Nuplazid (pimavanserin) is an oral medication approved by the U.S. Food and Drug Administration (FDA)  for the treatment of hallucinations and delusions associated with Parkinson’s disease. Parkinson’s symptoms are recognized by most people as tremors, limb stiffness, impaired balance, and slow movement. However, over the course of this disease, more than half of all patients are affected by what’s called Parkinson’s psychosis, which causes them to see, hear, or experience things that are not real (hallucinations), or believe things that are not true (delusions).

In clinical trials, Nuplazid was found to significantly reduce the severity of Parkinson’s psychosis, but had no effect on motor symptoms.

The treatment was developed by Acadia Pharmaceuticals and approved by the FDA in April 2016.

How Nuplazid works

Nuplazid is a selective serotonin inverse agonist (SSIA) targeting serotonin receptors called 5HT2A receptors. An inverse agonist is a molecule that binds to the same receptor as an agonist (a molecule that binds to a receptor and initiates a physiological response) but induces the opposite pharmacological response. Serotonin receptors are found throughout the nervous system and mediate the transmission of signals between nerve cells. The 5HT2A receptor has been implicated in mental disorders, but in ways that are still not clearly understood.

Parkinson’s therapies typically work to stimulate dopamine and treat motor symptoms such as tremors, muscle rigidity, and walking. Nuplazid has no binding affinity for dopamine receptors, so it does not interfere with dopaminergic therapy, and it does not bind to other receptors commonly targeted by antipsychotics

Nuplazid studies

A Phase 2 randomized, placebo-controlled and double-blind study (NCT00087542) in 60 Parkinson’s patients evaluated Nuplazid’s efficacy, tolerability and safety over four weeks of treatment, after which participants were invited to enroll in an open-label, safety extension study (NCT1518309).

A randomized, double-blind, Phase 3 study (NCT00658567) also evaluated the drug’s efficacy, tolerability, and safety. After the six-week treatment period, participants were again allowed to enroll in an open-label study (NCT00550238) to further evaluate safety and tolerability.

Patients in the open-label studies were treated for a median duration of more than 15 months.

Data from these Phase 3 and open-label studies, presented at the 19th International Congress of Parkinson’s Disease and Movement Disorders in 2015, showed that long-term use of Nuplazid was safe and well-tolerated, with no impact on patients’ motor function. Pooled Phase 3 analysis, covering data on 268 patients, also showed “significant improvement” on separate measures of hallucination and delusion, as well as on secondary psychoses measures, and improvements in nighttime sleep. In the open label study, participants’ Schedule for Assessment of Positive Symptoms–Parkinson’s disease (SAPS-PD) and the Clinical Global Impression-Severity (CGI-S) scores significantly improved at week four compared to their scores recorded at the end of the randomized study.

Data from two six-week Phase 3 placebo-controlled studies (NCT000477672 and NCT01174004) were also presented at the 19th congress. Nuplazid’s approval by the FDA was based on data from the second study as well as other supportive studies. In this study, participants were randomized to either receive 40 mg of the drug or a placebo. Nuplazid significantly reduced the frequency and severity of psychotic symptoms when compared to a placebo, again without impairing motor function. This trial’s results were published in The Lancet.

Other details

Nuplazid is to be taken orally as two 17 milligram tablets, once a day, at any time of the day or at a time recommended by a doctor. Common side effects include swelling in the legs or arms, nausea, and feelings of confusion. Other side effects may include hallucinations, constipation, and changes in normal walking.

People with certain heart conditions (irregular or slow heartbeat) should not take Nuplazid, as its use may increase the risk of arrhythmia. People with kidney or liver problems should inform their doctor before taking Nuplazid.

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