NUPLAZID™: A Closer Look at Parkinson’s Psychosis Medication

nuplazid a bunch of pills on a conveyor belt

NUPLAZID (or pimavanserin) is the brand name for the only FDA-approved medication for Parkinson’s disease psychosis (PDP). It was approved by the FDA to treat PDP in 2016. More recently, in September 2023, the FDA updated the prescribing information for NUPLAZID to make clear that the medication is approved for people experiencing PDP with or without dementia.   

The Challenge of Treating PDP 

PDP is characterized by illusions, delusions, and auditory or visual hallucinations 

One challenge in treating PDP is that many typical antipsychotic medications can cause drug-induced parkinsonism. Many of these drugs can also worsen other Parkinson’s symptoms 

Moreover, while psychotic symptoms can directly result from the pathology of Parkinson’s, psychotic symptoms can also be side effects of common Parkinson’s treatments. In an article describing treatment options for PDP, Professor in the College of Pharmacy at Marshall B. Ketchum University Jack Chen shares:

Although exposure to PD medications is not a requirement for development of Parkinson’s psychosis, multiple medication classes, such as amantadine, anticholinergics, COMT inhibitors, dopamine agonists, levodopa, and MAO-B inhibitors, have all been associated with triggering PDP. In particular, up to one third of patients exposed to chronic dopaminergic therapy will experience visual hallucinations. 

To treat PDP, your physician may start by lowering the amount of dopaminergic treatment you are taking. Another approach is to prescribe a medication off label. Both options have pros and cons. NUPLAZID’s 2016 approval provides you and your care team with another option worth considering to treat PDP.  

How NUPLAZID Helps with PDP 

The exact method of action of NUPLAZID is not known, but the drug affects the use of serotonin in the brain and is believed to work against Parkinson’s effects on the serotonin system. Overstimulation of serotonin receptors is involved in multiple causes of hallucination, and NUPLAZID works as an inverse agonist and antagonist of these receptors. 

Importantly, in clinical trials, there was no significant worsening of Parkinson’s motor symptoms associated with use of NUPLAZID. This is likely because, unlike many antipsychotic medications, NUPLAZID does not interact with other systems involved in Parkinson’s motor symptoms. 

Efficacy Data from Clinical Trials 

NUPLAZID was granted “breakthrough therapy designation” by the FDA, so the approval process was expedited, and the drug was approved based on one clinical trial. Typically, a new medication is approved after at least two positive results from phase three trials. Because of NUPLAZID’s expedited approval, there is less data about it than there is for many other Parkinson’s medications. This has contributed to differing perspectives about NUPLAZID’s efficacy. 

For example, in 2017, Katie B. Touma, PharmD, and Daniel C. Touma, MD, observed that only one of four trials they reviewed showed significant improvements in psychotic symptoms when comparing NUPLAZID to placebo. They question the utility of a new rating scale used in some trials for NUPLAZID.  

In contrast, more recent reviews were published in 2021 and 2022, and supported the perspective that NUPLAZID is both safe and effective in treating PDP.  

For example, in 2021, a review of a large, open-label extension of a placebo-controlled trial for NUPLAZID found that people who had received a placebo during the initial phase of the trial improved during the extension of the trial, during which they switched from receiving placebo to receiving NUPLAZID. By the end of the open-label extension, rating scores were similar for those who received NUPLAZID for the entire trial and those who received placebo and then transitioned to NUPLAZID during the open-label extension. The authors thus concluded NUPLAZID is effective in treating PDP. 

Moreover, in 2022, researchers published a meta-analysis of clinical trial data related to NUPLAZID; their main conclusion was that people living with PDP who took NUPLAZID experienced “significant improvement in psychosis symptoms.” The researchers also found that the risk of adverse events was similar for those who received a placebo and those who received NUPLAZID.  

Media Coverage 

In the years following NUPLAZID’s approval, some news coverage raised questions about the safety of the treatment because of reports of deaths while people were taking the medication. An FDA review found no new or unexpected risks of NUPLAZID. 

When encountering news stories or other information—including this blog post—it is critical to evaluate what is said and how claims are supported. For example, some news coverage of NUPLAZID fails to acknowledge that people who live with PDP are typically living with advanced Parkinson’s and often experience a variety of complicated health issues.

Moreover, the FDA review found “some potentially concerning prescribing patterns […] such as the concomitant use of other antipsychotic drugs or drugs that can cause QT prolongation, a potential cause of heart rhythm disorder.” 

We have discussed ways to evaluate medical information in conversation with Dr. Benzi Kluger and in this blog post, which includes references and links to some of the stories about NUPLAZID.  

Risks, Side Effects, and Other Concerns Related to NUPLAZID 

According to the FDA prescribing information for NUPLAZID, in the clinical trials that led to the drug’s approval, the most common side effects were leg swelling and confusion. Other side effects included nausea, constipation, and urinary tract infection. 

Since approval of NUPLAZID, the following additional adverse reactions have been reported: rash, hives, tongue swelling, throat tightness, drowsiness, falls, agitation, and aggression. 

NUPLAZID has a warning that elderly people with dementia-related psychosis have an increased risk of death when taking antipsychotic medication. This warning is also common for other classes of antipsychotic medication. Moreover, the FDA prescribing information notes that NUPLAZID is only appropriate for people experiencing psychosis and dementia if their psychosis is related to Parkinson’s. 

Because of the risks associated with QT prolongation, NUPLAZID is contraindicated for use by people who take drugs that prolong the QT interval. These include certain anti-arrhythmic, antipsychotic, and antibiotic medications. 

Additionally, there are interactions between NUPLAZID and the enzyme CYP3A4, which is involved in breakdown of toxins and drugs in the body. The FDA prescribing information notes that if you take medications that inhibit function of CYP3A4, your recommended dose of NUPLAZID should be 10 mg, 1X daily, which is a general recommendation. Only your medical team can provide the best course of action for you or your loved ones. 


Because NUPLAZID is not available in a generic form, it can be expensive, depending on your insurance coverage. Acadia, the drug’s manufacturer, has a program that may be able to help lower your cost for NUPLAZID. 

Reasons to Consider NUPLAZID 

PDP is one of the most challenging experiences of living with Parkinson’s. A 2021 article found that PDP increases the risk of nursing home placement and death. Moreover, PDP is a major source of care partner burden and can have dramatic effects on quality of life.  

Today, NUPLAZID is the only antipsychotic specifically approved for Parkinson’s. It can help decrease the burden of living with PDP, and it often does so with a low level of side effects. 

Other specific reasons you and your care team might consider NUPLAZID include: 

Lower Risk of Hospitalization Compared to Quetiapine 

Recent research found that users of NUPLAZID had a lower rate of hospitalization than users of quetiapine, a drug used off-label for PDP. 

Lower Risk of Orthostatic Hypotension 

Authors of the 2022 meta-analysis found that there was a lower incidence of orthostatic hypotension in people who took NUPLAZID in clinical trials. 

Lower Mortality Rates Compared to Other Antipsychotics 

Over six months of use, those who took NUPLAZID had a lower mortality rate than those who took other antipsychotic medications. This trend was only true for those who did not live in nursing homes.  

Another study that involved over 2,892 people taking NUPLAZID found that people who took NUPLAZID had a lower mortality rate than those who took other antipsychotic medications. 

Minimal Effect on Motor Symptoms 

Many antipsychotic medications can worsen impact on motor symptoms, but NUPLAZID has not shown to have these effects 

Multiple Advantages Over Other Atypical Antipsychotics 

A 2023 study comparing six antipsychotic medications found NUPLAZID had:

  • The greatest probability of being efficacious
  • The most significant effect size on two rating scales 
  • A lower likelihood of drowsiness than clozapine and quetiapine, two other common treatments for PDP

Additional Resources  

Knowledge, Responsibilities, and Peer Advice from Care Partners of People with PDP 

Letter to American Journal of Psychiatry about Safety of NUPLAZID/pimavanserin 

Inverse Agonists 

Psychiatric and Cognitive Complications Webinar With Dr. Weintraub 

Conversation with Dr. Goetz about Parkinson’s Psychosis 

QT Interval Information 

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