RESEARCH MONOGRAPH · KDC-MN-240
Pimavanserin
Pimavanserin (Nuplazid) is the first FDA-approved drug for Parkinson disease psychosis, brought to market by ACADIA in 2016. It is also the first antipsychotic without any dopamine receptor activity at all, which makes it pharmacologically unique in its class. Mechanistically it is a selective 5-HT2A inverse agonist (it actively turns off the receptor's baseline signaling rather than just blocking serotonin from binding). Because it leaves dopamine signaling alone, it does not worsen the motor symptoms of Parkinson disease the way standard antipsychotics do. The 2016 approval was politically contentious because mortality data in elderly trial patients was concerning, and a 2019 follow-up trial in dementia-related psychosis failed. Still in clinical use specifically for Parkinson psychosis. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
Selective 5-HT2A inverse agonist
The first FDA-approved drug for Parkinson disease psychosis; a selective 5-HT2A inverse agonist with no dopamine receptor activity.
Abstract
Pimavanserin (1-[(4-fluorophenyl)methyl]-1-[(1-methyl-4-piperidinyl)methyl]-3-{4-[(2-methylpropoxy)]phenyl}urea; CAS 706779-91-1; molecular formula C25H34FN3O2; molecular weight 427.56) is a selective 5-HT2A inverse agonist developed at ACADIA and approved by the FDA in 2016 under the trade name Nuplazid. Distinct among antipsychotics by absence of dopamine receptor activity: D2 affinity is greater than 1000 nM, with no clinically relevant binding. Selectivity is for 5-HT2A (Ki approximately 0.087 nM) over 5-HT2C (Ki approximately 0.4 nM, approximately 5-fold selective). The compound is a high-efficacy inverse agonist (not merely an antagonist), reducing constitutive 5-HT2A signaling below baseline. The dopaminergically clean profile is uniquely suited to Parkinson disease psychosis, where conventional antipsychotics' D2 antagonism worsens motor symptoms; pimavanserin treats hallucinations and delusions without aggravating bradykinesia or rigidity. Plasma half-life is 57 hours for parent compound, 200 hours for active metabolite. Metabolism is via CYP3A4 and CYP3A5. The compound carries an FDA black-box warning for increased mortality in elderly dementia patients (a class warning for all antipsychotics). Used as the reference selective 5-HT2A inverse agonist.
Mechanism of action
Selective 5-HT2A inverse agonist (no dopamine receptor activity). Approximately 5-fold selectivity over 5-HT2C. High-efficacy inverse agonism rather than simple antagonism.
Reported research dose ranges
Clinical 17 to 34 mg per oral administration daily. Rodent studies 0.1 to 3 mg/kg/day.
References
- Vanover KE, et al. Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide as a novel 5-hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther 2006.
- Cummings J, et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 2014.
- Stahl SM. Mechanism of action of pimavanserin in Parkinson's disease psychosis. CNS Spectr 2016.
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FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.