychotic use is common among people with Parkinson's disease (PD). In previous studies assessing antipsychotic initiations after PD diagnosis, 22%–51% of participants initiated antipsychotics [
      • Orayj K.
      Trends and contributing factors for prescribing antipsychotics in newly diagnosed Parkinson's disease patients: a population-based study.
      ,
      • van de Vijver D.A.
      • Roos R.A.
      • Jansen P.A.
      • Porsius A.J.
      • de Boer A.
      Antipsychotics and Parkinson's disease: association with disease and drug choice during the first 5 years of antiparkinsonian drug treatment.
      ,
      • Marras C.
      • Kopp A.
      • Qiu F.
      • Lang A.E.
      • Sykora K.
      • Shulman K.I.
      • Rochon P.A.
      Antipsychotic use in older adults with Parkinson's disease.
      ,
      • Wang M.T.
      • Lian P.W.
      • Yeh C.B.
      • Yen C.H.
      • Ma K.H.
      • Chan A.L.
      Incidence, prescription patterns, and determinants of antipsychotic use in patients with Parkinson's disease.
      ]. Almost 50% of people with PD have psychotic symptoms including hallucinations, delusions, and false sense of presence at some point of disease [
      • Aarsland D.
      • Marsh L.
      • Schrag A.
      Neuropsychiatric symptoms in Parkinson's disease.
      ,
      • Yuan M.
      • Sperry L.
      • Malhado‐Chang N.
      • Duffy A.
      • Wheelock V.
      • Farias S.
      • O'Connor K.
      • Olichney J.
      • Shahlaie K.
      • Zhang L.
      Atypical antipsychotic therapy in Parkinson's disease psychosis: a retrospective study.
      ]. These symptoms may occur even before the motor symptoms during the prodromal stage [
      • Pagonabarraga J.
      • Martinez-Horta S.
      • Fernandez de Bobadilla R.
      • Pérez J.
      • Ribosa-Nogué R.
      • Marín J.
      • Pascual-Sedano B.
      • García C.
      • Gironell A.
      • Kulisevsky J.
      Minor hallucinations occur in drug-naive Parkinson's disease patients, even from the premotor phase.
      ]. The underlying cause for prodromal psychotic symptoms as well Parkinson's disease psychosis is not yet understood [
      • Aarsland D.
      • Marsh L.
      • Schrag A.
      Neuropsychiatric symptoms in Parkinson's disease.
      ]. However, psychotic symptoms are more common in advanced stages of PD [
      • Schapira A.H.V.
      • Chaudhuri K.R.
      • Jenner P.
      Non-motor features of Parkinson disease.
      ]. In addition to PD, some PD medications, such as dopamine agonists, may cause psychotic symptoms [
      • Blandini F.
      • Armentero M.T.
      Dopamine receptor agonists for Parkinson's disease.
      ]. Therefore, the first treatment of psychotic symptoms is reduction of dopaminergic PD medication. In some cases, this is not enough and an antipsychotic drug is needed [
      • Samudra N.
      • Patel N.
      • Womack K.B.
      • Khemani P.
      • Chitnis S.
      Psychosis in Parkinson disease: a review of etiology, phenomenology, and management, drugs.
      ].
      Previous studies have assessed antipsychotic use after the PD diagnosis [
      • Orayj K.
      Trends and contributing factors for prescribing antipsychotics in newly diagnosed Parkinson's disease patients: a population-based study.
      ,
      • van de Vijver D.A.
      • Roos R.A.
      • Jansen P.A.
      • Porsius A.J.
      • de Boer A.
      Antipsychotics and Parkinson's disease: association with disease and drug choice during the first 5 years of antiparkinsonian drug treatment.
      ,
      • Marras C.
      • Kopp A.
      • Qiu F.
      • Lang A.E.
      • Sykora K.
      • Shulman K.I.
      • Rochon P.A.
      Antipsychotic use in older adults with Parkinson's disease.
      ,
      • Wang M.T.
      • Lian P.W.
      • Yeh C.B.
      • Yen C.H.
      • Ma K.H.
      • Chan A.L.
      Incidence, prescription patterns, and determinants of antipsychotic use in patients with Parkinson's disease.
      ]. However, the nonmotor symptoms are well known to occur also during the prodromal stage, but there is, as far as we know, no previous studies about the incidence of antipsychotic use before PD diagnosis. This information has clinical relevance in relation to understanding the burden of psychotic symptoms already in prodromal stage.
      We investigated the incidence of antipsychotic use in community-dwelling persons with PD compared to people without PD from 10 years before the PD diagnosis to 10 years after the diagnosis.

      2. Methods

      The FINPARK study contains people who received special reimbursement for PD drugs between 1996 and 2015 in Finland and were community-dwelling at the time of diagnosis. They were identified from the Special Reimbursement Register which is maintained by the Social Insurance Institution of Finland (SII). This register includes records of people who are eligible for higher reimbursement due to chronic diseases. A person is eligible for the reimbursement for PD medication after neurologists at SII review and accept a statement from a neurologist that has confirmed the diagnosis according to the United Kingdom's Parkinson's disease Society Brain Bank's criteria. The statement must entail anamnesis and a clinical description of the patient's symptoms. The special reimbursement does not cover drug-induced parkinsonism and therefore these persons are excluded from our study. If a person on antipsychotics is suspected to have PD, the applicant's neurologist discontinues antipsychotics, and the assessment of PD symptoms and possible diagnostic workup is conducted after several weeks (short-term use) or months (long-term use) withdrawal.
      Originally, 29,942 people eligible for reimbursed PD medication were included, but people aged <35 years at the time of diagnosis (N = 53), those who did not have the ICD-10 code G20 for PD (N = 1,244) or had diagnosis for other diseases that have similar symptoms as PD within two years of the PD diagnosis date were excluded (N = 6,456), leaving 22,189 people with PD. The exclusion diagnoses have been described by Hentilä et al. [
      • Hentilä E.
      • Tiihonen M.
      • Taipale H.
      • Hartikainen S.
      • Tolppanen A.M.
      Incidence of antidepressant use among community dwellers with and without Parkinson's disease - a nationwide cohort study.
      ]. For each person with PD up to seven comparison persons were matched by sex, age (±1 year) and region-matched comparison cohort (N = 148,009) The date of PD diagnosis was the index date for the matched comparison persons. Comparison persons who had bought PD medication (Anatomical Therapeutic Chemical (ATC) classification code N04) or had the reimbursement code before the index date or 12 months later were excluded.
      The incidence of antipsychotic use was studied from 10 years before to 10 years after the diagnosis of PD. The data on dispensed antipsychotics were gained from the Prescription Register that includes information of all reimbursed medication purchases of community-dwelling Finnish persons.
      A one-year washout-period 11 years–10 years before PD diagnosis was applied to both PD and comparison cohort. For those diagnosed before or during the year 2005, we used year 1995 as a one-year washout-period. We excluded persons or who had bought antipsychotics during the washout-period, or those who were hospitalised for over 50% of the washout period or hospitalised for the last 90 days of washout period (Supplementary Fig. 1). Persons with diagnosis of schizophrenia or other chronic psychosis were excluded. This led to a cohort of 20,994 people with PD and 142,944 comparison people without PD. Information of the hospitalisation was extracted from the Care Register for Health Care. Data on comorbidities was gathered from Care Register for Health Care, Special reimbursement register and Prescription register (Supplementary Table 1). Antipsychotics were defined as ATC class N05A (excluding lithium and prochlorperazine).
      The rate of antipsychotic initiations (initiation rate IR) per 100 persons-years was calculated for every six months beginning from 10 years to 10 years after the diagnosis or index date. The comparison of the incidence rates was executed by calculating the incidence rate ratios (IRR) with 95% confidence intervals (CI) by using Poisson regression between persons with PD and their comparison persons. The analyses were conducted using Stata MP 14.0.
      Collected data was de-identified thus no ethics committee approval was required according to Finnish legislation.

      3. Results

      Over half of the study cohort were men (55.3% with PD and 55.4% without PD). The mean age of persons with PD on the index date was 70.5 and 70.9 among persons without PD. During the entire study period 26.9% (n = 5,654) of people with PD and 9.7% (n = 13,887) people without PD initiated antipsychotics (initiation rates 20.3 and 6.3/1000 person-years for persons with and without PD, respectively, IRR 3.20, 95% CI 3.10–3.30). The initiation rates were higher in persons with PD before (6.5 and 3.0/1000 person-years for persons with and without PD, respectively, incidence rate ratio 2.18, 95%CI 2.03–2.33) and after the index date (43.3 and 11.7/1000 person-years for persons with and without PD, respectively, IRR 3.70, 95%CI 3.57–3.83). Persons with PD initiated antipsychotic use at younger age (mean age 74.6) than those without PD 77.7, Table 1). Antipsychotic initiators with PD were more likely to be men (n = 3,166, 56.0%) than antipsychotic initiators without PD (n = 6,738, 48.5%).
      Table 1Comparison of incident antipsychotic initiators and non-initiators with and without Parkinson's disease (PD). Comorbidities and university hospital district represent data on the index date (date of PD diagnosis).
      Parkinson's disease n = 20,994No Parkinson's disease n = 142,944
      Initiators (n = 5,654)Non-initiators (n = 15,340)P
      Difference between initiators and non-initiators.
      Initiators (n = 13,887)Non-initiators (n = 129,057)P
      Difference between initiators and non-initiators.
      P
      Difference between initiators with and without PD.
      Sex (men) (n, %)3,166 (56.0)8,441 (55.0)0.2106,738 (48.5)72,437 (56.1)<0.001<0.001
      Age at PD diagnosis/index date70.6 (70.4–70.9)71.0 (70.9–71.2)

      71.2)
      0.00173.3 (73.1–73.4)70.2 (70.1–70.2)<0.001
      Age at initiation (mean, 95% CI)74.6 (74.4–74.8)77.7 (77.5–77.9)<0.001
      Comorbidities (n, %)
       Any mood disorder48 (0.9)110 (0.7)0.327195 (1.4)752 (0.6)<0.0010.001
       Cardiovascular disease2,284 (40.4)5,933 (38.7)0.0246,068 (43.7)48,564 (37.6)<0.001<0.001
       Diabetes630 (11.1)2,054 (13.4)<0.0011,837 (13.2)15,776 (12.2)0.001<0.001
       Asthma/COPD397 (7.0)1,138 (7.4)0.3271,183 (8.5)9,551 (7.4)<0.001<0.001
       Rheumatoid arthritis172 (3.0)541 (3.5)0.085497 (3.6)4,801 (3.7)0.4030.061
      University hospital district (n, %)0.003<0.0010.384
       Helsinki1,608 (28.4)4,505 (29.4)3,844 (27.7)38,066 (29.5)
       Kuopio1,131 (20.0)2,757 (18.0)2,767 (19.9)23,423 (18.2)
       Oulu757 (13.4)2,192 (14.3)1,976 (14.2)17,936 (13.9)
       Tampere1,349 (23.9)3,750 (24.5)3,384 (24.4)31,559 (24.5)
       Turku789 (14.0)2,051 (13.4)1,881 (13.6)17,366 (13.5)
       Other (Åland)20 (0.4)85 (0.6)35 (0.3)707 (0.6)
      Drug use (n, %)
       Antidepressant use during 1-year washout440 (7.8)713 (4.7)<0.0011,281 (9.2)4,430 (3.4)<0.0010.001
       Benzodiazepine and related drug use during 1-year washout904 (16.0)1,703 (11.1)<0.0013,208 (23.1)12,342 (9.6)<0.001<0.001
      Number of purchased antipsychotics at initiation
       15,627 (99.5)13,719 (98.8)
       227 (0.5)165 (1.2)
       30 (0)3 (0.02)
      Antipsychotic
       Quetiapine3,642 (64.4)4,331 (31.2)
       Risperidone856 (15.1)5,232 (37.7)
       Haloperidole222 (3.9)1,388 (10.0)
       Clozapine220 (3.9)50 (0.4)
       Melperone192 (3.4)601 (4.3)
      Levomepromazine120 (2.1)610 (4.4)
      a Difference between initiators and non-initiators.
      b Difference between initiators with and without PD.
      Initiation of antipsychotic drug use was more common in people with PD throughout the whole study period, but the incidence rate started to increase in people with PD approximately four years before the diagnosis of PD (Fig. 1a). The greatest difference was observed 5 years after the diagnosis (IRR = 5.9, CI 4.9–7.0) (Supplementary Table 2). The initiation rate was highest among people with PD 7.5 years after the diagnosis (IR = 7.5, CI 6.3–9.0).
      Fig. 1
      Fig. 1Incidence of a) any antipsychotic b) quetiapine c) risperidone initiation in relation to Parkinson's disease (PD) diagnosis date.
      The most commonly initiated antipsychotic among people with PD was quetiapine (n = 3,642, 64.4%), followed by risperidone (n = 856, 15.1%), haloperidol (n = 222, 3.9%) and clozapine (n = 220, 3.9%) (Table 1). Among people without PD risperidone was the most initiated antipsychotic (n = 5,232, 37.7%), followed by quetiapine (n = 4,331, 31.2%), haloperidol (n = 1,388, 10.0%), melperone (n = 601, 4.3%), levomepromazine (n = 610, 4.4%) and clozapine (n = 50, 0.4%). There was variation in the initiated antipsychotics (Supplementary Table 3) Quetiapine was the most commonly initiated antipsychotic in people with PD after PD diagnosis (74.5%), followed by risperidone, while only 20.7% of those with PD who initiated before PD diagnosis initiated with quetiapine. Among people without PD both quetiapine and risperidone initiations increased after the index date.
      The incidence of quetiapine use followed the same trend in people with PD and without PD to four years before the index date (Fig. 1b). After this the incidence in persons with PD began to increase consistently until 5.5 years after the index date. The highest incidence among people with PD was observed 7.5 years after the index date (IR = 6.4, CI 5.3–7.8) while the largest difference between people with PD and without PD occurred 5 years after the index date (IRR = 10.8).
      The incidence of risperidone use was similar between the groups, although a transient increase among people with PD in comparison to people without PD was observed until the index date (Fig. 1c). In general, no significant difference between the groups was observed after the index date. The highest incidence occurred five years after the diagnosis among people with PD (IR = 1.1, CI 0.8–1.6) and ten years after the index date (IR = 1.2, CI 1.0–1.4) in persons without PD. The largest difference was observed eight years before the diagnosis (IRR 5.4).

      4. Discussion

      To our knowledge this is the first study that investigated the temporal changes in antipsychotic initiations in relation to PD diagnosis and evaluated also the prediagnostic period. The initiation of antipsychotic use was nearly three times more common in people with PD (26.9%) than in the comparison cohort (9.7%) during the entire follow-up. The incidence of antipsychotic use began to rise already four years before the diagnosis of PD. These findings support that neuropsychiatric symptoms of PD might start years before the diagnosis.
      The difference was mainly explained by the quetiapine use, which was the most commonly initiated antipsychotic among people with PD in our study. In addition to treating psychotic symptoms, quetiapine is used in off-label treatment of insomnia. This off-label use is relatively common in Finland. Risperidone was initiated less often, by only one sixth of persons with PD. This is according to recommendations since it can worsen the motor symptoms. Similar to our study, quetiapine and risperidone were the most common antipsychotics also in two previous studies [
      • Orayj K.
      Trends and contributing factors for prescribing antipsychotics in newly diagnosed Parkinson's disease patients: a population-based study.
      ,
      • Marras C.
      • Kopp A.
      • Qiu F.
      • Lang A.E.
      • Sykora K.
      • Shulman K.I.
      • Rochon P.A.
      Antipsychotic use in older adults with Parkinson's disease.
      ]. Although clozapine is approved and recommended antipsychotic for persons with PD due to lack of extrapyramidal adverse effects, it was not commonly used in our or previous studies [
      • Orayj K.
      Trends and contributing factors for prescribing antipsychotics in newly diagnosed Parkinson's disease patients: a population-based study.
      ,
      • Marras C.
      • Kopp A.
      • Qiu F.
      • Lang A.E.
      • Sykora K.
      • Shulman K.I.
      • Rochon P.A.
      Antipsychotic use in older adults with Parkinson's disease.
      ,
      • Wang M.T.
      • Lian P.W.
      • Yeh C.B.
      • Yen C.H.
      • Ma K.H.
      • Chan A.L.
      Incidence, prescription patterns, and determinants of antipsychotic use in patients with Parkinson's disease.
      ]. This may be due to risk of agranulocytosis and need for frequent blood monitoring during clozapine treatment.
      The underlying cause for Parkinson's disease psychosis is not yet fully known but is most likely a complex combination of extrinsic and intrinsic factors [
      • Samudra N.
      • Patel N.
      • Womack K.B.
      • Khemani P.
      • Chitnis S.
      Psychosis in Parkinson disease: a review of etiology, phenomenology, and management, drugs.
      ]. According to the Finnish care guidelines the first treatment for psychotic symptoms is to stop anticholinergic drug use, deprescribing (dose reduction or if needed, discontinuing the use) of dopaminergic PD medication and if these are not enough, stopping the use of MAO-B inhibitors or COMT inhibitors or both and after that levodopa dose should be reduced. If these changes in the medication do not provide sufficient relief of symptoms, prescribing antipsychotic should be considered [

      Parkinson’s disease: Current Care Guidelines. Working Group Appointed by the Finnish Medical Society Duodecim, the Finnish Neurological Society. Helsinki: The Finnish Medical Society Duodecim 2022. (referred June 17, 2022). Available online at: www.kaypahoito.fi.

      ]. The most preferred antipsychotics are quetiapine, pimavanserin (only available in the US) and clozapine as these drugs do not increase motor symptoms [

      Parkinson’s disease: Current Care Guidelines. Working Group Appointed by the Finnish Medical Society Duodecim, the Finnish Neurological Society. Helsinki: The Finnish Medical Society Duodecim 2022. (referred June 17, 2022). Available online at: www.kaypahoito.fi.

      ,
      • Schneider R.B.
      • Iourinets J.
      • Richard I.H.
      Parkinson's disease psychosis: presentation, diagnosis and management.
      ]. In accordance with care recommendations and guideline, quetiapine was clearly the most initiated antipsychotic after the diagnosis of PD in present study.
      In our study, antipsychotics were initiated by one quarter of persons with PD during the study period. Previous studies [
      • Orayj K.
      Trends and contributing factors for prescribing antipsychotics in newly diagnosed Parkinson's disease patients: a population-based study.
      ,
      • van de Vijver D.A.
      • Roos R.A.
      • Jansen P.A.
      • Porsius A.J.
      • de Boer A.
      Antipsychotics and Parkinson's disease: association with disease and drug choice during the first 5 years of antiparkinsonian drug treatment.
      ,
      • Marras C.
      • Kopp A.
      • Qiu F.
      • Lang A.E.
      • Sykora K.
      • Shulman K.I.
      • Rochon P.A.
      Antipsychotic use in older adults with Parkinson's disease.
      ,
      • Wang M.T.
      • Lian P.W.
      • Yeh C.B.
      • Yen C.H.
      • Ma K.H.
      • Chan A.L.
      Incidence, prescription patterns, and determinants of antipsychotic use in patients with Parkinson's disease.
      ] have followed antipsychotic initiations after the PD diagnosis. In earlier studies, the cumulative probability of persons with PD, who have initiated antipsychotics after PD diagnosis, has varied between 22 and 51%. The study with lowest probability was conducted in the 1992–1998 [
      • van de Vijver D.A.
      • Roos R.A.
      • Jansen P.A.
      • Porsius A.J.
      • de Boer A.
      Antipsychotics and Parkinson's disease: association with disease and drug choice during the first 5 years of antiparkinsonian drug treatment.
      ], while higher probability of initiations observed in more recent studies (35% in a Canadian study from 1998 to 2003 and 51% in a Taiwanese study from 2000 to 2006) [
      • Marras C.
      • Kopp A.
      • Qiu F.
      • Lang A.E.
      • Sykora K.
      • Shulman K.I.
      • Rochon P.A.
      Antipsychotic use in older adults with Parkinson's disease.
      ,
      • Wang M.T.
      • Lian P.W.
      • Yeh C.B.
      • Yen C.H.
      • Ma K.H.
      • Chan A.L.
      Incidence, prescription patterns, and determinants of antipsychotic use in patients with Parkinson's disease.
      ]. As those studies included newly diagnosed PD cases and had similar length of follow-up, the differences are more likely to be due to increased trend of quetiapine use. It is also possible that between-country differences in treatment traditions explain the variability in results. Recent study reported that among newly diagnosed patients with PD, 22% had psychotic symptoms during the first year of PD and 55% of those with psychotic symptoms were treated with antipsychotics [
      • Orayj K.
      Trends and contributing factors for prescribing antipsychotics in newly diagnosed Parkinson's disease patients: a population-based study.
      ].
      The strengths of our study were availability of nationwide data from different registers, long follow-up period and the possibility to compare the use to a matched group without PD. The diagnosis was clinically verified diagnosis of PD and exclusion of diagnoses with similar symptoms were applied before creating the final cohorts. One limitation of our study is that the collected data did not include the indication or dosage of the initiated antipsychotic. Prescription register does not include drugs used in nursing homes and hospitals in which the use is presumably higher.
      In conclusion, the initiation of antipsychotic drugs was higher in people with PD than without PD beginning already years before the PD diagnosis. Psychotic symptoms may be challenging to recognize as prodromal symptoms of PD since they can occur years before the motor symptoms and thus, they cannot be clinically associated with the diagnosis of PD.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Declaration of competing interest

      None.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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