Pimavanserin for Aggression

Overseen By Matthew A. Timmins, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Ohio State University

Must not be taking: Antipsychotics, Opiates

Disqualifiers: Bipolar, Schizophrenia, Depression, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 2 days

35 Participants Needed

Trial Summary

What is the purpose of this trial?

The investigators are studying how certain drugs can reduce anger outbursts in people with anger problems. In this study the investigators seek to determine if a single 34 mg (two 17 mg tablets) oral dose of the 5-HT2a receptor blocker, pimavanserin, will reduce aggressive responding in individuals with impulsive aggression (Intermittent Explosive Disorder: IED) on a laboratory task that assesses aggression (Taylor Aggression Paradigm: TAP). We will also be examining how this drug impacts hostile social cognition e.g., hostile attribution). If pimvanserin reduces aggression in this study a next step would be a placebo-controlled treatment trial of pimavanserin in study participants with IED. Participation will first involve a remote (e.g., TEAMS) screening session. If potential study participants appear eligible they will come into the lab for an in-person session where participants will complete interviews and questionnaires and have a medical evaluation (including a physical exam, electrocardiogram, and screens for alcohol and drug use). During the next study session, participants will complete a diagnostic interview and a series of questionnaires, all of which can all take place on-line. During the next two sessions (which will be in-person) participants will undergo two (2) study sessions during which study participants will be given a study drug (orally). The drug given, pimavanserin, is currently available and is known to block serotonin receptors thought to be involved in regulating anger. After participants take the study drug, study participants will complete questionnaires and computer tasks for assessment of aggression and of hostile social cognition. Each of these two in-person study sessions will take at least eight (8) hours. A final on-line session will be done to make certain the investigators have all the data required by the study protocol.

Will I have to stop taking my current medications?

The trial requires participants to be free of anti-psychotic medication for two weeks before starting. If you are on such medications, you will need to stop taking them for this period.

What data supports the effectiveness of the drug Pimavanserin for aggression?

Pimavanserin is effective in treating hallucinations and delusions in Parkinson's disease psychosis, showing significant improvement in symptoms compared to placebo in clinical trials. Its unique action on serotonin receptors may also help with psychosis in other conditions, suggesting potential benefits for aggression. ^{1 2 3 4 5}

Is pimavanserin safe for humans?

Pimavanserin, also known as Nuplazid, has been shown to be generally safe in humans, with clinical trials indicating it does not worsen motor symptoms in patients with Parkinson's disease psychosis. It has a relatively benign safety profile, but like many antipsychotics, it carries a warning for increased risk of mortality in elderly patients with dementia-related psychosis. ^{1 3 4 5 6}

How is the drug Pimavanserin unique for treating aggression?

Pimavanserin is unique because it is a selective serotonin 2A receptor inverse agonist and antagonist, originally approved for treating hallucinations and delusions in Parkinson's disease psychosis, which makes it different from other treatments that may not target this specific receptor. ^{4 7 8 9 10}

Research Team

Emil F. Coccaro

Principal Investigator

Ohio State University

Eligibility Criteria

This trial is for adults aged 21-55 with impulsive aggression or Intermittent Explosive Disorder. They must be in good physical health, not on psychotropic meds for the last four weeks, and able to consent. Women must test negative for pregnancy.

Inclusion Criteria

I am between 21 and 55 years old and can make my own medical decisions.

I haven't taken any anti-psychotic medication for the last two weeks.

Participants with a current (or past) DSM-5 diagnosis of Intermittent Explosive Disorder (IED)

Exclusion Criteria

Clinically significant medical condition

Unwilling/unable to sign informed consent document

Current alcohol/drug use disorder of greater than mild severity

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (virtual)

Baseline Assessment

Participants complete interviews, questionnaires, and a medical evaluation

1 day

1 visit (in-person)

Treatment

Participants receive a single dose of pimavanserin or placebo and complete aggression and social cognition tasks

2 days

2 visits (in-person)

Data Collection

Final online session to ensure all data required by the study protocol is collected

1 day

1 visit (virtual)

Follow-up

Participants are monitored for any adverse effects and overall safety after treatment

2 weeks

Treatment Details

Interventions

• Pimavanserin
• Placebo

Trial Overview The study tests if a single dose of Pimavanserin (34 mg), which blocks certain serotonin receptors, can reduce aggressive behavior and alter hostile social cognition in people with anger issues compared to a placebo.

Participant Groups

Group I: Pimavanserin Experimental Treatment 1 Intervention

One single dose of pimavanserin (34 mg oral)

Group II: Placebo Placebo Group 1 Intervention

One single dose of matching placebo

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?

Ohio State University

Lead Sponsor

Trials

891

Recruited

2,659,000+

ACADIA Pharmaceuticals Inc.

Industry Sponsor

Trials

49

Recruited

11,700+

Founded

1993

Headquarters

San Diego, USA

Known For

Neurological Disorders

Top Products

Nuplazid (pimavanserin), Daybue (trofinetide)

Findings from Research

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]

Pimavanserin is the first FDA-approved treatment for Parkinson's disease psychosis (PDP) and has been shown to be well-tolerated with minimal adverse effects and no worsening of motor symptoms, based on four randomized controlled trials.

A Phase III trial demonstrated that pimavanserin 40mg significantly improved PDP symptoms compared to placebo, with notable improvements in secondary outcomes such as caregiver burden and sleep quality, highlighting its efficacy as a treatment option for PDP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pimavanserin: A Novel Drug Approved to Treat Parkinson's Disease Psychosis. Kitten, AK., Hallowell, SA., Saklad, SR., et al.[2021]

Pimavanserin is a selective inverse agonist of the 5-HT2A receptor and has been shown to be a safe and effective treatment for Parkinson's disease psychosis (PDP), significantly reducing hallucinations and delusions without worsening motor symptoms.

Unlike traditional antipsychotics, which can exacerbate motor dysfunction and carry serious warnings for elderly patients, pimavanserin offers a promising alternative, having received breakthrough therapy status from the FDA due to the urgent need for effective treatments in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pimavanserin. Hunter, NS., Anderson, KC., Cox, A.[2017]

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]

Pimavanserin is the first FDA-approved drug specifically for treating hallucinations and delusions in Parkinson's disease psychosis, showing significant improvement in symptoms compared to placebo in a pivotal phase III clinical trial.

The drug works as a potent inverse agonist at serotonin 5-HT2A receptors, with a long half-life of 57 hours, allowing for once-daily dosing and demonstrating a favorable safety profile without impairing motor functions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pimavanserin: novel pharmacotherapy for Parkinson's disease psychosis. Sahli, ZT., Tarazi, FI.[2018]

Pimavanserin is the first and only medication specifically approved for treating Parkinson's disease psychosis (PDP), which affects up to 60% of Parkinson's patients and is associated with serious risks like increased mortality and nursing home placement.

Unlike traditional atypical antipsychotics, pimavanserin is a selective 5-HT2A inverse agonist that does not worsen motor symptoms or cause other adverse effects related to dopamine receptor blockade, making it a safer option for managing PDP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changing the treatment paradigm for Parkinson's disease psychosis with pimavanserin. Lyons, KE., Pahwa, R., Hermanowicz, N., et al.[2019]

In a randomized, double-blind, placebo-controlled trial involving 181 Alzheimer's disease patients, pimavanserin significantly reduced psychotic symptoms, especially in those with more severe symptoms (NPI-NH-PS ≥12), showing an 88.9% responder rate for ≥30% improvement compared to 43.3% for placebo.

Pimavanserin was well-tolerated, with similar rates of adverse events compared to placebo, and fewer patients discontinued treatment due to side effects, indicating it is a safe option for managing psychosis in Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pimavanserin in Alzheimer's Disease Psychosis: Efficacy in Patients with More Pronounced Psychotic Symptoms. Ballard, C., Youakim, JM., Coate, B., et al.[2020]

In a study involving 12 adults with Tourette syndrome, pimavanserin treatment led to a statistically significant reduction in tic severity, with a 12% decrease in the Yale Global Tic Severity Scale score after 8 weeks, although this improvement may not be clinically significant.

Pimavanserin was found to be safe, with no serious adverse events reported, and it also showed positive effects on non-motor symptoms and quality of life, suggesting potential benefits that merit further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot Study to Evaluate Pimavanserin for the Treatment of Motor and Behavioral Symptoms of Tourette Syndrome. Billnitzer, A., Jankovic, J.[2022]

Pimavanserin is a unique medication that works by blocking the 5-HT2A serotonin receptors, which helps reduce psychotic symptoms in patients with Parkinson's disease.

It is specifically approved for treating Parkinson's disease psychosis, and the article outlines which patients may benefit from this treatment, potential side effects, and recommended dosing guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can pimavanserin help patients with Parkinson disease psychosis? de la Cruz, J., Canal, C.[2020]

Pimavanserin, a selective serotonin 2A receptor inverse agonist, was evaluated as a PET-radioligand in pigs, showing good brain penetration and binding in areas consistent with 5-HT2AR distribution.

However, the study found that the binding of [(11)C]pimavanserin could not be blocked by known antagonists, indicating high nonspecific binding and suggesting that it may not be selective for the 5-HT2AR in this animal model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

(11)C-labeling and preliminary evaluation of pimavanserin as a 5-HT2A receptor PET-radioligand. Andersen, VL., Hansen, HD., Herth, MM., et al.[2016]

References

1. United States pubmed.ncbi.nlm.nih.gov

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

2. United States pubmed.ncbi.nlm.nih.gov

Pimavanserin: A Novel Drug Approved to Treat Parkinson's Disease Psychosis. [2021]

3. Spain pubmed.ncbi.nlm.nih.gov

Pimavanserin. [2017]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Pimavanserin: First Global Approval. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Pimavanserin: novel pharmacotherapy for Parkinson's disease psychosis. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Changing the treatment paradigm for Parkinson's disease psychosis with pimavanserin. [2019]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Pimavanserin in Alzheimer's Disease Psychosis: Efficacy in Patients with More Pronounced Psychotic Symptoms. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Pilot Study to Evaluate Pimavanserin for the Treatment of Motor and Behavioral Symptoms of Tourette Syndrome. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Can pimavanserin help patients with Parkinson disease psychosis? [2020]

10. England pubmed.ncbi.nlm.nih.gov

(11)C-labeling and preliminary evaluation of pimavanserin as a 5-HT2A receptor PET-radioligand. [2016]