Pimavanserin vs. Quetiapine for Psychosis in Parkinson's Disease

(C-SAPP Trial)

Recruiting at 18 trial locations

Overseen By John E Duda, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Trial Phase: Phase 4

Sponsor: VA Office of Research and Development

Must not be taking: Antipsychotics, CYP3A4 inducers, others

Disqualifiers: Severe psychosis, Schizophrenia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 4

Duration: 8 weeks

358 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine which medication, Quetiapine or Pimavanserin, is most effective and safest for treating psychosis (hallucinations or delusions) in people with Parkinson's disease. Both medications have FDA approval, but further research is needed to assess their effectiveness and safety. Veterans with Parkinson's disease who experience these symptoms, particularly if they impact daily life, may be suitable candidates. Interested individuals should consult their VA provider about participating in the study. As a Phase 4 trial, this research seeks to understand how these FDA-approved treatments benefit more patients, offering an opportunity to contribute to valuable insights.

Will I have to stop taking my current medications?

The trial requires that you have not been treated with an antipsychotic, including pimavanserin, in the past year, except for quetiapine at less than 50 mg/day, which must be stopped at least 1 month before joining the study. If you are taking medications that affect the heart's rhythm or certain other drugs, you may need to stop those as well.

What is the safety track record for Pimavanserin and Quetiapine?

A previous study showed that pimavanserin significantly reduced the number and intensity of hallucinations and delusions in people with Parkinson's disease psychosis. The FDA has already approved it for this condition, suggesting it is relatively safe. Research shows that pimavanserin is generally well-tolerated and does not worsen Parkinson's movement symptoms.

Quetiapine is often used to treat psychosis in Parkinson's disease. Although FDA-approved for other conditions, research suggests it has a relatively low risk of causing movement-related side effects. However, some studies have raised concerns about a higher risk of death in Parkinson's patients using antipsychotics like quetiapine.

Both treatments have advantages and disadvantages regarding safety. Pimavanserin has shown positive results in reducing psychosis symptoms without affecting movement. Quetiapine, although commonly used, requires more research to fully understand its safety for Parkinson’s disease patients. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for psychosis in Parkinson's Disease because they offer different approaches from standard options like clozapine and quetiapine. Pimavanserin is unique because it targets serotonin receptors rather than dopamine, which is the usual target for most antipsychotics. This could mean fewer side effects related to movement, which is crucial for people with Parkinson’s. Quetiapine, while already used, is being compared in a structured way to see how its effectiveness and side effects stack up against pimavanserin, potentially refining its use in this specific condition.

What evidence suggests that this trial's treatments could be effective for Parkinson's disease psychosis?

Research has shown that pimavanserin, one of the treatments in this trial, helps treat hallucinations and delusions in people with Parkinson's disease psychosis. In studies, 47% of patients experienced noticeable improvement in their symptoms. It is the only medication approved by the FDA specifically for this condition.

Quetiapine, the other treatment option in this trial, is also used for psychosis in Parkinson's disease, but its effectiveness remains uncertain. Some studies found that 80% of patients improved, while others saw no significant difference compared to a placebo. More research is needed to confirm its effectiveness. ^{4 6 7 8 9}

Who Is on the Research Team?

Daniel Weintraub, MD

Principal Investigator

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

Are You a Good Fit for This Trial?

This trial is for Veterans with Parkinson's Disease who are experiencing psychosis, such as hallucinations or delusions. Participants must be English-speaking adults over 40 years old, have regular contact with a caregiver, and not live in a nursing home. They can't have used certain antipsychotics recently, have heart rhythm problems, severe dementia or other disqualifying conditions.

Inclusion Criteria

I have been diagnosed with Parkinson's Disease.

I've been on a stable dose of an acetylcholinesterase inhibitor for at least 4 months.

Must have regular in-person contact with the patient (on average at least 5 days per week, and at least 4 hours per day that is spent with patient)

Exclusion Criteria

You had a mental health condition like schizophrenia or bipolar disorder before Parkinson's disease.

My psychosis is due to a toxic or metabolic disorder.

I couldn't tolerate quetiapine or pimavanserin.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Quetiapine or Pimavanserin for Parkinson's Disease Psychosis. Quetiapine is titrated over 6 weeks, while Pimavanserin is administered at a fixed dose with sham titration.

8 weeks

4 visits (in-person) at baseline, 3 weeks, 5 weeks, and 8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Pimavanserin
• Quetiapine

Trial Overview The study compares the safety and effectiveness of two antipsychotic drugs: Quetiapine (commonly used but not FDA-approved for PD psychosis) versus Pimavanserin (newer and FDA-approved specifically for PD psychosis). The goal is to determine which drug works best for treating psychosis in Parkinson's patients.

How Is the Trial Designed?

Group I: Quetiapine Active Control 1 Intervention

Participants assigned to Quetiapine will be titrated from 25mg/day to a maximum of 200mg/day based on tolerability. During the 8-week treatment phase, there is a maximum of 6 weeks for titration. Titration Schedule Visit/call Quetiapine Dose (Flexible)Quetiapine Notes Baseline visit (Visit 00)25 mg IR QHSAll participants must be up-titrated to at least 50 mg/day at week 1 Week 1 call (Visit 01)50 mg XR QHS Up-titration Week 3 visit (Visit 03)100 mg XR QHS (requiring two 50-mg quetiapine XR capsules)Up- or down-titration as appropriate based on psychosis symptoms and tolerability Week 5 visit (Visit 05)150 mg quetiapine XR QHS Up- or down-titration as appropriate based on psychosis symptoms and tolerability Week 6 call (Visit 06)200 mg quetiapine XR QHS Up- or down-titration as appropriate based on psychosis symptoms and tolerability

Group II: Pimavanserin 34mg Active Control 1 Intervention

Participants assigned to pimavanserin will receive 34mg (equivalent to 40 mg pimavanserin tartrate) daily without titration; however, because pimavanserin is blinded to quetiapine, participants will undergo sham titration based on tolerability.

Pimavanserin is already approved in United States for the following indications:

Approved in United States as Nuplazid for:

• Hallucinations and delusions associated with Parkinson's disease psychosis

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

Pimavanserin is an atypical antipsychotic that effectively treats hallucinations and delusions in Parkinson's disease without worsening motor symptoms, based on a review of 2 published randomized controlled trials.

While only 1 of the 4 trials showed significant improvement in psychotic symptoms compared to placebo, pimavanserin's selective action on serotonin 5-HT2a receptors suggests it may be a more tolerable treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pimavanserin (Nuplazid™) for the treatment of Parkinson disease psychosis: A review of the literature. Touma, KTB., Touma, DC.[2022]

In a study of 10 patients with Parkinson's disease experiencing psychosis due to antiparkinsonian drugs, quetiapine effectively eliminated psychotic symptoms in 9 out of 10 patients.

Quetiapine was associated with no significant worsening of parkinsonism, highlighting its safety and efficacy as a treatment for psychosis in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of quetiapine fumarate on drug-induced psychosis in patients with Parkinson's disease]. Kohmoto, J., Kihira, T., Miwa, H., et al.[2015]

In a study of 11 patients with Parkinson's disease and acute psychosis, quetiapine was found to be effective in controlling visual hallucinations in 6 patients, demonstrating its potential as a treatment option for psychotic symptoms in this population.

Quetiapine was well tolerated overall, with no exacerbation of parkinsonian symptoms observed, suggesting that atypical antipsychotics may be safer alternatives for managing psychosis in patients with Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of quetiapine in Parkinson's patients with psychosis. Targum, SD., Abbott, JL.[2019]

In three case histories of Parkinson's disease patients who had to stop clozapine, switching to quetiapine resulted in behavioral improvements without significantly worsening motor symptoms, indicating its potential as a safer alternative.

Quetiapine was well tolerated at doses ranging from 12.5 to 150 mg/day, suggesting it may effectively manage psychosis and agitation in Parkinson's disease patients while minimizing the risk of exacerbating parkinsonism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quetiapine as an alternative to clozapine in the treatment of dopamimetic psychosis in patients with Parkinson's disease. Menza, MM., Palermo, B., Mark, M.[2019]

In a 24-week trial involving 29 elderly patients with Parkinson's disease who did not respond to other antipsychotics, quetiapine significantly improved psychotic symptoms without worsening motor function.

Patients showed notable improvements in psychiatric assessments and cognitive recall, indicating that quetiapine is both effective and well-tolerated for treating psychosis in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quetiapine improves psychotic symptoms and cognition in Parkinson's disease. Juncos, JL., Roberts, VJ., Evatt, ML., et al.[2015]

Pimavanserin is the only FDA-approved medication specifically for treating hallucinations and delusions in Parkinson's disease psychosis, highlighting its importance in managing this serious nonmotor complication.

While off-label use of clozapine and quetiapine shows some effectiveness, there is a critical need for new treatments to minimize side effects and alleviate the financial and emotional burdens of Parkinson's disease psychosis on patients and caregivers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Parkinson's Disease Psychosis. Elsibai, H., Kualleny, M., Fandy, TE.[2022]

Pimavanserin is a selective serotonin 2A receptor inverse agonist that has been approved in the US specifically for treating hallucinations and delusions in patients with Parkinson's disease psychosis, a condition affecting up to 60% of Parkinson's patients.

The approval of pimavanserin is significant as it provides a treatment option for a condition that has limited therapeutic alternatives and is associated with increased morbidity and mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pimavanserin: First Global Approval. Markham, A.[2022]

In a study of 27 patients with Parkinson's disease and recent-onset psychosis, both quetiapine and clozapine were found to be effective treatments, with no worsening of parkinsonism observed during the 22-week treatment period.

Clozapine showed a greater ability to reduce delusions and had a trend towards better control of hallucinations compared to quetiapine, but it also posed a risk of leukopenia, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rater-blinded, prospective comparison: quetiapine versus clozapine for Parkinson's disease psychosis. Merims, D., Balas, M., Peretz, C., et al.[2022]

Pimavanserin (PIM) treatment for Parkinson's Disease Psychosis (PDP) is associated with significantly lower rates of all-cause hospitalizations and psychiatric-related inpatient hospitalizations compared to quetiapine (QUE), suggesting it may be a safer option for managing PDP.

In a study of over 8,000 patients, those on PIM had a 22% reduction in all-cause hospitalizations and a 37% reduction in psychiatric-related hospitalizations, indicating its potential efficacy in reducing healthcare resource utilization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patients treated with pimavanserin or quetiapine for Parkinson's disease psychosis: analysis of health resource utilization patterns among Medicare beneficiaries. Rajagopalan, K., Rashid, N., Doshi, D.[2023]

A retrospective analysis of 2,287 death reports associated with pimavanserin found that while it had a higher proportional reporting ratio (PRR) for death in the general population, this signal diminished significantly when focusing on patients with Parkinson's disease (PD), indicating no excess mortality risk compared to other treatments.

The study suggests that pimavanserin's safety profile is comparable to other antipsychotics for PD patients, and the findings should inform shared decision-making between physicians and patients regarding the risks and benefits of using pimavanserin for PD-related psychosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative pharmacovigilance assessment of mortality with pimavanserin in Parkinson disease-related psychosis. Brown, JD., Cicali, B., Henriksen, C., et al.[2023]

Pimavanserin is a safe and effective option for patients with Parkinson's disease psychosis (PDP) who are switching from atypical antipsychotics like quetiapine or clozapine, based on expert consensus and pharmacological considerations.

The recommended approach for switching involves adding pimavanserin at the full dose (34 mg) for 2-6 weeks while tapering off the previous medication, ensuring continued efficacy and minimizing withdrawal effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guidance for switching from off-label antipsychotics to pimavanserin for Parkinson's disease psychosis: an expert consensus. Black, KJ., Nasrallah, H., Isaacson, S., et al.[2019]

Citations

1. nuplazidhcp.com nuplazidhcp.com/efficacy-data

Efficacy Data - NUPLAZID® (pimavanserin) The mean SAPS-PD baseline score was 15.9 (6.12) for NUPLAZID and 14.7 (5.55) for placebo.1,2 The majority of patients were on PD medications at entry; these ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33933853/

Efficacy results of pimavanserin from a multi-center, open- ... The mean change from Core Study baseline for SAPS-PD score was similar among prior pimavanserin 34 mg and prior placebo-treated participants (-7.1 vs. -7.0).

3. sciencedirect.com sciencedirect.com/science/article/pii/S2590112522000147

Long-term outcomes with pimavanserin for psychosis in ... Initial improvement was seen in 47% of the entire group, and 50% of the DLB patients. Additional antipsychotic medication was needed concomitantly with ...

4. becarispublishing.com becarispublishing.com/doi/10.57264/cer-2025-0129

Real-world evidence of pimavanserin utilization among ... Pimavanserin (PIM) is the only US FDA-approved medication for treating hallucinations and delusions in people with Parkinson's disease psychosis ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35479873/

Long-term outcomes with pimavanserin for psychosis in ... Initial improvement was seen in 47% of the entire group, and 50% of the DLB patients. Additional antipsychotic medication was needed ...

6. nuplazidhcp.com nuplazidhcp.com/safety-tolerability-data

Safety and Tolerability Data | NUPLAZID® (pimavanserin) NUPLAZID® (pimavanserin) is indicated for the treatment of hallucinations and delusions associated with Parkinson's disease (PD) psychosis. NUPLAZID Safety Data ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9599742/

Pimavanserin and Parkinson's Disease Psychosis: A Narrative ... They observed that PMV was associated with a significant reduction in psychosis (SAPS, mean difference: –1.55 [–2.71, –0.379], p = 0.009).

8. clinicaltrials.gov clinicaltrials.gov/study/NCT00477672?term=Pimavanserin%20%2B%20schizophrenia&rank=10

A Study of the Safety and Efficacy of Pimavanserin (ACP- ... This study will evaluate the safety and efficacy of two dose levels of pimavanserin ( ACP-103 ) compared to placebo in patients with Parkinson's disease ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6007714/

Pimavanserin (Nuplazid™) for the treatment of Parkinson ... Pimavanserin has demonstrated no worsening of motor symptoms of Parkinson disease, but only 1 of 4 trials has shown consistent statistically significant ...