Pimavanserin

Pimavanserin is used in the treatment of Parkinson's disease psychosis.

Pimavanserin is available in the form of 10{{nbsp}}mg oral tablets and 34{{nbsp}}mg oral capsules.

Side effects of pimavanserin include peripheral edema and confusion, among others.

Pimavanserin acts as a selective inverse agonist or antagonist of the serotonin 5-HT_2A receptor.{{Cite web|url=https://www.nuplazid.com/pdf/NUPLAZID-Prescribing-Information-PI-v8-Sep-2018.pdf|title=NUPLAZID Prescribing Information|date=2018}} It is also an antagonist or inverse agonist of the serotonin 5-HT_2C receptor to a lesser extent.

The drug has an affinity (K_i) of 0.087 to 0.5{{nbsp}}nM for the serotonin 5-HT_2A receptor and 0.44 to 10{{nbsp}}nM at the serotonin 5-HT_2C receptor, whereas its functional inhibition ({{Abbrlink|IC₅₀|half-maximal inhibitory concentration}}) values have been reported to be 1.9{{nbsp}}nM at the serotonin 5-HT_2A receptor and 91{{nbsp}}nM at the serotonin 5-HT_2C receptor.{{cite journal | vauthors = Caraci F, Santagati M, Caruso G, Cannavò D, Leggio GM, Salomone S, Drago F | title = New antipsychotic drugs for the treatment of agitation and psychosis in Alzheimer's disease: focus on brexpiprazole and pimavanserin | journal = F1000Res | volume = 9 | issue = | date = 2020 | page = 686 | pmid = 32695312 | pmc = 7344175 | doi = 10.12688/f1000research.22662.1 | doi-access = free | url = }} Hence, it shows 3- to 50-fold greater affinity for the serotonin 5-HT_2A receptor over the serotonin 5-HT_2C receptor depending on the assay and 49-fold selectivity in terms of functional inhibition of the serotonin 5-HT_2A receptor compared to the serotonin 5-HT_2C receptor.

Pimavanserin shows low binding to σ₁ receptors (K_i = 120 nM) and has no appreciable affinity (K_i > 300 nM) to serotonin 5-HT_2B, dopamine (including D₂), muscarinic acetylcholine, histamine, or adrenergic receptors, or to calcium channels.{{cite journal | vauthors = Stahl SM | title = Mechanism of action of pimavanserin in Parkinson's disease psychosis: targeting serotonin 5HT2A and 5HT2C receptors | journal = CNS Spectrums | volume = 21 | issue = 4 | pages = 271–275 | date = August 2016 | pmid = 27503570 | doi = 10.1017/S1092852916000407 | doi-access = free }}

The elimination half-life of pimavanserin is 54 to 57{{nbsp}}hours. The half-life of its active metabolite N-desmethylpimavanserin is 200{{nbsp}}hours.

Pimavanserin was developed by Acadia Pharmaceuticals.

Pimavanserin is expected to improve the effectiveness and side effect profile of antipsychotics.{{cite journal | vauthors = 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 | title = ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 322 | issue = 2 | pages = 862–70 | date = August 2007 | pmid = 17519387 | doi = 10.1124/jpet.107.121715 | s2cid = 28861527 }}{{cite journal | vauthors = Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM, Davis RE, Chase TN, Salamone JD | title = A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model | journal = Pharmacology Biochemistry and Behavior | volume = 90 | issue = 4 | pages = 540–4 | date = October 2008 | pmid = 18534670 | pmc = 2806670 | doi = 10.1016/j.pbb.2008.04.010 }}{{cite journal|author2-link=Bryan Roth | vauthors = Abbas A, Roth BL | title = Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders | journal = Expert Opinion on Pharmacotherapy | volume = 9 | issue = 18 | pages = 3251–9 | date = December 2008 | pmid = 19040345 | doi = 10.1517/14656560802532707 | s2cid = 71240383 | url = https://zenodo.org/record/1236273 }} 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.{{cite journal | vauthors = Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, Hacksell U | title = 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 | journal = Schizophrenia Research | volume = 141 | issue = 2–3 | pages = 144–52 | date = November 2012 | pmid = 22954754 | doi = 10.1016/j.schres.2012.07.029 | doi-access = free }}

The drug met expectations for a Phase III clinical trial for the treatment of Parkinson's disease psychosis,{{cite web|url=http://www.acadia-pharm.com/programs/parkinsons.htm |title=Treating Parkinson's Disease - Clinical Trial Pimavanserin | work = Acadia Pharmaceuticals |access-date=11 April 2009 |url-status=dead |archive-url=https://web.archive.org/web/20090225122323/http://acadia-pharm.com/programs/parkinsons.htm |archive-date=25 February 2009 }} and has completed Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication.{{cite press release |title=Acadia Announces Positive Results From ACP-103 Phase II Schizophrenia Co-Therapy Trial |publisher=Acadia Pharmaceuticals |date=19 March 2007 |url=http://news.acadia-pharm.com/phoenix.zhtml?c=125180&p=irol-newsArticle&ID=974982&highlight |access-date=11 April 2009 |archive-date=7 November 2017 |archive-url=https://web.archive.org/web/20171107070715/http://news.acadia-pharm.com/phoenix.zhtml?c=125180&p=irol-newsArticle&ID=974982&highlight |url-status=dead }}

In September 2014, the United States Food and Drug Administration (FDA) granted breakthrough therapy status to Acadia's New Drug Application for pimavanserin.{{cite web | url = http://news.acadia-pharm.com/phoenix.zhtml?c=125180&p=irol-newsArticle&ID=1962810&highlight= | title = ACADIA Pharmaceuticals Receives FDA Breakthrough Therapy Designation for Nuplazid (Pimavanserin) for Parkinson's Disease Psychosis | publisher = Acadia Pharmaceuticals | date = 2 September 2014 | access-date = 27 October 2014 | archive-date = 16 September 2018 | archive-url = https://web.archive.org/web/20180916021247/http://news.acadia-pharm.com/phoenix.zhtml?c=125180&p=irol-newsArticle&ID=1962810&highlight= | url-status = dead }}

In April 2016, Nuplazid (pimavanserin) was approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis.{{cite press release |title=FDA approves first drug to treat hallucinations and delusions associated with Parkinson's disease|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm498442.htm|publisher=U.S. Food and Drug Administration |access-date=1 May 2016}}{{cite journal | vauthors = Cruz MP | title = Pimavanserin (Nuplazid): A Treatment for Hallucinations and Delusions Associated With Parkinson's Disease | journal = P & T | volume = 42 | issue = 6 | pages = 368–371 | date = June 2017 | pmid = 28579723 | pmc = 5440097 }} 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.{{Cite news|url=https://www.newspapers.com/clip/40244145/gov_panel_backs_drug_for_parkinsons/|title=Gov't panel backs drug for Parkinson's|date=30 March 2016|work=Beaver Dam Daily Citizen|access-date=7 December 2019|agency=Associated Press|issue=24|volume=105|page=A8|via=Newspapers.com}}

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 recommenced 34 mg dose per day. The 10 mg dose is indicated for people also taking CYP3A4 inhibitors (e.g., ketoconazole).{{Cite press release |url=https://www.businesswire.com/news/home/20180629005125/en/ACADIA-Pharmaceuticals-Announces-FDA-Approval-New-Dosing|title=Acadia Pharmaceuticals Announces FDA Approval of New Dosing Formulation and Strength for NUPLAZID® (Pimavanserin)|date=29 June 2018|publisher=Acadia Pharmaceuticals|via=Business Wire|access-date=19 February 2019}}

In a Phase III, double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov number NTC03325556) pimavanserin was given to people with dementia-related psychosis. The dementia was caused by Alzheimer's disease, dementia with lewy bodies, frontotemporal dementia, Parkinson's disease dementia, or vascular dementia. The trial was stopped early due to lack of efficacy. People treated with pimavanserin had a relapse in 13%, and those without 28%. Longer and larger trials are suggested.{{cite journal | vauthors = Tariot PN, Cummings JL, Soto-Martin ME, Ballard C, Erten-Lyons D, Sultzer DL, Devanand DP, Weintraub D, McEvoy B, Youakim JM, Stankovic S, Foff EP | display-authors = 6 | title = Trial of Pimavanserin in Dementia-Related Psychosis | journal = The New England Journal of Medicine | volume = 385 | issue = 4 | pages = 309–319 | date = July 2021 | pmid = 34289275 | doi = 10.1056/NEJMoa2034634 | s2cid = 236175470 | doi-access = free | hdl = 10871/124190 | hdl-access = free }}

In April 2018, CNN reported that some in the FDA were concerned that pimavanserin (Nuplazid) was "risky" when it was approved and noted there have been a substantial number of deaths reported by those using the drug. The story further noted that the drug was approved based on a "six-week study of about 200 patients".{{cite web | url = https://www.cnn.com/2018/04/09/health/parkinsons-drug-nuplazid-invs/index.html | title = FDA worried drug was risky; now reports of deaths spark concern| date = 9 April 2018|publisher=CNN|access-date=9 April 2018}} The FDA began post-market monitoring of the drug to assess the validity of these claims.{{Cite news|url=https://www.cnn.com/2018/04/25/health/fda-nuplazid-safety-evaluation-invs/index.html|title= FDA re-examines safety of controversial new drug | vauthors = Ellis B, Hicken M |work=CNN|access-date=30 July 2018}} In September 2018, the FDA stated their review "did not identify any new or unexpected safety findings with Nuplazid, or findings that are inconsistent with the established safety profile currently described in the drug label".{{Cite web |url= https://www.fda.gov/Drugs/DrugSafety/ucm621160.htm |title=Drug Safety and Availability - FDA analysis finds no new or unexpected safety risks associated with Nuplazid (pimavanserin), a medication to treat the hallucinations and delusions of Parkinson's disease psychosis|website=U.S. Food and Drug Administration (FDA)|access-date=25 September 2018}}

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.

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.{{Cite web |title=Acadia to Stop Trials Of Antipsychotic Drug After It Fails Schizophrenia Study |url=https://www.medscape.com/s/viewarticle/acadia-stop-trials-antipsychotic-drug-after-it-fails-2024a10004m5 |access-date=2024-03-15 |website=Medscape |language=en}}

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.{{cite journal | title=Psilocybin Mechanism of Action (MOA) | website=ClinicalTrials.gov | date=23 October 2024 | url=https://clinicaltrials.gov/study/NCT06592833 | access-date=13 November 2024 | last1=Murrough | first1=James }}

{{Reflist}}

{{Antipsychotics}}

{{Serotonin receptor modulators}}

Category:5-HT2A antagonists

Category:5-HT2C antagonists

Category:Atypical antipsychotics

Category:Experimental antidepressants

Category:Experimental drugs developed for schizophrenia

Category:Experimental psychiatric drugs

Category:4-Fluorophenyl compounds

Category:Inverse agonists

Category:Phenol ethers

Category:Piperidines

Category:Ureas