Nuplazid Review Endorses Treatment, But Pinpoints Additional Study Needs

Even though 60 percent of Parkinson’s Disease patients develop psychotic symptoms, it was only in 2016 that a treatment for the condition was approved.

Nuplazid (pimavanserin) employs an entirely different mechanism to control psychotic symptoms compared to the bulk of antipsychotic medications on the market.

The review, “Pimavanserin, a novel antipsychotic for management of Parkinson’s disease psychosis,” took a look at the drug’s specific features, and its potential to early on prevent psychotic symptoms from bringing on more severe disease and premature death among Parkinson’s patients.

Researchers from Feinberg School of Medicine at Northwestern University, published the review in the journal Expert Review of Clinical Pharmacology.

Why not common antipsychotics?

Treatments capable of treating hallucinations and delusions have existed since the 1950s. So, why then do people with Parkinson’s disease require a specific type of medication?

People with Parkinson’s disease suffer neurodegeneration, particularly affecting neurons producing the neurotransmitter dopamine; medications aim to replace lost dopamine signaling by adding more of the substance.

The problem is that the majority of antipsychotic treatments work to block dopamine receptors. Using such drugs, therefore, would worsen motor symptoms. Moreover, some studies show that antipsychotics may increase the risk of death among Parkinson’s patients, although the issue is a topic of debate.

The brain, however, is complex and some newer compounds exist that target other signaling substances to treat psychosis.

Clozapine is considered the most effective antipsychotic on the market. But its widespread use, in Parkinson’s as well as other patients, is prevented by severe and potentially fatal side effects linked to the treatment. Patients need to be closely monitored with blood cell counts because a loss of neutrophil cells can be life-threatening.

Another so-called atypical antipsychotic, quetiapine, is sometimes used in Parkinson’s psychosis. But clinical trials have failed to prove the treatment is more effective than a placebo.

Moreover, both clozapine and quetiapine cause sedation and postural hypotension, which can be difficult to tolerate for someone with Parkinson’s disease, and may increase the risk of falls and worsen cognition, researchers underscored.

The novelty of Nuplazid

Unlike these medications, Nuplazid blocks brain receptors for the neurotransmitter serotonin. The drug has been studied in five Phase 2 or 3 clinical trials, and a sixth is ongoing. So, there is plenty of data showing the safety and effectiveness of this approach.

An analysis of pooled data from four of these trials showed that Nuplazid effectively reduced hallucinations and delusions in patients with Parkinson’s disease psychosis. It also has a good benefit-safety balance, researchers say.

While the side effects of earlier antipsychotics often made doctors delay treating Parkinson’s patients until the hallucinations and delusions became more severe, Nuplazid’s safety profile allows early treatment, the Feinberg researchers underscored.

Studies show that psychotic symptoms in Parkinson’s disease are linked to worsening disease and early death. Moreover, a psychotic Parkinson’s patient is extremely difficult to manage for family caregivers, often making early nursing home placements necessary.

Early treatment, researchers argued, may prevent this development. Since it takes several weeks for the drug to be fully effective, it also is important to start treatment early to prevent a potential exacerbation, they said.

More studies are needed, however, to explore if early treatment really does change the course of negative outcomes linked to psychosis in Parkinson’s disease.

Future directions

Nevertheless, although Nuplazid is approved for use in Parkinson’s disease, it carries a boxed warning that patients with dementia taking antipsychotics are at an increased risk of death.

Many patients with Parkinson’s psychosis also develop dementia, so more information is needed to assess the safety and effectiveness of Nuplazid in this patient group, the reviewers noted.

Acadia Pharmaceuticals, Nuplazid’s developer, recently launched a Phase 3 trial (NCT03325556) testing the drug in patients with dementia-related psychosis. The study enrolls patients with Parkinson’s disease, among others.

The review, however, pointed out that further studies examining the drug are necessary. For instance, the treatment is available in one dose only. Studies should explore other doses, and assess the safety of combining Nuplazid with atypical antipsychotics for people who fail to respond to Nuplazid alone.