Pimavanserin as treatment for Parkinson's disease psychosis

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logistical challenges, including: settling on the type of HPV screening test to be used; ascertaining appropriate screening ages and intervals; defining triage and management policies for HPV-positive women; and ensuring quality of and adherence to revised policies.

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Sandra D Isidean, *Eduardo L Franco Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada H3A 1A2; and Department of Oncology, McGill University, Montreal, QC, Canada H2W 1S6 [email protected] ELF has served as a consultant or advisory board member for companies involved in HPV vaccination (Merck, GlaxoSmithKline), HPV diagnostics (Roche, Qiagen, Gen-Probe), and cytology (Cytyc, Ikonisys). McGill University has received grants from Merck to support investigator-initiated research by ELF. SDI declares that she has no conflicts of interest. 1

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Arbyn M, Ronco G, Anttila A, et al. Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer. Vaccine 2012; 30 (suppl 5): F88–99. Sankaranarayanan R, Nene BM, Shastri SS, et al. HPV screening for cervical cancer in rural India. N Engl J Med 2009; 360: 1385–94. Canadian Task Force on Preventive Health Care. Recommendations on screening for cervical cancer. CMAJ 2013; 185: 35–45.

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Arbyn M, Anttila A, Jordan J, et al. European guidelines for quality assurance in cervical cancer screening: 2nd edn—summary document. Ann Oncol 2010; 21: 448–58. Ronco G, Dillner J, Elfström KM, et al, and the International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet 2013; published online Nov 3. http://dx.doi.org/10.1016/S01406736(13)62218-7. Naucler P, Ryd W, Tornberg S, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med 2007; 357: 1589–97. Bulkmans NWJ, Berkhof J, Rozendaal L, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet 2007; 370: 1764–72. Rijkaart DC, Berkhof J, Rozendaal L, et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol 2012; 13: 78–88. Kitchener HC, Almonte M, Thomson C, et al. HPV testing in combination with liquid-based cytology in primary cervical screening (ARTISTIC): a randomised controlled trial. Lancet Oncol 2009; 10: 672–82. Ronco G, Giorgi-Rossi P, Carozzi F, et al, and the New Technologies for Cervical Cancer screening (NTCC) Working Group. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol 2010; 11: 249–57. Franco EL, Mahmud SM, Tota J, Ferenczy A, Coutlee F. The expected impact of HPV vaccination on the accuracy of cervical cancer screening: the need for a paradigm change. Arch Med Res 2009; 40: 478–85.

Lysia Forno/Science Photo Library

Pimavanserin as treatment for Parkinson’s disease psychosis

Published Online November 1, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)62157-1 See Articles page 533

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Parkinson’s disease psychosis is common and causes substantial caregiver burden, resulting in a high rate of visits to emergency rooms and admission to nursing homes. The symptoms typically consist of illusions, hallucinations, and more bothersome and distressing paranoid delusions.1 Management includes exclusion of medical causes of delirium (especially infection), modification of drug treatment that might be the trigger of psychosis, and use of specific antipsychotic drugs. Notably, treatment of patients with Parkinson’s disease with classic dopamine antagonists is not recommended because of a propensity to worsen Parkinson’s disease motor symptoms; moreover, this drug class can be life-threatening in individuals with associated dementia (eg, Lewy body dementia). Present reviews of evidence-based medicine suggest that low doses of the atypical antipsychotic clozapine can provide benefit without worsening of Parkinson’s disease motor symptoms.2 However, concerns remain about use of antipsychotics in this susceptible population3 and clozapine use requires mandatory blood monitoring. The alternative atypical antipsychotic quetiapine is more widely used because of its ease of use, but this drug has

no convincing support for efficacy from randomised controlled trials.2 In The Lancet, Jeffrey Cummings and colleagues4 present a randomised, double-blind, placebocontrolled trial showing benefit and safety of the nondopaminergic drug pimavanserin for the treatment of psychosis in patients with Parkinson’s disease. Pimavanserin might offer an alternative therapy for patients with Parkinson’s disease psychosis without worsening motor symptoms. Pimavanserin is a 5-HT2A receptor inverse agonist.5 5-HT2A receptors are constitutively active, in that they are active even in the absence of the agonist 5-HT and an inverse agonist is able to inhibit such a receptor more effectively than is an antagonist. Atypical antipsychotics are 5-HT2A inverse agonists and this property was targeted in high throughput drug discovery screens, which led to the development of pimavanserin.6 Pimavanserin has highest affinity for 5-HT2A receptors, with a lower affinity for the 5-HT2C receptor and, notably, negligible binding at dopamine D2 or histamine receptors.5 Thus the pharmacological profile predicts better efficacy without motor or sedative side-effects. www.thelancet.com Vol 383 February 8, 2014

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The study4 enrolled 199 patients with Parkinson’s disease (mean age 72 years); overall Parkinson’s disease duration was not stated but all participants had a unified Parkinson’s disease rating scale part III (UPDRS-III) score of more than 30, suggesting moderately advanced disease. Psychosis was present for nearly 3 years and was of mild-to-moderate severity according to the neuropsychiatric inventory (NPI). 15–19% of participants reported previous use of quetiapine or clozapine and about a third were on a cholinesterase inhibitor. Enrolled participants were randomly allocated to pimavanserin or placebo for 6 weeks. The study showed a significant benefit of pimavanserin on all endpoints, including reduced scale for assessment of positive symptoms in Parkinson’s disease (SAPS-PD) scores, clinical global impression of change scores, improved night-time sleep without daytime somnolence, and reduced caregiver burden. Importantly, no worsening of Parkinson’s disease motor symptoms occurred. No differences in outcomes were noted when participants were analysed according to age (<65 years, 66–74 years, and >75 years) or minimental state examination scores (<25 vs ≥25). The most common adverse events were infections, although incidence was much the same in the two groups (13% in the pimavanserin group and 12% in the placebo group). However, because of the known effect of infections on triggering of psychosis, treatment of such infections with antibiotics might have affected psychosis scores. The study was well designed and followed up participants for longer than did many previous doubleblind randomised controlled trials in Parkinson’s disease psychosis. The investigators used a novel runin phase of daily psychosocial interaction to reduce the common placebo effect encountered in clinical trials of Parkinson’s disease. Measurement of Parkinson’s disease psychosis is difficult because of the subjective nature of the condition and because patients might lack insight. To reduce bias and potentially improve symptom evaluation, SAPS-PD was assessed with a live video-conferenced interview with a central masked rater. Despite this technique, SAPS-PD still improved by 14% in the placebo group compared with 37% in the pimavanserin group. The other issue in assessment of an intervention for Parkinson’s disease psychosis is a lack of validated rating scales that are specific for the symptoms of the disorder.7 SAPS-PD focuses on hallucinations and delusions and was adapted from the www.thelancet.com Vol 383 February 8, 2014

schizophrenia SAPS scale.8 This study was the first to use this scale, and comparison of effect size with other treatments for Parkinson’s disease psychosis cannot be made. Further studies will be needed to determine relative efficacy of pimavanserin and clozapine or quetiapine. The ability of a drug to show significance in all endpoints in a Parkinson’s disease trial is unusual, and might reflect the relatively short period of the study (6 weeks) and the fluctuating nature of psychosis. Longterm benefits of pimavanserin will be important to ascertain. Nevertheless, no major safety concerns were noted in the study.4 Pimavanserin can prolong the QTc interval and thus a baseline electrocardiogram will be needed before use. Long-term issues with binding to 5-HT2A and potentially 5-HT2C receptors will need to be monitored (eg, weight gain and metabolic syndrome), although 2 year data suggest no increased incidence of weight gain or metabolic syndrome.9 Cummings and colleagues also present exciting new information about the pathophysiology of Parkinson’s disease psychosis in their study. Pimavanserin was shown to reduce Parkinson’s disease psychosis, confirming the suggestion that atypical antipsychotics work via blockade of 5-HT2A receptors.10 The potential site of action might be increased 5-HT2A receptors in visual and limbic circuits in Parkinson’s disease psychosis.11,12 Dopamine can bind to 5-HT2A receptors and this binding might be a mechanism through which dopaminergic drugs can trigger Parkinson’s disease psychosis. Overall, the study opens up a new therapeutic avenue in treatment of Parkinson’s disease psychosis. With a potentially improved safety profile, pimavanserin might be useful for treatment of patients with Parkinson’s disease and mild symptoms of psychosis and help prevent progression to more bothersome symptoms13 as well as targeting psychosis in other disorders such as Alzheimer’s disease. Susan H Fox Movement Disorder Clinic, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada M5T 2S8 [email protected] I have received consultancy or speaker fees from Acadia, Ipsen, Merck Serono, Merz, Novartis, Teva, and UCB, and research funding from Avanir, Merck Serono, and Phytopharm. 1

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Fenelon G, Soulas T, Zenasni F, Cleret de Langavant L. The changing face of Parkinson’s disease-associated psychosis: a cross-sectional study based on the new NINDS-NIMH criteria. Mov Disord 2010; 25: 763–66. 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: S42–80.

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Weintraub D, Chen P, Ignacio RV, et al. Patterns and trends in antipsychotic prescribing for Parkinson disease psychosis. Arch Neurol 2011; 68: 899–904. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 2013; published Nov 1. http://dx.doi.org/10.1016/S01406736(13)62106-6. Vanover KE, Weiner DM, Makhay M, et al. Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2methylpropyloxy)phenylmethyl) carbamide (2R,3R)dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther 2006; 317: 910–18. Weiner DM, Burstein ES, Nash N, et al. 5-hydroxytryptamine 2A receptor inverse agonists as antipsychotics. J Pharmacol Exp Ther 2001; 299: 268–76. Fernandez HH, Aarsland D, Fénelon G, et al. Scales to assess psychosis in Parkinson’s disease: critique and recommendations. Mov Disord 2008; 23: 484–500. Voss T, Bahr D, Cummings J, et al. Performance of a shortened scale for assessment of positive symptoms for Parkinson’s disease psychosis. Parkinsonism Relat Disord 2013; 19: 295–99.

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Mills R, Williams H, Bahr D, Chi-Burris K, Ballard C. Long term pimavanserin treatment for Parkinson’s disease psychosis (PDP)—an interim analysis of safety and tolerability. 17th International Congress of Parkinson’s Disease and Movement Disorders; Sydney, NSW, Australia; June 16–20, 2013. Meltzer HY, Massey BW. The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol 2011; 11: 59–67. Ballanger B, Strafella AP, van Eimeren T, et al. Serotonin 2A receptors and visual hallucinations in Parkinson disease. Arch Neurol 2010; 67: 416–21. Huot P, Johnston TH, Darr T, et al. Increased 5-HT2A receptors in the temporal cortex of parkinsonian patients with visual hallucinations. Mov Disord 2010; 25: 1399–408. Goetz CG, Fan W, Leurgans S. Antipsychotic medication treatment for mild hallucinations in Parkinson’s disease: positive impact on long-term worsening. Mov Disord 2008; 23: 1541–45.

Yang Bo/ColorChinaPhoto/Associated Press

Can closure of live poultry markets halt the spread of H7N9?

Published Online October 31, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)62109-1 See Articles page 541

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After isolation of avian influenza A H7N9 virus from live poultry markets (LPMs), and reports that several people who were infected with the virus had visited such markets a few days before disease onset, LPMs were suspected to be a main source of human exposure to H7N9 in China.1 After LPM closure was enforced in several Chinese cities, the incidence of H7N9 human cases rapidly reduced.2 In The Lancet, Hongjie Yu and colleagues3 quantify the risk of human infections before and after LPM closure in the Chinese cities of Nanjing, Shanghai, Hangzhou, and Huzhou. The investigators used information about laboratory-confirmed cases of avian influenza A H7N9 virus infection reported in the four cities by June 7, 2013, to fit a statistical model to assess the daily probability of infection for each susceptible individual before and after LPM closure. They report that closure of LPMs reduced the mean daily number of infections by 99% (95% credibility interval 93–100%) in Shanghai, 99% (92–100%) in Hangzhou, 97% (68–100%) in Huzhou, and 97% (81–100%) in Nanjing.3 They conclude that LPM closure should be sustained in areas with high risk of disease spread, and implemented in any urban areas where avian influenza A H7N9 virus appears in the future. LPMs are known to be a high-risk environment for pathogen transmission between birds and for zoonotic transfer to people. If birds spend a sufficient amount of time in LPMs to become infected and transmit the virus to other susceptible birds, sustained virus circulation in LPMs can occur.4 LPMs can then become a permanent source of infection for poultry flocks and for people

who are in close contact with infected poultry and contaminated fomites. LPM closure would therefore be expected to stop human infections caused by a zoonotic pathogen transmitted within markets. Although LPM closure seems to have had an important effect on incidence of avian influenza A H7N9 virus infection in people, the underlying epidemiological and socioeconomic system is complex. LPM closure might not have been the most important cause of a reduction in incidence. Indeed, soon after LPM closures in Nanjing, Shanghai, Hangzhou, and Huzhou, human infections were also interrupted in other cities where this measure was not implemented.3 An example of the complex chain of interacting socioeconomic and epidemiological factors is that reports that poultry is a source of avian influenza A H7N9 virus triggered a drop in demand for poultry meat and consequently in poultry prices.5 Some producers were even forced to destroy their flocks because poultry rearing became cost prohibitive,6 which probably reduced the absolute number of poultry substantially in affected areas and reduced viral circulation, irrespective of LPM closure. Strong consumer reactions to zoonotic health hazards are not uncommon. Fears of avian influenza A H5N1 virus led to reduced consumption of poultry products in Asia in early 2004.7 However, these reductions were temporary: consumers’ anxiety decreased rapidly after the first wave of the outbreak.8 Consumption of poultry products resumed within a few months, sometimes exceeding levels recorded before the outbreak,7 even www.thelancet.com Vol 383 February 8, 2014