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{{short description|Antipsychotic medication}}
{{Short description|Antipsychotic medication}}
{{Use mdy dates|date=October 2016}}
{{Use mdy dates|date=June 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Drugbox
{{Drugbox
| Watchedfields = changed
| Watchedfields = changed
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| legal_AU = S4
| legal_AU = S4
| legal_BR = C1
| 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_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=March 31, 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=August 3, 2023 |access-date=August 16, 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=April 4, 2023}}</ref>
| legal_US = Rx-only
| legal_US = Rx-only
| routes_of_administration = [[Oral administration|By mouth]], [[intramuscular injection]] (IM)
| routes_of_administration = [[Oral administration|By mouth]], [[intramuscular injection]] (IM)
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<!-- Adverse effects and mechanism -->
<!-- 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>
Common side effects include [[Tremor|tremors]], [[Fasciculation|tics]], [[dizziness]], [[dry mouth]], [[Akathisia|restlessness]], [[nausea]], and mild [[Somnolence|sedation]].<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=May 8, 2019 |language=en}}</ref>


<!-- Society and culture -->
<!-- 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>
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 = October 7, 2022}}</ref><ref>{{cite web | title = Ziprasidone - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Ziprasidone | access-date = October 7, 2022}}</ref>
{{TOC limit}}
{{TOC limit}}


==Medical uses==
==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>
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 = July 4, 2012 | 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. 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>
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==
==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>
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 = January 26, 2009 | 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>
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>
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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.
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]], 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>
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===
===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/>
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/>
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==
==Pharmacology==
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{{See also|Atypical antipsychotic#Pharmacodynamics|Antipsychotic#Comparison of medications}}
{{See also|Atypical antipsychotic#Pharmacodynamics|Antipsychotic#Comparison of medications}}
{| class="wikitable floatright" style="font-size:small;"
{| class="wikitable floatright" style="font-size:small;"
|+ Ziprasidone<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=ziprasidone&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}</ref>
|+ Ziprasidone<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 = August 14, 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<sub>i</sub> (nM) !! Action !! Ref
! Site !! K<sub>i</sub> (nM) !! Action !! Ref
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| [[Dopamine D1 receptor|D<sub>1</sub>]] || 30–130 || {{abbr|ND|No data}} || <ref name="PDSP" /><ref name="pmid11513838" />
| [[Dopamine D1 receptor|D<sub>1</sub>]] || 30–130 || {{abbr|ND|No data}} || <ref name="PDSP" /><ref name="pmid11513838" />
|-
|-
| [[Dopamine D2 receptor|D<sub>2</sub>]] || 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 = }}</ref><ref name="pmid11513838" /><ref name="pmid12629531" />
| [[Dopamine D2 receptor|D<sub>2</sub>]] || 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<sub>2L</sub>]] || 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<sub>2L</sub>]] || 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>
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The systemic [[bioavailability]] of ziprasidone is 100% when administered intramuscularly and 60% when administered orally without food.<ref name=2011rev/>
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.
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=February 2, 2016}}</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>
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>
Line 221: Line 222:
==History==
==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>
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=January 24, 2012| 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>
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>
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 = September 13, 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 = July 19, 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 = July 14, 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==
==Society and culture==


===Lawsuit===
===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.
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=September 2, 2009}}</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}}

=== Brand names ===
In the US, Geodon is marketed by [[Viatris]] after [[Upjohn]] was spun off from [[Pfizer]].<ref>{{cite web | title=Pfizer Completes Transaction to Combine Its Upjohn Business with Mylan | publisher=Pfizer | via=Business Wire | date=November 16, 2020 | url=https://www.businesswire.com/news/home/20201116005378/en/ | access-date=June 17, 2024}}</ref><ref>{{cite web | title=Geodon | website=Pfizer | url=https://www.pfizer.com/products/product-detail/geodon | access-date=June 17, 2024}}</ref><ref>{{cite web | title=Brands | website=Viatris | date=November 16, 2020 | url=https://www.viatris.com/en/products/brands | access-date=June 17, 2024}}</ref>
{{-}}
{{-}}


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[[Category:Benzoisothiazoles]]
[[Category:Benzoisothiazoles]]
[[Category:Dopamine antagonists]]
[[Category:Dopamine antagonists]]
[[Category:Hallucinogen antidotes]]
[[Category:Mood stabilizers]]
[[Category:Mood stabilizers]]
[[Category:Drugs developed by Pfizer]]
[[Category:Drugs developed by Pfizer]]

Latest revision as of 21:15, 21 November 2024

Ziprasidone
Clinical data
Trade namesGeodon, Zeldox, Zipwell, other
AHFS/Drugs.comMonograph
MedlinePlusa699062
License data
Pregnancy
category
  • AU: C
Routes of
administration		By mouth, intramuscular injection (IM)
Drug classAtypical antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60% (oral)[3]
100% (IM)
MetabolismLiver (aldehyde reductase)
Elimination half-life7 to 10 hours[4]
ExcretionUrine and feces
Identifiers
  • 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-6-chloro-1,3-dihydro-2H-indol-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.106.954 Edit this at Wikidata
Chemical and physical data
FormulaC21H21ClN4OS
Molar mass412.94 g·mol−1
3D model (JSmol)
  • O=C1Cc2c(N1)cc(Cl)c(c2)CCN3CCN(CC3)c4nsc5ccccc45
  • InChI=1S/C21H21ClN4OS/c22-17-13-18-15(12-20(27)23-18)11-14(17)5-6-25-7-9-26(10-8-25)21-16-3-1-2-4-19(16)28-24-21/h1-4,11,13H,5-10,12H2,(H,23,27) checkY
  • Key:MVWVFYHBGMAFLY-UHFFFAOYSA-N checkY
  (verify)
3D-animation of a ziprasidone molecule.
Ziprasidon Krka brand medicine.
Wikimedia Commons has media related to Ziprasidone.

Ziprasidone, sold under the brand name Geodon among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder.[5] It may be used by mouth and by injection into a muscle (IM).[5] The IM form may be used for acute agitation in people with schizophrenia.[5]

Common side effects include tremors, tics, dizziness, dry mouth, restlessness, nausea, and mild sedation.[6][7] Although it can also cause weight gain, the risk is much lower than for other atypical antipsychotics.[8] How it works is not entirely clear but is believed to involve effects on serotonin and dopamine in the brain.[5]

Ziprasidone was approved for medical use in the United States in 2001.[5] 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 million prescriptions.[9][10]

Medical uses

[edit]

Ziprasidone is approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia as well as acute mania and 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.[11]

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.[12] 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.[13]

Adverse effects

[edit]

Ziprasidone (and all other second generation antipsychotics (SGAs)) received a black box warning due to increased mortality in elderly patients with dementia-related psychosis.[14]

Sleepiness and headache are very common adverse effects (>10%).[6][7]

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[8]), rashes, fast heart beats, blood pressure falling when standing up quickly, muscle pain, weakness, twitches, dizziness, and anxiety.[6][7] 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.[15]

Ziprasidone is known to trigger mania in some bipolar patients.[16][17][18]

This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans.[14]

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.[19][20][21][22] In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall.[14] According to the manufacturer insert, ziprasidone caused an average weight gain of 2.2 kg (4.8 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.[23]

Discontinuation

[edit]

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[24] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[25] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[25] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[25] Symptoms generally resolve after a short period of time.[25]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[26] It may also result in reoccurrence of the condition that is being treated.[27] Rarely tardive dyskinesia can occur when the medication is stopped.[25]

Pharmacology

[edit]

Pharmacodynamics

[edit]
See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
Ziprasidone[28]
Site Ki (nM) Action Ref
SERTTooltip Serotonin transporter 112 Blocker [28]
NETTooltip Norepinephrine transporter 44 Blocker [28]
DATTooltip Dopamine transporter >10,000 ND [28]
5-HT1A 2.5–76 Partial agonist [29][30][31]
5-HT1B 0.99–4.0 Partial agonist [30][28]
5-HT1D 5.1–9.0 Partial agonist [30][28]
5-HT1E 360–1,279 ND [30][28]
5-HT2A 0.08–1.4 Antagonist [32][29][30]
5-HT2B 27.2 Antagonist [28]
5-HT2C 0.72–13 Antagonist [29]
5-HT3 >10,000 ND [28]
5-HT5A 291 ND [28]
5-HT6 61–76 Antagonist [31][29]
5-HT7 6.0–9.3 Antagonist [28][31][29]
α1A 18 Antagonist [28][31]
α1B 9.0 Antagonist [28]
α2A 160 Antagonist [28][30][31]
α2B 48 Antagonist [28][30][31]
α2C 59–77 Antagonist [28][30][31]
β1 ≥2,570 ND [30][28]
β2 >10,000 ND [30][28]
D1 30–130 ND [28][29]
D2 4.8 Antagonist [33][29][31]
D2L 4.6 Antagonist [30][34]
D2S 4.2 Antagonist [30]
D3 7.2 Antagonist [33][29][30]
D4 0.8–105 Antagonist [33][29][28]
D4.2 28–39 Antagonist [34]
D4.4 14.9 Antagonist [35]
D5 152 ND [28]
H1 15–130 Antagonist [30][29][28]
H2 3,500 ND [28]
H3 >10,000 ND [28]
H4 >10,000 ND [28]
M1 ≥300 ND [36][28][29]
M2 ≥3,000 ND [36][28]
M3 ≥1,300 ND [36][31][28]
M4 ≥1,600 ND [36][28]
M5 ≥1,600 ND [36][28]
σ1 110 ND [30]
σ2 ND ND ND
Opioid >1,000 ND [30]
nAChTooltip Nicotinic acetylcholine receptor >10,000 ND [28]
NMDA
(PCP)		 >10,000 ND [28]
VDCCTooltip Voltage-dependent calcium channel >10,000 ND [28][30]
VGSCTooltip Voltage-gated sodium channel 2,620 ND [30]
hERGTooltip Human Ether-à-go-go-Related Gene 169 Blocker [37]
Values are Ki (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), NMDA/PCP (rat), VDCC, and VGSC.[28]

Correspondence to clinical effects

[edit]

Ziprasidone mostly affects the receptors of dopamine (D2), serotonin (5-HT2A, partially 5-HT1A, 5-HT2C, and 5-HT1D)[3][38][39] and epinephrine/norepinephrine (α1) to a high degree, while of histamine (H1) - moderately.[40][41] It also somewhat inhibits reuptake of serotonin and norepinephrine, though not dopamine.[40][42]

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-HT2A 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.[43] Blockade of 5-HT2A and 5-HT2C and activation of 5-HT1A as well as inhibition of the reuptake of serotonin and norepinephrine may all contribute to its ability to alleviate negative symptoms.[44]; however, its effects on the 5-HT1A receptor may be limited as a study[45] found ziprasidone would likely "produce detectable occupancy [of 5-HT1A 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.[46][47]

Pharmacokinetics

[edit]

The systemic bioavailability of ziprasidone is 100% when administered intramuscularly and 60% when administered orally without food.[3]

After a single dose intramuscular administration, the peak serum concentration typically occurs at about 60 minutes after the dose is administered, or earlier.[48] 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.[14][49]

Ziprasidone is hepatically metabolized by aldehyde oxidase; minor metabolism occurs via cytochrome P450 3A4 (CYP3A4).[50] Medications that induce (e.g. carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.[51][52]

Its biological half-life time is 10 hours at doses of 80–120 milligrams.[4]

History

[edit]

Ziprasidone is chemically similar to risperidone,[53] of which it is a structural analogue.[54] It was first synthesized in 1987 at the Pfizer central research campus in Groton, Connecticut.[55]

Phase I trials started in 1995.[56] In 1998 ziprasidone was approved in Sweden.[57][58] 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.[56][59][60]

Society and culture

[edit]

Lawsuit

[edit]

In September 2009, the U.S. Justice Department announced that Pfizer had been ordered to pay a historic fine of $2.3 billion as a penalty for fraudulent marketing of several drugs, including Geodon.[61] 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.[citation needed]

Brand names

[edit]

In the US, Geodon is marketed by Viatris after Upjohn was spun off from Pfizer.[62][63][64]

References

[edit]
  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved October 22, 2023.
  2. ^ Anvisa (March 31, 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published April 4, 2023). Archived from the original on August 3, 2023. Retrieved August 16, 2023.
  3. ^ a b c Mattei C, Rapagnani MP, Stahl SM (February 2011). "Ziprasidone hydrocloride: what role in the management of schizophrenia?". Journal of Central Nervous System Disease. 3: JCNSD.S4138. doi:10.4137/JCNSD.S4138. PMC 3663608. PMID 23861634.
  4. ^ a b Nicolson SE, Nemeroff CB (December 2007). "Ziprasidone in the treatment of mania in bipolar disorder". Neuropsychiatric Disease and Treatment. 3 (6): 823–834. doi:10.2147/NDT.S794. PMC 2656324. PMID 19300617.
  5. ^ a b c d e "Ziprasidone Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved May 8, 2019.
  6. ^ a b c "Product Information: Zeldox IM (ziprasidone mesilate)". Australia Therapeutic Goods Administration. February 24, 2016.
  7. ^ a b c "Product Information: Zeldox (ziprasidone hydrochloride)". Australia Therapeutic Goods Administration. February 24, 2016.
  8. ^ a b FDA Psychopharmacological Drugs Advisory Committee (July 19, 2000). "Briefing Document for Zeldoz Capsules" (PDF). FDA.
  9. ^ "The Top 300 of 2020". ClinCalc. Retrieved October 7, 2022.
  10. ^ "Ziprasidone - Drug Usage Statistics". ClinCalc. Retrieved October 7, 2022.
  11. ^ "Pfizer to pay $2.3 billion to resolve criminal and civil health care liability relating to fraudulent marketing and the payment of kickbacks". Stop Medicare Fraud, US Dept of Health & Human Svc, and of US Dept of Justice. Archived from the original on August 30, 2012. Retrieved July 4, 2012.
  12. ^ Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet. 382 (9896): 951–962. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. S2CID 32085212.{{cite journal}}: CS1 maint: overridden setting (link)
  13. ^ Citrome L, Yang R, Glue P, Karayal ON (June 2009). "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". Schizophrenia Research. 111 (1–3): 39–45. doi:10.1016/j.schres.2009.03.009. PMID 19375893. S2CID 34910599.
  14. ^ a b c d "Geodon Prescribing Information" (PDF). Pfizer, Inc. Archived from the original (PDF) on October 17, 2005. Retrieved January 26, 2009.
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Further reading

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