Ziprasidone

Ziprasidone
Systematic (IUPAC) name
5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-6-chloro-1,3-dihydro-2H-indol-2-one
Clinical data
Trade names Geodon, Zeldox, Zipwell
AHFS/Drugs.com monograph
MedlinePlus a699062
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration		 Oral (capsules), IM
Legal status
Legal status
Pharmacokinetic data
Bioavailability 60% (oral)
100% (IM)
Metabolism Hepatic (aldehyde reductase)
Biological half-life 7 hours
Excretion Urine and feces
Identifiers
CAS Number 146939-27-7 YesY
ATC code N05AE04 (WHO)
PubChem CID 60854
IUPHAR/BPS 59
DrugBank DB00246 YesY
ChemSpider 54841 YesY
UNII 6UKA5VEJ6X YesY
KEGG D08687 YesY
ChEBI CHEBI:10119 YesY
ChEMBL CHEMBL708 YesY
Chemical data
Formula C21H21ClN4OS
Molar mass 412.936 g/mol
  (verify)

Ziprasidone (marketed as Geodon, Zeldox by Pfizer and Zipwell by Actavis) was the fifth atypical antipsychotic to gain approval (February 2001) in the United States. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia, and acute mania and mixed states associated with bipolar disorder.[1] Its intramuscular injection form is approved for acute agitation in schizophrenic patients for whom treatment with just ziprasidone is appropriate. Ziprasidone is also used off-label for depression, bipolar maintenance, and PTSD.[2]

The oral form of ziprasidone is the hydrochloride salt, ziprasidone hydrochloride. The intramuscular form, on the other hand, is the mesylate salt, ziprasidone mesylate trihydrate, and is provided as a lyophilized powder.

Medical uses

Ziprazidone is approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia, and 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.[3]

Schizophrenia

Ziprasidone is effective in the treatment of schizophrenia, though evidence from the CATIE trials suggests it is less effective than olanzapine and of around equal effectiveness to quetiapine. Doses of around 120 mg daily and higher are usually required.[4]

Pharmacology

Binding profile

Ziprasidone acts as an antagonist/inverse agonist (unless otherwise noted) of the following receptors and transporters:[5][6][7][8][9]

Correspondence to clinical effects

Ziprasidone's affinities for most of the dopamine and serotonin receptors and the α1-adrenergic receptor are high and its affinity for the histamine H1 receptor is moderate.[5][14] It also displays some inhibition of synaptic reuptake of serotonin and norepinephrine, though not dopamine.[5][15]

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.[16] 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.[17] The relatively weak antagonistic actions of ziprasidone on the α1-adrenergic and H1 receptors likely in part explain some of its side effects, such as sedation and orthostatic hypotension. Unlike many other antipsychotics, ziprasidone has no significant affinity for the mACh receptors, and as such lacks any anticholinergic side effects.

Pharmacokinetics

The systemic bioavailability of ziprasidone is 100% when administered intramuscularly and 60% when administered orally with food. After a single dose intramuscular administration, the peak serum concentration typically occurs at about 60 minutes after the dose is administered, or earlier.[18] 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.

Ziprasidone absorption is optimally achieved when administered with food. Without a meal preceding dose, the bioavailability of the drug is reduced by approximately 50%.[19][20]

Ziprasidone is hepatically metabolized by aldehyde oxidase; minor metabolism occurs via cytochrome P450 3A4 (CYP3A4).[21] Medications that induce (e.g. carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.[22][23]

Adverse effects

Ziprasidone received a black box warning due to increased mortality in elderly patients with dementia-related psychosis.[19]

Sources for the following lists of adverse effects[24][25][26][27][28]

Note: The percentages given are incidences of respective adverse effects.

Very common adverse effects (>10%)
Common adverse effects (1-10%)
- Tremor
- Dystonia
- Akathisia
- Parkinsonism
- Muscle rigidity
Uncommon (0.1-1%) adverse effects
Rare (<0.1%) side effects


Ziprasidone is known to cause activation into mania in some bipolar patients.[30][31][32]

This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans.[19]

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 Zyprexa. Weight gain is also less of a concern with Ziprasidone compared to other atypical antipsychotics.[33][34][35][36] In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall;[19] 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, although this was believed to occur only rarely.[37]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[38]

References

  1. ↑ Drugs.com http://www.drugs.com/pro/geodon.html. Retrieved 4 June 2015. Missing or empty |title= (help)
  2. ↑ Poole, Jerod. "Geodon Approved Uses". CrazyMeds. Retrieved 19 June 2015.
  3. ↑ "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. Retrieved 2012-07-04.
  4. ↑ Greenberg, William M.; Citrome, Leslie (2007). "Ziprasidone for Schizophrenia and Bipolar Disorder: A Review of the Clinical Trials". CNS Drug Reviews 13 (2): 137–77. doi:10.1111/j.1527-3458.2007.00008.x.
  5. 1 2 3 Hagop S. Akiskal; Mauricio Tohen (24 June 2011). Bipolar Psychopharmacotherapy: Caring for the Patient. John Wiley & Sons. p. 209. ISBN 978-1-119-95664-8. Retrieved 13 May 2012.
  6. ↑ Seeger TF, Seymour PA, Schmidt AW, et al. (October 1995). "Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity". The Journal of Pharmacology and Experimental Therapeutics 275 (1): 101–13. PMID 7562537.
  7. ↑ Schotte A, Janssen PF, Gommeren W, et al. (March 1996). "Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding". Psychopharmacology 124 (1-2): 57–73. doi:10.1007/bf02245606. PMID 8935801.
  8. 1 2 "PDSP Database - UNC". Retrieved 2 February 2016.
  9. ↑ Brunton, Laurence (2011). Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th Edition. China: McGraw-Hill. pp. 406–410. ISBN 978-0-07-162442-8.
  10. ↑ Newman-Tancredi A, Gavaudan S, Conte C, et al. (August 1998). "Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study". European Journal of Pharmacology 355 (2-3): 245–56. doi:10.1016/S0014-2999(98)00483-X. PMID 9760039.
  11. ↑ Roland Seifert; Thomas Wieland; Raimund Mannhold; Hugo Kubinyi; Gerd Folkers (17 July 2006). G Protein-Coupled Receptors as Drug Targets: Analysis of Activation and Constitutive Activity. John Wiley & Sons. p. 227. ISBN 978-3-527-60695-5. Retrieved 13 May 2012.
  12. ↑ Wood MD, Scott C, Clarke K, et al. (August 2006). "Pharmacological profile of antipsychotics at monoamine receptors: atypicality beyond 5-HT2A receptor blockade". CNS & Neurological Disorders Drug Targets 5 (4): 445–52. doi:10.2174/187152706777950693. PMID 16918396.
  13. 1 2 Daniel DG, Zimbroff DL, Potkin SG, Reeves KR, Harrigan EP, Lakshminarayanan M (May 1999). "Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group". Neuropsychopharmacology 20 (5): 491–505. doi:10.1016/S0893-133X(98)00090-6. PMID 10192829.
  14. ↑ Nemeroff CB, Lieberman JA, Weiden PJ, et al. (November 2005). "From clinical research to clinical practice: a 4-year review of ziprasidone". CNS Spectrums 10 (11 Suppl 17): 1–20. PMID 16381088.
  15. ↑ Tatsumi M, Jansen K, Blakely RD, Richelson E (March 1999). "Pharmacological profile of neuroleptics at human monoamine transporters". European Journal of Pharmacology 368 (2-3): 277–83. doi:10.1016/S0014-2999(99)00005-9. PMID 10193665.
  16. ↑ Heinz Lüllmann; Klaus Mohr (2006). 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. Georg Thieme Verlag. ISBN 978-3-13-368516-0. Retrieved 13 May 2012.
  17. ↑ Alan F. Schatzberg; Charles B. Nemeroff (10 February 2006). Essentials of Clinical Psychopharmacology. American Psychiatric Pub. p. 297. ISBN 978-1-58562-243-6. Retrieved 13 May 2012.
  18. ↑ "Ziprasidone (Professional Patient Advice)". Drugs.com. Retrieved 2016-02-02.
  19. 1 2 3 4 "Geodon Prescribing Information" (PDF). Pfizer, Inc. Retrieved 2009-01-26.
  20. ↑ Miceli JJ, Glue P, Alderman J, Wilner K (2007). "The effect of food on the absorption of oral ziprasidone". Psychopharmacology Bulletin 40 (3): 58–68. PMID 18007569.
  21. ↑ Sandson NB, Armstrong SC, Cozza KL (2005). "An overview of psychotropic drug-drug interactions". Psychosomatics 46 (5): 464–94. doi:10.1176/appi.psy.46.5.464. PMID 16145193.
  22. ↑ Miceli JJ, Anziano RJ, Robarge L, Hansen RA, Laurent A (2000). "The effect of carbamazepine on the steady-state pharmacokinetics of ziprasidone in healthy volunteers". British Journal of Clinical Pharmacology. 49 Suppl 1: 65S–70S. doi:10.1046/j.1365-2125.2000.00157.x. PMC 2015057. PMID 10771457.
  23. ↑ Miceli JJ, Smith M, Robarge L, Morse T, Laurent A (2000). "The effects of ketoconazole on ziprasidone pharmacokinetics--a placebo-controlled crossover study in healthy volunteers". British Journal of Clinical Pharmacology. 49 Suppl 1: 71S–76S. doi:10.1046/j.1365-2125.2000.00156.x. PMC 2015056. PMID 10771458.
  24. ↑ PRODUCT INFORMATION ZELDOX® (ziprasidone hydrochloride) [Internet]. 2013 [cited 2013 Sep 29]. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05917-3
  25. ↑ PRODUCT INFORMATION ZELDOX IM® (ziprasidone mesilate) [Internet]. 2013 [cited 2013 Sep 29]. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06852-3
  26. ↑ Truven Health Analytics, Inc. DrugPoint® System (Internet) [cited 2013 Sep 29]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  27. ↑ ziprasidone (Rx) - Geodon [Internet]. Medscape Reference. [cited 2013 Sep 29]. Available from: http://reference.medscape.com/drug/geodon-ziprasidone-342985#4
  28. ↑ Joint Formulary Committee. British National Formulary (BNF) 65. Pharmaceutical Pr; 2013.
  29. 1 2 3 Leucht, S; Cipriani, A; Spineli, L; Mavridis, D; Örey, D; Richter, F; et al. (2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". The Lancet 382: 951–962. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019.
  30. ↑ Baldassano CF, Ballas C, Datto SM, et al. (February 2003). "Ziprasidone-associated mania: a case series and review of the mechanism". Bipolar Disorders 5 (1): 72–5. doi:10.1034/j.1399-5618.2003.02258.x. PMID 12656943.
  31. ↑ Keating AM, Aoun SL, Dean CE (2005). "Ziprasidone-associated mania: a review and report of 2 additional cases". Clinical Neuropharmacology 28 (2): 83–6. doi:10.1097/01.wnf.0000159952.64640.28. PMID 15795551.
  32. ↑ Davis R, Risch SC (April 2002). "Ziprasidone induction of hypomania in depression?". The American Journal of Psychiatry 159 (4): 673–4. doi:10.1176/appi.ajp.159.4.673. PMID 11925314.
  33. ↑ Tschoner A, Engl J, Rettenbacher M, et al. (January 2009). "Effects of six second generation antipsychotics on body weight and metabolism - risk assessment and results from a prospective study". Pharmacopsychiatry 42 (1): 29–34. doi:10.1055/s-0028-1100425. PMID 19153944.
  34. ↑ Guo JJ, Keck PE, Corey-Lisle PK, et al. (January 2007). "Risk of diabetes mellitus associated with atypical antipsychotic use among Medicaid patients with bipolar disorder: a nested case-control study". Pharmacotherapy 27 (1): 27–35. doi:10.1592/phco.27.1.27. PMID 17192159.
  35. ↑ Sacher J, Mossaheb N, Spindelegger C, et al. (June 2008). "Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers". Neuropsychopharmacology 33 (7): 1633–41. doi:10.1038/sj.npp.1301541. PMID 17712347.
  36. ↑ Newcomer JW (2005). "Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review". CNS Drugs. 19 Suppl 1: 1–93. doi:10.2165/00023210-200519001-00001. PMID 15998156.
  37. ↑ "FDA Drug Safety Communication: FDA reporting mental health drug ziprasidone (Geodon) associated with rare but potentially fatal skin reactions". FDA. 11 December 2014. Retrieved 12 December 2014.
  38. ↑ Group, BMJ, ed. (March 2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISSN 0260-535X. 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.

Further reading

External links

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