Pimavanserin

Overview

Pimavanserin, sold under the brand name Nuplazid, is an atypical antipsychotic which is approved for the treatment of Parkinson's disease psychosis. It is taken by mouth.[1][2] WP

Side effects of pimavanserin include peripheral edema and confusion. Unlike other antipsychotics, pimavanserin is not a dopamine receptor antagonist, but rather is a selective antagonist or inverse agonist of the serotonin 5-HT2A receptor and to a lesser extent of the serotonin 5-HT2C receptor.[1][3] WP

Pimavanserin was first approved for medical use in 2016. It was approved as a generic medication in 2024.[1][4] WP

Uses, dosage and effects

Medical uses

Pimavanserin is used in the treatment of Parkinson's disease psychosis.[1] WP

Available forms

Pimavanserin is available in the form of 10 mg oral tablets and 34 mg oral capsules.[1] WP

Risks and side effects

Side effects

Side effects of pimavanserin include peripheral edema and confusion, among others.[1] WP

Pharmacology

Pharmacodynamics

Pimavanserin acts as a selective inverse agonist or antagonist of the serotonin 5-HT2A receptor. It is also an antagonist or inverse agonist of the serotonin 5-HT2C receptor to a lesser extent.[1][5–8] WP

The drug has an affinity (Kᵢ) of 0.087 to 0.5 nM for the serotonin 5-HT2A receptor and 0.44 to 10 nM at the serotonin 5-HT2C receptor, whereas its functional inhibition (IC₅₀ (half-maximal inhibitory concentration)) values have been reported to be 1.9 nM at the serotonin 5-HT2A receptor and 91 nM at the serotonin 5-HT2C receptor. Hence, it shows 3- to 50-fold greater affinity for the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor depending on the assay and 49-fold selectivity in terms of functional inhibition of the serotonin 5-HT2A receptor compared to the serotonin 5-HT2C receptor.[6][7] WP

Pimavanserin shows low binding to σ₁ receptors (Kᵢ = 120 nM) and has no appreciable affinity (Kᵢ > 300 nM) to serotonin 5-HT2B, dopamine (including D₂), muscarinic acetylcholine, histamine, or adrenergic receptors, or to calcium channels.[9][10] WP

Pharmacokinetics

Pimavanserin is slowly absorbed and has a time to peak levels of 6 hours. The elimination half-life of pimavanserin is 54 to 57 hours. The half-life of its active metabolite N-desmethylpimavanserin is 200 hours.[1][5][11][12][13] WP

Research

Research

Pimavanserin was studied as a therapeutic agent in Phase III clinical trials for major depressive disorder and schizophrenia and Phase II trials for agitation. It was also under development for the treatment of insomnia, drug-induced akathisia, and drug-induced dyskinesia, but development for these indications was discontinued.[2] WP

In March 2024, Acadia Pharmaceuticals announced its decision to stop any further clinical trials of pimavanserin after the drug did not improve negative symptoms of schizophrenia better than placebo.[14] WP

As of November 2024, a phase 2 clinical trial is underway assessing the ability of pimavanserin to block the effects of the serotonergic psychedelic psilocybin.[15] WP

History

Development

Pimavanserin was developed by Acadia Pharmaceuticals. WP

Pimavanserin is expected to improve the effectiveness and side effect profile of antipsychotics. The results of a clinical trial examining the efficacy, tolerability and safety of adjunctive pimavanserin to risperidone and haloperidol were published in November 2012, and the results showed that pimavanserin potentiated the antipsychotic effects of subtherapeutic doses of risperidone and improved the tolerability of haloperidol treatment by reducing the incidence of extrapyramidal symptoms.[16–19] WP

The drug met expectations for a Phase III clinical trial for the treatment of Parkinson's disease psychosis, and has completed Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication.[20][21] WP

In September 2014, the United States Food and Drug Administration (FDA) granted breakthrough therapy status to Acadia's New Drug Application for pimavanserin.[22] WP

FDA approval

In April 2016, Nuplazid (pimavanserin) was approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. The non-binding advisory panel recommendation of 12-to-2 in support of approval that preceded the FDA approval action noted that the drug met an important need, despite its only providing modest benefits and posing serious safety issues.[23][24][25] WP

In June 2018, the FDA approved new dosages of pimavanserin to treat hallucinations and delusions associated with Parkinson's disease psychosis. A 34 mg capsule and 10 mg tablet formulation were approved. Previously, people were required to take two 17 mg tablets to achieve the recommended 34 mg dose per day. The 10 mg dose is indicated for people also taking CYP3A4 inhibitors (e.g., ketoconazole).[26] WP

Chemistry

Formula

C25H34FN3O2 PC

CAS number

706779-91-1 PC

Molar mass (g/mol)

427.6 PC

IUPAC name (computed by PubChem)

1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[[4-(2-methylpropoxy)phenyl]methyl]urea PC

SMILES

CC(C)COC1=CC=C(C=C1)CNC(=O)N(CC2=CC=C(C=C2)F)C3CCN(CC3)C PC

InChIKey

RKEWSXXUOLRFBX-UHFFFAOYSA-N PC

PubChem CID

10071196

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Journal / agency Highlights of prescribing information - NUPLAZID
2. Journal / agency Pimavanserin - Acadia Pharmaceuticals - AdisInsight
3. Journal / agency Howland RH. Pimavanserin: An Inverse Agonist Antipsychotic Drug. Journal of Psychosocial Nursing and Mental Health Services. June 2016. doi:10.3928/02793695-20160523-01 · PMID 27245248
4. Journal / agency First-Time Generic Drug Approvals 2024. 8 March 2024
5. Journal / agency Friedman JH. Pimavanserin for the treatment of Parkinson's disease psychosis. Expert Opinion on Pharmacotherapy. October 2013. doi:10.1517/14656566.2013.819345 · PMID 24016069
6. Journal / agency Caraci F, Santagati M, Caruso G, Cannavò D, Leggio GM, Salomone S, Drago F. New antipsychotic drugs for the treatment of agitation and psychosis in Alzheimer's disease: focus on brexpiprazole and pimavanserin. F1000Res. 2020. doi:10.12688/f1000research.22662.1 · PMID 32695312 · PMC7344175
7. Journal / agency Vanover KE, Weiner DM, Makhay M, Veinbergs I, Gardell LR, Lameh J, Del Tredici AL, Piu F, Schiffer HH, Ott TR, Burstein ES, Uldam AK, Thygesen MB, Schlienger N, Andersson CM, Son TY, Harvey SC, Powell SB, Geyer MA, Tolf BR, Brann MR, Davis RE. Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther. May 2006. doi:10.1124/jpet.105.097006 · PMID 16469866
8. Other NUPLAZID Prescribing Information. 2018
9. Journal / agency Nuplazid- pimavanserin tartrate capsule Nuplazid- pimavanserin tartrate tablet, coated. 21 December 2022
10. Journal / agency Stahl SM. Mechanism of action of pimavanserin in Parkinson's disease psychosis: targeting serotonin 5HT2A and 5HT2C receptors. CNS Spectrums. August 2016. doi:10.1017/S1092852916000407 · PMID 27503570
11. Journal / agency Monti JM, Pandi Perumal SR, Warren Spence D, Torterolo P. 5-HT2A Receptors in the Central Nervous System. 2018. doi:10.1007/978-3-319-70474-6_13
12. Journal / agency Ancoli-Israel S, Vanover KE, Weiner DM, Davis RE, van Kammen DP. Pimavanserin tartrate, a 5-HT(2A) receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers. Sleep Med. February 2011. doi:10.1016/j.sleep.2010.10.004 · PMID 21256805 · PMC3137254
13. Journal / agency Vanover KE, Robbins-Weilert D, Wilbraham DG, Mant TG, van Kammen DP, Davis RE, Weiner DM. Pharmacokinetics, tolerability, and safety of ACP-103 following single or multiple oral dose administration in healthy volunteers. J Clin Pharmacol. June 2007. doi:10.1177/0091270007299431 · PMID 17473118
14. Other Acadia to Stop Trials Of Antipsychotic Drug After It Fails Schizophrenia Study
15. Other Murrough J. Psilocybin Mechanism of Action (MOA). 23 October 2024
16. Journal / agency Gardell LR, Vanover KE, Pounds L, Johnson RW, Barido R, Anderson GT, Veinbergs I, Dyssegaard A, Brunmark P, Tabatabaei A, Davis RE, Brann MR, Hacksell U, Bonhaus DW. ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models. The Journal of Pharmacology and Experimental Therapeutics. August 2007. doi:10.1124/jpet.107.121715 · PMID 17519387
17. Journal / agency Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM, Davis RE, Chase TN, Salamone JD. A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model. Pharmacology Biochemistry and Behavior. October 2008. doi:10.1016/j.pbb.2008.04.010 · PMID 18534670 · PMC2806670
18. Journal / agency Abbas A, Roth BL. Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders. Expert Opinion on Pharmacotherapy. December 2008. doi:10.1517/14656560802532707 · PMID 19040345
19. Journal / agency Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, Hacksell U. Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day: comparison with reference dose risperidone, 6mg/day. Schizophrenia Research. November 2012. doi:10.1016/j.schres.2012.07.029 · PMID 22954754
20. Other Treating Parkinson's Disease - Clinical Trial Pimavanserin
21. Other Acadia Announces Positive Results From ACP-103 Phase II Schizophrenia Co-Therapy Trial. 19 March 2007
22. Other ACADIA Pharmaceuticals Receives FDA Breakthrough Therapy Designation for Nuplazid (Pimavanserin) for Parkinson's Disease Psychosis. 2 September 2014
23. Journal / agency FDA approves first drug to treat hallucinations and delusions associated with Parkinson's disease
24. Journal / agency Cruz MP. Pimavanserin (Nuplazid): A Treatment for Hallucinations and Delusions Associated With Parkinson's Disease. P & T. June 2017. PMID 28579723 · PMC5440097
25. Other Gov't panel backs drug for Parkinson's. 30 March 2016
26. Other Acadia Pharmaceuticals Announces FDA Approval of New Dosing Formulation and Strength for NUPLAZID® (Pimavanserin). 29 June 2018

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