Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Ziprasidone: Difference between pages

{{short description|Antipsychotic medication}}

{{cs1 config|name-list-style=vanc}}

{{Use mdy dates|date=October 2016}}

{{Drugbox

| Watchedfields = changed

| verifiedrevid = 470637441

| IUPAC_name = 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-6-chloro-1,3-dihydro-2''H''-indol-2-one

| width = 250

| image2 = Ziprasidone ball-and-stick model.png

| width2 = 250

| tradename = Geodon, Zeldox, Zipwell, other

| DailyMedID = Ziprasidone

| pregnancy_AU = C

| legal_AU = S4

| legal_BR = C1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |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=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_US = Rx-only

| routes_of_administration = [[Oral administration|By mouth]], [[intramuscular injection]] (IM)

| class = [[Atypical antipsychotic]]

| bioavailability = 60% (oral)<ref name=2011rev>{{cite journal | vauthors = Mattei C, Rapagnani MP, Stahl SM | title = Ziprasidone hydrocloride: what role in the management of schizophrenia? | journal = Journal of Central Nervous System Disease | volume = 3 | pages = 1–16 | date = February 2011 | pmid = 23861634 | pmc = 3663608 | doi = 10.4137/JCNSD.S4138 }}</ref>

<br />100% (IM)

| metabolism = Liver ([[aldehyde reductase]])

| elimination_half-life = 7 to 10 hours<ref name=2007rev>{{cite journal | vauthors = Nicolson SE, Nemeroff CB | title = Ziprasidone in the treatment of mania in bipolar disorder | journal = Neuropsychiatric Disease and Treatment | volume = 3 | issue = 6 | pages = 823–834 | date = December 2007 | pmid = 19300617 | pmc = 2656324 | doi = 10.2147/NDT.S794 | doi-access = free }}</ref>

| ChEBI_Ref = {{ebicite|correct|EBI}}

| C=21 | H=21 | Cl=1 | N=4 | O=1 | S=1

| SMILES = O=C1Cc2c(N1)cc(Cl)c(c2)CCN3CCN(CC3)c4nsc5ccccc45

[[Image:Ziprasidone3Dan.gif|thumb|250px|3D-animation of a ziprasidone molecule.]]

[[Image:GEODON60MG.png|thumb|250px|Ziprasidon Krka brand medicine.]]

{{commonscat}}

<!-- Medical uses -->

'''Ziprasidone''', sold under the brand name '''Geodon''' among others, is an [[atypical antipsychotic]] used to treat [[schizophrenia]] and [[bipolar disorder]].<ref name=AHFS2019/> It may be used [[oral administration|by mouth]] and by [[intramuscular|injection into a muscle]] (IM).<ref name=AHFS2019/> The IM form may be used for acute [[psychomotor agitation|agitation]] in people with schizophrenia.<ref name=AHFS2019/>

<!-- Adverse effects and mechanism -->

Common side effects include [[dizziness]], [[drowsiness]], [[dry mouth]], and [[Fasciculation|twitches]].<ref name=TGA-Zeldox-IM/><ref name=TGA-Zeldox/> Although it can also cause [[weight gain]], the risk is much lower than for other atypical antipsychotics.<ref name=PsychDrugsComm/> How it works is not entirely clear but is believed to involve effects on [[serotonin]] and [[dopamine]] in the [[brain]].<ref name=AHFS2019>{{cite web |title=Ziprasidone Monograph for Professionals |url=https://www.drugs.com/monograph/ziprasidone.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=8 May 2019 |language=en}}</ref>

<!-- Society and culture -->

Ziprasidone was approved for medical use in the United States in 2001.<ref name=AHFS2019/> The pills are made up of the hydrochloride salt, ziprasidone hydrochloride. The intramuscular form is the [[mesylate]], ziprasidone mesylate trihydrate, and is provided as a [[lyophilized]] powder. In 2020, it was the 282nd most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web | title = The Top 300 of 2020 | url = https://clincalc.com/DrugStats/Top300Drugs.aspx | website = ClinCalc | access-date = 7 October 2022}}</ref><ref>{{cite web | title = Ziprasidone - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Ziprasidone | access-date = 7 October 2022}}</ref>

{{TOC limit}}

==Medical uses==

Ziprasidone is approved by the U.S. [[Food and Drug Administration]] (FDA) for the treatment of [[schizophrenia]] as well as acute [[mania]] and [[agitated depression|mixed states]] associated with [[bipolar disorder]]. Its intramuscular injection form is approved for acute agitation in schizophrenic patients for whom treatment with just ziprasidone is appropriate.<ref name = "Off-label">{{cite web | url = http://www.stopmedicarefraud.gov/pfizerfactsheet.html | title = Pfizer to pay $2.3&nbsp;billion to resolve criminal and civil health care liability relating to fraudulent marketing and the payment of kickbacks | publisher = Stop Medicare Fraud, US Dept of Health & Human Svc, and of US Dept of Justice | access-date = 2012-07-04 | archive-date = August 30, 2012 | archive-url = https://web.archive.org/web/20120830023954/http://www.stopmedicarefraud.gov/pfizerfactsheet.html | url-status = dead }}</ref>

In a 2013 study in a comparison of 15 antipsychotic drugs in effectiveness in treating schizophrenic symptoms, ziprasidone demonstrated mild-standard effectiveness. Ziprasidone was 15% more effective than [[lurasidone]] and [[iloperidone]], approximately as effective as [[chlorpromazine]] and [[asenapine]], and 9–13% less effective than [[haloperidol]], [[quetiapine]], and [[aripiprazole]].<ref>{{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 | display-authors = 6 | title = Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis | journal = Lancet | volume = 382 | issue = 9896 | pages = 951–962 | date = September 2013 | pmid = 23810019 | doi = 10.1016/S0140-6736(13)60733-3 | s2cid = 32085212 }}</ref> Ziprasidone is effective in the treatment of schizophrenia, though evidence from the CATIE trials suggests it is less effective than [[olanzapine]], and equally as effective compared to [[quetiapine]]. There are higher discontinuation rates for lower doses of ziprasidone, which are also less effective than higher doses.<ref>{{cite journal | vauthors = Citrome L, Yang R, Glue P, Karayal ON | title = Effect of ziprasidone dose on all-cause discontinuation rates in acute schizophrenia and schizoaffective disorder: a post-hoc analysis of 4 fixed-dose randomized clinical trials | journal = Schizophrenia Research | volume = 111 | issue = 1–3 | pages = 39–45 | date = June 2009 | pmid = 19375893 | doi = 10.1016/j.schres.2009.03.009 | s2cid = 34910599 }}</ref>

==Adverse effects==

Ziprasidone (and all other second generation antipsychotics (SGAs)) received a [[black box warning]] due to increased mortality in elderly patients with [[dementia]]-related [[psychosis]].<ref name="package_insert">{{cite web | url = http://www.pfizer.com/pfizer/download/uspi_geodon.pdf | title = Geodon Prescribing Information | publisher = Pfizer, Inc. | access-date = 2009-01-26 | archive-date = October 17, 2005 | archive-url = https://web.archive.org/web/20051017034327/http://www.pfizer.com/pfizer/download/uspi_geodon.pdf | url-status = dead }}</ref>

Sleepiness and headache are very common adverse effects (>10%).<ref name=TGA-Zeldox-IM>{{cite web|title=Product Information: Zeldox IM (ziprasidone mesilate)|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06852-3|publisher=Australia Therapeutic Goods Administration|date=February 24, 2016}}</ref><ref name=TGA-Zeldox>{{cite web|title=Product Information: Zeldox (ziprasidone hydrochloride)|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05917-3&d=2016100716114622483|publisher=Australia Therapeutic Goods Administration|date=February 24, 2016}}</ref>

Common adverse effects (1–10%), include producing too much saliva or having dry mouth, runny nose, respiratory disorders or coughing, nausea and vomiting, stomach aches, constipation or diarrhea, loss of appetite, weight gain (but the smallest risk for weight gain compared to other antipsychotics<ref name=PsychDrugsComm>{{cite web|last1=FDA Psychopharmacological Drugs Advisory Committee|title=Briefing Document for Zeldoz Capsules|url=https://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1a.pdf|publisher=FDA|date=July 19, 2000}}</ref>), rashes, fast heart beats, blood pressure falling when standing up quickly, muscle pain, weakness, twitches, dizziness, and anxiety.<ref name=TGA-Zeldox-IM/><ref name=TGA-Zeldox/> [[Extrapyramidal symptoms]] are also common and include tremor, [[dystonia]] (sustained or repetitive muscle contractions), [[akathisia]] (the feeling of a need to be in motion), [[parkinsonism]], and muscle rigidity; in a 2013 meta-analysis of 15 antipsychotic drugs, ziprasidone ranked 8th for such side effects.<ref name = "Lancet">{{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 | display-authors = 6 | title = Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis | journal = Lancet | volume = 382 | issue = 9896 | pages = 951–962 | date = September 2013 | pmid = 23810019 | doi = 10.1016/s0140-6736(13)60733-3 | s2cid = 32085212 }}</ref>

Ziprasidone is known to trigger mania in some bipolar patients.<ref name="pmid12656943">{{cite journal | vauthors = Baldassano CF, Ballas C, Datto SM, Kim D, Littman L, O'Reardon J, Rynn MA | title = Ziprasidone-associated mania: a case series and review of the mechanism | journal = Bipolar Disorders | volume = 5 | issue = 1 | pages = 72–75 | date = February 2003 | pmid = 12656943 | doi = 10.1034/j.1399-5618.2003.02258.x }}</ref><ref name="pmid15795551">{{cite journal | vauthors = Keating AM, Aoun SL, Dean CE | title = Ziprasidone-associated mania: a review and report of 2 additional cases | journal = Clinical Neuropharmacology | volume = 28 | issue = 2 | pages = 83–86 | year = 2005 | pmid = 15795551 | doi = 10.1097/01.wnf.0000159952.64640.28 }}</ref><ref name="pmid11925314">{{cite journal | vauthors = Davis R, Risch SC | title = Ziprasidone induction of hypomania in depression? | journal = The American Journal of Psychiatry | volume = 159 | issue = 4 | pages = 673–674 | date = April 2002 | pmid = 11925314 | doi = 10.1176/appi.ajp.159.4.673 }}</ref>

This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans.<ref name="package_insert"/>

Recently, the FDA required the manufacturers of some atypical antipsychotics to include a warning about the risk of [[hyperglycemia]] and [[Type II diabetes]] with atypical antipsychotics. Some evidence suggests that ziprasidone does not cause [[insulin resistance]] to the degree of other atypical antipsychotics, such as [[olanzapine]]. Weight gain is also less of a concern with ziprasidone compared to other atypical antipsychotics.<ref name="pmid19153944">{{cite journal | vauthors = Tschoner A, Engl J, Rettenbacher M, Edlinger M, Kaser S, Tatarczyk T, Effenberger M, Patsch JR, Fleischhacker WW, Ebenbichler CF | display-authors = 6 | title = Effects of six second generation antipsychotics on body weight and metabolism - risk assessment and results from a prospective study | journal = Pharmacopsychiatry | volume = 42 | issue = 1 | pages = 29–34 | date = January 2009 | pmid = 19153944 | doi = 10.1055/s-0028-1100425 | s2cid = 43803033 }}</ref><ref name="pmid17192159">{{cite journal | vauthors = Guo JJ, Keck PE, Corey-Lisle PK, Li H, Jiang D, Jang R, L'Italien GJ | title = Risk of diabetes mellitus associated with atypical antipsychotic use among Medicaid patients with bipolar disorder: a nested case-control study | journal = Pharmacotherapy | volume = 27 | issue = 1 | pages = 27–35 | date = January 2007 | pmid = 17192159 | doi = 10.1592/phco.27.1.27 | s2cid = 22445126 | citeseerx = 10.1.1.453.7866 }}</ref><ref name="pmid17712347">{{cite journal | vauthors = Sacher J, Mossaheb N, Spindelegger C, Klein N, Geiss-Granadia T, Sauermann R, Lackner E, Joukhadar C, Müller M, Kasper S | display-authors = 6 | title = Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers | journal = Neuropsychopharmacology | volume = 33 | issue = 7 | pages = 1633–1641 | date = June 2008 | pmid = 17712347 | doi = 10.1038/sj.npp.1301541 | doi-access = free }}</ref><ref name="pmid15998156">{{cite journal | vauthors = Newcomer JW | title = Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review | journal = CNS Drugs | volume = 19 | issue = Suppl 1 | pages = 1–93 | year = 2005 | pmid = 15998156 | doi = 10.2165/00023210-200519001-00001 | s2cid = 36435377 }}</ref> In fact, in a trial of long term therapy with ziprasidone, overweight patients ([[Body mass index|BMI]] > 27) actually had a mean weight loss overall.<ref name="package_insert" /> According to the manufacturer insert, ziprasidone caused an average weight gain of 2.2&nbsp;kg (4.8&nbsp;lbs), which is significantly lower than other atypical antipsychotics, making this medication better for patients that are concerned about their weight.

In December 2014, the FDA warned that ziprasidone could cause a potentially fatal skin reaction, [[Drug Reaction with Eosinophilia and Systemic Symptoms]] (DRESS), although this was believed to occur only rarely.<ref>{{cite web | url=https://www.fda.gov/Drugs/DrugSafety/ucm426391.htm | title=FDA Drug Safety Communication: FDA reporting mental health drug ziprasidone (Geodon) associated with rare but potentially fatal skin reactions | website=FDA | date=December 11, 2014 | access-date=December 12, 2014}}</ref>

===Discontinuation===

The [[British National Formulary]] recommends a gradual withdrawal when [[discontinuing antipsychotics]] to avoid acute withdrawal syndrome or rapid relapse.<ref name="Group 2009 192">{{cite book |editor1-first=BMJ | 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, Dursun S, Deakin B |title=Adverse Syndromes and Psychiatric Drugs: A Clinical Guide |date=2004 |publisher=OUP Oxford |isbn=9780198527480 |pages=207–216 |url=https://books.google.com/books?id=CWR7DwAAQBAJ&pg=PA207 |language=en}}</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/>

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.<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 |language=en}}</ref> Rarely [[tardive dyskinesia]] can occur when the medication is stopped.<ref name=Had2004/>

==Pharmacology==

===Pharmacodynamics===

{{See also|Atypical antipsychotic#Pharmacodynamics|Antipsychotic#Comparison of medications}}

{| class="wikitable floatright" style="font-size:small;"

|+ Ziprasidone<ref name="PDSP">{{cite web | title = PDSP K_i 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=ziprasidone&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}</ref>

|-

! Site !! K_i (nM) !! Action !! Ref

|-

| {{abbrlink|SERT|Serotonin transporter}} || 112 || Blocker || <ref name="PDSP" />

|-

| {{abbrlink|NET|Norepinephrine transporter}} || 44 || Blocker || <ref name="PDSP" />

|-

| {{abbrlink|DAT|Dopamine transporter}} || >10,000 || {{abbr|ND|No data}} || <ref name="PDSP" />

|-

| [[5-HT1A receptor|5-HT_1A]] || 2.5–76 || Partial agonist || <ref name="pmid11513838">{{cite journal | vauthors = Schmidt AW, Lebel LA, Howard HR, Zorn SH | title = Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile | journal = European Journal of Pharmacology | volume = 425 | issue = 3 | pages = 197–201 | date = August 2001 | pmid = 11513838 | doi = 10.1016/s0014-2999(01)01188-8 }}</ref><ref name="pmid8935801">{{cite journal | vauthors = Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE | display-authors = 6 | title = Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding | journal = Psychopharmacology | volume = 124 | issue = 1–2 | pages = 57–73 | date = March 1996 | pmid = 8935801 | doi = 10.1007/bf02245606 | s2cid = 12028979 }}</ref><ref name="pmid12629531">{{cite journal | vauthors = Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL | display-authors = 6 | 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 | author9-link = Bryan Roth }}</ref>

|-

| [[5-HT1B receptor|5-HT_1B]] || 0.99–4.0 || Partial agonist || <ref name="pmid8935801" /><ref name="PDSP" />

|-

| [[5-HT1D receptor|5-HT_1D]] || 5.1–9.0 || Partial agonist || <ref name="pmid8935801" /><ref name="PDSP" />

|-

| [[5-HT1E receptor|5-HT_1E]] || 360–1,279 || {{abbr|ND|No data}} || <ref name="pmid8935801" /><ref name="PDSP" />

|-

| [[5-HT2A receptor|5-HT_2A]] || 0.08–1.4 || Antagonist || <ref name="pmid18160289">{{cite journal | vauthors = Graham JM, Coughenour LL, Barr BM, Rock DL, Nikam SS | title = 1-Aminoindanes as novel motif with potential atypical antipsychotic properties | journal = Bioorganic & Medicinal Chemistry Letters | volume = 18 | issue = 2 | pages = 489–493 | date = January 2008 | pmid = 18160289 | doi = 10.1016/j.bmcl.2007.11.106 }}</ref><ref name="pmid11513838" /><ref name="pmid8935801" />

|-

| [[5-HT2B receptor|5-HT_2B]] || 27.2 || Antagonist || <ref name="PDSP" />

|-

| [[5-HT2C receptor|5-HT_2C]] || 0.72–13 || Antagonist || <ref name="pmid11513838" />

|-

| [[5-HT3 receptor|5-HT₃]] || >10,000 || {{abbr|ND|No data}} || <ref name="PDSP" />

|-

| [[5-HT5A receptor|5-HT_5A]] || 291 || {{abbr|ND|No data}} || <ref name="PDSP" />

|-

| [[5-HT6 receptor|5-HT₆]] || 61–76 || Antagonist || <ref name="pmid12629531" /><ref name="pmid11513838" />

|-

| [[5-HT7 receptor|5-HT₇]] || 6.0–9.3 || Antagonist || <ref name="PDSP" /><ref name="pmid12629531" /><ref name="pmid11513838" />

|-

| [[Alpha-1A adrenergic receptor|α_1A]] || 18 || Antagonist || <ref name="PDSP" /><ref name="pmid12629531" />

|-

| [[Alpha-1B adrenergic receptor|α_1B]] || 9.0 || Antagonist || <ref name="PDSP" />

|-

| [[Alpha-2A adrenergic receptor|α_2A]] || 160 || Antagonist || <ref name="PDSP" /><ref name="pmid8935801" /><ref name="pmid12629531" />

|-

| [[Alpha-2B adrenergic receptor|α_2B]] || 48 || Antagonist || <ref name="PDSP" /><ref name="pmid8935801" /><ref name="pmid12629531" />

|-

| [[Alpha-2C adrenergic receptor|α_2C]] || 59–77 || Antagonist || <ref name="PDSP" /><ref name="pmid8935801" /><ref name="pmid12629531" />

|-

| [[Beta-1 adrenergic receptor|β₁]] || ≥2,570 || {{abbr|ND|No data}} || <ref name="pmid8935801" /><ref name="PDSP" />

|-

| [[Beta-2 adrenergic receptor|β₂]] || >10,000 || {{abbr|ND|No data}} || <ref name="pmid8935801" /><ref name="PDSP" />

|-

| [[Dopamine D1 receptor|D₁]] || 30–130 || {{abbr|ND|No data}} || <ref name="PDSP" /><ref name="pmid11513838" />

|-

| [[Dopamine D2 receptor|D₂]] || 4.8 || Antagonist || <ref name="pmid9577836">{{cite journal | vauthors = Seeman P, Tallerico T | title = Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors | journal = Molecular Psychiatry | volume = 3 | issue = 2 | pages = 123–134 | date = March 1998 | pmid = 9577836 | doi = 10.1038/sj.mp.4000336 | doi-access = | s2cid = 16484752 }}</ref><ref name="pmid11513838" /><ref name="pmid12629531" />

|-

| [[Dopamine D2 receptor|D_2L]] || 4.6 || Antagonist || <ref name="pmid8935801" /><ref name="pmid9430133">{{cite journal | vauthors = Arnt J, Skarsfeldt T | title = Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence | journal = Neuropsychopharmacology | volume = 18 | issue = 2 | pages = 63–101 | date = February 1998 | pmid = 9430133 | doi = 10.1016/S0893-133X(97)00112-7 | doi-access = free }}</ref>

|-

| [[Dopamine D2 receptor|D_2S]] || 4.2 || Antagonist || <ref name="pmid8935801" />

|-

| [[Dopamine D3 receptor|D₃]] || 7.2 || Antagonist || <ref name="pmid9577836" /><ref name="pmid11513838" /><ref name="pmid8935801" />

|-

| [[Dopamine D4 receptor|D₄]] || 0.8–105 || Antagonist || <ref name="pmid9577836" /><ref name="pmid11513838" /><ref name="PDSP" />

|-

| [[Dopamine D4 receptor|D_4.2]] || 28–39 || Antagonist || <ref name="pmid9430133" />

|-

| [[Dopamine D4 receptor|D_4.4]] || 14.9 || Antagonist || <ref name="pmid9223553">{{cite journal | vauthors = Newman-Tancredi A, Audinot V, Chaput C, Verrièle L, Millan MJ | title = [35S]Guanosine-5'-O-(3-thio)triphosphate binding as a measure of efficacy at human recombinant dopamine D4.4 receptors: actions of antiparkinsonian and antipsychotic agents | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 282 | issue = 1 | pages = 181–191 | date = July 1997 | pmid = 9223553 }}</ref>

|-

| [[Dopamine D5 receptor|D₅]] || 152 || {{abbr|ND|No data}} || <ref name="PDSP" />

|-

| [[Histamine H1 receptor|H₁]] || 15–130 || Antagonist || <ref name="pmid8935801" /><ref name="pmid11513838" /><ref name="PDSP" />

|-

| [[Histamine H2 receptor|H₂]] || 3,500 || {{abbr|ND|No data}} || <ref name="PDSP" />

|-

| [[Histamine H3 receptor|H₃]] || >10,000 || {{abbr|ND|No data}} || <ref name="PDSP" />

|-

| [[Histamine H4 receptor|H₄]] || >10,000 || {{abbr|ND|No data}} || <ref name="PDSP" />

|-

| [[Muscarinic acetylcholine receptor M1|M₁]] || ≥300 || {{abbr|ND|No data}} || <ref name="pmid14642972">{{cite journal | vauthors = Bymaster FP, Felder CC, Tzavara E, Nomikos GG, Calligaro DO, Mckinzie DL | title = Muscarinic mechanisms of antipsychotic atypicality | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 27 | issue = 7 | pages = 1125–1143 | date = October 2003 | pmid = 14642972 | doi = 10.1016/j.pnpbp.2003.09.008 | s2cid = 28536368 }}</ref><ref name="PDSP" /><ref name="pmid11513838" />

|-

| [[Muscarinic acetylcholine receptor M2|M₂]] || ≥3,000 || {{abbr|ND|No data}} || <ref name="pmid14642972" /><ref name="PDSP" />

|-

| [[Muscarinic acetylcholine receptor M3|M₃]] || ≥1,300 || {{abbr|ND|No data}} || <ref name="pmid14642972" /><ref name="pmid12629531" /><ref name="PDSP" />

|-

| [[Muscarinic acetylcholine receptor M4|M₄]] || ≥1,600 || {{abbr|ND|No data}} || <ref name="pmid14642972" /><ref name="PDSP" />

|-

| [[Muscarinic acetylcholine receptor M5|M₅]] || ≥1,600 || {{abbr|ND|No data}} || <ref name="pmid14642972" /><ref name="PDSP" />

|-

| [[Sigma-1 receptor|σ₁]] || 110 || {{abbr|ND|No data}} || <ref name="pmid8935801" />

|-

| [[Sigma-2 receptor|σ₂]] || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}}

|-

| [[Opioid receptor|Opioid]] || >1,000 || {{abbr|ND|No data}} || <ref name="pmid8935801" />

|-

| {{abbrlink|nACh|Nicotinic acetylcholine receptor}} || >10,000 || {{abbr|ND|No data}} || <ref name="PDSP" />

|-

| [[NMDA receptor|{{abbr|NMDA|N-Methyl-D-aspartate receptor}}<br />({{abbr|PCP|Phencyclidine site}})]] || >10,000 || {{abbr|ND|No data}} || <ref name="PDSP" />

|-

| {{abbrlink|VDCC|Voltage-dependent calcium channel}} || >10,000 || {{abbr|ND|No data}} || <ref name="PDSP" /><ref name="pmid8935801" />

|-

| {{abbrlink|VGSC|Voltage-gated sodium channel}} || 2,620 || {{abbr|ND|No data}} || <ref name="pmid8935801" />

|-

| {{abbrlink|hERG|Human Ether-à-go-go-Related Gene}} || 169 || Blocker || <ref name="pmid12176106">{{cite journal | vauthors = Kongsamut S, Kang J, Chen XL, Roehr J, Rampe D | title = A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs | journal = European Journal of Pharmacology | volume = 450 | issue = 1 | pages = 37–41 | date = August 2002 | pmid = 12176106 | doi = 10.1016/s0014-2999(02)02074-5 }}</ref>

|- class="sortbottom"

| colspan="5" style="width: 1px;" | Values are K_i (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except H₃ (guinea pig), σ₁ (guinea pig), opioid (rodent), {{abbr|NMDA|N-Methyl-D-aspartate receptor}}/{{abbr|PCP|Phencyclidine site}} (rat), {{abbr|VDCC|Voltage-dependent calcium channel}}, and {{abbr|VGSC|Voltage-gated calcium channel}}.<ref name="PDSP" />

|}

====Correspondence to clinical effects====

Ziprasidone mostly [[affinity (pharmacology)|affects]] the receptors of [[dopamine receptor|dopamine]] ([[Dopamine receptor D2|D₂]]), [[serotonin receptor|serotonin]] ([[5-HT2A receptor|5-HT_2A]], partially [[5-HT1A|5-HT_1A]], [[5-HT2C|5-HT_2C]], and [[5-HT1D|5-HT_1D]])<ref name=2011rev/><ref name="pmid7562537">{{cite journal | vauthors = Seeger TF, Seymour PA, Schmidt AW, Zorn SH, Schulz DW, Lebel LA, McLean S, Guanowsky V, Howard HR, Lowe JA | display-authors = 6 | title = Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 275 | issue = 1 | pages = 101–113 | date = October 1995 | pmid = 7562537 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7562537 }}</ref><ref name=Goodman>{{cite book| vauthors = Brunton L |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th Edition|year=2011|publisher=McGraw-Hill|location=China|isbn=978-0-07-162442-8|pages=406–410}}</ref> and [[alpha-1 adrenergic receptor|epinephrine/norepinephrine]] (α₁) to a high degree, while of [[H1 receptor|histamine (H₁)]] - moderately.<ref name="AkiskalTohen2011">{{cite book | vauthors = Akiskal HS, Tohen M | title = Bipolar Psychopharmacotherapy: Caring for the Patient | url = https://books.google.com/books?id=u0fO8RRIE1MC&pg=PT209 | access-date = May 13, 2012 | date = June 24, 2011 | publisher = John Wiley & Sons | isbn = 978-1-119-95664-8 | page = 209}}</ref><ref name="pmid16381088">{{cite journal | vauthors = Nemeroff CB, Lieberman JA, Weiden PJ, Harvey PD, Newcomer JW, Schatzberg AF, Kilts CD, Daniel DG | display-authors = 6 | title = From clinical research to clinical practice: a 4-year review of ziprasidone | journal = CNS Spectrums | volume = 10 | issue = 11 Suppl 17 | pages = 1–20 | date = November 2005 | pmid = 16381088 | doi = 10.1017/S1092852900019842 | s2cid = 26738197 }}</ref> It also somewhat [[Reuptake inhibitor|inhibits]] [[reuptake]] of [[selective serotonin reuptake inhibitor|serotonin]] and [[Serotonin–norepinephrine reuptake inhibitor|norepinephrine]], though not [[dopamine]].<ref name="AkiskalTohen2011" /><ref name="pmid10193665">{{cite journal | vauthors = Tatsumi M, Jansen K, Blakely RD, Richelson E | title = Pharmacological profile of neuroleptics at human monoamine transporters | journal = European Journal of Pharmacology | volume = 368 | issue = 2–3 | pages = 277–283 | date = March 1999 | pmid = 10193665 | doi = 10.1016/S0014-2999(99)00005-9 }}</ref>

Ziprasidone's efficacy in treating the positive symptoms of schizophrenia is believed to be mediated primarily via antagonism of the dopamine receptors, specifically D₂. Blockade of the 5-HT_2A receptor may also play a role in its effectiveness against positive symptoms, though the significance of this property in antipsychotic drugs is still debated among researchers.<ref name="LüllmannMohr2006">{{cite book | vauthors = Lüllmann H, Mohr K | title = Pharmakologie und Toxikologie: Arzneimittelwirkungen verstehen- Medikamente gezielt einsetzen; ein Lehrbuch für Studierende der Medizin, der Pharmazie und der Biowissenschaften, eine Informationsquelle für Ärzte, Apotheker und Gesundheitspolitiker | url = https://books.google.com/books?id=7ewS8QAClYEC&pg=PP1 | access-date = May 13, 2012 | year = 2006 | publisher = Georg Thieme Verlag | isbn = 978-3-13-368516-0 }}</ref> Blockade of 5-HT_2A and 5-HT_2C and activation of 5-HT_1A as well as inhibition of the reuptake of serotonin and norepinephrine may all contribute to its ability to alleviate negative symptoms.<ref name="SchatzbergNemeroff2006">{{cite book | vauthors = Schatzberg AF, Nemeroff CB | title = Essentials of Clinical Psychopharmacology | url = https://books.google.com/books?id=i5zrVD1PAwEC&pg=PA297 | access-date = May 13, 2012 | date = February 10, 2006 | publisher = American Psychiatric Pub | isbn = 978-1-58562-243-6 | page = 297}}</ref>; however, its effects on the 5-HT_1A receptor may be limited as a study<ref>{{cite journal | vauthors = Bantick RA, Rabiner EA, Hirani E, de Vries MH, Hume SP, Grasby PM | title = Occupancy of agonist drugs at the 5-HT1A receptor | journal = Neuropsychopharmacology | volume = 29 | issue = 5 | pages = 847–859 | date = May 2004 | pmid = 14985704 | doi = 10.1038/sj.npp.1300390 | s2cid = 11509050 | doi-access = free }}</ref> found ziprasidone would likely "produce detectable occupancy [of 5-HT_1A receptors] only at higher doses that would produce unacceptable levels of side effects in man, although lower doses are sufficient to produce pharmacological effects." The relatively weak antagonistic actions of ziprasidone on the α₁-adrenergic receptor likely in part explains some of its side effects, such as [[orthostatic hypotension]]. Unlike many other antipsychotics, ziprasidone has no significant affinity for the mACh receptors, and as such lacks any [[anticholinergic]] side effects. Like most other antipsychotics, ziprasidone is sedating due primarily to serotonin and dopamine blockade.<ref name="pmid20467592">{{cite journal | vauthors = Monti JM | title = Serotonin 5-HT(2A) receptor antagonists in the treatment of insomnia: present status and future prospects | journal = Drugs of Today | volume = 46 | issue = 3 | pages = 183–193 | date = March 2010 | pmid = 20467592 | doi = 10.1358/dot.2010.46.3.1437247 }}</ref><ref name="pmid10817605">{{cite journal | vauthors = Salmi P, Ahlenius S | title = Sedative effects of the dopamine D1 receptor agonist A 68930 on rat open-field behavior | journal = NeuroReport | volume = 11 | issue = 6 | pages = 1269–1272 | date = April 2000 | pmid = 10817605 | doi = 10.1097/00001756-200004270-00025 | s2cid = 35263421 }}</ref>

===Pharmacokinetics===

The systemic [[bioavailability]] of ziprasidone is 100% when administered intramuscularly and 60% when administered orally without food.<ref name=2011rev/>

After a single dose intramuscular administration, the peak serum concentration typically occurs at about 60 minutes after the dose is administered, or earlier.<ref>{{cite web|url=https://www.drugs.com/ppa/ziprasidone.html|title=Ziprasidone (Professional Patient Advice)|website=Drugs.com|access-date=2016-02-02}}</ref> Steady state plasma concentrations are achieved within one to three days. Exposure increases in a dose-related manner and following three days of intramuscular dosing, little accumulation is observed.

The bioavailability of the drug is reduced by approximately 50% if a meal is not eaten before Ziprasidone ingestion.<ref name="package_insert" /><ref name="pmid18007569">{{cite journal | vauthors = Miceli JJ, Glue P, Alderman J, Wilner K | title = The effect of food on the absorption of oral ziprasidone | journal = Psychopharmacology Bulletin | volume = 40 | issue = 3 | pages = 58–68 | year = 2007 | pmid = 18007569 }}</ref>

Ziprasidone is hepatically metabolized by [[aldehyde oxidase]]; minor metabolism occurs via [[CYP3A4|cytochrome P450 3A4]] (CYP3A4).<ref name=Sandson>{{cite journal | vauthors = Sandson NB, Armstrong SC, Cozza KL | title = An overview of psychotropic drug-drug interactions | journal = Psychosomatics | volume = 46 | issue = 5 | pages = 464–494 | year = 2005 | pmid = 16145193 | doi = 10.1176/appi.psy.46.5.464 | s2cid = 21838792 | doi-access = free }}</ref> Medications that induce (e.g. [[carbamazepine]]) or inhibit (e.g. [[ketoconazole]]) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.<ref name="pmid10771457">{{cite journal | vauthors = Miceli JJ, Anziano RJ, Robarge L, Hansen RA, Laurent A | title = The effect of carbamazepine on the steady-state pharmacokinetics of ziprasidone in healthy volunteers | journal = British Journal of Clinical Pharmacology | volume = 49 | issue = Suppl 1 | pages = 65S–70S | year = 2000 | pmid = 10771457 | pmc = 2015057 | doi = 10.1046/j.1365-2125.2000.00157.x }}</ref><ref name="pmid10771458">{{cite journal | vauthors = Miceli JJ, Smith M, Robarge L, Morse T, Laurent A | title = The effects of ketoconazole on ziprasidone pharmacokinetics--a placebo-controlled crossover study in healthy volunteers | journal = British Journal of Clinical Pharmacology | volume = 49 | issue = Suppl 1 | pages = 71S–76S | year = 2000 | pmid = 10771458 | pmc = 2015056 | doi = 10.1046/j.1365-2125.2000.00156.x }}</ref>

Its biological half-life time is 10 hours at doses of 80–120 milligrams.<ref name=2007rev/>

==History==

Ziprasidone is chemically similar to [[risperidone]],<ref>{{Cite book | url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA465 | title=Foye's Principles of Medicinal Chemistry| isbn=9781609133450| vauthors = Lemke TL, Williams DA | date=2012-01-24| publisher=Lippincott Williams & Wilkins}}</ref> of which it is a [[structural analogue]].<ref>{{cite journal | vauthors = Farah A | title = Atypicality of atypical antipsychotics | journal = Primary Care Companion to the Journal of Clinical Psychiatry | volume = 7 | issue = 6 | pages = 268–274 | year = 2005 | pmid = 16498489 | pmc = 1324958 | doi = 10.4088/pcc.v07n0602 }}</ref>

It was first synthesized in 1987 at the [[Pfizer]] central research campus in [[Groton, Connecticut]].<ref>{{cite book| vauthors = Newcomer JW, Fallucco EM | veditors = Schatzberg AF, Nemeroff CB |title=The American Psychiatric Publishing textbook of psychopharmacology|date=2009|publisher=American Psychiatric Pub.|location=Washington, D.C.|isbn=9781585623099|page=641|edition=4th|chapter-url=https://books.google.com/books?id=Xx7iNGdV25IC&pg=PA641|chapter=Ziprasidone}}</ref>

Phase I trials started in 1995.<ref name="fda.gov1">{{cite web|title=Approval Package For: Application Number 20-919|url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/20-919_geodon_biopharmr.pdf|publisher=FDA Center For Drug Evaluation And Research|date=May 26, 1998}}</ref> In 1998 ziprasidone was approved in Sweden.<ref>{{cite web|url=http://www.thepharmaletter.com/article/first-approval-for-pfizer-s-zeldox|title=First Approval For Pfizer's Zeldoxs|website=The Pharma Letter|access-date=October 15, 2016}}</ref><ref>{{cite web|url=http://www.thepharmaletter.com/article/pfizer-s-zeldox-approvable-in-usa|title=Pfizer's Zeldox approvable in USA – Pharmaceutical industry news | date = 13 September 2000 |work = The Pharma Letter |access-date=October 15, 2016}}</ref> After the FDA raised concerns about [[long QT syndrome]], more clinical trials were conducted and submitted to the FDA, which approved the drug on February 5, 2001.<ref name="fda.gov1"/><ref>{{cite web|title=FDA Background On ZeldoxTM (ziprasidone hydrochloride capsules) Pfizer, Inc. | author = PsychoPharmacological Drugs Advisory Committee | work = Center for Drug Evaluation and Research (CDER) | publisher = U.S. Food and Drug Administration | date = 19 July 2000 |url=https://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1b.pdf | archive-url = https://web.archive.org/web/20070714081841/https://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1b.pdf | archive-date = 14 July 2007 }}</ref><ref>{{cite web|url=http://www.prnewswire.com/news-releases/pfizer-to-launch-zeldox-in-9-european-union-countries-beginning-next-month-76154202.html|title=Pfizer to Launch Zeldox in 9 European Union Countries Beginning Next Month|work = Pfizer Inc| via = prnewswire.com|access-date=October 16, 2016}}</ref>

==Society and culture==

===Lawsuit===

In September 2009, the [[United States Department of Justice|U.S. Justice Department]] announced that Pfizer had been ordered to pay a historic fine of $2.3&nbsp;billion as a penalty for fraudulent marketing of several drugs, including Geodon.<ref>{{cite web|url=https://www.justice.gov/opa/pr/justice-department-announces-largest-health-care-fraud-settlement-its-history|title=Justice Department Announces Largest Health Care Fraud Settlement in Its History|website=justice.gov|access-date=October 6, 2016|date=2009-09-02}}</ref> Pfizer had illegally promoted Geodon and submitted false claims to government health care programs for uses that were not medically accepted indications. The civil settlement also resolves allegations that Pfizer paid kickbacks to health care providers to induce them to prescribe Geodon, as well as other drugs. This was the largest civil fraud settlement in history against a pharmaceutical company.{{cn|date=March 2024}}

{{-}}

== References ==

{{Reflist}}

== Further reading ==

* {{cite book | vauthors = Taylor D | title = Schizophrenia in Focus | url = https://books.google.com/books?id=CyEUUKDScOIC&pg=PA123 | access-date = May 13, 2012 | year = 2006 | publisher = Pharmaceutical Press | isbn = 978-0-85369-607-0 | page = 123}}

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