Elsevier

The Lancet

Volume 383, Issue 9916, 8–14 February 2014, Pages 533-540
The Lancet

Articles
Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial

https://doi.org/10.1016/S0140-6736(13)62106-6Get rights and content

Summary

Background

Parkinson's disease psychosis, which includes hallucinations and delusions, is frequent and debilitating in people with Parkinson's disease. We aimed to assess safety and efficacy of pimavanserin, a selective serotonin 5-HT2A inverse agonist, in this population.

Methods

In our 6 week, randomised, double-blind, placebo-controlled study, we enrolled adults (aged ≥40 years) with Parkinson's disease psychosis. Antipsychotic treatments were not permitted during the study, but controlled antiparkinsonian medication or deep brain stimulation was allowed. Eligible participants entered a 2 week non-pharmacological lead-in phase to limit the placebo response, after which they were randomly allocated (1:1) to receive pimavanserin 40 mg per day or matched placebo. The primary outcome was antipsychotic benefit as assessed by central, independent raters with the Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD) in all patients who received at least one dose of study drug and had a SAPS assessment at baseline and at least one follow-up. We assessed safety and tolerability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01174004.

Findings

Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a −5·79 decrease in SAPS-PD scores compared with −2·73 for placebo (difference −3·06, 95% CI −4·91 to −1·20; p=0·001; Cohen's d 0·50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function.

Interpretation

Pimavanserin may benefit patients with Parkinson's disease psychosis for whom few other treatment options exist. The trial design used in this study to manage placebo response could have applicability to other studies in neuropsychiatric disease.

Funding

ACADIA Pharmaceuticals.

Introduction

7–10 million people worldwide have Parkinson's disease.1 The combined global cost of the disorder is estimated to be nearly £41 billion per year. Parkinson's disease is a synucleinopathy resulting in progressive neurodegeneration marked by motor dysfunction and non-motor symptoms including psychosis. More than 50% of patients with Parkinson's disease have psychosis at some time.2 Psychosis affects up to 75% of patients with Parkinson's disease dementia, and symptoms are more intractable in this group.3 Such psychosis is expressed primarily as hallucinations and delusions, which can cause great distress for patients and their caregivers. These episodes present a major challenge for treatment and care, increase the likelihood of placement in nursing homes, and are associated with increased mortality.2

Best-practice treatment guidelines promote initial consideration of comorbidities and reduction of dopaminergic therapy. However, these approaches are often insufficient and few other therapeutic options exist. Typical antipsychotics can cause profound dopamine D2 antagonism and worsen parkinsonism. Therefore, atypical antipsychotics are commonly used. Among these drugs, risperidone and olanzapine are poorly tolerated. Quetiapine seems better tolerated, with a small trial of 16 patients showing some clinical benefit.4 However, the four largest randomised controlled trials of quetiapine (including 153 patients) showed no evidence of efficacy,5, 6, 7, 8 suggesting that quetiapine is not efficacious for control of Parkinson's disease psychosis.

Clozapine has shown antipsychotic benefit without worsening motor symptoms in several randomised controlled trials, including two 4 week trials that had large effect sizes (Cohen's d >0·8) in the treatment groups and in one longer trial.9, 10, 11 However, clozapine is associated with increased risk of agranulocytosis, mortality, seizures, myocarditis and other cardiovascular and respiratory effects. These risks have particular relevance for frail elderly people with neurodegenerative disease and require strict monitoring protocols. The UK's National Institute for Health and Care Excellence (NICE) Parkinson's disease guideline indicates that clozapine is rarely used. Thus, safe and efficacious treatment options for Parkinson's disease psychosis are a clinical priority.

Pimavanserin (ACADIA Pharmaceuticals, San Diego, CA, USA) is a selective serotonin 5-HT2A inverse agonist without dopaminergic, adrenergic, histaminergic, or muscarinic affinity, and is in development as a treatment for Parkinson's disease psychosis.12 In Parkinson's disease, the binding of 5-HT2A receptors is increased in the neocortex, and visual hallucinations are associated with increased numbers of 5-HT2A receptors in visual processing areas.13 Post-mortem and genetic studies also suggest that in Parkinson's disease dementia, dementia with Lewy bodies, and Alzheimer's disease, delusions and hallucinations are linked to alterations in the 5-HT system.14, 15 Polymorphisms of 5-HT2A, 5-HT2C, and the 5-HT transporter are linked to psychosis, and possibly with treatment response to atypical antipsychotics in Alzheimer's disease.16, 17, 18 Atypical antipsychotics target the 5-HT2A pathway but at varying levels and also affect other receptor families. With its receptor selectivity, pimavanserin has been developed to provide antipsychotic benefit without the adverse effects of current antipsychotics. Previous randomised controlled trials and ongoing open-label safety extension studies in Parkinson's disease psychosis provide preliminary evidence of pimavanserin's antipsychotic benefits and good tolerability.19, 20 We aimed to assess efficacy and safety of pimavanserin for treatment of Parkinson's disease psychosis in a phase 3 trial, incorporating design features on the basis of results of a previous trial20 intended to minimise placebo response and optimise trial quality.

Section snippets

Study design and participants

In our randomised, double-blind, parallel group, placebo-controlled trial, we enrolled participants at 52 centres (academic hospitals or other experienced neurology research centres) in the USA and two centres in Canada. Eligibility criteria were unchanged throughout. Eligible participants had to be aged 40 years or older, meet established diagnostic criteria for Parkinson's disease psychosis,21 including idiopathic Parkinson's disease consistent with UK Brain Bank criteria22 lasting at least 1

Results

Between Aug 11, 2010, and Aug 29, 2012, we screened 314 participants, of whom 199 were randomly allocated to treatment and 185 were included in the full analysis set (figure 1). Demographics and clinical characteristics did not differ at baseline (table 1). Mean duration of symptoms of Parkinson's disease psychosis was 30·9 months (SD 30·01) in the pimavanserin group and 36·4 months (39·57) in the placebo group.

In the primary analysis, SAPS-PD scores at day 43 showed a significant improvement

Discussion

In our study, pimavanserin was able to significantly reduce psychotic symptoms in patients with moderate to severe Parkinson's disease (panel). The 6 week duration is consistent with the accepted precedent for psychosis studies according to the FDA and is longer than most trials of other antipsychotics in Parkinson's disease psychosis. Notably, efficacy was achieved without worsening parkinsonism and without other tolerability or safety concerns.

Although hallucinations are more common than

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