| Revision as of 20:11, 6 August 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'ChEBI').← Previous edit |
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{{Short description|Atypical antipsychotic}} |
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{{Drugbox |
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{{Use dmy dates|date=July 2024}} |
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| verifiedrevid = 421232540 |
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{{cs1 config|name-list-style=vanc|display-authors=6}} |
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| IUPAC_name= 7-{4-butoxy}-3,4-dihydroquinolin-2(1''H'')-one |
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{{Infobox drug |
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| image = Aripiprazole.svg |
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| Verifiedfields = verified |
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| width = 150 |
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| Watchedfields = verified |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| verifiedrevid = 443398218 |
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| image = Aripiprazole2D1.svg |
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| alt = Structural formula of aripiprazole |
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| width = 250px |
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| image2 = Aripiprazole molecule from xtal ball.png |
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| alt2 = Ball-and-stick model of the aripiprazole molecule |
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| width2 = 250px |
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| caption = |
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<!-- Clinical data --> |
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| pronounce = {{IPAc-en|ˌ|ɛər|ᵻ|ˈ|p|ɪ|p|r|ə|z|oʊ|l}}<br />{{respell|AIR|ih|PIP|rə|zohl}}<br />Abilify {{IPAc-en|ə|ˈ|b|ɪ|l|ɪ|f|aɪ}}<br />{{respell|ə|BIL|if|eye}} |
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| tradename = Abilify, Aristada, others |
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| Drugs.com = {{drugs.com|monograph|aripiprazole}} |
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| MedlinePlus = a603012 |
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| DailyMedID = Aripiprazole |
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| pregnancy_AU = C |
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| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Aripiprazole Use During Pregnancy | website=Drugs.com | date=22 August 2019 | url=https://www.drugs.com/pregnancy/aripiprazole.html | access-date=7 February 2020 | archive-date=12 November 2020 | archive-url=https://web.archive.org/web/20201112020613/https://www.drugs.com/pregnancy/aripiprazole.html | url-status=live }}</ref> |
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| pregnancy_category = |
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| routes_of_administration = ], ] |
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| class = ] |
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| ATC_prefix = N05 |
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| ATC_suffix = AX12 |
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| ATC_supplemental = |
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<!-- Legal status --> |
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| legal_AU = S4 |
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| legal_AU_comment = |
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| legal_BR = C1 |
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| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=] |language=pt-BR |publication-date=4 April 2023}}</ref> |
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| legal_CA = Rx-only |
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| legal_CA_comment = |
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| legal_DE = <!-- Anlage I, II, III or Unscheduled --> |
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| legal_DE_comment = |
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| legal_NZ = <!-- Class A, B, C --> |
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| legal_NZ_comment = |
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| legal_UK = POM |
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| legal_UK_comment = |
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| legal_US = Rx-only |
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| legal_US_comment = <ref name="Abilify FDA label" /> |
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| legal_EU = Rx-only |
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| legal_EU_comment = <ref name="Abilify EPAR">{{cite web | title=Abilify EPAR | website=] | date=4 June 2004 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/abilify | access-date=4 July 2024 | archive-date=15 April 2024 | archive-url=https://web.archive.org/web/20240415010310/https://www.ema.europa.eu/en/medicines/human/EPAR/abilify | url-status=live }}</ref> |
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| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> |
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| legal_UN_comment = |
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| legal_status = <!-- For countries not listed above --> |
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<!-- Pharmacokinetic data --> |
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| bioavailability = 87%<ref name="Abilify FDA label" /><ref name = EMC>{{cite web|title=Abilify Tablets, Orodispersible Tablets, Oral Solution – Summary of Product Characteristics (SPC)|date=20 September 2013|access-date=22 October 2013|publisher=Otsuka Pharmaceuticals (UK) Ltd|website=electronic Medicines Compendium|url=http://www.medicines.org.uk/emc/medicine/18494/SPC/Abilify+Tablets%2c+Orodispersible+Tablets%2c+Oral+Solution/|archive-url=https://web.archive.org/web/20160304001126/http://www.medicines.org.uk/emc/medicine/18494/SPC/Abilify+Tablets,+Orodispersible+Tablets,+Oral+Solution/|archive-date=4 March 2016|url-status=dead}}</ref><ref name = EMA>{{cite web|title=ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS|website=European Medicines Agency|publisher=Otsuka Pharmaceutical Europe Ltd.|access-date=22 October 2013|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000471/WC500020170.pdf|archive-date=23 October 2013|archive-url=https://web.archive.org/web/20131023060322/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000471/WC500020170.pdf|url-status=dead}}</ref> |
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| protein_bound = >99%<ref name="Abilify FDA label" /><ref name = EMC /><ref name = EMA /> |
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| metabolism = ] (mostly via ] and ]<ref name="Abilify FDA label" /><ref name = EMC /><ref name = EMA />) |
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| metabolites = |
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| onset = |
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| elimination_half-life = 75 hours (active metabolite is 94 hours)<ref name="Abilify FDA label" /><ref name = EMC /><ref name = EMA /> |
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| duration_of_action = |
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| excretion = ] (27%; <1% unchanged)<br />] (60%; 18% unchanged)<ref name="Abilify FDA label" /><ref name = EMC /><ref name = EMA /> |
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<!-- Identifiers --> |
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| CAS_number_Ref = {{cascite|correct|CAS}} |
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| CAS_number = 129722-12-9 |
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| CAS_supplemental = |
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| PubChem = 60795 |
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| IUPHAR_ligand = 34 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = DB01238 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 54790 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 82VFR53I78 |
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| UNII = 82VFR53I78 |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| InChI = 1/C23H27Cl2N3O2/c24-19-4-3-5-21(23(19)25)28-13-11-27(12-14-28)10-1-2-15-30-18-8-6-17-7-9-22(29)26-20(17)16-18/h3-6,8,16H,1-2,7,9-15H2,(H,26,29) |
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| KEGG = D01164 |
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| InChIKey = CEUORZQYGODEFX-UHFFFAOYAE |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 31236 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 1112 |
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| ChEMBL = 1112 |
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| NIAID_ChemDB = |
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| PDB_ligand = |
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| synonyms = OPC-14597; OPC14597; OPC-31; OPC31; RDC-3317 |
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<!-- Chemical data --> |
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| IUPAC_name = 7-{4-butoxy}-3,4-dihydroquinolin-2(1''H'')-one |
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| C=23 | H=27 | Cl=2 | N=3 | O=2 |
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| SMILES = Clc4cccc(N3CCN(CCCCOc2ccc1c(NC(=O)CC1)c2)CC3)c4Cl |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C23H27Cl2N3O2/c24-19-4-3-5-21(23(19)25)28-13-11-27(12-14-28)10-1-2-15-30-18-8-6-17-7-9-22(29)26-20(17)16-18/h3-6,8,16H,1-2,7,9-15H2,(H,26,29) |
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| StdInChI = 1S/C23H27Cl2N3O2/c24-19-4-3-5-21(23(19)25)28-13-11-27(12-14-28)10-1-2-15-30-18-8-6-17-7-9-22(29)26-20(17)16-18/h3-6,8,16H,1-2,7,9-15H2,(H,26,29) |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = CEUORZQYGODEFX-UHFFFAOYSA-N |
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| StdInChIKey = CEUORZQYGODEFX-UHFFFAOYSA-N |
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| CAS_number = 129722-12-9 |
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<!-- Physical data --> |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 54790 |
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| density = |
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| ATC_prefix = N05 |
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| density_notes = |
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| ATC_suffix = AX12 |
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| melting_point = |
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| ChEBI = 31236 |
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| melting_high = |
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| PubChem = 60795 |
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| melting_notes = |
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| IUPHAR_ligand = 34 |
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| boiling_point = |
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| boiling_notes = |
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| DrugBank = APRD00638 |
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| solubility = |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D01164 |
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| sol_units = |
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| specific_rotation = |
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| C=23 | H=27 | Cl=2 | N=3 | O=2 |
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| molecular_weight = 448.385 |
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| smiles = Clc4cccc(N3CCN(CCCCOc2ccc1c(NC(=O)CC1)c2)CC3)c4Cl |
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| bioavailability = 87% |
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| protein_bound = >99% |
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| metabolism = liver |
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| elimination_half-life = 75h (active metabolite : 94h) |
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| excretion = feces and urine |
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| licence_EU = Abilify |
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| licence_US = Aripiprazole |
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| pregnancy_category = C (USA) |
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| legal_status = Rx-only |
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| routes_of_administration = oral (via tablets, orodispersable tablets, and oral solution); intramuscular |
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}} |
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}} |
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] |
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<!-- Medical uses --> |
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'''Aripiprazole''', sold under the brand names '''Abilify''' and '''Aristada''', among others, is an ].<ref name=AHFS2019>{{cite web |title=Aripiprazole, ARIPiprazole Lauroxil Monograph for Professionals |url=https://www.drugs.com/monograph/aripiprazole-aripiprazole-lauroxil.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=26 February 2019 |archive-date=1 October 2020 |archive-url=https://web.archive.org/web/20201001213744/https://www.drugs.com/monograph/aripiprazole-aripiprazole-lauroxil.html |url-status=live }}</ref> It is primarily used in the treatment of ], ], and irritability associated with ];<ref name="AHFS2019" /> other uses include as an ] in ] and ].<ref name=AHFS2019 /> Aripiprazole is taken by mouth or via ].<ref name=AHFS2019 /> A ] review found low-quality evidence of effectiveness in treating schizophrenia.<ref name=Coch2011>{{cite journal | vauthors = Belgamwar RB, El-Sayeh HG | title = Aripiprazole versus placebo for schizophrenia | journal = The Cochrane Database of Systematic Reviews | issue = 8 | pages = CD006622 | date = August 2011 | pmid = 21833956 | doi = 10.1002/14651858.CD006622.pub2 }}</ref> |
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<!-- Adverse effects and mechanism --> |
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'''Aripiprazole''' ({{IPAc-en|icon|ˌ|ɛər|ɨ|ˈ|p|ɪ|p|r|ə|z|oʊ|l}} {{respell|AIR|i|PIP|rə-zohl}}; brand names: '''Abilify''', '''Aripiprex''') is an ] and ] used in the treatment of ], ], and ]. It was approved by the US ] (FDA) for schizophrenia on November 15, 2002; for acute ] and ] associated with bipolar disorder on October 1, 2004; as an adjunct for ] on November 20, 2007; and to treat irritability in children with autism on 20 November 2009.<ref>{{cite web |url=http://www.webmd.com/depression/news/20071120/fda-oks-abilify-for-depression |title=FDA OKs Abilify for Depression |accessdate=8 December 2008 |last=Hitti |first=Miranda |publisher=WebMD |date=20 November 2007}}</ref><ref>{{cite web |url=http://www.reuters.com/article/idUSN2023065120091121/ |title=FDA OKs Abilify for child autism irritability |accessdate=22 September 2010 |last=Keating |first=Gina |publisher=Reuters |date=23 November 2009}}</ref> Aripiprazole was developed by ] in ], and in the ], ] markets it jointly with ]. |
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Common side effects include ], ], transient ], ], ], ], ], and mild ].<ref name="AHFS2019" /> Serious side effects may include ], ], and ].<ref name="AHFS2019" /> It is not recommended for older people with ]-related psychosis due to an increased risk of death.<ref name="AHFS2019" /> In ], there is evidence of possible harm to the fetus.<ref name="AHFS2019" /><ref>{{cite web|title=Prescribing medicines in pregnancy database|url=http://www.tga.gov.au/hp/medicines-pregnancy.htm|website=Australian Government|access-date=22 April 2014|date=3 March 2014|archive-date=8 April 2014|archive-url=https://web.archive.org/web/20140408040902/http://www.tga.gov.au/hp/medicines-pregnancy.htm|url-status=live}}</ref> It is not recommended in women who are ].<ref name="AHFS2019" /> It has not been very well studied in people less than 18 years old.<ref name="AHFS2019" /> |
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<!-- Society and culture --> |
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Aripiprazole was approved for medical use in the United States in 2002.<ref name=AHFS2019 /> It is available as a ].<ref name=BNF76>{{cite book |title=British national formulary: BNF 76 |date=2018 |publisher=Pharmaceutical Press |isbn=978-0-85711-338-2 |pages=392 |edition=76th}}</ref> In 2022, it was the 106th most commonly prescribed medication in the United States, with more than 6{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Aripiprazole Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Aripiprazole | access-date = 30 August 2024 }}</ref> It is on the ].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> |
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== Medical uses == |
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== Medical uses == |
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Aripiprazole is used for the treatment of ] or ].<ref name=AHFS>{{cite web|title=abilify|url=http://www.drugs.com/monograph/abilify.html|work=The American Society of Health-System Pharmacists|accessdate=3 April 2011}}</ref> |
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Aripiprazole is primarily used for the treatment of ] or ].<ref name = EMA /><ref name= AHFS2019 /><ref name="Abilify FDA label">{{cite web | title=Abilify- aripiprazole tablet Abilify- aripiprazole solution Abilify- aripiprazole tablet, orally disintegrating Abilify- aripiprazole injection, solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c040bd1d-45b7-49f2-93ea-aed7220b30ac | access-date=20 October 2020 | archive-date=3 December 2020 | archive-url=https://web.archive.org/web/20201203171648/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c040bd1d-45b7-49f2-93ea-aed7220b30ac | url-status=live }}</ref> |
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=== Schizophrenia === |
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The 2016 ] (NICE) guidance for treating psychosis and schizophrenia in children and young people recommended aripiprazole as a second-line treatment after ] for people between 15 and 17 who are having an acute exacerbation or recurrence of psychosis or schizophrenia.<ref>{{cite web |title= Psychosis and schizophrenia in children and young people: recognition and management |url= https://www.nice.org.uk/guidance/cg155/chapter/Recommendations |website= ] |location= UK |date= October 2016 |access-date= 22 October 2018 |archive-date= 22 June 2020 |archive-url= https://web.archive.org/web/20200622164548/https://www.nice.org.uk/guidance/cg155/chapter/Recommendations |url-status= live }}</ref> A 2014 NICE review of the depot formulation of the drug found that it might have a role in treatment as an alternative to other depot formulations of second-generation antipsychotics for people who have trouble taking medication as directed or who prefer it.<ref>{{cite web |title= Schizophrenia: aripiprazole prolonged-release suspension for injection {{!}} Guidance and guidelines |url= https://www.nice.org.uk/advice/esnm39/chapter/Key-points-from-the-evidence |publisher= National Institute for Health and Care Excellence |location= UK |date= 24 July 2013 |access-date= 22 October 2018 |archive-date= 23 October 2018 |archive-url= https://web.archive.org/web/20181023120127/https://www.nice.org.uk/advice/esnm39/chapter/Key-points-from-the-evidence |url-status= live }}</ref> |
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A 2014 ] review comparing aripiprazole and other atypical antipsychotics found that it is difficult to determine differences as data quality is poor.<ref>{{cite journal | vauthors = Khanna P, Suo T, Komossa K, Ma H, Rummel-Kluge C, El-Sayeh HG, Leucht S, Xia J | title = Aripiprazole versus other atypical antipsychotics for schizophrenia | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD006569 | date = January 2014 | volume = 2014 | pmid = 24385408 | pmc = 4164478 | doi = 10.1002/14651858.CD006569.pub5 }}</ref> A 2011 Cochrane review comparing aripiprazole with placebo concluded that high dropout rates in clinical trials, and a lack of outcome data regarding general functioning, behavior, mortality, economic outcomes, or cognitive functioning make it difficult to definitively conclude that aripiprazole is useful for the prevention of relapse.<ref name=Coch2011 /> A Cochrane review found only low-quality evidence of effectiveness in treating schizophrenia.<ref name=Coch2011 /> Accordingly, part of its methodology on quality of evidence is based on the quantity of qualified studies.<ref>{{cite web |title= Levels of Evidence |url=https://consumers.cochrane.org/levels-evidence |website=Cochrane.org |access-date=12 September 2019 |archive-date=23 September 2020 |archive-url=https://web.archive.org/web/20200923120907/https://consumers.cochrane.org/levels-evidence |url-status=dead }}</ref> |
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A 2013 review placed aripiprazole in the middle range of 15 antipsychotics for effectiveness, approximately as effective as ] and ]<ref>{{Cite journal |date=11 July 2019 |title=Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis |journal= ]| vauthors = Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N|volume=394 |issue=10202 |pages=939–951 |doi=10.1016/S0140-6736(19)31135-3 |pmid=31303314 |pmc=6891890 }}</ref> and slightly more effective than ], ], and ], with better tolerability compared to the other antipsychotic drugs (4th best for reducing weight gain, 5th best for reducing ], best for reducing ] levels, 2nd best for prolongated ] interval, and 5th best for sedative symptoms). The authors concluded that for acute psychotic episodes, aripiprazole results in benefits in some aspects of the condition.<ref name= "Lancet2013">{{cite journal | vauthors = Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM | title = Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis | journal = The Lancet | volume = 382 | issue = 9896 | pages = 951–962 | date = September 2013 | pmid = 23810019 | doi = 10.1016/S0140-6736(13)60733-3 | s2cid = 32085212 }}</ref> |
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In 2013 the ] recommended aripiprazole for the treatment of acute exacerbations of schizophrenia as a Grade 1 recommendation and evidence level A.<ref name="Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ 2013 2–44">{{cite journal | vauthors = Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ | title = World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects | journal = The World Journal of Biological Psychiatry | volume = 14 | issue = 1 | pages = 2–44 | date = February 2013 | pmid = 23216388 | doi = 10.3109/15622975.2012.739708 | s2cid = 28750563 }}</ref> |
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The ] similarly recommends that all persons presenting with psychosis receive treatment with an antipsychotic and that such treatment should continue for at least 1–2 years, as "There is no doubt that antipsychotic discontinuation is strongly associated with relapse during this period". The guideline further notes that "Established schizophrenia requires continued maintenance with doses of antipsychotic medication within the recommended range (Evidence level A)".<ref name="Barnes TR 2011 567–620">{{cite journal | vauthors = Barnes TR | title = Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology | journal = ] | volume = 25 | issue = 5 | pages = 567–620 | date = May 2011 | pmid = 21292923 | doi = 10.1177/0269881110391123 | s2cid = 40089561 }}</ref> |
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The ]<ref name="Barnes TR 2011 567–620" /> and the ] suggest that there is little difference in effectiveness between antipsychotics in the prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on each person's preference and side effect profile. The latter group recommends switching to aripiprazole when excessive weight gain is encountered during treatment with other antipsychotics.<ref name="Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Möller HJ 2013 2–44" /> |
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=== Bipolar disorder === |
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=== Bipolar disorder === |
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Aripiprazole is effective for the treatment of acute manic episodes of bipolar disorder in adults, children, and adolescents.<ref>{{cite web | url = http://www.nice.org.uk/guidance/cg185/chapter/1-recommendations | title = Bipolar disorder: assessment and management | quote = 1.1 Care for adults, children, and young people across all phases of bipolar disorder | website = Recommendations; Guidance and guidelines | date = 24 September 2014 | publisher = National Institute for Health and Care Excellence | location = UK | access-date = 1 December 2014 | archive-date = 6 August 2020 | archive-url = https://web.archive.org/web/20200806041846/https://www.nice.org.uk/guidance/cg185/chapter/1-Recommendations | url-status = live }}</ref><ref>{{cite journal | vauthors = Brown R, Taylor MJ, Geddes J | title = Aripiprazole alone or in combination for acute mania | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 12 | pages = CD005000 | date = December 2013 | pmid = 24346956 | doi = 10.1002/14651858.CD005000.pub2 | pmc = 11330668 }}</ref> Used as maintenance therapy, it is useful for the prevention of manic episodes but is not useful for bipolar depression.<ref>{{cite journal | vauthors = De Fruyt J, Deschepper E, Audenaert K, Constant E, Floris M, Pitchot W, Sienaert P, Souery D, Claes S | title = Second generation antipsychotics in the treatment of bipolar depression: a systematic review and meta-analysis | journal = Journal of Psychopharmacology | volume = 26 | issue = 5 | pages = 603–617 | date = May 2012 | pmid = 21940761 | doi = 10.1177/0269881111408461 | s2cid = 57249815 | hdl = 2268/196468 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Gitlin M, Frye MA | title = Maintenance therapies in bipolar disorders | journal = Bipolar Disorders | volume = 14 | issue = Suppl 2 | pages = 51–65 | date = May 2012 | pmid = 22510036 | doi = 10.1111/j.1399-5618.2012.00992.x | s2cid = 21101054 }}</ref> Thus, it is often used in combination with an additional ]; however, co-administration with a mood stabilizer increases the risk of extrapyramidal side effects.<ref>{{cite journal | vauthors = de Bartolomeis A, Perugi G | title = Combination of aripiprazole with mood stabilizers for the treatment of bipolar disorder: from acute mania to long-term maintenance | journal = Expert Opinion on Pharmacotherapy | volume = 13 | issue = 14 | pages = 2027–2036 | date = October 2012 | pmid = 22946707 | doi = 10.1517/14656566.2012.719876 | s2cid = 39065786 }}</ref> In September 2014, aripiprazole had a UK marketing authorization for up to twelve weeks of treatment for moderate to severe manic episodes in bipolar I disorder in young people aged thirteen and older. Aripiprazole in low doses of 2.5 mg can cause mania in those with Bipolar disorder.<ref name="NICE2014B">{{cite web | title=1 Recommendations - Bipolar disorder: assessment and management - Guidance | publisher=National Institute for Health and Care Excellence | date=24 September 2014 | url=https://www.nice.org.uk/guidance/cg185/chapter/1-recommendations | access-date=3 April 2023 | archive-date=29 December 2021 | archive-url=https://web.archive.org/web/20211229193239/https://www.nice.org.uk/guidance/cg185/chapter/1-Recommendations | url-status=live }}</ref><ref>{{cite web | url=https://www.nice.org.uk/guidance/ta292/documents/bipolar-disorder-children-aripirazole-final-appraisal-determintation-document2 | title=Aripiprazole for treating moderate to severe manic episodes in adolescents with bipolar I disorder | publisher=National Institute for Health and Care Excellence | date=May 2013 | access-date=3 April 2023 | archive-date=4 November 2022 | archive-url=https://web.archive.org/web/20221104172557/http://www.nice.org.uk/guidance/ta292/documents/bipolar-disorder-children-aripirazole-final-appraisal-determintation-document2 | url-status=live }}</ref><ref>{{Cite journal |date=10 November 2014 |title=The risks and benefits of high dose antipsychotic medication |url=https://www.rcpsych.ac.uk/docs/default-source/improving-care/better-mh-policy/college-reports/college-report-cr190.pdf?sfvrsn=54f5d9a2_2 |journal=Royal College of Psychiatrists |access-date=16 April 2024 |archive-date=4 July 2024 |archive-url=https://web.archive.org/web/20240704193012/https://www.rcpsych.ac.uk/docs/default-source/improving-care/better-mh-policy/college-reports/college-report-cr190.pdf?sfvrsn=54f5d9a2_2 |url-status=live }}</ref> |
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Aripiprazole has been approved by the FDA for the treatment of acute manic and mixed episodes, in both pediatric patients aged 10–17 and in adults.<ref name="orangeBook" /> Several double-blind, placebo-controlled trials support this use.<ref name="keck">{{cite journal |
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|author=Keck PE, Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, Ingenito G |
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|title=A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania |
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|journal=Am J Psychiatry |
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|volume=160 |
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|issue=9 |
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|pages=1651–8 |
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|year=2003 |
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|month=September |
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|pmid=12944341 |
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|doi=10.1176/appi.ajp.160.9.1651 |
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|url=http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=12944341 |
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}}</ref><ref name="pmid16401666">{{cite journal |
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|author=Sachs G, Sanchez R, Marcus R, Stock E, McQuade R, Carson W, Abou-Gharbia N, Impellizzeri C, Kaplita S, Rollin L, Iwamoto T |
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|title=Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study |
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|journal=J. Psychopharmacol. (Oxford) |
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|volume=20 |
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|issue=4 |
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|pages=536–46 |
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|year=2006 |
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|month=July |
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|pmid=16401666 |
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|doi=10.1177/0269881106059693 |
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}}</ref><ref name="pmid18381903">{{cite journal |
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|author=Vieta E, T'joen C, McQuade RD, Carson WH, Marcus RN, Sanchez R, Owen R, Nameche L |
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|title=Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients partially nonresponsive to valproate/lithium monotherapy: a placebo-controlled study |
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|journal=Am J Psychiatry |
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|volume=165 |
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|issue=10 |
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|pages=1316–25 |
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|year=2008 |
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|month=October |
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|pmid=18381903 |
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|doi=10.1176/appi.ajp.2008.07101560 |
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}}</ref><ref name="pmid18835043">{{cite journal |
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|author=Keck PE, Orsulak PJ, Cutler AJ, Sanchez R, Torbeyns A, Marcus RN, McQuade RD, Carson WH |
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|title=Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study |
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|journal=J Affect Disord |
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|volume=112 |
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|issue=1-3 |
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|pages=36–49 |
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|year=2009 |
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|month=January |
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|pmid=18835043 |
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|doi=10.1016/j.jad.2008.05.014 |
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|url= |
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}}</ref> In addition, it is often used as maintenance therapy, either on its own or in conjunction with a ] such as ] or ]. This use is also supported by a handful of studies.<ref name="pmid17960961">{{cite journal |
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|author=Keck PE, Calabrese JR, McIntyre RS, McQuade RD, Carson WH, Eudicone JM, Carlson BX, Marcus RN, Sanchez R |
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|title=Aripiprazole monotherapy for maintenance therapy in bipolar I disorder: a 100-week, double-blind study versus placebo |
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|journal=J Clin Psychiatry |
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|volume=68 |
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|issue=10 |
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|pages=1480–91 |
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|year=2007 |
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|month=October |
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|pmid=17960961 |
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|doi= |
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}}</ref><ref name="pmid16669728">{{cite journal |
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|author=Keck PE, Calabrese JR, McQuade RD, Carson WH, Carlson BX, Rollin LM, Marcus RN, Sanchez R |
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|title=A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder |
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|journal=J Clin Psychiatry |
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|volume=67 |
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|issue=4 |
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|pages=626–37 |
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|year=2006 |
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|month=April |
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|pmid=16669728 |
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|doi=10.4088/JCP.v67n0414 |
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}}</ref> Aripiprazole is at least as effective as ] at reducing manic symptoms,<ref name="pmid19118324">{{cite journal |
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|author=Young AH, Oren DA, Lowy A, McQuade RD, Marcus RN, Carson WH, Spiller NH, Torbeyns AF, Sanchez R |
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|title=Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study |
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|journal=Br J Psychiatry |
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|volume=194 |
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|issue=1 |
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|pages=40–8 |
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|year=2009 |
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|month=January |
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|pmid=19118324 |
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|doi=10.1192/bjp.bp.108.049965 |
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|url= |
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}}</ref>{{Verify credibility|date=July 2009}} and is much better tolerated by patients.<ref name="pmid16135860">{{cite journal |
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|author=Vieta E, Bourin M, Sanchez R, Marcus R, Stock E, McQuade R, Carson W, Abou-Gharbia N, Swanink R, Iwamoto T |
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|title=Effectiveness of aripiprazole v. haloperidol in acute bipolar mania: double-blind, randomised, comparative 12-week trial |
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|journal=Br J Psychiatry |
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|volume=187 |
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|issue= |
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|pages=235–42 |
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|year=2005 |
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|month=September |
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|pmid=16135860 |
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|doi=10.1192/bjp.187.3.235 |
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|url= |
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}}</ref> |
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=== Depression === |
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Aripiprazole's use as a monotherapy in bipolar depression is more controversial. While a few pilot studies have found some effectiveness<ref name="pmid19040335">{{cite journal |
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Aripiprazole is an effective add-on treatment for major depressive disorder; however, there is a greater rate of side effects such as weight gain and ].<ref name= "Spielmans_2013">{{cite journal | vauthors = Spielmans GI, Berman MI, Linardatos E, Rosenlicht NZ, Perry A, Tsai AC | title = Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes | journal = PLOS Medicine | volume = 10 | issue = 3 | pages = e1001403 | date = March 2013 | pmid = 23554581 | pmc = 3595214 | doi = 10.1371/journal.pmed.1001403 | doi-access = free }}</ref><ref name= "pmid19687129">{{cite journal | vauthors = Nelson JC, Papakostas GI | title = Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials | journal = The American Journal of Psychiatry | volume = 166 | issue = 9 | pages = 980–991 | date = September 2009 | pmid = 19687129 | doi = 10.1176/appi.ajp.2009.09030312 | doi-access = free | title-link = doi }}</ref><ref name= "pmid21154393">{{cite journal | vauthors = Komossa K, Depping AM, Gaudchau A, Kissling W, Leucht S | title = Second-generation antipsychotics for major depressive disorder and dysthymia | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD008121 | date = December 2010 | pmid = 21154393 | doi = 10.1002/14651858.CD008121.pub2 }}</ref> The overall benefit is small to moderate and its use appears to neither improve ] nor functioning.<ref name= "Spielmans_2013" /> Aripiprazole may interact with some antidepressants, especially ]s (SSRIs) that are metabolized by ]. There are known interactions with ] and ]<ref>{{cite journal | vauthors = Azuma J, Hasunuma T, Kubo M, Miyatake M, Koue T, Higashi K, Fujiwara T, Kitahara S, Katano T, Hara S | title = The relationship between clinical pharmacokinetics of aripiprazole and CYP2D6 genetic polymorphism: effects of CYP enzyme inhibition by coadministration of paroxetine or fluvoxamine | journal = European Journal of Clinical Pharmacology | volume = 68 | issue = 1 | pages = 29–37 | date = January 2012 | pmid = 21739267 | pmc = 3249179 | doi = 10.1007/s00228-011-1094-4 }}</ref> and it appears lesser interactions with ], ], ] and ]. ] inhibitors increase aripiprazole concentrations to 2–3 times their normal level.<ref name = Abilify /> When strong CYP2D6 ]s (such as ], ]) are co-administered, the ] recommends dose monitoring, although it is not clear the SSRI dose should be lowered.<ref name="Abilify FDA label" /><ref>{{cite journal | vauthors = Hahn M, Roll SC | title = Dosing Recommendations of Aripiprazole Depot with Strong Cytochrome P450 3A4 Inhibitors: A Relapse Risk | journal = Drug Safety: Case Reports | volume = 3 | issue = 1 | pages = 5 | date = December 2016 | pmid = 27747685 | pmc = 5005780 | doi = 10.1007/s40800-016-0027-7 }}</ref><ref>{{cite journal | vauthors = Jallaq SA, Verba M, Strawn JR, Martin LJ, DelBello MP, Ramsey LB | title = CYP2D6 Phenotype Influences Aripiprazole Tolerability in Pediatric Patients with Mood Disorders | journal = Journal of Child and Adolescent Psychopharmacology | volume = 31 | issue = 1 | pages = 56–62 | date = February 2021 | pmid = 32845723 | pmc = 8255312 | doi = 10.1089/cap.2020.0058 }}</ref><ref>{{cite journal | vauthors = Hoffelt C, Gross T | title = A review of significant pharmacokinetic drug interactions with antidepressants and their management | journal = The Mental Health Clinician | volume = 6 | issue = 1 | pages = 35–41 | date = January 2016 | pmid = 29955445 | pmc = 6009245 | doi = 10.9740/mhc.2016.01.035 }}</ref> |
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|author=Mazza M, Squillacioti MR, Pecora RD, Janiri L, Bria P |
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|title=Beneficial acute antidepressant effects of aripiprazole as an adjunctive treatment or monotherapy in bipolar patients unresponsive to mood stabilizers: results from a 16-week open-label trial |
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|journal=Expert Opin Pharmacother |
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|volume=9 |
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|issue=18 |
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|pages=3145–9 |
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|year=2008 |
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|month=December |
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|pmid=19040335 |
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|doi=10.1517/14656560802504490 |
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|url= |
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}}</ref><ref name="pmid18272230">{{cite journal |
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|author=Dunn RT, Stan VA, Chriki LS, Filkowski MM, Ghaemi SN |
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|title=A prospective, open-label study of Aripiprazole mono- and adjunctive treatment in acute bipolar depression |
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|journal=J Affect Disord |
|
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|volume=110 |
|
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|issue=1-2 |
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|pages=70–4 |
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|year=2008 |
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|month=September |
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|pmid=18272230 |
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|doi=10.1016/j.jad.2008.01.004 |
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}}</ref> (with one finding a reduction in ] symptoms<ref name="pmid18973955">{{cite journal |
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|author=Mazza M, Squillacioti MR, Pecora RD, Janiri L, Bria P |
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|title=Effect of aripiprazole on self-reported anhedonia in bipolar depressed patients |
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|journal=Psychiatry Res |
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|volume=165 |
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|issue=1-2 |
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|pages=193–6 |
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|year=2009 |
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|month=January |
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|pmid=18973955 |
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|doi=10.1016/j.psychres.2008.05.003 |
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}}</ref>), two large, double-blind, placebo-controlled studies found no difference between aripiprazole and placebo.<ref name="pmid18204335">{{cite journal |
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|author=Thase ME, Jonas A, Khan A, Bowden CL, Wu X, McQuade RD, Carson WH, Marcus RN, Owen R |
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|title=Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies |
|
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|journal=J Clin Psychopharmacol |
|
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|volume=28 |
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|issue=1 |
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|pages=13–20 |
|
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|year=2008 |
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|month=February |
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|pmid=18204335 |
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|doi=10.1097/jcp.0b013e3181618eb4 |
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}}</ref> One study reported depression as a side effect of the drug.<ref name="pmid18373615">{{cite journal |
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|author=Muzina DJ, Momah C, Eudicone JM, Pikalov A, McQuade RD, Marcus RN, Sanchez R, Carlson BX |
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|title=Aripiprazole monotherapy in patients with rapid-cycling bipolar I disorder: an analysis from a long-term, double-blind, placebo-controlled study |
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|journal=Int. J. Clin. Pract. |
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|volume=62 |
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|issue=5 |
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|pages=679–87 |
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|year=2008 |
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|month=May |
|
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|pmid=18373615 |
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|pmc=2324208 |
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|doi=10.1111/j.1742-1241.2008.01735.x |
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}}</ref> |
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===Major depression=== |
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=== Autism === |
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Short-term data (8 weeks) shows reduced irritability, hyperactivity, inappropriate speech, and ], but no change in lethargic behaviours.<ref name =Hirsch2016>{{cite journal | vauthors = Hirsch LE, Pringsheim T | title = Aripiprazole for autism spectrum disorders (ASD) | journal = The Cochrane Database of Systematic Reviews | issue = 6 | pages = CD009043 | date = June 2016 | volume = 2016 | pmid = 27344135 | pmc = 7120220 | doi = 10.1002/14651858.CD009043.pub3 }}</ref> Adverse effects include weight gain, sleepiness, drooling, and tremors.<ref name=Hirsch2016 /> It is suggested that children and adolescents need to be monitored regularly while taking this medication to evaluate if this treatment option is still effective after long-term use and note if side effects are worsening. Further studies are needed to understand if this drug is helpful for children after long-term use.<ref name=Hirsch2016 /> |
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In 2007, aripiprazole was approved by the FDA for the treatment of ] when used adjunctively with an antidepressant medication.<ref>http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021436s21,021713s16,021729s8,021866s8lbl.pdf Section 2.3 pp 7-8</ref> It has not been FDA-approved for use as monotherapy in unipolar depression. |
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===Autism=== |
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=== Tic disorders === |
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Aripiprazole is approved for the treatment of ] and other ]s.<ref name="AdisInsight">{{cite web |title=Aripiprazole |url=http://adisinsight.springer.com/drugs/800001612 |access-date=21 September 2021 |publisher=Springer |website=adisInsight. springer.com |archive-date=2 October 2017 |archive-url=https://web.archive.org/web/20171002174227/http://adisinsight.springer.com/drugs/800001612 |url-status=live }}</ref><ref name="pmid29154107">{{cite journal | vauthors = Janik P, Szejko N | title = Aripiprazole in treatment of Gilles de la Tourette syndrome – New therapeutic option | journal = Neurologia I Neurochirurgia Polska | volume = 52 | issue = 1 | pages = 84–87 | date = 2018 | pmid = 29154107 | doi = 10.1016/j.pjnns.2017.10.015 | url = https://journals.viamedica.pl/neurologia_neurochirurgia_polska/article/view/61311 | access-date = 20 November 2021 | archive-date = 24 December 2022 | archive-url = https://web.archive.org/web/20221224140235/https://journals.viamedica.pl/neurologia_neurochirurgia_polska/article/view/61311 | url-status = live }}</ref><ref name="Müller-Vahl_2022">{{cite journal | vauthors = Müller-Vahl KR, Szejko N, Verdellen C, Roessner V, Hoekstra PJ, Hartmann A, Cath DC | title = European clinical guidelines for Tourette syndrome and other tic disorders: summary statement | journal = European Child & Adolescent Psychiatry | volume = 31 | issue = 3 | pages = 377–382 | date = March 2022 | pmid = 34244849 | pmc = 8940881 | doi = 10.1007/s00787-021-01832-4 }}</ref> It is effective, safe, and well-tolerated for this use per ]s and ].<ref name= "pmid28441584">{{cite journal | vauthors = Wang S, Wei YZ, Yang JH, Zhou YM, Cheng YH, Yang C, Zheng Y | title = The efficacy and safety of aripiprazole for tic disorders in children and adolescents: A systematic review and meta-analysis | journal = Psychiatry Research | volume = 254 | issue = | pages = 24–32 | date = August 2017 | pmid = 28441584 | doi = 10.1016/j.psychres.2017.04.013 | s2cid = 13792422 }}</ref><ref name= "pmid29388585">{{cite journal | vauthors = Cox JH, Seri S, Cavanna AE | title = Safety and efficacy of aripiprazole for the treatment of pediatric Tourette syndrome and other chronic tic disorders | journal = Pediatric Health, Medicine and Therapeutics | volume = 7 | issue = | pages = 57–64 | date = 2016 | pmid = 29388585 | pmc = 5683285 | doi = 10.2147/PHMT.S87121 | doi-access = free }}</ref><ref name="pmid26310194">{{cite journal | vauthors = Zheng W, Li XB, Xiang YQ, Zhong BL, Chiu HF, Ungvari GS, Ng CH, Lok GK, Xiang YT | title = Aripiprazole for Tourette's syndrome: a systematic review and meta-analysis | journal = Human Psychopharmacology | volume = 31 | issue = 1 | pages = 11–18 | date = January 2016 | pmid = 26310194 | doi = 10.1002/hup.2498 | s2cid = 5353158 }}</ref><ref name="pmid26220447">{{cite journal | vauthors = Yang CS, Huang H, Zhang LL, Zhu CR, Guo Q | title = Aripiprazole for the treatment of tic disorders in children: a systematic review and meta-analysis | journal = BMC Psychiatry | volume = 15 | issue = | pages = 179 | date = July 2015 | pmid = 26220447 | pmc = 4518630 | doi = 10.1186/s12888-015-0504-z | doi-access = free }}</ref> |
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In 2009, the United States FDA approved aripiprazole to treat irritability in persons with ].<ref>{{cite web |url=http://www.medscape.com/viewarticle/713006 |title=FDA Approves Aripiprazole to Treat Irritability in Autistic Children |author=Yael Waknine |date=24 November 2009 |work=Medscape Today |publisher=WebMD |accessdate=23 February 2010}}</ref> It was approved on the basis of two studies that showed it reduced aggression towards others, self-injury, quickly changing moods, and irritability. |
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=== Obsessive-compulsive disorder === |
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===Cocaine dependency=== |
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A 2014 ] and ] concluded that add-on therapy with low-dose aripiprazole is an effective treatment for obsessive-compulsive disorder (OCD) that does not improve with ]s (SSRIs) alone.<ref name="pmid25432131">{{cite journal | vauthors = Veale D, Miles S, Smallcombe N, Ghezai H, Goldacre B, Hodsoll J | title = Atypical antipsychotic augmentation in SSRI treatment refractory obsessive-compulsive disorder: a systematic review and meta-analysis | journal = BMC Psychiatry | volume = 14 | issue = 1 | pages = 317 | date = November 2014 | pmid = 25432131 | pmc = 4262998 | doi = 10.1186/s12888-014-0317-5 | doi-access = free }}</ref> The conclusion was based on the results of two relatively small, short-term trials, each of which demonstrated improvements in symptoms.<ref name="pmid25432131" /><ref>{{cite journal | vauthors = Veale D, Miles S, Smallcombe N, Ghezai H, Goldacre B, Hodsoll J | title = Atypical antipsychotic augmentation in SSRI treatment refractory obsessive-compulsive disorder: a systematic review and meta-analysis | journal = BMC Psychiatry | volume = 14 | pages = 317 | date = November 2014 | pmid = 25432131 | pmc = 4262998 | doi = 10.1186/s12888-014-0317-5 | doi-access = free }}</ref><ref name= "pmid17849776">{{cite journal | vauthors = Koran LM, Hanna GL, Hollander E, Nestadt G, Simpson HB | title = Practice guideline for the treatment of patients with obsessive-compulsive disorder | journal = The American Journal of Psychiatry | volume = 164 | issue = 7 Suppl | pages = 5–53 | date = July 2007 | pmid = 17849776 }}</ref><ref>{{cite journal | vauthors = Fornaro M, Gabrielli F, Mattei C, Vinciguerra V, Fornaro P | title = Aripiprazole augmentation in poor insight obsessive-compulsive disorder: a case report | journal = Annals of General Psychiatry | volume = 7 | issue = 1 | pages = 26 | date = December 2008 | pmid = 19105842 | pmc = 2621216 | doi = 10.1186/1744-859X-7-26 | doi-access = free }}</ref> However, aripiprazole is cautiously recommended by a 2017 review on antipsychotics for OCD.<ref name= "Pignon et al Review">{{cite journal | vauthors = Pignon B, Tezenas du Montcel C, Carton L, Pelissolo A | title = The Place of Antipsychotics in the Therapy of Anxiety Disorders and Obsessive-Compulsive Disorders | journal = Current Psychiatry Reports | volume = 19 | issue = 12 | pages = 103 | date = November 2017 | pmid = 29110139 | doi = 10.1007/s11920-017-0847-x | s2cid = 41312623 }}</ref> Aripiprazole is not currently approved for the treatment of OCD and is instead used ] for this indication.<ref name="AdisInsight" /> Depending on the dose, aripiprazole can increase impulse control issues in a small percentage of people. The FDA Drug Safety Communication warned about this side effect.<ref>{{cite web |date=9 February 2019 |title=l FDA warns about new impulse-control problems associated with mental health drug aripiprazole (Abilify, Abilify Maintena, Aristada) |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-new-impulse-control-problems-associated-mental-health |website=FDA.gov |publisher=U.S. ] |access-date=3 April 2023 |archive-date=2 April 2023 |archive-url=https://web.archive.org/web/20230402021450/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-new-impulse-control-problems-associated-mental-health |url-status=live }}</ref> |
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Perhaps owing to its mechanism of action relating to dopamine receptors, there is some evidence to suggest that aripiprazole blocks cocaine-seeking behaviour in animal models without significantly affecting other rewarding behaviours (such as food self-administration). |
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<ref>'Aripiprazole Blocks Reinstatement of Cocaine Seeking in an Animal Model of Relapse' Biological Psychiatry. Volume 61, Issue 5, Pages 582-590 (1 March 2007) http://www.journals.elsevierhealth.com/periodicals/bps/article/S0006-3223%2806%2900484-7/abstract</ref> |
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===Available forms=== |
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== Side effects == |
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{{See also|Aripiprazole lauroxil}} |
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{{refimprove|section|date=April 2010}} |
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Aripiprazole is available in the form of ] ]s, ]s, oral ]s, oral films, and as ]s for ].<ref name="Drugs@FDA">{{cite web | title=Drugs@FDA: FDA-Approved Drugs | website=accessdata.fda.gov | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm | access-date=22 October 2024}}</ref>{{failed verification|date=November 2024}} It is also available in the form of ], a ] ] ] of aripiprazole for use as a ].<ref name="Drugs@FDA" />{{failed verification|date=November 2024}} |
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=== Frequent === |
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*]<ref name="urlDose-dependent rapid-onset akathisia with aripiprazole in patients with schizoaffective disorder">{{cite web | url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671776/ | title = Dose-dependent rapid-onset akathisia with aripiprazole in patients with schizoaffective disorder | author = | authorlink = | coauthors = | date = | format = | work = | publisher = | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2010-08-07}}</ref> |
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*headache |
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*agitation |
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*anxiety |
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*unusual tiredness or weakness |
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*nausea and vomiting |
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*an uncomfortable feeling in the stomach |
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*constipation |
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*increased production of ] |
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*light-headedness |
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*] |
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*sleepiness |
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*shaking |
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*blurred vision |
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*sexual dysfunction |
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=== Infrequent === |
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== Contraindications == |
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]s to aripiprazole include known ] to aripiprazole, among others.<ref name="AHFS2019" /> |
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*Uncontrollable twitching or jerking movements, ]s, seizure, and weight gain. Some people may feel ], especially when getting up from a lying or sitting position, or may experience a fast heart rate. |
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*] (Combination of ], muscle stiffness, ], ], reduced consciousness, and sudden change in ] and ].) |
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*Suicidal thoughts and ] attempts |
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*Painful and/or sustained ] |
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*] (As with all antipsychotic medication, patients using aripiprazole may develop the permanent neurological disorder tardive dyskinesia.<ref name="pmid18515468">{{cite journal|author=Abbasian C, Power P|title=A case of aripiprazole and tardive dyskinesia|journal=J Psychopharmacol (Oxford)|volume=23|issue=2|pages=214–5|year=2009|month=March|pmid=18515468|doi=10.1177/0269881108089591|url=}}</ref><ref name="pmid18183513">{{cite journal|author=Zaidi SH, Faruqui RA|title=Aripiprazole is associated with early onset of Tardive Dyskinesia like presentation in a patient with ABI and psychosis|journal=Brain Inj|volume=22|issue=1|pages=99–102|year=2008|month=January|pmid=18183513|doi=10.1080/02699050701822493|url=}}</ref><ref name="pmid16816781">{{cite journal|author=Maytal G, Ostacher M, Stern TA|title=Aripiprazole-related tardive dyskinesia|journal=CNS Spectr|volume=11|issue=6|pages=435–9|year=2006|month=June|pmid=16816781|doi=|url=}}</ref>) |
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*] (While taking aripiprazole some elderly patients with ] have suffered from ] or ].) |
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*] reaction (such as swelling in the ] or ], ]ing, ]), ], ], ], ], reports of abnormal ] values, ], ], weakness, stiffness, or cramps. |
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== Adverse effects == |
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===Discontinuation=== |
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{{See also|List of adverse effects of aripiprazole}} |
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Aripiprazole should be discontinued gradually, with careful consideration from the prescribing doctor, to avoid withdrawal symptoms or relapse. |
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In the elderly with dementia, there is an increased risk of death.<ref name=MedlinePlus>{{cite web |title=Aripiprazole: MedlinePlus Drug Information |url=https://medlineplus.gov/druginfo/meds/a603012.html |website=medlineplus.gov |access-date=13 October 2023 |archive-date=4 October 2023 |archive-url=https://web.archive.org/web/20231004231705/https://medlineplus.gov/druginfo/meds/a603012.html |url-status=live }}</ref> |
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The ] recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse.<ref>{{cite book |editor1-first=BMJ |editor1-last=Group |title=British National Formulary |edition=57 |year=2009 |month=March |publisher=Royal Pharmaceutical Society of Great Britain |location=United Kingdom |isbn=0260-535X |page=192 |chapter=4.2.1 |quote=Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.}}</ref> Due to compensatory changes at dopamine, serotonin, adrenergic and histamine receptor sites in the central nervous system, withdrawal symptoms can occur during abrupt or over-rapid reduction in dosage. Withdrawal symptoms reported to occur after discontinuation of antipsychotics include nausea, ], lightheadedness, ], ], ], ], nervousness, dizziness, headache, excessive non-stop crying, and ]. The present evidence suggests that these symptoms affect a small number of susceptible individuals treated with antipsychotics.<ref>{{Cite journal | last1 = Kim | first1 = DR. | last2 = Staab | first2 = JP. | title = Quetiapine discontinuation syndrome. | url = http://ajp.psychiatryonline.org/cgi/content/full/162/5/1020 | journal = Am J Psychiatry | volume = 162 | issue = 5 | pages = 1020 | month = May | year = 2005 | doi = 10.1176/appi.ajp.162.5.1020 | pmid = 15863814 }}</ref><ref>{{Cite journal | last1 = Michaelides | first1 = C. | last2 = Thakore-James | first2 = M. | last3 = Durso | first3 = R. | title = Reversible withdrawal dyskinesia associated with quetiapine. | journal = Mov Disord | volume = 20 | issue = 6 | pages = 769–70 | month = Jun | year = 2005 | doi = 10.1002/mds.20427 | pmid = 15747370 }}</ref> Complicated and long-lasting ] symptoms can also occur after withdrawing from antipsychotics.{{Citation needed|date=May 2011}} |
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<!-- |
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NB: It carries a ] that states, "Increased risk of suicidal thinking and behavior in '''children, adolescents, and young adults''' taking antidepressants. " <ref name=dailymed /> |
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--> |
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In children, adolescents, and young adults, there is an increased risk of ].<ref name=MedlinePlus /><ref name=dailymed>{{cite web |title=DailyMed - ARIPIPRAZOLE- aripiprazole tablet |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7df4c83e-13d8-25b1-57eb-08d26ba03565 |website=dailymed.nlm.nih.gov |access-date=4 November 2023 |quote=BOXED WARNING WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS WITH ANTIDEPRESSANT DRUGS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Aripiprazole tablets are not approved for the treatment of patients with dementia-related psychosis . Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older . In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber . |archive-date=4 November 2023 |archive-url=https://web.archive.org/web/20231104195818/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7df4c83e-13d8-25b1-57eb-08d26ba03565 |url-status=live }}</ref> |
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In adults, side effects with greater than 10% incidence include weight gain, mania, headache, ], insomnia, delirium, and gastrointestinal effects like nausea, constipation, and lightheadedness.<ref name="Abilify FDA label" /><ref name = EMC /><ref name = EMA /><ref name = Abilify /><ref name="WebMD">{{cite web |title=Abilify Discmelt, Abilify Maintena (aripiprazole) dosing, indications, interactions, adverse effects, and more |url=http://reference.medscape.com/drug/abilify-discmelt-abilify-maintena-aripiprazole-342983 |url-status=live |archive-url=https://web.archive.org/web/20131023060856/http://reference.medscape.com/drug/abilify-discmelt-abilify-maintena-aripiprazole-342983 |archive-date=23 October 2013 |access-date=22 October 2013 |website=Medscape Reference |publisher=WebMD}}</ref> Side effects in children are similar, and include sleepiness, increased appetite, and stuffy nose.<ref name = Abilify /> A strong desire to gamble, binge eat, shop, and engage in sexual activity may also occur rarely.<ref name="FDA impulse control">{{cite web |date=3 May 2016 |title=Aripiprazole (Abilify, Abilify Maintena, Aristada): Drug Safety Communication – FDA Warns About New Impulse-control Problems |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-new-impulse-control-problems-associated-mental-health |access-date=4 May 2016 |website=U.S. ] (FDA) |archive-date=2 May 2019 |archive-url=https://web.archive.org/web/20190502101304/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-new-impulse-control-problems-associated-mental-health |url-status=live }}</ref><ref name="pmid26658263">{{cite journal | vauthors = Grall-Bronnec M, Sauvaget A, Perrouin F, Leboucher J, Etcheverrigaray F, Challet-Bouju G, Gaboriau L, Derkinderen P, Jolliet P, Victorri-Vigneau C | title = Pathological Gambling Associated With Aripiprazole or Dopamine Replacement Therapy: Do Patients Share the Same Features? A Review | journal = Journal of Clinical Psychopharmacology | volume = 36 | issue = 1 | pages = 63–70 | date = February 2016 | pmid = 26658263 | pmc = 4700874 | doi = 10.1097/JCP.0000000000000444 }}</ref> These urges can be uncontrollable.<ref name="FDA impulse control" /> |
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===Overdosage=== |
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Children or adults who ingested acute overdoses have usually manifested central nervous system depression ranging from mild sedation to coma; serum concentrations of aripiprazole and dehydroaripiprazole in these patients were elevated by up to 3-4 fold over normal therapeutic levels, yet to date no deaths have been recorded.<ref>R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 105-106.</ref> |
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Uncontrolled movement such as restlessness, tremors, and ] may occur.<ref name = Abilify /> |
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=== Drug interactions === |
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Aripiprazole is a substrate of ] and ]. Coadministration with medications that inhibit (e.g. ], ]) or induce (e.g. ]) these metabolic enzymes are known to increase and decrease, respectively, plasma levels of aripiprazole.<ref name="drugLabelWP">{{cite web |url=http://www.druglib.com/druginfo/abilify/warnings_precautions/ |title=Abilify (Aripiprazole) - Warnings and Precautions |accessdate=8 December 2008 |publisher=DrugLib.com |date=14 February 2007}}</ref> As such, anyone taking aripiprazole should be aware that their dosage of aripiprazole may need to be decreased. |
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=== Discontinuation === |
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Aripiprazole may change the subjective effects of alcohol. One study<ref name="Kranzler2008">{{cite journal |
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The ] recommends a gradual withdrawal when ] to avoid acute withdrawal syndrome or rapid relapse.<ref>{{cite book | editor = Joint Formulary Committee | title = British National Formulary | edition = 57 | date = March 2009 |publisher=Royal Pharmaceutical Society of Great Britain |location=United Kingdom |isbn=978-0-85369-845-6 |page=192 |chapter=4.2.1 |quote=Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.}}</ref> Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.<ref name=Had2004>{{cite book |vauthors=Haddad P, Haddad PM, Dursun S, Deakin B |title=Adverse Syndromes and Psychiatric Drugs: A Clinical Guide |date=2004 |publisher=OUP Oxford |isbn=978-0-19-852748-0 |pages=207–216 |url=https://books.google.com/books?id=CWR7DwAAQBAJ&pg=PA207 |access-date=19 September 2020 |archive-date=10 January 2023 |archive-url=https://web.archive.org/web/20230110164012/https://books.google.com/books?id=CWR7DwAAQBAJ&pg=PA207 |url-status=live }}</ref> Other symptoms may include restlessness, increased sweating, and trouble sleeping.<ref name=Had2004 /> Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.<ref name=Had2004 /> Symptoms generally resolve after a short period of time.<ref name=Had2004 /> |
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|author=Kranzler, Henry R. et al. |
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|title=Effects of Aripiprazole on Subjective and Physiological Responses to Alcohol |
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There is tentative evidence that discontinuation of antipsychotics can result in psychosis as a part of a withdrawal syndrome.<ref>{{cite journal | vauthors = Moncrieff J | title = Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse | journal = Acta Psychiatrica Scandinavica | volume = 114 | issue = 1 | pages = 3–13 | date = July 2006 | pmid = 16774655 | doi = 10.1111/j.1600-0447.2006.00787.x | s2cid = 6267180 }}</ref> It may also result in reoccurrence of the condition that is being treated.<ref>{{cite book |vauthors=Sacchetti E, Vita A, Siracusano A, Fleischhacker W |title=Adherence to Antipsychotics in Schizophrenia |date=2013 |publisher=Springer Science & Business Media |isbn=9788847026797 |page=85 |url=https://books.google.com/books?id=odE-AgAAQBAJ&pg=PA85 |access-date=19 September 2020 |archive-date=10 January 2023 |archive-url=https://web.archive.org/web/20230110164029/https://books.google.com/books?id=odE-AgAAQBAJ&pg=PA85 |url-status=live }}</ref> Rarely tardive dyskinesia can occur when the medication is stopped.<ref name=Had2004 /> |
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|journal=Alcoholism: Clinical and Experimental Research |
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|volume=32 |
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== Overdose == |
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|issue=4 |
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Children or adults who ingested acute overdoses have usually manifested central nervous system depression ranging from mild sedation to coma; serum concentrations of aripiprazole and dehydroaripiprazole in these people were elevated by up to 3–4 fold over normal therapeutic levels; as of 2008, no deaths had been recorded.<ref>{{cite book | vauthors = Baselt RC | title = Disposition of Toxic Drugs and Chemicals in Man | date = 2008 | publisher = Biomedical Publications | location = Foster City, CA | isbn = 978-0-9626523-7-0 | edition = 8th | pages = 105–6 }}</ref><ref name="Skov 2015 41-44">{{cite journal | vauthors = Skov L, Johansen SS, Linnet K | title = Postmortem femoral blood reference concentrations of aripiprazole, chlorprothixene, and quetiapine | journal = Journal of Analytical Toxicology | volume = 39 | issue = 1 | pages = 41–44 | date = Jan 2015 | pmid = 25342720 | doi = 10.1093/jat/bku121 | doi-access = free | title-link = doi }}</ref> |
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|pages=573–579 |
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|year=2008 |
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== Interactions == |
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|pmid=18261195 |
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Aripiprazole is a substrate of ] and ]. Coadministration with medications that inhibit (e.g. ], ]) or induce (e.g. ]) these metabolic enzymes are known to increase and decrease, respectively, plasma levels of aripiprazole.<ref name="drugLabelWP">{{cite web | url = http://www.druglib.com/druginfo/abilify/warnings_precautions/ | title = Abilify (Aripiprazole) – Warnings and Precautions | access-date = 8 December 2008 | publisher = DrugLib.com | date = 14 February 2007 | archive-url = https://web.archive.org/web/20081204161824/http://www.druglib.com/druginfo/abilify/warnings_precautions/ | archive-date= 4 December 2008 | url-status= live}}</ref><ref name="Abilify FDA label" /> |
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|doi=10.1111/j.1530-0277.2007.00608.x}}</ref> |
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found that aripiprazole increased the sedative effect and reduced the sense of euphoria normally associated with alcohol consumption. However, another alcohol study<ref name="Voronin2008">{{cite journal |
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Precautions should be taken in people with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics along with other medications that affect blood sugar levels and should be monitored regularly for worsening of glucose control. The liquid form (oral solution) of this medication may contain up to 15 grams of sugar per dose.<ref name=AHFS2019 /> |
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|author=Konstantin Voronin, Patrick Randall, Hugh Myrick, Raymond Anton |
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|title=Aripiprazole Effects on Alcohol Consumption and Subjective Reports in a Clinical Laboratory Paradigm—Possible Influence of Self-Control |
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Antipsychotics like aripiprazole and stimulant medications, such as ], are traditionally thought to have opposing effects because both drugs affect dopaminergic neurons. However, both stimulants and antipsychotics lead to increases in synaptic dopamine levels.<ref>{{cite journal | vauthors = Westerink BH, Kawahara Y, De Boer P, Geels C, De Vries JB, Wikström HV, Van Kalkeren A, Van Vliet B, Kruse CG, Long SK | title = Antipsychotic drugs classified by their effects on the release of dopamine and noradrenaline in the prefrontal cortex and striatum | journal = European Journal of Pharmacology | volume = 412 | issue = 2 | pages = 127–138 | date = January 2001 | pmid = 11165224 | doi = 10.1016/S0014-2999(00)00935-3 }}</ref> In antipsychotics, this is caused by the inhibition of dopamine autoreceptors as well as the effects of antipsychotics on non-] receptors, while in amphetamine this is caused by non-competitive inhibition of dopamine reuptake and agonism of intracellular ]. Therefore aripiprazole may interact with amphetamine to synergistically increase postsynaptic levels of dopamine. This interaction frequently occurs in the setting of comorbid ] (ADHD) (for which stimulants are commonly prescribed) and off-label treatment of aggression with antipsychotics. Aripiprazole has been reported to provide some benefit in improving cognitive functioning in people with ADHD without other psychiatric comorbidities, though the results have been disputed. The combination of antipsychotics like aripiprazole with stimulants should not be considered an absolute contraindication.<ref name="Yanofski review">{{cite journal | vauthors = Yanofski J | title = The dopamine dilemma: using stimulants and antipsychotics concurrently | journal = Psychiatry | volume = 7 | issue = 6 | pages = 18–23 | date = June 2010 | pmid = 20622942 | pmc = 2898838 }}</ref> |
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|journal=Alcoholism: Clinical and Experimental Research |
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|volume=32 |
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|issue=11 |
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|pages=1954–1961 |
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|year=2008 |
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|pmid=18782344 |
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|doi=10.1111/j.1530-0277.2008.00783.x |
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|pmc=2588475}}</ref> |
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found that there was no difference in subjective effect between a placebo group and a group taking aripiprazole. |
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== Pharmacology == |
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== Pharmacology == |
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{{multicol}} |
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* D<sub>2</sub> Partial Agonist (K<sub>i</sub> = 0.34 nM) |
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* D<sub>3</sub> Antagonist (K<sub>i</sub> = 0.8 nM) |
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* D<sub>4</sub> Antagonist (K<sub>i</sub> = 44 nM) |
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{{multicol-break}} |
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* 5-HT<sub>1A</sub> Partial Agonist (K<sub>i</sub> = 0.34 nM) |
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* 5-HT<sub>2A</sub> Partial Agonist (K<sub>i</sub> = 0.8 nM) |
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* 5-HT<sub>2C</sub> Partial Agonist (K<sub>i</sub> = 15 nM) |
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* 5-HT<sub>7</sub> Antagonist (K<sub>i</sub> = 39 nM) |
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{{multicol-break}} |
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* SRI (K<sub>i</sub> = 98 nM) |
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* Antihistamine (K<sub>i</sub> = 61 nM) |
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* α-adrenergic antagonist (K<sub>i</sub> = 57 nM) |
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* mACh receptor antagonist (IC<sub>50</sub> >1000 nM) |
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{{multicol-end}} |
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=== Pharmacodynamics === |
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Aripiprazole's ] is different from those of the other FDA-approved ]s (e.g., ], ], ], ], and ]). Rather than ] the ], aripiprazole acts as a D<sub>2</sub> ] (K<sub>i</sub> = 0.34 nM).<ref name=lawler>{{cite journal |
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{{See also|Atypical antipsychotic#Pharmacodynamics|Antipsychotic#Comparison of medications}} |
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|author=Lawler CP et al. |
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|title=Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes |
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|journal=Neuropsychopharmacology |
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|year=1999 |
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|volume=20 |
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|issue=6 |
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|pages=612–27 |
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|pmid=10327430 |
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|doi=10.1016/S0893-133X(98)00099-2}}</ref><ref name="burstein">{{cite journal |
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|author=Burstein ES, Ma J, Wong S, Gao Y, Pham E, Knapp AE, Nash NR, Olsson R, Davis RE, Hacksell U, Weiner DM, Brann MR |
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|title=Intrinsic Efficacy of Antipsychotics at Human D<sub>2</sub>, D<sub>3</sub>, and D<sub>4</sub> Dopamine Receptors: Identification of the Clozapine Metabolite N-Desmethylclozapine as a D<sub>2</sub>/D<sub>3</sub> Partial Agonist |
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|journal=J Pharmacol Exp Ther |
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|year=2005 |
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|month=December |
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|volume=315 |
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|issue=3 |
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|pages=1278–87 |
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|pmid=16135699 |
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|doi=10.1124/jpet.105.092155}}</ref> Aripiprazole is also a partial agonist at the ] (K<sub>i</sub> = 1.65 nM), and like the other atypical antipsychotics displays an antagonist profile at the ] (K<sub>i</sub> = 0.8 nM).<ref name="jordan">{{cite journal |
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|author = Jordan, S et al. |
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|title = The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor |
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|journal = Eur J Pharmacol |
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|volume = 441 |
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|issue = 3 |
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|pages = 137–140 |
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|doi = 10.1016/S0014-2999(02)01532-7 |
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|pmid = 12063084 |
|
|
|year = 2002}}</ref><ref name="shapiro">{{cite journal |
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|
|author = Shapiro, DA et al. |
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|title = Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology |
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|journal = Neuropsychopharmacology |
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|volume = 28 |
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|
|issue = 8 |
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|pages = 1400–1411 |
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|doi = 10.1016/S0014-2999(02)01532-7 |
|
|
|pmid = 12063084 |
|
|
|year = 2003}}</ref> It also antagonizes the ] (K<sub>i</sub> = 39 nM) and acts as a partial agonist at the ] (K<sub>i</sub> = 15 nM), both with high affinity. The latter action may underlie the minimal weight gain seen in the course of therapy.<ref name="pmid16336943">{{cite journal |
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|
|author=Zhang JY, Kowal DM, Nawoschik SP, Lou Z, Dunlop J |
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|title=Distinct functional profiles of aripiprazole and olanzapine at RNA edited human 5-HT2C receptor isoforms |
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|journal=Biochem Pharmacol |
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|volume=71 |
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|issue=4 |
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|pages=521–9 |
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|year=2006 |
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|month=February |
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|pmid=16336943 |
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|doi=10.1016/j.bcp.2005.11.007 |
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|url= |
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|
}}</ref> Aripiprazole has moderate affinity for histamine (K<sub>i</sub> = 61 nM), α-adrenergic (K<sub>i</sub> = 57 nM), and D4 receptors as well as the ], while it has no appreciable affinity for cholinergic muscarinic receptors.<ref name="drugLabelPC" /> |
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{| class="wikitable floatright" style="font-size:small;" |
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D<sub>2</sub> and ] occupancy levels are high, with average levels ranging between ~71% at 2 mg/day to ~96% at 40 mg/day.<ref name="kegeles">{{cite journal |
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|+ Aripiprazole<ref name="PDSP">{{cite web | title = PDSP K<sub>i</sub> Database | website = Psychoactive Drug Screening Program (PDSP) | vauthors = Roth BL, Driscol J | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 14 August 2017 | url = https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=aripiprazole&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query | archive-date = 27 August 2021 | archive-url = https://web.archive.org/web/20210827224128/https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=aripiprazole&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query | url-status = live }}</ref><ref name="pmid12784105">{{cite journal | vauthors = Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, Roth BL, Mailman R | title = Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology | journal = Neuropsychopharmacology | volume = 28 | issue = 8 | pages = 1400–1411 | date = August 2003 | pmid = 12784105 | doi = 10.1038/sj.npp.1300203 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Mohr P, Masopust J, Kopeček M | title = Dopamine Receptor Partial Agonists: Do They Differ in Their Clinical Efficacy? | journal = Frontiers in Psychiatry | volume = 12 | pages = 781946 | date = 25 January 2022 | pmid = 35145438 | pmc = 8821167 | doi = 10.3389/fpsyt.2021.781946 | doi-access = free }}</ref> |
|
|author=Kegeles, LS et al. |
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|- |
|
|title=Dose–Occupancy Study of Striatal and Extrastriatal Dopamine D<sub>2</sub> Receptors by Aripiprazole in Schizophrenia with PET and Fallypride |
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|
! Site !! K<sub>i</sub> (nM) |
|
|journal=Neuropsychopharmacology |
|
|
|
! IA (%) !! Action !! Ref |
|
|volume=33 |
|
|
|
|- |
|
|issue=13 |
|
|
|
| {{abbrlink|SERT|Serotonin transporter}} || 900 – 1260 |
|
|pmid=18418366 |
|
|
|
| || Reuptake Inhibitor || <ref name="pmid12665420" /><ref name="pmid12784105" /> |
|
|pages=3111–3125 |
|
|
|
|- |
|
|doi=10.1038/npp.2008.33 |
|
|
|
| {{abbrlink|NET|Norepinephrine transporter}} || 1340 – 2840 |
|
|year=2008}}</ref><ref name="pmid12093598">{{cite journal |
|
|
|
| || Reuptake inhibitor || <ref name="pmid12784105" /> |
|
|author=Yokoi F, Gründer G, Biziere K, Stephane M, Dogan AS, Dannals RF, Ravert H, Suri A, Bramer S, Wong DF |
|
|
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|- |
|
|title=Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and raclopride |
|
|
|
| {{abbrlink|DAT|Dopamine transporter}} || 2560 – 3880 |
|
|journal=Neuropsychopharmacology |
|
|
|
| || Reuptake inhibitor || <ref name="pmid12784105" /> |
|
|volume=27 |
|
|
|
|- |
|
|issue=2 |
|
|
|
| ] || 1.7 – 6.4 |
|
|pages=248–59 |
|
|
|
| ~68% || Partial agonist || <ref name="pmid12784105" /><ref name="pmid12629531">{{cite journal | vauthors = Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL | title = H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs | journal = Neuropsychopharmacology | volume = 28 | issue = 3 | pages = 519–526 | date = March 2003 | pmid = 12629531 | doi = 10.1038/sj.npp.1300027 | doi-access = free | title-link = doi }}</ref><ref name="pmid12665420">{{cite journal | vauthors = Keck PE, McElroy SL | title = Aripiprazole: a partial dopamine D2 receptor agonist antipsychotic | journal = Expert Opinion on Investigational Drugs | volume = 12 | issue = 4 | pages = 655–662 | date = April 2003 | pmid = 12665420 | doi = 10.1517/13543784.12.4.655 | s2cid = 8654102 }}</ref> |
|
|year=2002 |
|
|
|
|- |
|
|month=August |
|
|
|
| ] || 570 – 1090 |
|
|pmid=12093598 |
|
|
|
| || {{abbr|ND|No data}} || <ref name="pmid12784105" /> |
|
|doi=10.1016/S0893-133X(02)00304-4 |
|
|
|
|- |
|
}}</ref> |
|
|
|
| ] || 57 – 79 |
|
Most atypical antipsychotics bind preferentially to ] receptors, but aripiprazole appears to be less preferential in this regard, as binding rates are high throughout the brain.<ref name="editorial1">{{cite journal |
|
|
|
| || {{abbr|ND|No data}} || <ref name="pmid12784105" /> |
|
|title = In This Issue |
|
|
|
|- |
|
|journal = Am J Psychiatry |
|
|
|
| ] || 3000 – >10,000 |
|
|volume = 165 |
|
|
|
| || {{abbr|ND|No data}} || <ref name="pmid12784105" /> |
|
|issue = 8 |
|
|
|
|- |
|
|pages = A46 |
|
|
|
| ] || 6.7 – 39 |
|
|doi = 10.1176/appi.ajp.2008.165.8.A46 |
|
|
|
| 12.7% || Very weak partial<br />agonist or antagonist |
|
|month = August |
|
|
|
| <ref name="pmid12665420" /><ref name="pmid12784105" /><ref name="pmid12629531" /> |
|
|year = 2008}}</ref> |
|
|
|
|- |
|
|
| ] || 0.25 – 0.47 |
|
|
| || Inverse agonist || <ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] || 11 – 197 |
|
|
| 82% || Partial agonist || <ref name="pmid12665420" /><ref name="pmid12784105" /><ref name="pmid12629531" /> |
|
|
|- |
|
|
| ] || 520 – 740 |
|
|
| || {{abbr|ND|No data}} || <ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] || 960 – 1520 |
|
|
| 87% || Near-full Agonist || <ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] || 475 – 665 |
|
|
| || Antagonist || <ref name="pmid12665420" /><ref name="pmid12784105" /><ref name="pmid12629531" /> |
|
|
|- |
|
|
| ] || 6.6 – 14 |
|
|
| 58% || Partial agonist |
|
|
| <ref name="pmid12784105" /><ref name="pmid12629531" /><ref name="pmid12665420" /> |
|
|
|- |
|
|
| ] || 26 |
|
|
| || Antagonist || <ref name="pmid12784105" /><ref name="pmid12629531" /> |
|
|
|- |
|
|
| ] || 35 |
|
|
| || Antagonist || <ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] || 74.3 |
|
|
| || Antagonist || <ref name="pmid12784105" /><ref name="pmid12629531" /> |
|
|
|- |
|
|
| ] || 102 |
|
|
| || {{abbr|ND|No data}} || <ref name="pmid12784105" /><ref name="pmid12629531" /> |
|
|
|- |
|
|
| ] || 38 |
|
|
| || Antagonist || <ref name="pmid12784105" /><ref name="pmid12629531" /> |
|
|
|- |
|
|
| ] || 141 |
|
|
| || Antagonist || <ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] || 163 |
|
|
| || Antagonist || <ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] || 1290 – 2630 |
|
|
| || Partial agonist || <ref name="pmid12665420" /><ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] || 2.2 – 4.4 |
|
|
| ~60% || Partial agonist / functional antagonist || <ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] |
|
|
| 0.65 – 0.83 |
|
|
| ~50% |
|
|
| Partial agonist |
|
|
| |
|
|
|- |
|
|
| ] || 4.3 – 15.1 |
|
|
| ~40% || Partial agonist / full agonist || <ref name="pmid12665420" /><ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] || 417 – 603 |
|
|
| ~30% || Partial agonist / functional antagonist || <ref name="pmid12665420" /><ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] || 1240 – 3940 |
|
|
| || Antagonist || <ref name="pmid12665420" /><ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] || 22.5 – 27.7 |
|
|
| || Neutral Antagonist |
|
|
| <ref name="pmid12784105" /><ref name="pmid12629531" /><ref name="pmid12665420" /> |
|
|
|- |
|
|
| ] || >10,000 |
|
|
| || {{abbr|ND|No data}} || <ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] || 60 – 388 |
|
|
| || {{abbr|ND|No data}} || <ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] || >10,000 |
|
|
| || {{abbr|ND|No data}} || <ref name="pmid12784105" /> |
|
|
|- |
|
|
| ]|| 6,780 |
|
|
| || {{abbr|ND|No data}} || <ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] || 3,510 |
|
|
| || {{abbr|ND|No data}} || <ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] || 4,680 |
|
|
| || {{abbr|ND|No data}} || <ref name="pmid12784105" /><ref name="pmid12629531" /> |
|
|
|- |
|
|
| ] || 1,520 |
|
|
| || {{abbr|ND|No data}} || <ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] || 2,330 |
|
|
| || {{abbr|ND|No data}} || <ref name="pmid12784105" /> |
|
|
|- |
|
|
| ] |
|
|
| |
|
|
| || Orthostatic<br />Negative allosteric modulator |
|
|
|- |
|
|
| ] |
|
|
| 1824 |
|
|
| || Uncompetitive channel blocker<br />Antagonist |
|
|
| <ref name="pmid12784105" /> |
|
|
|- |
|
|
| | ] |
|
|
| 1824 |
|
|
| || Uncompetitive agonist |
|
|
| <ref name="pmid12784105" /> |
|
|
|- class="sortbottom" |
|
|
| colspan="5" style="width: 1px;" | Values are K<sub>i</sub> (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except 5-HT<sub>3</sub> (rat), D<sub>4</sub> (human/rat), H<sub>3</sub> (guinea pig), and NMDA/PCP (rat).<ref name="pmid12784105" /> IA = Intrinsic Activity |
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|} |
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|
|
Aripiprazole's ] is different from those of the other FDA-approved ]s (e.g., ], ], ], ], and ]).<ref name="Starrenburga 2009 164–170">{{cite journal | vauthors = Starrenburg FC, Bogers JP | title = How can antipsychotics cause Diabetes Mellitus? Insights based on receptor-binding profiles, humoral factors and transporter proteins | journal = European Psychiatry | volume = 24 | issue = 3 | pages = 164–170 | date = April 2009 | pmid = 19285836 | doi = 10.1016/j.eurpsy.2009.01.001 | s2cid = 42636469 }}</ref><ref name="drugLabelPC" /><ref name=Goodman>{{cite book| vauthors = Brunton L |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics | edition = 12th |year=2011|publisher=McGraw-Hill|location=China|isbn=978-0-07-162442-8|pages=406–410}}</ref><ref name="Davies_2004">{{cite journal | vauthors = Davies MA, Sheffler DJ, Roth BL | title = Aripiprazole: a novel atypical antipsychotic drug with a uniquely robust pharmacology | journal = CNS Drug Reviews | volume = 10 | issue = 4 | pages = 317–336 | year = 2004 | pmid = 15592581 | pmc = 6741761 | doi = 10.1111/j.1527-3458.2004.tb00030.x | author3-link = Bryan Roth }}</ref> It shows ] at the ] (D<sub>2</sub><ref name="pmid12784105" />). Aripiprazole is a ] at dopamine D<sub>2</sub> receptors, a partial agonist at ] receptors, and an ] or very weak partial agonist and at ]s.<ref>{{cite journal | vauthors = Pae CU, Serretti A, Patkar AA, Masand PS | title = Aripiprazole in the treatment of depressive and anxiety disorders: a review of current evidence | journal = CNS Drugs | volume = 22 | issue = 5 | pages = 367–388 | date = 2008 | pmid = 18399707 | doi = 10.2165/00023210-200822050-00002 | s2cid = 19757151 }}</ref><ref>{{cite journal | vauthors = Tuplin EW, Holahan MR | title = Aripiprazole, A Drug that Displays Partial Agonism and Functional Selectivity | journal = Current Neuropharmacology | volume = 15 | issue = 8 | pages = 1192–1207 | date = November 2017 | pmid = 28412910 | pmc = 5725548 | doi = 10.2174/1570159X15666170413115754 }}</ref> |
|
Recently, it has been demonstrated that in 5-HT<sub>7</sub> receptor ], aripiprazole does not reduce immobility time in the ] (FST), and actually increases it.<ref name="pmid19649616">{{cite journal | author = Hedlund PB | title = The 5-HT7 receptor and disorders of the nervous system: an overview | journal = Psychopharmacology | volume = 206 | issue = 3 | pages = 345–54 | year = 2009 | month = October | isbn = 0021300916260 | pmid = 19649616 | doi = 10.1007/s00213-009-1626-0 | pmc = 2841472}}</ref><ref name="pmid20097233">{{cite journal | author = Sarkisyan G, Roberts AJ, Hedlund PB | title = The 5-HT(7) receptor as a mediator and modulator of antidepressant-like behavior | journal = Behavioural Brain Research | volume = 209| issue = 1| pages = 99–108| year = 2010 | month = January | pmid = 20097233 | doi = 10.1016/j.bbr.2010.01.022 | url = http://linkinghub.elsevier.com/retrieve/pii/S0166-4328(10)00046-X | pmc = 2832919}}</ref> This implicates 5-HT<sub>7</sub> antagonism as playing a major role in aripiprazole's antidepressant effects, similarly to ].<ref name="pmid19649616"/><ref name="pmid20097233"/><ref name="pmid19337725">{{cite journal | author = Abbas AI, Hedlund PB, Huang XP, Tran TB, Meltzer HY, Roth BL | title = Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo | journal = Psychopharmacology | volume = 205 | issue = 1 | pages = 119–28 | year = 2009 | month = July | isbn = 0021300915218 | pmid = 19337725 | doi = 10.1007/s00213-009-1521-8 | pmc = 2821721}}</ref> |
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It appears to show predominantly partial agonistic activity on postsynaptic D<sub>2</sub> receptors and partial agonist activity on presynaptic D<sub>2</sub> receptors,<ref name="pmid17501690">{{cite journal | vauthors = Wood M, Reavill C | title = Aripiprazole acts as a selective dopamine D2 receptor partial agonist | journal = Expert Opinion on Investigational Drugs | volume = 16 | issue = 6 | pages = 771–775 | date = June 2007 | pmid = 17501690 | doi = 10.1517/13543784.16.6.771 | s2cid = 42171115 }}</ref> D<sub>3</sub>,<ref name="pmid12784105" /><ref name="kegeles">{{cite journal | vauthors = Kegeles LS, Slifstein M, Frankle WG, Xu X, Hackett E, Bae SA, Gonzales R, Kim JH, Alvarez B, Gil R, Laruelle M, Abi-Dargham A | title = Dose-occupancy study of striatal and extrastriatal dopamine D2 receptors by aripiprazole in schizophrenia with PET and fallypride | journal = Neuropsychopharmacology | volume = 33 | issue = 13 | pages = 3111–3125 | date = December 2008 | pmid = 18418366 | doi = 10.1038/npp.2008.33 | doi-access = free | title-link = doi }}</ref><ref name="pmid12093598">{{cite journal | vauthors = Yokoi F, Gründer G, Biziere K, Stephane M, Dogan AS, Dannals RF, Ravert H, Suri A, Bramer S, Wong DF | title = Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and raclopride | journal = Neuropsychopharmacology | volume = 27 | issue = 2 | pages = 248–259 | date = August 2002 | pmid = 12093598 | doi = 10.1016/S0893-133X(02)00304-4 | doi-access = free | title-link = doi }}</ref> and partially D<sub>4</sub><ref name="pmid12784105" /><ref name="drugLabelPC" /> and is a ] of ] (],<ref name="pmid12784105" /><ref name="pmid12063084">{{cite journal | vauthors = Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar CA | title = The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor | journal = European Journal of Pharmacology | volume = 441 | issue = 3 | pages = 137–140 | date = April 2002 | pmid = 12063084 | doi = 10.1016/S0014-2999(02)01532-7 }}</ref><ref name="pmid17728427" /> ],<ref name="pmid12784105" /> ],<ref name="pmid12784105" /> 5-HT<sub>6</sub>, and ]).<ref name="pmid12784105" /><ref name="Davies_2004" /> It also shows lower effect on ] (]), as well as the ].<ref name="pmid12784105" /><ref name="drugLabelPC" /> Aripiprazole acts by modulating neurotransmission overactivity of dopamine, which is thought to mitigate schizophrenia symptoms.<ref name="pmid19909227">{{cite journal | vauthors = Mailman RB, Murthy V | title = Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? | journal = Current Pharmaceutical Design | volume = 16 | issue = 5 | pages = 488–501 | date = May 2010 | pmid = 19909227 | pmc = 2958217 | doi = 10.2174/138161210790361461 }}</ref> |
|
Aripiprazole produces ] (DCPP) as a ] similarly to how ] and ] reduce to ] (''m''CPP) and ] converts to ] (pFPP).<ref name="pmid17691920">{{cite journal | author = Caccia S | title = N-dealkylation of arylpiperazine derivatives: disposition and metabolism of the 1-aryl-piperazines formed | journal = Current Drug Metabolism | volume = 8 | issue = 6 | pages = 612–22 | year = 2007 | month = August | pmid = 17691920 | doi = 10.2174/138920007781368908| url = http://www.bentham-direct.org/pages/content.php?CDM/2007/00000008/00000006/0005F.SGM}}</ref> It is unknown whether DCPP contributes to aripiprazole's pharmacology in any way, but the possibility cannot be excluded. |
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There are studies to date confirming aripiprazole as an antagonist at ] receptors such as ], ] and ], the orthostatic hypotension observed with aripiprazole may be explained by its ] activity at adrenergic ] receptors.<ref>{{cite web |title=Aristada Initio (Aripiprazole Lauroxil Injectable Suspension): Uses, Dosage, Side Effects, Interactions, Warning |url=https://www.rxlist.com/aristada-initio-drug.htm |access-date=22 November 2022 |website=RxList |archive-date=22 November 2022 |archive-url=https://web.archive.org/web/20221122054242/https://www.rxlist.com/aristada-initio-drug.htm |url-status=live }}</ref> |
|
== Pharmacokinetics == |
|
|
Aripiprazole displays linear kinetics and has an elimination half-life of approximately 75 hours. Steady-state plasma concentrations are achieved in about 14 days. C<sub>max</sub> (maximum plasma concentration) is achieved 3–5 hours after oral dosing. ] of the oral tablets is about 90% and the drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and N-dealkylation), principally by the enzymes ] and ]. Its only known active metabolite is dehydro-aripiprazole, which typically accumulates to approximately 40% of the aripiprazole concentration. The parenteral drug is excreted only in traces, and its metabolites, active or not, are excreted via feces and urine.<ref name="drugLabelPC">{{cite web |url=http://www.druglib.com/druginfo/abilify/pharmacology/ |title=Abilify (Aripiprazole) - Clinical Pharmacology |accessdate=8 December 2008 |publisher=DrugLib.com |date=14 February 2007 }}</ref> When dosed daily, brain concentrations of aripiprazole will increase for a period of 10–14 days, before reaching stable constant levels.{{Citation needed|date=July 2011}} |
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As a pharmacologically unique antipsychotic with pronounced ], characterization of this dopamine D<sub>2</sub> partial agonist (with an intrinsic activity of ~50%)<ref>{{cite journal | vauthors = Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB | title = Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 302 | issue = 1 | pages = 381–389 | date = July 2002 | pmid = 12065741 | doi = 10.1124/jpet.102.033175 | s2cid = 12919430 }}</ref> as being similar to a full agonist but at a reduced level of activity presents a misleading oversimplification of its actions; for example, among other effects, aripiprazole has been shown, ], to bind to and/or induce receptor conformations (i.e., facilitate receptor shapes) in such a way as to not only prevent receptor internalization (and, thus, lower receptor density) but even to lower the rate of receptor internalization below that of neurons not in the presence of agonists (including dopamine) or antagonists.<ref>{{cite journal | vauthors = Urban JD, Vargas GA, von Zastrow M, Mailman RB | title = Aripiprazole has functionally selective actions at dopamine D2 receptor-mediated signaling pathways | journal = Neuropsychopharmacology | volume = 32 | issue = 1 | pages = 67–77 | date = January 2007 | pmid = 16554739 | doi = 10.1038/sj.npp.1301071 | s2cid = 31846731 | doi-access = free | title-link = doi }}</ref> It is often the nature of partial agonists, including aripiprazole, to display a stabilizing effect (such as on mood in this case) with agonistic activity when there are low levels of endogenous neurotransmitters (such as dopamine) and antagonistic activity in the presence of high levels of agonists associated with events such as mania, psychosis, and drug use. In addition to aripiprazole's partial agonism and functional selectivity characteristics, its effectiveness may be mediated by its very high dopamine D<sub>2</sub> receptor occupancy (approximately 31%, 44%, 75%, 80%, and 95% at daily dosages of 0.5 mg, 2 mg, 10 mg, 30mg and 40 mg respectively)<ref>{{cite journal | vauthors = Yokoi F, Gründer G, Biziere K, Stephane M, Dogan AS, Dannals RF, Ravert H, Suri A, Bramer S, Wong DF | title = Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and raclopride | journal = Neuropsychopharmacology | volume = 27 | issue = 2 | pages = 248–259 | date = August 2002 | pmid = 12093598 | doi = 10.1016/S0893-133X(02)00304-4 | s2cid = 26101524 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Kegeles LS, Slifstein M, Frankle WG, Xu X, Hackett E, Bae SA, Gonzales R, Kim JH, Alvarez B, Gil R, Laruelle M, Abi-Dargham A | title = Dose-occupancy study of striatal and extrastriatal dopamine D2 receptors by aripiprazole in schizophrenia with PET and fallypride | journal = Neuropsychopharmacology | volume = 33 | issue = 13 | pages = 3111–3125 | date = December 2008 | pmid = 18418366 | doi = 10.1038/npp.2008.33 | s2cid = 33993650 | doi-access = free | title-link = doi }}</ref> Aripiprazole has been characterized as possessing predominantly partial agonist activity on postsynaptic D<sub>2</sub> receptors and partial agonist activity on presynaptic D<sub>2</sub> receptors;<ref name="pmid17501690" /> however, while this explanation intuitively explains the drug's efficacy as an antipsychotic, as the degree of agonism is a function of more than a drug's inherent properties as well as in vitro demonstration of aripiprazole's partial agonism in cells expressing postsynaptic (D<sub>2L</sub>) receptors, it was noted that "It is unlikely that the differential actions of aripiprazole as an agonist, antagonist, or partial agonist were entirely due to differences in relative D<sub>2</sub> receptor expression since aripiprazole was an antagonist in cells with the highest level of expression (4.6 pmol/mg) and a partial agonist in cells with an intermediate level of expression (0.5–1 pmol/mg). Instead, the current data are most parsimoniously explained by the "functional selectivity" hypothesis of Lawler et al. (1999)".<ref>{{cite journal | vauthors = Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, Roth BL, Mailman R | title = Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology | journal = Neuropsychopharmacology | volume = 28 | issue = 8 | pages = 1400–1411 | date = August 2003 | pmid = 12784105 | doi = 10.1038/sj.npp.1300203 | s2cid = 22568982 | doi-access = free | title-link = doi }}</ref> Aripiprazole is also a partial agonist of the ].<ref name="pmid12784105" /> In healthy human volunteers, D<sub>2</sub> and D<sub>3</sub> receptor occupancy levels are high, with average levels ranging between approximately 75% at 2 mg/day to approximately 95% at 40 mg/day.<ref name="kegeles" /><ref name="pmid12093598" /> Most atypical antipsychotics bind preferentially to ] receptors, but aripiprazole appears to be less preferential in this regard, as binding rates are high throughout the brain.<ref name="editorial1">{{cite journal | title = In This Issue | journal = Am J Psychiatry | volume = 165 | issue = 8 | pages = A46 | doi = 10.1176/appi.ajp.2008.165.8.A46 | date = August 2008 }}</ref> |
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== Patent status == |
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Otsuka's US patent on aripiprazole expires on October 20, 2014;<ref name="patent_5006528">{{Cite journal |
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| inventor1-last = Oshiro |
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| inventor1-first = Yasuo |
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| inventor2-last = Sato |
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| inventor2-first = Seiji |
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| inventor3-last = Kurahashi |
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| inventor3-first = Nobuyuki |
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| publication-date = October 20, 1989 |
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| date = April 9, 1991 |
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| country-code = US |
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| title = Carbostyril derivatives |
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| patent-number = 5006528 |
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| postscript = <!--None-->}}</ref> |
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however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.<ref name="orangeBook">{{cite web |url=http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021436&Product_No=001&table1=OB_Rx |title=Patent and Exclusivity Search Results |accessdate=8 December 2008 |work=Electronic Orange Book |publisher=US Food and Drug Administration}}</ref> ] (now ]) initiated a patent challenge under the ] in March 2007.<ref> |
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{{cite press release |
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| title = Barr Confirms Filing an Application with a Paragraph IV Certification for ABILIFY(R) Tablets |
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| publisher = Barr Pharmaceuticals, Inc. |
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| date = 2007-03-20 |
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| url = http://phx.corporate-ir.net/phoenix.zhtml?c=60908&p=irol-newsArticle&ID=975763&highlight= |
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| accessdate = 2008-12-23 |
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}}</ref> On November 15, 2010, this challenge was rejected by a ] in ]. |
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Aripiprazole is also a partial agonist of the postsynaptic ] ] (intrinsic activity = 68%).<ref name="pmid12784105" /><ref name="pmid12063084" /><ref name="pmid17728427" /> a PET scan study of 12 patients receiving doses ranging from 10 to 30 mg found ] occupancy to be only 16% compared to ~90% for D<sub>2</sub>.<ref name="pmid17728427" /> It is a very weak partial agonist of the Postsynaptic ] (] = 12.7%).<ref name="pmid12784105" /> The drug differs from other atypical antipsychotics in having higher ] for the D<sub>2</sub> receptor than for the 5-HT<sub>2A</sub> receptor.<ref name="pmid17728427" /> At the ], aripiprazole has both great binding affinity and acts as a potent ], "Aripiprazole decreased PI hydrolysis from a basal level of 61% down to a low of 30% at 1000 nM, with an EC<sub>50</sub> of 11 nM".<ref name="pmid12784105" /> Unlike other antipsychotics, aripiprazole is a high-efficacy partial agonist of the postsynaptic ] (intrinsic activity = 82%) this property may underlie the minimal weight gain seen in the course of therapy, however if used while taking antidepressants it will become a functional antagonist and increase weight gain.<ref name="pmid16336943">{{cite journal | vauthors = Zhang JY, Kowal DM, Nawoschik SP, Lou Z, Dunlop J | title = Distinct functional profiles of aripiprazole and olanzapine at RNA edited human 5-HT2C receptor isoforms | journal = Biochemical Pharmacology | volume = 71 | issue = 4 | pages = 521–529 | date = February 2006 | pmid = 16336943 | doi = 10.1016/j.bcp.2005.11.007 }}</ref> At the presynaptic ], aripiprazole is a very weak partial agonist with barely measurable intrinsic activity, and hence is a functional antagonist of this receptor.<ref name="pmid12784105" /><ref name="Davies_2004" /> Aripiprazole also shows lower but likely clinically insignificant affinity for a number of other sites such as the ], while it has negligible affinity for the ]s<ref name="pmid12784105" /><ref name="drugLabelPC" /> |
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== Dosage forms == |
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])]] |
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Since the actions of aripiprazole differ markedly across receptor systems aripiprazole was sometimes an antagonist (e.g., at 5-HT<sub>6</sub>), sometimes an inverse agonist (e.g., 5-HT<sub>2B</sub>), sometimes a partial agonist (e.g., ], ], ], D<sub>2L</sub>). Aripiprazole was frequently found to be a partial agonist or full agonist, with an intrinsic activity that could be low (5-HT<sub>2A</sub>, 5-HT<sub>7</sub>), intermediate (D<sub>2L,</sub> ]), or high (5-HT<sub>2C</sub>). This mixture of ] actions at ]-dopamine receptors is consistent with the hypothesis that aripiprazole has "functionally selective" actions.<ref>{{cite journal | vauthors = Lawler CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA, Gonzalez AM, Sibley DR, Mailman RB | title = Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes | journal = Neuropsychopharmacology | volume = 20 | issue = 6 | pages = 612–627 | date = June 1999 | pmid = 10327430 | doi = 10.1016/S0893-133X(98)00099-2 | doi-access = free | title-link = doi }}</ref> The "functional-selectivity" hypothesis proposes that a mixture of agonist/partial agonist/antagonist actions are likely. According to this hypothesis, agonists may induce structural changes in receptor conformations that are differentially "sensed" by the local complement of ]s to induce a variety of functional actions depending upon the precise cellular milieu. The diverse actions of aripiprazole at D<sub>2</sub>-dopamine receptors are clearly cell-type specific (e.g., agonism, antagonism, partial agonism), and are most parsimoniously explained by the "functional selectivity" hypothesis.<ref name="pmid12784105" /> |
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* Intramuscular injection, solution: 9.75 mg/mL (1.3 mL) |
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* Solution, oral: 1 mg/mL (150 mL) ], ] 400 mg/mL, and ] 200 mg/mL; orange cream flavor] |
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* Tablet: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg |
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* Tablet, orally disintegrating: 10 mg ] 1.12 mg; creme de vanilla flavor]; 15 mg |
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Since 5-HT<sub>2C</sub> receptors have been implicated in the control of ], obsessive–compulsive disorder (OCD), and appetite, postsynaptic partial agonism at the 5-HT<sub>2C</sub> receptor might be associated with therapeutic potential in obsessive-compulsive disorder, ], and depression. ] agonism has been demonstrated to induce ] via enhancement of ] neurotransmission via activation of postsynaptic ] receptors; it is conceivable that the 5-HT<sub>2C</sub> partial agonist actions of aripiprazole may, thus, be partly responsible for the minimal weight gain associated with this compound in clinical trials. In terms of potential action as an antiobsessional agent, it is worthwhile noting that a variety of 5-HT<sub>2A</sub>/5-HT<sub>2C</sub> agonists have shown promise as antiobsessional agents, yet many of these compounds are hallucinogenic. Aripiprazole has a favorable pharmacological profile in being a 5-HT<sub>2C</sub> partial agonist. Based on this profile, one can predict that aripiprazole may have antiobsessional and anorectic actions in humans.<ref name="pmid12784105" /> |
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== Synthesis == |
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] |
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Wood and Reavill's (2007) review of published and unpublished data proposed that, at therapeutically relevant doses, aripiprazole may act essentially as a selective partial agonist of the D<sub>2</sub> receptor without significantly affecting the majority of serotonin receptors.<ref name="pmid17501690" /> A ] imaging study found that 10 to 30 mg/day aripiprazole resulted in 85 to 95% occupancy of the D<sub>2</sub> receptor in various brain areas (], ], ]) versus 54 to 60% occupancy of the 5-HT<sub>2A</sub> receptor and only 16% occupancy of the ] receptor.<ref name="pmid26417330">{{cite journal | vauthors = Mauri MC, Paletta S, Maffini M, Colasanti A, Dragogna F, Di Pace C, Altamura AC | title = Clinical pharmacology of atypical antipsychotics: an update | journal = EXCLI Journal | volume = 13 | pages = 1163–1191 | year = 2014 | pmid = 26417330 | pmc = 4464358 }}</ref><ref name="pmid17728427">{{cite journal | vauthors = Mamo D, Graff A, Mizrahi R, Shammi CM, Romeyer F, Kapur S | title = Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study | journal = The American Journal of Psychiatry | volume = 164 | issue = 9 | pages = 1411–1417 | date = September 2007 | pmid = 17728427 | doi = 10.1176/appi.ajp.2007.06091479 }}</ref> It has been suggested that the low occupancy of the ] receptor by aripiprazole may have been an erroneous measurement however.<ref name="pmid17728411">{{cite journal | vauthors = Kessler RM | title = Aripiprazole: what is the role of dopamine D(2) receptor partial agonism? | journal = The American Journal of Psychiatry | volume = 164 | issue = 9 | pages = 1310–1312 | date = September 2007 | pmid = 17728411 | doi = 10.1176/appi.ajp.2007.07071043 | s2cid = 1891586 }}</ref> |
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{{US Patent|5,006,528}} |
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Aripiprazole acts by modulating neurotransmission overactivity on the dopaminergic ], which is thought to be a cause of positive schizophrenia symptoms.<ref name="pmid19909227" /> Due to its partial agonist activity on D<sub>2L</sub> receptors, aripiprazole may also increase dopaminergic activity to optimal levels in the ]s where it is reduced.<ref name="pmid19909227" /> |
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=== Pharmacokinetics === |
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Aripiprazole displays linear kinetics and has an elimination half-life of approximately 75 hours. Steady-state plasma concentrations are achieved in about 14 days. C<sub>max</sub> (maximum plasma concentration) is achieved 3–5 hours after oral dosing. ] of the oral tablets is about 90% and the drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and ''N''-dealkylation), principally by the enzymes ] and ]. Its only known active metabolite is dehydro-aripiprazole, which typically accumulates to approximately 40% of the aripiprazole concentration. The parenteral drug is excreted only in traces, and its metabolites, active or not, are excreted via feces and urine.<ref name="drugLabelPC">{{cite web |url=http://www.druglib.com/druginfo/abilify/pharmacology/ |title=Abilify (Aripiprazole) – Clinical Pharmacology |access-date=8 December 2008 |publisher=DrugLib.com |date=14 February 2007 |archive-date=22 May 2008 |archive-url=https://web.archive.org/web/20080522100535/http://www.druglib.com/druginfo/abilify/pharmacology/ |url-status=dead }}</ref><ref name="Abilify FDA label" /> |
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{{Pharmacokinetics of long-acting injectable antipsychotics}} |
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== Chemistry == |
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Aripiprazole belongs to the chemical class of drugs called ]s and is chemically related to ], ], ], and ].<ref>{{cite book | vauthors = Akritopoulou-Zanze I | veditors = Dinges J, Lamberth C | title = Bioactive heterocyclic compound classes pharmaceuticals | date = 2012 | publisher = Wiley-VCH | location = Weinheim | isbn = 978-3-527-66445-0 | chapter = 6. Arylpiperazine-Based 5-HT1A Receptor Partial Agonists and 5-HT2A Antagonists for the Treatment of Autism, Depression, Anxiety, Psychosis, and Schizophrenia }}</ref><ref>{{cite book | veditors = Dörwald FZ | title = Lead optimization for medicinal chemists: pharmacokinetic properties of functional groups and organic compounds | date = 2012 | publisher = Wiley-VCH | location = Weinheim | isbn = 978-3-527-64564-0 | chapter = 46. Arylalkylamines }}</ref> It is unusual in having twelve known crystalline ].<ref>{{cite journal |doi=10.1021/acs.cgd.9b01645 |title=Application of the Method of Molecular Voronoi–Dirichlet Polyhedra for Analysis of Noncovalent Interactions in Aripiprazole Polymorphs |year=2020 | vauthors = Serezhkin VN, Savchenkov AV |journal=Crystal Growth & Design |volume=20 |issue=3 |pages=1997–2003 |s2cid=213824513 }}</ref><ref name=Warren>{{cite journal | vauthors = Warren LR, McGowan E, Renton M, Morrison CA, Funnell NP | title = Direct evidence for distinct colour origins in ROY polymorphs | journal = Chemical Science | volume = 12 | issue = 38 | pages = 12711–12718 | date = October 2021 | pmid = 34703557 | pmc = 8494124 | doi = 10.1039/d1sc04051k }}</ref> |
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== History == |
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])|alt=]] |
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Aripiprazole was ] in 1988 by scientists at the Japanese firm ] and was called OPC-14597.<ref name="AdisInsight" /><ref name=NatDD>{{cite journal | vauthors = Grady MA, Gasperoni TL, Kirkpatrick P | title = Aripiprazole | journal = Nature Reviews. Drug Discovery | volume = 2 | issue = 6 | pages = 427–428 | date = June 2003 | pmid = 12790153 | doi = 10.1038/nrd1114 }}</ref><ref>{{cite book |vauthors=Behere PB, Das A, Behere AP |url=https://books.google.com/books?id=i9p1DwAAQBAJ&pg=PA66 |title=Clinical Psychopharmacology: An Update |date=2018 |publisher=Springer |isbn=9789811320927 |page=66 |access-date=19 September 2020 |archive-date=4 July 2024 |archive-url=https://web.archive.org/web/20240704193014/https://books.google.com/books?id=i9p1DwAAQBAJ&pg=PA66#v=onepage&q&f=false |url-status=live }}</ref><ref name="Update on the Mechanism of Action o">{{cite journal | vauthors = de Bartolomeis A, Tomasetti C, Iasevoli F | title = Update on the Mechanism of Action of Aripiprazole: Translational Insights into Antipsychotic Strategies Beyond Dopamine Receptor Antagonism | journal = CNS Drugs | volume = 29 | issue = 9 | pages = 773–799 | date = September 2015 | pmid = 26346901 | pmc = 4602118 | doi = 10.1007/s40263-015-0278-3 }}</ref><ref>{{cite web |title=Otsuka's Antipsychotic Abilify Is Approved in Japan, January 23, 2006｜News Releases |url=https://www.otsuka.co.jp/en/company/newsreleases/2006/20060125_1.html |access-date=6 October 2022 |website=Otsuka Pharmaceutical Co., Ltd. |archive-date=4 July 2024 |archive-url=https://web.archive.org/web/20240704193016/https://www.otsuka.co.jp/en/company/newsreleases/2006/20060125_1.html |url-status=live }}</ref><ref>{{cite journal | vauthors = Kikuchi T, Maeda K, Suzuki M, Hirose T, Futamura T, McQuade RD | title = Discovery research and development history of the dopamine D<sub>2</sub> receptor partial agonists, aripiprazole and brexpiprazole | journal = Neuropsychopharmacology Reports | volume = 41 | issue = 2 | pages = 134–143 | date = June 2021 | pmid = 33960741 | pmc = 8340839 | doi = 10.1002/npr2.12180 }}</ref> It was first published in 1995.<ref name=NatDD /><ref>{{cite journal | vauthors = Kikuchi T, Tottori K, Uwahodo Y, Hirose T, Miwa T, Oshiro Y, Morita S | title = 7-(4-butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 274 | issue = 1 | pages = 329–336 | date = July 1995 | pmid = 7616416 }}</ref> Otsuka initially ] the drug, and partnered with ] (BMS) in 1999 to complete development, obtain approvals, and market aripiprazole.<ref>{{cite news|title=B-MS reveals Ph III aripiprazole data – Pharmaceutical industry news|url=https://www.thepharmaletter.com/article/b-ms-reveals-ph-iii-aripiprazole-data|work=The Pharma Letter|date=17 May 2000|access-date=4 June 2017|archive-date=27 January 2019|archive-url=https://web.archive.org/web/20190127035438/https://www.thepharmaletter.com/article/b-ms-reveals-ph-iii-aripiprazole-data|url-status=live}}</ref> |
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It was approved by the US ] (FDA) for schizophrenia in November 2002, and by the ] in June 2004;<ref>{{cite web | title=Abilify Product information | website=Union Register of medicinal products | date=8 June 2004 | url=https://ec.europa.eu/health/documents/community-register/html/h276.htm | access-date=1 October 2023 | archive-date=1 October 2023 | archive-url=https://web.archive.org/web/20231001045647/https://ec.europa.eu/health/documents/community-register/html/h276.htm | url-status=live }}</ref> for acute ] and ] associated with bipolar disorder on 1 October 2004; as an adjunct for ] on 20 November 2007;<ref>{{cite web |url=http://www.webmd.com/depression/news/20071120/fda-oks-abilify-for-depression |title=FDA OKs Abilify for Depression |access-date=8 December 2008 | vauthors = Hitti M |publisher=WebMD |date=20 November 2007| archive-url= https://web.archive.org/web/20081205110249/http://www.webmd.com/depression/news/20071120/fda-oks-abilify-for-depression| archive-date= 5 December 2008 | url-status= live}}</ref> and to treat irritability in children with autism on 20 November 2009.<ref>{{cite web |url=https://www.reuters.com/article/idUSN2023065120091121/ |title=FDA OKs Abilify for child autism irritability |access-date=22 September 2010 |vauthors=Keating G |publisher=Reuters |date=23 November 2009 |archive-date=25 January 2010 |archive-url=https://web.archive.org/web/20100125033718/http://www.reuters.com/article/idUSN2023065120091121 |url-status=live }}</ref> Likewise it was approved for use as a treatment for schizophrenia by the ] (TGA) of Australia in May 2003.<ref name = Abilify>{{cite web|title=Product Information for Abilify Aripiprazole Tablets & Orally Disintegrating Tablets|website=TGA eBusiness Services|publisher=Bristol-Myers Squibb Australia Pty Ltd|date=1 November 2012|access-date=22 October 2013|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03820-3|archive-date=10 November 2017|archive-url=https://web.archive.org/web/20171110172138/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03820-3|url-status=live}}</ref> |
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Aripiprazole has been approved by the FDA for the treatment of both acute manic and mixed episodes, in people older than ten years.<ref name="orangeBook" /> |
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In 2006, the FDA required manufacturers to add a ] to the label, warning that older people who were given the drug for dementia-related psychosis were at greater risk of death.<ref name=Settle>{{cite news|vauthors=Mitchell M|title=Bristol-Myers Squibb Agrees to $19.5M Settlement Over Abilify Marketing|url=http://www.thelegalintelligencer.com/id=1202774278168/BristolMyers-Squibb-Agrees-to-195M-Settlement-Over-Abilify-Marketing?mcode=0&curindex=0&curpage=ALL|work=The Legal Intelligencer|date=8 December 2016|access-date=4 June 2017|archive-date=27 August 2021|archive-url=https://web.archive.org/web/20210827224129/https://www.law.com/thelegalintelligencer/almID/1202774278168/BristolMyers-Squibb-Agrees-to-195M-Settlement-Over-Abilify-Marketing/?mcode=0&curindex=0&curpage=ALL%2F&slreturn=20210727184129|url-status=live}}</ref> |
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In 2007, aripiprazole was approved by the FDA for the treatment of ] when used adjunctively with an antidepressant medication.<ref name="Abilify FDA label" /> That same year, BMS settled a case with the US government in which it paid $515 million; the case covered several drugs but the focus was on BMS's ] of aripiprazole for children and older people with dementia.<ref>{{cite news|vauthors=Staton T|title=Pharma's Top 11 Marketing Settlements: Bristol-Myers Squibb – Abilify|url=http://www.fiercepharma.com/special-report/bristol-myers-squibb-abilify|access-date=4 June 2017|work=FiercePharma|archive-date=8 June 2017|archive-url=https://web.archive.org/web/20170608185142/http://www.fiercepharma.com/special-report/bristol-myers-squibb-abilify|url-status=live}}</ref> |
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In 2011 Otsuka and ] signed a collaboration to develop a depot formulation of aripiprazole.<ref>{{cite web|title=Press Release: Lundbeck and Otsuka Pharmaceutical sign historic agreement to deliver innovative medicines targeting psychiatric disorders worldwide (OMX:LUN)|url=http://investor.lundbeck.com/releasedetail.cfm?releaseid=622993|publisher=Lundbeck|date=11 November 2011|access-date=4 June 2017|archive-url=https://web.archive.org/web/20120401191731/http://investor.lundbeck.com/releasedetail.cfm?ReleaseID=622993|archive-date=1 April 2012|url-status=dead}}</ref> |
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As of 2013, Abilify had annual sales of {{US$|7 billion}}.<ref>{{cite web|url=http://www.medscape.com/viewarticle/820011|title=Top 100 Selling Drugs of 2013|author=Megan Brooks|publisher=]|date=30 January 2014|access-date=15 October 2015|archive-date=31 October 2015|archive-url=https://web.archive.org/web/20151031000635/http://www.medscape.com/viewarticle/820011|url-status=live}}</ref> In 2013 BMS returned marketing rights to Otsuka, but kept manufacturing the drug.<ref>{{cite news|title=BMS cuts salesforce on revised Abilify deal|url=http://www.pmlive.com/pharma_news/bms_cuts_salesforce_on_revised_abilify_deal_447617|work=PM Live|date=7 November 2012|access-date=4 June 2017|archive-date=26 September 2020|archive-url=https://web.archive.org/web/20200926113245/http://www.pmlive.com/pharma_news/bms_cuts_salesforce_on_revised_abilify_deal_447617|url-status=live}}</ref> Also in 2013, Otsuka and Lundbeck received US and European marketing approval for an injectable depot formulation of aripiprazole.<ref>{{cite news |vauthors=Sagonowsky E |title=Lundbeck, Otsuka seek Abilify Maintena nod in bipolar disorder |url=http://www.fiercepharma.com/pharma/lundbeck-otsuka-seek-abilify-maintena-nod-bipolar-disorder |work=FiercePharma |date=1 December 2016 |access-date=4 June 2017 |archive-date=4 August 2020 |archive-url=https://web.archive.org/web/20200804104536/https://www.fiercepharma.com/pharma/lundbeck-otsuka-seek-abilify-maintena-nod-bipolar-disorder |url-status=live }}</ref><ref>{{cite web|title=Abilify Maintena 300mg & 400mg powder and solvent for prolonged-release suspension for injection and suspension for injection in pre filled syringe – Summary of Product Characteristics (SPC)|url=https://www.medicines.org.uk/emc/medicine/31386|publisher=UK Electronic Medicines Compendium|access-date=4 June 2017|archive-date=16 June 2017|archive-url=https://web.archive.org/web/20170616060538/http://www.medicines.org.uk/emc/medicine/31386|url-status=live}}</ref> |
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Otsuka's US patent on aripiprazole expired on 20 October 2014, but due to a pediatric extension, a generic did not become available until 20 April 2015.<ref name="orangeBook">{{cite web |url=http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021436&Product_No=001&table1=OB_Rx |title=Patent and Exclusivity Search Results |access-date=8 December 2008 |website=Electronic Orange Book |publisher=U.S. ] (FDA) |archive-date=4 May 2010 |archive-url=https://web.archive.org/web/20100504180450/http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021436&Product_No=001&table1=OB_Rx |url-status=live }}</ref> ] (now ]) initiated a patent challenge under the ] in March 2007.<ref>{{cite press release| title = Barr Confirms Filing an Application with a Paragraph IV Certification for Abilify Tablets| publisher = Barr Pharmaceuticals, Inc.| date = 20 March 2007| url = http://phx.corporate-ir.net/phoenix.zhtml?c=60908&p=irol-newsArticle&ID=975763&highlight=| access-date = 23 December 2008| archive-date = 16 September 2018| archive-url = https://web.archive.org/web/20180916031606/http://phx.corporate-ir.net/phoenix.zhtml?c=60908&p=irol-newsArticle&ID=975763&highlight=| url-status = live}}</ref> On 15 November 2010, this challenge was rejected by the ].<ref>{{cite news|url=https://www.bloomberg.com/news/2010-11-15/bristol-myers-partner-otsuka-wins-ruling-on-schizophrenia-treatment-patent.html|title=Bristol-Myers Partner Otsuka Wins Abilify Ruling – Bloomberg Business| vauthors = Decker S, Randall T |date=15 November 2010|work=]|access-date=13 May 2015 |archive-url=https://web.archive.org/web/20160722071603/http://www.bloomberg.com/news/articles/2010-11-15/bristol-myers-partner-otsuka-wins-ruling-on-schizophrenia-treatment-patent |archive-date=22 July 2016}}</ref> |
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Otsuka's European patent EP0367141 which would have expired on 26 October 2009, was extended by a ] (SPC) to 26 October 2014.,<ref name="EP0367141">{{cite patent | country = EP | number = 0367141 B1 | status = application | title = Carbostyril derivatives | pubdate = 1 October 1996 | fdate = 27 October 1989 | pridate = 13 October 1988 | inventor = Oshiro Y, Sato S, Kurahashi N | assign1 = Otsuka Pharmaceutical Co., Ltd. }}</ref> The UK Intellectual Property Office decided<ref>{{cite web | url = https://www.ipo.gov.uk/p-challenge-decision-results/p-challenge-decision-results-bl?BL_Number=O/098/15 | title = Patent decision | publisher = UK Intellectual Property Office | date = 19 September 2006 | access-date = 7 April 2015 | archive-date = 24 November 2020 | archive-url = https://web.archive.org/web/20201124090605/https://www.ipo.gov.uk/p-challenge-decision-results/p-challenge-decision-results-bl?BL_Number=O%2F098%2F15 | url-status = live }}</ref> on 4 March 2015 that the SPC could not be further extended by six months under Regulation (EC) No 1901/2006. Even if the decision is successfully appealed, protection in Europe will not extend beyond 26 April 2015. |
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From April 2013 to March 2014, sales of Abilify amounted to almost $6.9 billion.<ref name="thedailybeast.com">{{cite news | url = http://www.thedailybeast.com/articles/2014/11/09/mother-s-little-anti-psychotic-is-worth-6-9-billion-a-year.html | title = Mother's Little Anti-Psychotic Is Worth $6.9 Billion A Year | newspaper = The Daily Beast | date = 9 November 2014 | vauthors = Michaelson J | access-date = 10 November 2014 | archive-date = 18 March 2017 | archive-url = https://web.archive.org/web/20170318134047/http://www.thedailybeast.com/articles/2014/11/09/mother-s-little-anti-psychotic-is-worth-6-9-billion-a-year.html | url-status = live }}</ref> |
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In April 2015, the FDA announced the first generic versions.<ref>{{cite web|title=FDA approves first generic Abilify to treat mental illnesses|website=U.S. ]|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm444862.htm|access-date=28 April 2015|archive-date=1 May 2015|archive-url=https://web.archive.org/web/20150501034132/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm444862.htm|url-status=dead}}</ref><ref>{{cite web|url=https://www.tevapharm.com/news-and-media/latest-news/|title=Latest News | Teva Pharmaceuticals|website=www.tevapharm.com|date=20 May 2023|access-date=24 December 2022|archive-date=24 December 2022|archive-url=https://web.archive.org/web/20221224142618/https://www.tevapharm.com/news-and-media/latest-news/|url-status=live}}</ref> In October 2015, ], a ] of aripiprazole that is administered via intramuscular injection once every four to six weeks for the treatment of schizophrenia, was approved by the FDA.<ref name="pmid26573020">{{cite journal | vauthors = Citrome L | title = Aripiprazole long-acting injectable formulations for schizophrenia: aripiprazole monohydrate and aripiprazole lauroxil | journal = Expert Review of Clinical Pharmacology | volume = 9 | issue = 2 | pages = 169–186 | year = 2015 | pmid = 26573020 | doi = 10.1586/17512433.2016.1121809 | s2cid = 207208248 }}</ref><ref>{{cite web|title=Aristada (aripiprazole lauroxil) FDA Approval History|url=https://www.drugs.com/history/aristada.html|publisher=Drugs.com|access-date=11 May 2018|archive-date=11 May 2018|archive-url=https://web.archive.org/web/20180511214631/https://www.drugs.com/history/aristada.html|url-status=live}}</ref> |
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In 2016, BMS settled cases with 42 US states that had charged BMS with off-label marketing to older people with dementia; BMS agreed to pay $19.5 million.<ref name=Settle /><ref>{{cite news|vauthors=Staton T|title=Bristol-Myers to pay $19.5 million in Abilify off-label marketing settlement|url=http://www.fiercepharma.com/marketing/bristol-myers-to-pay-19-5-million-abilify-off-label-marketing-settlement|work=FiercePharma|date=14 December 2016|access-date=4 June 2017|archive-date=29 October 2020|archive-url=https://web.archive.org/web/20201029175542/https://www.fiercepharma.com/marketing/bristol-myers-to-pay-19-5-million-abilify-off-label-marketing-settlement|url-status=live}}</ref> |
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In November 2017, the FDA approved Abilify MyCite, a ] containing a sensor intended to record when its consumer takes their medication.<ref name=FDAdigital>{{cite press release|url=https://www.fda.gov/news-events/press-announcements/fda-approves-pill-sensor-digitally-tracks-if-patients-have-ingested-their-medication|title=FDA approves pill with sensor that digitally tracks if patients have ingested their medication|publisher=U.S. ] (FDA)|access-date=29 November 2017|archive-date=29 May 2019|archive-url=https://web.archive.org/web/20190529195555/https://www.fda.gov/news-events/press-announcements/fda-approves-pill-sensor-digitally-tracks-if-patients-have-ingested-their-medication|url-status=live}}</ref><ref>{{cite news|url=https://www.nytimes.com/2017/11/13/health/digital-pill-fda.html|title=First Digital Pill Approved to Worries About Biomedical 'Big Brother'|vauthors=Belluck P|date=13 November 2017|work=The New York Times|access-date=29 November 2017|issn=0362-4331|archive-date=28 November 2017|archive-url=https://web.archive.org/web/20171128051922/https://www.nytimes.com/2017/11/13/health/digital-pill-fda.html|url-status=live}}</ref> |
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A long-acting injectable version of aripiprazole was approved by the FDA for the treatment of ] and ] in April 2023.<ref>{{cite web | title=Abilify Asimtufii- aripiprazole injection, suspension, extended release | website=DailyMed | date=30 January 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=da4c07fd-1130-4341-bb44-63acfa4162be | access-date=27 December 2024}}</ref><ref>{{cite web | title=Drug Approval Package: Abilify Asimtufii | website=accessdata.fda.gov | date=16 February 2024 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/217006Orig1s000TOC.cfm | access-date=27 December 2024}}</ref><ref>{{Cite web |date=28 April 2023 |title=FDA Approves Aripiprazole as First Once-Every-2-Months Long-Acting Injectable for Schizophrenia, Bipolar I Disorder |url=https://www.pharmacytimes.com/view/fda-approves-aripiprazole-as-first-once-every-2-months-long-acting-injectable-for-schizophrenia-bipolar-i-disorder |access-date=16 April 2024 |website=Pharmacy Times |archive-date=30 May 2024 |archive-url=https://web.archive.org/web/20240530142558/https://www.pharmacytimes.com/view/fda-approves-aripiprazole-as-first-once-every-2-months-long-acting-injectable-for-schizophrenia-bipolar-i-disorder |url-status=live }}</ref> |
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In 2024, the European Commission approved the long-acting injectable formulation of aripiprazole for the maintenance treatment of schizophrenia.<ref>{{Cite web |date=28 March 2024 |title=Otsuka and Lundbeck's schizophrenia treatment gains EC approval |url=https://www.pharmaceutical-technology.com/news/otsuka-lundbeck-schizophrenia/ |access-date=16 April 2024 |website=Pharmaceutical Technology |archive-date=4 July 2024 |archive-url=https://web.archive.org/web/20240704193017/https://www.pharmaceutical-technology.com/news/otsuka-lundbeck-schizophrenia/ |url-status=live }}</ref> |
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== Society and culture == |
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=== Legal status === |
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{| class="wikitable" |
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! Regulatory administration (country)<ref>Joint Formulary Committee. British National Formulary (BNF) 79. Pharmaceutical Pr; 2020.</ref><ref>{{cite web | title = Australian Medicines Handbook 2013 | access-date = 20 September 2013 | url = http://www.psa.org.au/shop/amh | archive-date = 25 September 2013 | archive-url = https://web.archive.org/web/20130925022937/http://www.psa.org.au/shop/amh | url-status = live }}</ref><ref>Truven Health Analytics, Inc. DRUGDEX System (Internet) . Greenwood Village, CO: Thomsen Healthcare; 2013.</ref> !! Schizophrenia !! Acute mania !! Bipolar maintenance !! Major depressive disorder (as an adjunct) !! Irritability in autism |
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| ] (US)<ref name="Abilify FDA label" /> || Yes || Yes || Yes (as an adjunct to lithium/]) || Yes || Yes (children and adolescents) |
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| ] (AU) || Yes || Yes (as an adjunct to lithium/valproate) || Yes || No || No |
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| ] (UK) || Yes || Yes || Yes (to prevent mania) || No || No |
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| ] (EU)<ref name="Abilify EPAR" /> || Yes || No || Yes || No || No |
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=== Classification === |
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Aripiprazole has been described as the prototypical third-generation antipsychotic, as opposed to first-generation (typical) antipsychotics like ] and second-generation (atypical) antipsychotics like ].<ref name="pmid28368577">{{cite journal | vauthors = Casey AB, Canal CE | title = Classics in Chemical Neuroscience: Aripiprazole | journal = ACS Chemical Neuroscience | volume = 8 | issue = 6 | pages = 1135–1146 | date = June 2017 | pmid = 28368577 | pmc = 5495458 | doi = 10.1021/acschemneuro.7b00087 }}</ref> It has received this classification due to its partial agonism of dopamine receptors, and is the first of its kind in this regard among antipsychotics, which before aripiprazole acted only as dopamine receptor antagonists.<ref name="pmid28368577" /> The introduction of aripiprazole has led to a paradigm shift from a dopamine antagonist-based approach to a dopamine agonist-based approach for antipsychotic drug development.<ref name="pmid28368577" /><ref name="Update on the Mechanism of Action o"/> |
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=== Brand names === |
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Brand names of aripiprazole include Abilify, Aristada (as ]), Arip MT, Explemed, and Arivitae, among numerous others.<ref name="Drugs.com-International">{{cite web | title=Aripiprazole (International database) | website=Drugs.com | date=6 October 2024 | url=https://www.drugs.com/international/aripiprazole.html | access-date=22 October 2024}}</ref> |
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== Research == |
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=== Attention deficit hyperactivity disorder === |
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Aripiprazole was under development for the treatment of ] (ADHD), but development for this indication was discontinued.<ref name="AdisInsight" /> A 2017 meta review found only preliminary evidence (studies with small sample sizes and methodological problems) for aripiprazole in the treatment of ADHD.<ref name="pmid27993933">{{cite journal | vauthors = De Crescenzo F, Cortese S, Adamo N, Janiri L | title = Pharmacological and non-pharmacological treatment of adults with ADHD: a meta-review | journal = Evidence-Based Mental Health | volume = 20 | issue = 1 | pages = 4–11 | date = February 2017 | pmid = 27993933 | doi = 10.1136/eb-2016-102415 | s2cid = 24904076 | doi-access = free | title-link = doi | pmc = 10699262 }}</ref> A 2013 systematic review of aripiprazole for ADHD similarly reported that there is insufficient evidence of effectiveness to support aripiprazole as a treatment for the condition.<ref name="pmid24141455">{{cite journal | vauthors = Ghanizadeh A | title = Systematic review of clinical trials of aripiprazole for treating attention deficit hyperactivity disorder | journal = Neurosciences | volume = 18 | issue = 4 | pages = 323–329 | date = October 2013 | pmid = 24141455 }}</ref> Although all 6 ] ] in the review reported effectiveness, two small ]s found that aripiprazole did not significantly decrease ADHD symptoms.<ref name="pmid24141455" /> A high rate of adverse effects with aripiprazole such as ], ], and ] was noted.<ref name="pmid24141455" /> Most research on aripiprazole for ADHD is in children and adolescents.<ref name="pmid24141455" /><ref name="pmid27993933" /> Evidence on aripiprazole specifically for ] appears to be limited to a single ].<ref name="pmid26693882">{{cite journal | vauthors = Buoli M, Serati M, Cahn W | title = Alternative pharmacological strategies for adult ADHD treatment: a systematic review | journal = Expert Review of Neurotherapeutics | volume = 16 | issue = 2 | pages = 131–144 | date = 2016 | pmid = 26693882 | doi = 10.1586/14737175.2016.1135735 | s2cid = 33004517 }}</ref><ref name="pmid18208634">{{cite journal | vauthors = Kikukawa S | title = Effectiveness of aripiprazole in treatment of adults with attention deficit disorder and restless legs syndrome | journal = The International Journal of Neuropsychopharmacology | volume = 11 | issue = 3 | pages = 439–440 | date = May 2008 | pmid = 18208634 | doi = 10.1017/S1461145707008310 | doi-access = free | title-link = doi }}</ref> |
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=== Substance dependence === |
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Aripiprazole has been studied for the treatment of ] and other ]s, but more research is needed to support aripiprazole for these potential uses.<ref name="pmid22095579">{{cite journal | vauthors = Brackins T, Brahm NC, Kissack JC | title = Treatments for methamphetamine abuse: a literature review for the clinician | journal = Journal of Pharmacy Practice | volume = 24 | issue = 6 | pages = 541–550 | date = December 2011 | pmid = 22095579 | doi = 10.1177/0897190011426557 | s2cid = 37335642 }}</ref><ref name="pmid23104650">{{cite journal | vauthors = Brunetti M, Di Tizio L, Dezi S, Pozzi G, Grandinetti P, Martinotti G | title = Aripiprazole, alcohol and substance abuse: a review | journal = European Review for Medical and Pharmacological Sciences | volume = 16 | issue = 10 | pages = 1346–1354 | date = October 2012 | pmid = 23104650 }}</ref><ref name="pmid20565449">{{cite journal | vauthors = Karila L, Weinstein A, Aubin HJ, Benyamina A, Reynaud M, Batki SL | title = Pharmacological approaches to methamphetamine dependence: a focused review | journal = British Journal of Clinical Pharmacology | volume = 69 | issue = 6 | pages = 578–592 | date = June 2010 | pmid = 20565449 | pmc = 2883750 | doi = 10.1111/j.1365-2125.2010.03639.x }}</ref><ref name="pmid19042205">{{cite journal | vauthors = Elkashef A, Vocci F, Hanson G, White J, Wickes W, Tiihonen J | title = Pharmacotherapy of methamphetamine addiction: an update | journal = Substance Abuse | volume = 29 | issue = 3 | pages = 31–49 | date = 2008 | pmid = 19042205 | pmc = 2597382 | doi = 10.1080/08897070802218554 }}</ref> Available evidence of aripiprazole for amphetamine dependence is mixed.<ref name="pmid22095579" /><ref name="pmid23104650" /><ref name="pmid20565449" /><ref name="pmid19042205" /> Some studies have reported attenuation of the effects of amphetamines by aripiprazole, whereas other studies have reported both enhancement of the effects of amphetamines and increased use of amphetamines by aripiprazole.<ref name="pmid22095579" /><ref name="pmid23104650" /><ref name="pmid20565449" /><ref name="pmid19042205" /> As such, aripiprazole may not only be ineffective but potentially harmful for treatment of amphetamine dependence, and caution is warranted with regard to its use for such purposes.<ref name="pmid22095579" /><ref name="pmid23104650" /><ref name="pmid20565449" /><ref name="pmid19042205" /> |
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=== Other uses === |
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As of May 2021, aripiprazole is in ] ]s for the treatment of ] and ]s.<ref name="AdisInsight" /> |
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== References == |
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== References == |
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{{Reflist|2}} |
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{{Reflist}} |
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== Further reading == |
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{{refbegin}} |
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* {{cite book | title=Medical Genetics Summaries | chapter=Aripiprazole Therapy and CYP2D6 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK385288/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=] (NCBI) | year=2016 | pmid=28520375 | id=Bookshelf ID: NBK385288 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ | access-date=7 February 2020 | archive-date=26 October 2020 | archive-url=https://web.archive.org/web/20201026145821/https://www.ncbi.nlm.nih.gov/books/NBK61999/ | url-status=live }} |
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{{refend}} |
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== External links == |
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== External links == |
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{{Commons category}} |
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* {{cite web | title=Mechanism of Action of Aripiprazole | website=Psychopharmacology Institute | url=https://psychopharmacologyinstitute.com/publication/mechanism-of-action-of-aripiprazole-2119 }} |
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