By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Medical Director, Pharmacy, Northern California Kaiser Permanente, and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved the first drug to treat hallucinations and delusions associated with Parkinson’s disease (PD). Pimavanserin, an atypical antipsychotic agent, is an inverse agonist and antagonist at serotonin 5-HT2A receptors and to a lesser extent the serotonin 5-HT2C receptors.1 The drug was granted breakthrough designation and given a priority review.2 Pimavanserin is marketed as Nuplazid.

INDICATION

Pimavanserin is indicated for the treatment of hallucination and delusions associated with PD psychosis.1

DOSAGE

The recommended dose is 34 mg taken as two 17 mg tablets once daily with or without food.1 Dose titration is not recommended.

POTENTIAL ADVANTAGES

Pimavanserin is currently the only drug approved for this indication.

POTENTIAL DISADVANTAGES

Pimavanserin carries the same boxed warning for increased mortality in elderly patients with dementia-related psychosis as other atypical antipsychotics. Pimavanserin prolongs QT interval. Do not give it to patients with known QT prolongation, history of cardiac arrhythmias, or with other drugs known to prolong QT interval.1 Adverse events reported, compared to placebo, during placebo-controlled studies were nausea (7% vs. 4%), peripheral edema (7% vs. 2%), and confusion state (6% vs. 3%).1 Eight percent of patients discontinued treatment due to adverse events compared to 4% on placebo.

COMMENTS

The efficacy of pimavanserin was demonstrated in a six-week, randomized, placebo-controlled, parallel-group study (n = 199).1,2 These subjects received a PD diagnosis at least one year prior to study entry (Mini-Mental State Examination [MMSE] score ≥ 21) and exhibited psychotic symptoms that were severe enough to require antipsychotic treatment. Subjects were randomized (1:1) to pimavanserin 34 mg or placebo. Efficacy was assessed using the PD-adapted Scale for the Assessment of Positive Symptoms (SAPS-PD). This is a nine-item scale for the hallucination and delusions domain of SAPS, with each item scored between 0 and 5, with 0 representing no symptoms and 5 severe and frequent symptoms. Pimavanserin treatment showed a mean change from a mean baseline of 15.9 of -5.79 vs. a mean change with placebo of -2.73 from a mean baseline of 14.7 (a difference of -3.06; 95% confidence interval, -4.91 to -1.20). This represented a 36.4% and 18.6% reduction, respectively, and a medium effect size (Cohen’s d, 0.50). The magnitude of change was similar for both hallucinations and delusions. Placebo-subtracted changes were approximately -20% for both total and subgroups. A pooled analysis of four randomized trials also found pimavanserin to be beneficial.3

CLINICAL IMPLICATIONS

A complication of PD, psychotic symptoms can occur in up to 50% of patients and may be associated with medications used to treat the disease, particularly those that elevate dopamine levels. Current treatment options include a reduction of anti-Parkinson drugs as well as off-label clozapine and quetiapine.4-6 Reduction of drugs may worsen motor problems; clozapine has been associated with agranulocytosis, while the efficacy of quetiapine is uncertain. Pimavanserin is the first FDA-approved treatment. The wholesale cost for pimavanserin is $1,950 for a 30-day supply.

REFERENCES

  1. Nuplazid Prescribing Information. April 2016. Acadis Pharmaceutical Inc.
  2. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson’s disease psychosis: A randomised, placebo-controlled phase 3 trial. Lancet 2014;383:533-540.
  3. Yasue I, Matsunaga S, Kishi T, et al. Serotonin 2A receptor inverse agonist as a treatment for Parkinson’s disease psychosis: A systematic review and meta-analysis of serotonin 2A receptor negative modulators. J Alzheimers Dis 2016;50:733-740.
  4. Hasnain M. Psychosis in Parkinson’s disease: Therapeutic options. Drugs Today (Bac);2011:353-367.
  5. Hermanowicz S, Hermanowicz N. The safety, tolerability and efficacy of pimavanserin tartrate in the treatment of psychosis in Parkinson’s disease. Exper Rev Neurother 2016 Feb 24 [Epub ahead of print].
  6. National Parkinson Foundation homepage. Available at: www.parkinson.org. Accessed May 17, 2016.