Parkinson’s Antipsychotic Looks Good in Phase 3 Trial

More than half of all people with Parkinson’s disease experience some form of psychosis, typically hallucinations or delusions. However, the FDA has approved no drug to treat such symptoms in these patients. Now, results of a Phase 3 clinical trial suggest that might change soon. In the November 1 Lancet, scientists led by Clive Ballard, Kings College London, and Jeffrey Cummings, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, report that pimavanserin, under development by Acadia Pharmaceuticals, San Diego, reduced psychosis in patients with Parkinson’s disease (PD). The drug had few side effects in this six-week trial. Alzforum briefly reported on these results when they were presented at a recent conference (see April 2013 conference story). “If this medication is eventually FDA-approved, it almost certainly will be the first-line drug for treatment of psychosis in PD,” said William Ondo, University of Texas, Houston.

Researchers have tested antipsychotic drugs approved for psychiatric disorders for their ability to control PD psychosis, with mixed success. Quetiapine, approved to treat symptoms of schizophrenia, seemed effective against PD psychosis in a small trial (see Fernandez et al., 2009), but failed in four larger ones (see for example, Shotbolt et al., 2009). Clozapine seems effective (see Pollak et al., 2004), but causes a host of side effects, including low white blood cell count; physicians rarely prescribe it. Neither drug has the right mix of safety and efficacy necessary to gain FDA approval for PD psychosis. Other antipsychotics can worsen the motor symptoms of PD because they block dopamine receptors. Clozapine and quetiapine have a weaker affinity for those receptors, antagonizing serotonergic receptors mostly, while quetiapine also hits adrenergic receptors.

Enter pimavanserin, a serotonin inverse agonist. It elicits the opposite response of serotonin by blocking the intrinsic basal activity of 5-HT2A receptors, which are associated with PD psychosis (see Ballanger et al., 2010). Pimavanserin leaves dopaminergic, adrenergic, muscarinic, and histaminergic receptors untouched. A previous Phase 3 trial had hinted at the drug’s efficacy, but unusually big improvements in the placebo group may have masked a more significant benefit. This second trial aimed to minimize placebo effects and reevaluate the safety and efficacy of pimavanserin.

From centers in the United States and Canada, the scientists recruited 199 people, 40 and older, who had a diagnosis of PD psychosis. To limit placebo effects, the scientists first gave patients two weeks of non-pharmacological psychosocial therapy. Anyone who improved to a predetermined score on the Parkinson’s disease-adapted scale for assessment of positive symptoms (SAPS-PD)—a test of hallucinations, delusions, and agitation—was excluded from the rest of the trial. Ninety-five of the remaining patients received pimavanserin, while 90 took placebo pills for six weeks.

Overall, pimavanserin alleviated psychotic symptoms in patients without worsening motor symptoms. Treated patients improved 37 percent on the SAPS-PD, compared with a 14 percent bump for those on placebo. The former also reported sleeping better at night and remaining more alert during the day, while caregivers reported being burdened less. Scores of motor performance showed no decline, even trending toward a slight improvement. That three different types of blinded observers—central raters who scored videos of the SAPS-PD tests, local site investigators who administered global assessments, and caregivers who completed a standard caregiver assessment form—all saw significant improvements, suggesting pimavanserin’s effect is robust, remarked Cummings.

One red flag was that 10 patients in the treatment group left the study, versus two in the placebo group. A high dropout rate is typical in this type of patient population, yet Cummings acknowledged that the higher rate in the treated group likely reflects side effects for which clinicians should be alert. They include peripheral edema (typically excess fluid in the legs) and confusion. Two deaths occurred in the drug group and one in the placebo cohort, though the authors claim that none appeared to be caused by pimavanserin.

Of the choices for the treatment of PD psychosis, how does pimavanserin measure up? It is hard to say, because no study has compared them head-to-head, said commentators. Joseph Friedman, Butler Hospital, Brown University, Providence, Rhode Island, guessed that pimavanserin falls somewhere between quetiapine and clozapine in terms of effectiveness, and would be better tolerated than any other antipsychotic. Ondo pointed out that pimavanserin led to improvements on secondary endpoints as well. “That’s fairly impressive because it points to global improvement in patients taking this drug,” he said. In an accompanying editorial, Susan Fox of Toronto Western Hospital, in Ontario, Canada, cautioned that the trial was brief. Psychosis itself fluctuates over short periods, which could explain these short-term benefits, she wrote.

The authors acknowledged that they cannot make inferences about long-term treatment based on this trial. Many of its participants continue to take pimavanserin on an “open-label” basis. Based on unpublished data, these patients have thus far tolerated pimavanserin over several years with lasting benefits, wrote the authors.

Cummings noted that the FDA has indicated that no further trials need to be completed, so he thinks approval seems likely. “This would be a huge step for the field, because so few drugs have been shown in rigorous clinical trials to treat behavioral changes in neurological disorders,” Cummings said. He anticipates that researchers will next explore pimavanserin’s ability to treat psychotic symptoms in other neurodegenerative diseases, such as Alzheimer’s and dementia with Lewy bodies. In these diseases, antipsychotic drugs are widely used, particularly in nursing homes, but they have come under fire for their safety record (see Oct 2005 news story and Jan 2009 news story).—Gwyneth Dickey Zakaib

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References

News Citations

  1. Drug Data Dash at AAN Annual Conference
  2. More Trouble for Atypical Antipsychotics—Dementia Patients at Risk
  3. Antipsychotics on Trial Again—DART-AD Confirms Increased Mortality

Paper Citations

  1. Fernandez HH, Okun MS, Rodriguez RL, Malaty IA, Romrell J, Sun A, Wu SS, Pillarisetty S, Nyathappa A, Eisenschenk S. 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):2196-205. PubMed.
  2. Shotbolt P, Samuel M, Fox C, David AS. A randomized controlled trial of quetiapine for psychosis in Parkinson's disease. Neuropsychiatr Dis Treat. 2009;5:327-32. PubMed.
  3. Pollak P, Tison F, Rascol O, Destée A, Péré JJ, Senard JM, Durif F, Bourdeix I. Clozapine in drug induced psychosis in Parkinson's disease: a randomised, placebo controlled study with open follow up. J Neurol Neurosurg Psychiatry. 2004 May;75(5):689-95. PubMed.
  4. Ballanger B, Strafella AP, van Eimeren T, Zurowski M, Rusjan PM, Houle S, Fox SH. Serotonin 2A receptors and visual hallucinations in Parkinson disease. Arch Neurol. 2010 Apr;67(4):416-21. PubMed.

External Citations

  1. pimavanserin

Further Reading

Papers

  1. Ricotti GC, Apicella P, Macconi A, Parisi L, Martini R, Consumi I. [Alobar holoprosencephaly. Prenatal diagnosis and autopsy findings in 2 cases]. Pathologica. 1989 Nov-Dec;81(1076):635-42. PubMed.
  2. Friedman JH. Pimavanserin for the treatment of Parkinson's disease psychosis. Expert Opin Pharmacother. 2013 Oct;14(14):1969-75. PubMed.
  3. Price DL, Bonhaus DW, McFarland K. Pimavanserin, a 5-HT2A receptor inverse agonist, reverses psychosis-like behaviors in a rodent model of Alzheimer's disease. Behav Pharmacol. 2012 Aug;23(4):426-33. PubMed.
  4. Ballanger B, Strafella AP, van Eimeren T, Zurowski M, Rusjan PM, Houle S, Fox SH. Serotonin 2A receptors and visual hallucinations in Parkinson disease. Arch Neurol. 2010 Apr;67(4):416-21. PubMed.
  5. Pollak P, Tison F, Rascol O, Destée A, Péré JJ, Senard JM, Durif F, Bourdeix I. Clozapine in drug induced psychosis in Parkinson's disease: a randomised, placebo controlled study with open follow up. J Neurol Neurosurg Psychiatry. 2004 May;75(5):689-95. PubMed.
  6. Shotbolt P, Samuel M, Fox C, David AS. A randomized controlled trial of quetiapine for psychosis in Parkinson's disease. Neuropsychiatr Dis Treat. 2009;5:327-32. PubMed.
  7. Fernandez HH, Okun MS, Rodriguez RL, Malaty IA, Romrell J, Sun A, Wu SS, Pillarisetty S, Nyathappa A, Eisenschenk S. 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):2196-205. PubMed.

Primary Papers

  1. Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, Dhall R, Ballard C. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2013 Oct 31; PubMed.
  2. Fox SH. Pimavanserin as treatment for Parkinson's disease psychosis. Lancet. 2013 Oct 31; PubMed.

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