Continuing Education Activity

Pimavanserin is a medication used to treat and manage the hallucinations and delusions associated with Parkinson disease psychosis. It is in the atypical antipsychotic class of drugs. This activity reviews the indication, action, and contraindications for pimavanserin as a valuable agent in managing Parkinson disease psychosis. This activity will highlight the mechanism of action, adverse event profile, dosing, monitoring, relevant interactions, and other key factors pertinent for healthcare team members in the care of patients with Parkinson disease psychosis.

Objectives:

• Identify the indications for pimavanserin.
• Review the typical adverse effects of pimavanserin.
• Summarize the risks associated with initiating pimavanserin, summarizing key patient counseling points.
• Outline the importance of collaboration and coordination among the interprofessional team to enhance patient care when initiating and monitoring pimavanserin to improve patient outcomes for patients receiving treatment for Parkinson disease psychosis.

Indications

Pimavanserin is an atypical antipsychotic that received FDA approval in the U.S. in 2016 for hallucinations and delusions that accompany Parkinson disease psychosis (PDP).[1] It is the first and only FDA-approved medication for PDP. It had initially received Breakthrough Therapy status from the FDA in 2014. In the phase III clinical trial that paved the way for FDA approval, patients receiving pimavanserin demonstrated significant improvement in the frequency and/or severity of hallucinations and/or delusions without worsening motor function compared to patients receiving a placebo.[2] A separate study using data from the same trial found a more robust response to pimavanserin in PDP patients with impaired cognitive functioning.[3] Besides its use in PDP, pimavanserin has no other FDA or non-FDA-approved indications. However, there are various ongoing studies on the potential uses of pimavanserin.

In addition to Parkinson disease, psychotic symptoms can also manifest in different subtypes of dementia. At present, there are no FDA-approved agents indicated for dementia-related psychosis (DRP). Pimavanserin is under evaluation for its potential use in DRP.[4] In a phase II clinical trial of patients with Alzheimer disease psychosis, patients treated with pimavanserin versus placebo showed significant improvement in psychosis at the 6-week primary endpoint (p=0·045). The significance did not progress to the week 12 follow-up (p=0·561).[5] Notably, there was no observable negative impact on cognition in either group.[5] Further evaluation of a severe subgroup of patients with Alzheimer disease psychosis demonstrated more significant improvement of symptoms.[6] 

In a study examining the discontinuation rate of patients with PDP or dementia with Lewy bodies (DLB) given either pimavanserin or quetiapine, the discontinuation rate of patients treated with pimavanserin was lower earlier on and higher later on in comparison to quetiapine.[7] Outside of the realm of DRP, pimavanserin has also shown promise in treating positive as well as challenging to treat negative symptoms of schizophrenia. A recent study reported success with pimavanserin in patients with schizophrenia and schizoaffective disorder with refractory psychosis.[8] The manufacturer of the drug reported that as of March 2022, they were conducting a phase 3 clinical trial to evaluate pimavanserin for major depressive disorder and schizophrenia, as well as phase 2 trials for agitation and phase 1 trials examining its effectiveness in psychiatric disorders.[9][10]

Researchers further observed that there was a consequential improvement in social functioning and negative symptoms.[8] Pimavanserin has also shown considerable promise as an adjunctive treatment in patients with major depressive disorder (MDD) refractory to SSRI and SNRI medications alone.[11] It may also have implications in treating insomnia as it has been shown to significantly increase slow-wave sleep and decrease the frequency of nighttime awakenings.[12]

Mechanism of Action

Pimavanserin is an antagonist/inverse agonist at the 5HT2A receptor and has a 40-fold weaker antagonism/inverse agonism at the 5HT2C receptor.[13] Unlike other atypical antipsychotics, pimavanserin lacks dopaminergic activity, namely at the D2 receptor. Pimavanserin is the first drug without dopamine D2 blocking activity that displays antipsychotic actions. Thus, fulfilling a particular niche by treating the psychotic symptoms without worsening the motor symptoms of parkinsonism, an adverse effect commonly observed with other antipsychotics.[2] Additionally, pimavanserin does not cause sedation, seen in quetiapine or clozapine, which are currently used off-label to treat PDP.[2]

Pimavanserin metabolism primarily occurs in the liver; it is a CYP450 enzyme-substrate, primarily CYP3A4/5, but also CYP2D6 and CYP2J2. It has an active metabolite. The drug has a half-life of 57 hours for the parent drug and 200 hours for the active metabolite. It is excreted in the urine and feces.

Administration

The recommended dose for Parkinson disease-associated psychosis is 34 mg orally once daily. Pimavanserin is only available for oral administration. Patients may take pimavanserin with or without food. Titration is not required. It is only available as an immediate-release formulation. No significant drug interactions with carbidopa/levodopa have been observed, and therefore, no dosage adjustments are necessary.[14] 

As mentioned above, pimavanserin undergoes significant hepatic metabolization by CYP450 3A4 and 3A5. Thus, the recommendation is to reduce when co-administered with a potent CYP3A4 inhibitor (i.e., itraconazole, ketoconazole, clarithromycin, indinavir) pimavanserin dose by 50%. In contrast, when given in the presence of a strong CYP450 34A and 3A5 inducer (for example, rifampin, carbamazepine, phenytoin, and St. John’s wort), providers should monitor for reduced efficacy and increase the pimavanserin dose as needed.[15]

Pimavanserin requires no renal dosing adjustment, although clinicians should exercise caution for patients with a creatinine clearance below 30. Peritoneal and hemodialysis dosing are undefined. 

Pimavanserin has no pediatric dosing or indications.

Adverse Effects

In the controlled trial setting, common adverse effects at an incidence of 5% or more included peripheral edema, confusional state, and nausea. Adverse reactions at an incidence of 2% or greater included hallucinations, peripheral edema, nausea, confusion, constipation, and gait disturbances. Instances in which treatment was discontinued in patients treated with pimavanserin (8%), as well as patients treated with placebo (4%), included hallucinations (2% pimavanserin 34 mg versus less than 1% placebo), urinary tract infection (1% pimavanserin 34 mg versus less than 1% placebo), and fatigue (1% pimavanserin 34 mg versus 0% placebo).[16] 

As is the case with other antipsychotics, pimavanserin may cause QTc prolongation; this raises concern as it could potentially lead to the life-threatening tachyarrhythmia called torsades de pointes.[17] Another potentially severe adverse reaction is angioedema.

While the mechanism of action of pimavanserin differs from other atypical antipsychotics, namely the resulting lack of dopamine D2 receptor blockade, there is a remaining concern for the risk of death in elderly patients with dementia-related psychosis since pimavanserin could potentially have a similar effect. Therefore, like other antipsychotics, pimavanserin has a black box warning of increased mortality in elderly patients with dementia-related psychosis. Pimavanserin is safe to use in patients with mild to moderate renal impairment, and dosage adjustment is not required. Pimavanserin is not recommended for use in patients with severe renal impairment or any degree of hepatic impairment.[16]

Contraindications

Contraindications to taking pimavanserin include hypersensitivity to pimavanserin or any of its constituents. Other contraindications or cautions include:

• Uncorrected electrolyte abnormalities
• QT prolongation or a family history of QT prolongation, including congenital long QT syndrome
• A history of torsades des pointes
• Ventricular arrhythmias
• Recent history of myocardial infarct
• Bradycardia
• Congestive heart failure

Caution is also recommended in the elderly, patients with end-stage renal disease (ESDRD) or a CrCl below 30, and patients with psychosis related to dementia.

There is presently no human data regarding the use of pimavanserin in pregnancy; clinicians need to weigh the risk vs. benefit in this patient population; animal studies showed no teratogenicity at ten times the maximum recommended human dose (MRHD). Similarly, clinicians should weigh the risk vs. benefit in breastfeeding patients; there is no data available to assess the drug's effect on milk production or the risk of infant harm.

Contraindicated drug interactions include concomitant use with pimozide or thioridazine. As already discussed, caution and dosing adjustments may be necessary with potent CYP450 inducers and inhibitors.

Monitoring

Pimavanserin may cause QTc prolongation. Patients should receive instructions to report any new onset palpitations, syncope, or near-syncope. Likewise, clinical illnesses such as gastroenteritis or the initiation of diuretic therapy, which could lead to hypokalemia, should also be reported as prompt identification and correction of electrolyte abnormalities minimizes the risk of arrhythmias. Pimanversin is not associated with the constellation of weight gain, hyperlipidemia, and hyperglycemia, called metabolic syndrome seen in other atypical antipsychotics. However, it is still beneficial for the patient to eat a healthy diet, engage in an exercise regimen, and abstain from or stop smoking while taking the medication. Given that pimavanserin undergoes hepatic metabolization via the same cytochrome P450 pathways as various other medications, providers should be aware of drugs that may inhibit or induce the metabolism of pimavanserin and adjust dosing accordingly.  

Toxicity

There have been no reported overdoses to date, and there is no specific antidote for pimavanserin. 

Enhancing Healthcare Team Outcomes

Care is necessary across the interprofessional spectrum to ensure proper medication safety, efficacy, and adherence. The prescribing clinician should continually monitor and educate the patient on the risks and benefits of pimavanserin; it may be beneficial to consult with a geriatric or psychiatric Board of Pharmacy specialty pharmacist. All pharmacists involved in patient care need to be alert for changes in the patient's medications that may lead to drug interactions with pimavanserin and be prepared to make recommendations to change the patient's drug regimen if necessary.

In long-term care, nursing home, or home care settings, nursing staff can continually monitor patients for the common and life-threatening adverse effects of pimavanserin and either consult with the pharmacist or report their observations to the prescribing clinician immediately. Nursing staff can also monitor patient compliance and provide educational support to patients. As pimavanserin is a newer medication, other specialists working with the patient can familiarize themselves with the side effects and drug interactions of pimavanserin.

Lastly, pimavanserin is expensive. In patients that would benefit from pimavanserin, the prescribing clinician, social workers, insurance companies, and other staff members can work together to make pimavanserin accessible, as affordability is a concern that must be addressed, even if pimavanserin is the optimal therapeutic agent for a particular patient case. These types of interprofessional team interactions are but a few examples of how the interprofessional team model should work, which can lead to more successful outcomes with pimavanserin. [Level 5]