Impact of Current Antipsychotic Medications on Comparative Mortality and Adverse Events in People With Parkinson Disease Psychosis



      To establish the mortality risk and adverse events associated with the use of atypical antipsychotic medications in people with Parkinson disease psychosis (PDP) in a clinically defined trial cohort.


      Post hoc analysis of data from a multicenter, open-label extension study of pimavanserin comparing people taking and not taking current antipsychotics.


      Primary and secondary care medical centers in the United States, Canada, Europe, and India.


      A total of 459 people with PDP enrolled in the extension study. Participants were between ages 30 and 80 years, and had an established diagnosis of idiopathic Parkinson disease and moderate to severe psychosis.


      Participants were categorized into 2 groups: those receiving concomitant antipsychotic medications (“concurrent APD”) and those who did not take antipsychotic medications at any time during the study (“no APD”). Participants were receiving 40 mg pimavanserin daily in addition to concurrent antipsychotics and Parkinson disease medications.

      Main Outcome Measures

      Safety assessments at 2 weeks; 1, 3, 6, 9, and 12 months; and every 6 months thereafter, including evaluation of adverse events (AEs), vital signs, weight, physical examinations, 12-lead electrocardiograms, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and the Unified Parkinson's Disease Rating Scale Parts II and III (UPDRS-II+III, activities of daily living and motor impairment, respectively). Differences between participants taking and not taking current antipsychotics were evaluated using incidence rate ratios (IRRs) with 95% confidence intervals (CIs).


      There was significant increase in the mortality rate for participants taking concurrent antipsychotics compared with the group not taking antipsychotic medications (IRR 4.20, 95% CI 2.13–7.96). Participants who received a concurrent antipsychotic were also significantly more likely to experience overall a serious AE (IRR 2.95, 95% CI 2.02–4.24), any antipsychotic-related event (IRR 1.66, 95% CI 1.18–2.29), cognition-related events (IRR 2.70, 95% CI 1.19–5.58), infections (IRR 1.97, 95% CI 1.17–3.16), and edema (IRR 2.61, 95% CI 1.09–5.59). The risk of falls, stroke, sedation, orthostatic hypotension, and thromboembolic events was also increased in these individuals but this was not significant.


      This study highlights a significant risk of mortality, and severe AEs in patients with Parkinson disease receiving atypical antipsychotics. This is similar to or greater than the risks seen in people with Alzheimer disease, although with a less clear-cut risk of stroke and a longer delay to increased mortality.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of the American Medical Directors Association
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


      1. Parkinson's Disease Foundation, Inc. Statistics on Parkinson's. New York, NY. Available at: Accessed August 13, 2014.

        • Starkstein S.E.
        • Brockman S.
        • Hayhow B.D.
        Psychiatric syndromes in Parkinson's disease.
        Curr Opin Psychiatry. 2012; 25: 468-472
        • Aarsland D.
        • Ballard C.
        • Larsen J.P.
        • McKeith I.
        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: 528-536
        • The French Clozapine Parkinson Study Group
        Clozapine in drug-induced psychosis in Parkinson's disease.
        Lancet. 1999; 353: 2041-2042
        • The Parkinson Study Group
        Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease.
        N Engl J Med. 1999; 340: 757-763
        • Pollak P.
        • Tison F.
        • Rascol O.
        • 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: 689-695
        • Seppi K.
        • Weintraub D.
        • Coelho M.
        • et al.
        The movement Disorder society evidence-based medicine review Update: Treatments for the non-motor symptoms of Parkinson's disease.
        Mov Disord. 2011; 26: S42-S80
        • Kurlan R.
        • Cummings J.
        • Raman R.
        • Thal L.
        Quetiapine for agitation or psychosis in patients with dementia and parkinsonism.
        Neurology. 2007; 68: 1356-1363
        • Rabey J.M.
        • Prokhorov T.
        • Miniovitz A.
        • et al.
        Effect of quetiapine in psychotic Parkinson's disease patients: A double-blind labeled study of 3 months' duration.
        Mov Disord. 2007; 22: 313-318
        • Tariot P.N.
        • Schneider L.
        • Katz I.R.
        • et al.
        Quetiapine treatment of psychosis associated with dementia: A double-blind, randomized, placebo-controlled clinical trial.
        Am J Geriatr Psychiatry. 2006; 14: 767-776
        • Ondo W.G.
        • Tintner R.
        • Voung K.D.
        • et al.
        Double-blind, placebo-controlled, unforced titration parallel trial of quetiapine for dopaminergic-induced hallucinations in Parkinson's disease.
        Mov Disord. 2005; 20: 958-963
        • Shotbolt P.
        • Samuel M.
        • Fox C.
        • David A.S.
        A randomized controlled trial of quetiapine for psychosis in Parkinson's disease.
        Neuropsychiatr Dis Treat. 2009; 5: 327-332
        • Breier A.
        • Sutton V.K.
        • Feldman P.D.
        • et al.
        Olanzapine in the treatment of dopamimetic-induced psychosis in patients with Parkinson's disease.
        Biol Psychiatry. 2002; 52: 438-445
        • Ondo W.G.
        • Levy J.K.
        • Vuong K.D.
        • et al.
        Olanzapine treatment for dopaminergic-induced hallucinations.
        Mov Disord. 2002; 17: 1031-1035
        • Nichols M.J.
        • Hartlein J.M.
        • Eicken M.G.
        • et al.
        A fixed-dose randomized controlled trial of olanzapine for psychosis in Parkinson disease.
        F1000Res. 2013; 2: 150
        • Rich S.S.
        • Friedman J.H.
        • Ott B.R.
        Risperidone versus clozapine in the treatment of psychosis in six patients with Parkinson's disease and other akinetic-rigid syndromes.
        J Clin Psychiatry. 1995; 56: 556-559
        • Friedman J.H.
        • Berman R.M.
        • Goetz C.G.
        • et al.
        Open-label flexible-dose pilot study to evaluate the safety and tolerability of aripiprazole in patients with psychosis associated with Parkinson's disease.
        Mov Disord. 2006; 21: 2078-2081
        • Factor S.A.
        • Friedman J.H.
        • Lannon M.C.
        • 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: 135-139
        • Wolters E.C.
        • Hurwitz T.A.
        • Mak E.
        • et al.
        Clozapine in the treatment of parkinsonian patients with dopaminomimetic psychosis.
        Neurology. 1990; 40: 832-834
        • Fernandez H.H.
        • Trieschmann M.E.
        • Burke M.A.
        • Friedman J.H.
        Quetiapine for psychosis in Parkinson's disease versus dementia with Lewy bodies.
        J Clin Psychiatry. 2002; 63: 513-515
        • Morgante L.
        • Epifanio A.
        • Spina E.
        • et al.
        Quetiapine and clozapine in parkinsonian patients with dopaminergic psychosis.
        Clin Neuropharmacol. 2004; 27: 153-156
        • Klein C.
        • Gordon J.
        • Pollak L.
        • Rabey J.M.
        Clozapine in Parkinson's disease psychosis: 5-Year follow-up review.
        Clin Neuropharmacol. 2003; 26: 8-11
        • Cummings J.
        • Isaacson S.
        • Mills R.
        • et al.
        Pimavanserin for patients with Parkinson's disease psychosis: A randomised, placebo-controlled phase 3 trial.
        Lancet. 2014; 383: 533-540
      2. Mills R, Williams, H., Bahr, D. Optimization of Phase III study design for pimavanserin in the treatment of Parkinson's disease psychosis. Abstract presented at XIX World Congress on Parkinson's Disease and Related Disorders; Shanghai, China; December 11-14, 2011.

      3. A study of safety and efficacy of pimavanserin (ACP-103) in patients with Parkinson’s disease psychosis. Available at: Accessed August 13, 2014.

        • Shulman L.M.
        • Gruber-Baldini A.L.
        • Anderson K.E.
        • et al.
        The clinically important difference on the unified Parkinson's disease rating scale.
        Arch Neurol. 2010; 67: 64-70