2.2 Dementia-Related Psychosis

Pimavanserin – Dementia-Related Psychosis


Pimavanserin is a proprietary small molecule currently being researched and developed for dementia-related psychosis. Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors that are thought to play an important role in dementia-related psychosis.

About Dementia-Related Psychosis

Around 8 million people in the United States are living with dementia and studies suggest that approximately 30% of people with dementia, or 2.4 million people, experience dementia-related hallucinations and delusion.

Dementia-related psychosis occurs in many type of dementia, including:
–  Alzheimer’s disease
–  Dementia with Lewy bodies
–  Parkinson’s disease dementia
–  Vascular dementia
–  Frontotemporal dementia

Serious consequences have been associated with psychosis in patients with dementia, such as repeated hospital admissions, increased likelihood of nursing home placement, faster progression of dementia, and increased risk of morbidity and mortality. No drug is approved by the FDA for the treatment of dementia-related psychosis.


On July 20, 2020, Acadia  announced that the U.S. Food and Drug Administration (FDA) has accepted for filing its supplemental New Drug Application (sNDA) for NUPLAZID® (pimavanserin) for the treatment of hallucinations and delusions associated with dementia-related psychosis (DRP).

The FDA has assigned a standard review with a PDUFA (Prescription Drug User Fee Act) action date of April 3, 2021. The FDA has also informed the Company that it has not identified any potential review issues at this point in their evaluation and at this time they are not planning to hold an Advisory Committee meeting.

The sNDA is supported by results from the pivotal Phase 3 HARMONY study, which met its primary endpoint, demonstrating that pimavanserin significantly reduced the risk of relapse of psychosis by 2.8 fold compared to placebo (hazard ratio = 0.353; one-sided p=0.0023). The sNDA also includes positive efficacy results from two additional placebo-controlled studies, both of which met their respective primary endpoints: The Phase 2 (-019) study in patients with Alzheimer’s disease psychosis and the Phase 3 (-020) study in patients with Parkinson’s disease psychosis. The sNDA includes a large safety database from completed and ongoing studies representing over 1500 patients with neurodegenerative disease.

The FDA previously granted Breakthrough Therapy Designation for NUPLAZID (pimavanserin) for the treatment of dementia-related psychosis in October 2017.

In April 2021, the FDA issued a Complete Response Letter (CRL) to indicate that they have completed their review of the sNDA and has determined that the application cannot be approved in its present form. Acadia is immediately requesting a Type A meeting to work with the FDA to address issues identified in the CRL. Read more here.

On December 20, 2021, Acadia announced that it plans to resubmit its sNDA for NUPLAZID® (pimavanserin) for the treatment of hallucinations and delusions associated with dementia focused on Alzheimer’s disease psychosis (ADP). Resubmission of the sNDA to the FDA is planned for the first quarter of 2022. The resubmission is intended to demonstrate pimavanserin’s clinically meaningful benefit in ADP patients, without worsening of cognition or motor function in this elderly population. The resubmission will include data from two positive, placebo-controlled studies that prospectively met their primary endpoints: the pivotal Phase 3 HARMONY study and the -019 study. Additional analyses from HARMONY and -019 will also be provided that validate the primary conclusions from each study and address the concerns raised in the CRL. Read more here.

Important Note:

Information presented above is related to an investigational use of  NUPLAZID® (pimavanserin). NUPLAZID is not approved by the FDA for the treatment of hallucinations and delusions  associated with dementia-related psychosis. Please see below FDA approved Indication for NUPLAZID, including Important Safety Information & Boxed WARNING.

Important Safety Information and Indication for NUPLAZID (pimavanserin)

NUPLAZID is indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.

Important Safety Information


    • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
    • NUPLAZID is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson’s disease psychosis.
    • Contraindication: NUPLAZID is contraindicated in patients with a history of a hypersensitivity reaction to pimavanserin or any of its components.  Rash, urticaria, and reactions consistent with angioedema (e.g., tongue swelling, circumoral edema, throat tightness, and dyspnea) have been reported.


    • Warnings and Precautions: QT Interval Prolongation
      • NUPLAZID prolongs the QT interval. The use of NUPLAZID should be avoided in patients with known QT prolongation or in combination with other drugs known to prolong QT interval including Class 1A antiarrhythmics or Class 3 antiarrhythmics, certain antipsychotic medications, and certain antibiotics.
      • NUPLAZID should also be avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and presence of congenital prolongation of the QT interval.
    • Adverse Reactions: The common adverse reactions (≥2% for NUPLAZID and greater than placebo) were peripheral edema (7% vs 2%), nausea (7% vs 4%), confusional state (6% vs 3%), hallucination (5% vs 3%), constipation (4% vs 3%), and gait disturbance (2% vs <1%).


  • Drug Interactions:
    • Coadministration with strong CYP3A4 inhibitors (e.g., ketoconazole) increases NUPLAZID exposure. Reduce NUPLAZID dose to 10 mg taken orally as one tablet once daily.
    • Coadministration with strong or moderate CYP3A4 inducers reduces NUPLAZID exposure. Avoid concomitant use of strong or moderate CYP3A4 inducers with NUPLAZID.

Dosage and Administration
Recommended dose: 34 mg capsule taken orally once daily, without titration.

NUPLAZID is available as 34 mg capsules and 10 mg tablets.

Please see full Prescribing Information including Boxed WARNING for NUPLAZID.