Psychosis can be a paralyzing dilemma for patients with Parkinson’s disease (PD). Most antipsychotics worsen the motor symptoms of PD, while the dopaminergic drugs that treat PD can worsen the psychosis. Psychosis afflicts up to 60% of patients with PD, and it is the leading cause of nursing home placement in these patients (Hacksell U et al, Neurochem Res 2014;39(10):2008–2017).

In 2016, the FDA approved pimavanserin (Nuplazid) for Parkinson’s-related psychosis. This medication does not worsen the motor symptoms of Parkinson’s. Pimavanserin is a highly selective 5-HT2A inverse agonist that binds minimally with dopaminergic, histaminergic, and muscarinic receptors. Research suggests that overactive 5-HT2A signaling contributes to psychosis in PD (Hawkins T et al, Neurol Clin Pract 2017;7:157–162). Clinical evidence for this concept comes from clozapine, which, in low doses, blocks 5-HT2A receptors with minimal dopamine blockade. A review found that low doses of clozapine have proven efficacious in treating Parkinson’s psychosis (Cook K et al, Mov Disord 2017;32(S2)).

Safety and efficacy
Pimavanserin’s benefits in Parkinson’s psychosis are real, but very modest. In a meta-analysis of four randomized controlled trials, pimavanserin led to a 2.3 point reduction in psychotic symptoms compared to placebo on a 100-point rating scale, the SAPS H+D, a modified version of the Scale for the Assessment of Positive Symptoms (Yasue I et al, J Alzheimers Dis 2016;50:733–740). This 2-point difference could be achieved by resolution of a mild delusion, an improvement that may not always be clinically significant.

There was also a concerning risk of bias in these studies. Problems included neglecting to report the primary outcome in one of the treatment arms, leaving out important details about the randomization and blinding, relying on an unvalidated rating scale, and excluding patients with cognitive impairment (Mini Mental Status Exam < 21) (Cummings J et al, Lancet 2014;383(9916):533–540).

Outside of pimavanserin, clozapine is the best-studied antipsychotic for Parkinson’s psychosis. In low doses (12.5–50 mg), clozapine outperformed placebo without worsening motor symptoms in two randomized controlled trials. However, clozapine’s numerous medical risks make it a difficult choice for this syndrome. Quetia­pine and ziprasidone also have low levels of extrapyramidal side effects, though the evidence for their efficacy in Parkinson’s psychosis is minimal or mixed (Cook K et al, Mov Disord 2017;32(S2)).

Like other antipsychotics, pimavanserin’s benefits build up over about 2 weeks. The recommended dose is 34 mg daily. Assess the patient’s psychotic symptoms carefully before and after prescribing it, and consider discontinuing it if there is no clear improvement. Monitor for side effects, which include nausea, imbalance, and peripheral edema. Although pimavanserin is indicated for delusions and hallucinations, it can also cause new hallucinations (the rate was 5% with pimavanserin vs 3% with placebo). Other psychiatric side effects include aggression and confusional states.

Antipsychotics may have only modest benefits in Parkinson’s psychosis, but other interventions that can help (Schubmehl S et al, Am J Geriatr Psychiatry 2018;26(10):1014) include:

1. Reduce dopaminergic medications


2. Teach caregivers how to redirect patients


3. Keep the lights on during the day to minimize visual hallucinations


4. Play soothing music and address any hearing loss or tinnitus to minimize auditory hallucinations

Expanding use
Since its approval for Parkinson’s psychosis, pimavanserin has been tested in a variety of other conditions, including schizophrenia, Alzheimer’s disease with psychosis, depression, and antidepressant-induced sexual dysfunction. The ­majority of the available studies for off-label uses constitute low-quality and often negative evidence.

In major depression, pimavanserin successfully augmented an SSRI or SNRI in patients who had failed to respond to the antidepressant (n­ = 207). Pimavanserin separated from placebo at 1 week in this 10-week study, with a medium effect size (0.5–0.6). It’s a promising result, but the study needs replication (Fava M et al, J Clin Psychiatry 2019;80(6)).

Costs and coverage
Without insurance, pimavanserin costs over $3,000 per month. Most Medicare plans and commercial insurers cover it, though prior authorizations are often required. CoverMyMeds.com can assist with prior authorizations, and the Nuplazid website has a handy program (www.nuplazid.com/nuplazidconnect) that quickly checks coverage. Commercial insurers benefit from a $0 copay card, but the copay can be prohibitive for patients who are on governmental insurance.

TCPR Verdict: Antipsychotics are not particularly effective in Parkinson’s psychosis. Pimavanserin has FDA approval for this condition, but its benefits are modest and the price is high. Low-dose clozapine, though not FDA approved, is also helpful. For many of these patients, the psychosis will persist despite antipsychotic therapy. Other options, including minimizing dopaminergics and non-pharmacologic interventions, are an essential part of the plan.