Pimavanserin is an atypical antipsychotic that received FDA approval in the U.S. since 2016 for hallucinations and delusions that accompany Parkinson disease psychosis (PDP).[1] It is the first, and only FDA approved medication for PDP. In 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 of motor function compared to patients receiving 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] Other than its use in PDP, pimavanserin has no other FDA, or non-FDA approved indications to date. However, there are various ongoing studies on 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 phase II clinical trial of patients with Alzheimer's 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's disease psychosis demonstrated greater 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 difficult to treat negative symptoms of schizophrenia. A recent study reported success with pimavanserin in patients with schizophrenia and schizoaffective disorder with refractory psychosis.[8]. 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.[9] It may also have implications in the treatment of insomnia as it has shown to significantly increase slow-wave sleep and decrease the frequency of nighttime awakenings.[10]

Pimavanserin is an antagonist/inverse agonist at the 5HT2A receptor and has a 40-fold weaker antagonism/inverse agonism at the 5HT2C receptor.[11] 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]

The recommended dose 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.[12] Pimavanserin undergoes hepatic metabolization by CYP450 3A4 and 3A5. Thus, when co-administered with a strong CYP3A4 inhibitor (i.e., itraconazole, ketoconazole, clarithromycin, indinavir), it is recommended to reduce the pimavanserin dose by 50%. In contrast, when given in the presence of a strong CYP450 34A and 3A5 inducer (i.e., rifampin, carbamazepine, phenytoin, and St. John’s wort), providers should monitor for reduced efficacy, and increase the pimavanserin dose as needed.[13]

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, 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).[14] As described in other antipsychotics, pimavanserin may cause QTc prolongation; this raises concern as it could potentially lead to the life-threatening tachyarrhythmia called torsades de pointes.[15] While the mechanism of action of pimavanserin differs from other atypical antipsychotics, namely the consequential lack of dopamine D2 receptor blockade, there is a remaining concern for risk of death in elderly patients with dementia-related psychosis, as 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.[14]

The only true contraindication to taking pimavanserin is a hypersensitivity reaction to pimavanserin or any of its constituents.