Nuplazid, clozapine treat Parkinson’s psychosis without motor decline

Review study into various antipsychotics used on- and off-label in patients

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Among several atypical antipsychotics, Nuplazid (pimavanserin) seems to be the most effective at easing Parkinson’s disease psychosis (PDP) while sparing motor function, according to a review study.

Clozapine, used off-label in people with Parkinson’s, also helped, but its effect was not as large and patients were more likely to stop the medication due to side effects.

Notably, off-label use of quetiapine for Parkinson’s psychosis was linked to a decline in cognitive function. Therefore, “clinicians should avoid the use of quetiapine in patients with evidence of reduced cognitive abilities,” the researchers wrote.

The study, “Comparative Efficacy, Safety, and Acceptability of Pimavanserin and Other Atypical Antipsychotics for Parkinson’s Disease Psychosis: Systematic Review and Network Meta-Analysis,” was published in the Journal of Geriatric Psychiatry and Neurology.

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While Parkinson’s motor symptoms are the most common and well known, people with the disease can experience a range of nonmotor symptoms, such as psychosis. Psychosis is defined by sensing things that are not real (hallucinations) and/or holding irrational beliefs not based in reality (delusions).

Antipsychotics are a class of medications used to treat psychosis. The use of these medications in Parkinson’s patients is complicated, however, because antipsychotics modulate the activity of dopamine, which is abnormally low in Parkinson’s. As a result, some antipsychotics can worsen disease symptoms.

Nuplazid, an atypical antipsychotic by Acadia Pharmaceuticals, is currently the only medication approved in the U.S. to treat hallucinations and delusions in Parkinson’s. An atypical antipsychotic is a second-generation medication designed to cause fewer motor side effects than a typical antipsychotic.

Despite evidence of Nuplazid’s “effectiveness, and more favorable adverse-effect profile, treatment guidelines continue to recommend quetiapine and clozapine,” two other atypical antipsychotics, and they “continue to be commonly prescribed to treat PDP,” the researchers wrote.

To learn how safe, effective, and well-accepted these atypical antipsychotics are, a team in the U.S. retrospectively analyzed published studies up to October 2021 reporting such data on people with PDP. The team’s lead author is a professor of clinical pharmacy at the University of South Carolina, another is an Acadia employee, and the remaining three authors are employees of a data analytics company.

Treatment acceptability was assessed through rates of treatment discontinuation due to lack of efficacy, side effects, or other reasons. A previous study showed that more than one-third of Parkinson’s patients stopped taking antipsychotics within six months of starting.

“Determining the comparative acceptability, in addition to the relative efficacy and safety … provides more comprehensive evidence to clinicians,” the researchers wrote, adding that this could help “better inform treatment decisions.”

A total of 19 studies, covering 1,242 people with PDP, were included in the meta-analysis. Studies evaluated outcomes with Nuplazid and other atypical antipsychotics such as clozapine, quetiapine, olanzapine, ziprasidone, and risperidone.

Patients’ median age was 72, and almost two-thirds (63.8%) were men. They had been followed for a median of about three months, ranging from one to 12 months.

Compared with a placebo, treatment with Nuplazid significantly eased patients’ psychosis symptoms — as reflected by a 4.81-point drop in the Clinical Global Impression Severity (CGI-S) scale score, results showed.

The CGI-S scale is a seven-point scale used by doctors to assess the severity of a patient’s symptoms, with higher scores indicating worse symptoms.

Clozapine treatment also was associated with a mean decrease of 4.25 points in the CGI-S scale score relative to a placebo.

Side effects frequent reason for stopping antipsychotic medications

Based on changes in the Brief Psychiatric Rating Scale, clozapine and ziprasidone treatment significantly eased psychosis compared with a placebo, while quetiapine did not. Nuplazid was not evaluated here because pimavanserin trials did not report data using this scale, the researchers noted.

Changes in the Scale for Assessment of Positive Symptoms for Parkinson’s showed that Nuplazid-treated patients were 16% more likely to experience a reduction in psychosis than those on a placebo. Data also favored Nuplazid over clozapine, olanzapine, and ziprasidone, but score differences here failed to reach statistical significance.

Neither Nuplazid or clozapine were reported to worsen patients’ motor symptoms, as measured by the Unified Parkinson’s Disease Rating Scale, compared with a placebo.

Quetiapine also did not impair motor function, but its use led to a significant decline in cognitive abilities as measured by the Mini-Mental State Examination.

Regarding treatment acceptability, olanzapine-treated patients were eight times more likely to discontinue treatment due to side effects than those on a placebo. Those using clozapine were 60% more likely to stop treatment, while discontinuation rates of 44% was observed for Nuplazid and 25% for quetiapine.

Patients on Nuplazid were also 44% more likely to stop treatment due to adverse events compared with those on a placebo, but this difference did not reach statistical significance.

Further ranking analyses showed that Nuplazid and clozapine “were most efficacious and most safe … with [Nuplazid] having the greatest probability of being efficacious,” the team wrote, while “olanzapine was the least acceptable and least efficacious,” along with quetiapine.

“This study’s results support and add critical data to existing studies and clinical practice guidelines for treating patients with PDP,” the researchers wrote.

Research for this study was funded by Acadia Pharmaceuticals.