Understanding Pimavanserin: A Novel Approach to Parkinson Disease Psychosis

Parkinson disease (PD) is a brain disorder best known for causing tremors, stiffness, and slow movements. However, many patients do not realize that PD can also affect the mind. Many patients develop hallucinations and delusions, a syndrome known as Parkinson disease psychosis (PDP). PDP is associated with increased caregiver burden, institutionalization, and mortality.¹

Management of PDP is clinically challenging. Conventional antipsychotics often act by blocking dopamine D₂ receptors, reducing dopaminergic signaling and worsening motor symptoms in PD. In contrast, pimavanserin (Nuplazid; Acadia Pharmaceuticals, Inc) was specifically developed to treat PDP by targeting serotonergic (5-HT₂A) pathways, allowing mitigation of hallucinations and delusions with minimal effect on dopaminergic transmission in the movement areas of the brain.²

Pharmacology of Pimavanserin

Unlike most antipsychotics that work mainly by blocking dopamine receptors, pimavanserin focuses on the serotonin system. It acts as an inverse agonist and antagonist at serotonin 5-HT2A receptors (and to a lesser extent 5-HT2C receptors), with no meaningful affinity for dopamine receptors. By working as an inverse agonist at these serotonin receptors rather than blocking dopamine, it helps reduce hallucinations and delusions in PDP while avoiding worsening of motor function.^1-3

Clinical Trials

The FDA approval of pimavanserin for PDP was based on a 6-week, randomized, double-blind, placebo-controlled trial of patients with hallucinations and/or delusions related to PDP. It included 199 adults with PD and psychosis who were randomized to pimavanserin 34 mg once daily or placebo. PD medications were kept stable during the trial.³ 

The primary outcome was change from baseline in the PD–adapted Scale for the Assessment of Positive Symptoms (SAPS-PD) total score, which measures hallucinations and delusions. The results showed that pimavanserin 34 mg was statistically superior to placebo in reducing hallucinations and delusions without worsening motor function. Improvements were seen in both hallucination and delusion.³ These data established pimavanserin as an effective option for PDP and highlight its ability to treat psychosis in PD while maintaining motor control.^1,3

Safety Profile and Considerations

Like other antipsychotic medications used in elderly patients with dementia-related psychosis, pimavanserin carries a boxed warning regarding increased mortality in this population. The drug is not approved for the treatment of dementia-related psychosis unrelated to PD.¹

Pimavanserin is contraindicated in patients with a history of hypersensitivity to pimavanserin or any component of the product. The reported reactions have included rash, hives, and reactions consistent with angioedema (eg, tongue swelling, throat tightness, and dyspnea).¹

Pimavanserin can prolong the QT interval on the ECG. It should be avoided in patients with known QT prolongation, history of serious cardiac arrhythmias, conditions that increase the risk of torsade de pointes (eg, significant bradycardia, low potassium or magnesium, congenital long QT), or concomitant use of other drugs that prolong the QT interval (such as certain antiarrhythmics, antipsychotics, or antibiotics).^1,2

In placebo-controlled trials of patients with PDP, adverse reactions that occurred in 2% or more of patients on pimavanserin and more often than with placebo included peripheral edema, nausea, confused state, hallucination, constipation, and gait disturbance.¹ Patients should be monitored for these adverse effects, especially if they already have cardiovascular disease, are on other QT-prolonging medications, or have risk factors for falls.

Pimavanserin should be used with caution in patients with severe renal impairment or end-stage renal disease, because drug exposure is increased in this group, even though formal dose adjustment is not required per health care provider guidance. It should also be used with caution in patients with significant hepatic impairment, as earlier labeling noted limited data in this population.¹

Conclusion

Pimavanserin represents a major breakthrough in treating PDP. By working on serotonin rather than dopamine, it helps patients manage distressing psychiatric symptoms while keeping movement intact. However, like all medications, it requires careful patient selection and monitoring.

For patients and caregivers, understanding how pimavanserin works can empower informed discussions with health care providers. As research continues, this medication may pave the way for new treatments for other brain disorders involving serotonin dysfunction.

REFERENCES

1. Nuplazid [prescribing information]. 2016; Acadia Pharmaceuticals, Inc. Accessed December 19, 2025. https://www.nuplazid.com/pdf/nuplazid-prescribing-information.pdf \

2. Nuplazid (pimavanserin): dosing and administration. Accessed December 3, 2025. https://www.nuplazidhcp.com/dosing 

3. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson’s disease psychosis: a randomized, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533-540. doi:10.1016/S0140-6736(13)62106-6