|Systematic (IUPAC) name|
|Trade names||Geodon, Zeldox, Zipwell|
|Oral (capsules), IM|
|Metabolism||Hepatic (aldehyde reductase)|
|Biological half-life||7 hours|
|Excretion||Urine and feces|
|ATC code||N05AE04 (WHO)|
|Molar mass||412.936 g/mol|
Ziprasidone (marketed as Geodon, Zeldox by Pfizer and Zipwell by Actavis) was the fifth atypical antipsychotic to gain approval (February 5, 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. 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.
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.
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.
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. There are higher discontinuation rates for lower doses of Ziprasidone, which are also less effective than higher doses.
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), rashes, fast heart beats, blood pressure falling when standing up quickly, muscle pain, weakness, twitches, dizziness, and anxiety. 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.
This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans.
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) In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall; 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.
When the 5-HT2C-receptor is activated, a blockade of dopamine and serotonin occurs as well as the inhibition of norepinephrine release. Ziprasidone works by strongly blocking the 5-HT2C-receptor, increasing serotonin, norepinephrine and dopamine. The blocking of the 5-HT2C-receptor releases norepinephrine (norepinephrine increase implies increased blood sugar), but the neuronal reuptake of norepinephrine is limited heavily by Ziprasidone from another part of it's mechanism. Ziprasidone has no relationship to the 5-HT3-receptor (inactivated).
5-HT2A activation can upregulate D2 receptors. Ziprasidone blocks the 5-HT2A-receptor. The blockade of 5-HT2A-receptor also releases dopamine, just like a blockade of 5-HT2C. Ziprasidone is most potent at the 5-HT2A-receptor, next-most potent at 5-HT2C, and almost as much potent for the 5-HT1A-receptor. However, at the 5-HT1A-receptor a partial agonism occurs, providing a theory as to the correlation between Ziprasidone and lack of weight gain. The 5-HT6-receptor and 5-HT7-receptors may also be of some importance.
It has bovine binding affinity for the 5-HT1D-receptor. Ziprasidone has an unusually high affinity for 5-HT2A-receptor. The affinity for this 5HT-receptor is 11 times higher than the dopamine D2. The affinity for the 5-HT2C-receptor is 10 times higher than for the dopamine D2. Thus, a high affinity for the 5-HT2A-receptor will downregulate the D2-receptor. It blocks the dopamine D1 and the D3. Ziprasidone inhibits neuronal reuptake of norepinephrine and effects the H1D-receptor, which medications that do that stabilize mood in humans. Data from Pfizer suggest that 5-HT1A-receptor agonist function is unusually high with the drug Ziprasidone compared to other antipsychotics (agonism action at this 5HT-receptor improves cognition). At the same time even touch of the 5-HT6-receptor, why improved cognition is seen with Ziprasidone patients switched from other drugs. Ziprasidone's block of histamine H1-receptors can explain the somnolence seen with patients.  The affinity rate for these H1-receptors is up to moderate.
- 5-HT1A receptor (Ki = 12 nM) (partial agonist)
- 5-HT1B receptor (Ki = 4.0 nM) (partial agonist)
- 5-HT1D receptor (Ki = 2.3 nM)
- 5-HT2A receptor (Ki = 0.6 nM)
- 5-HT2C receptor (Ki = 13 nM)
- 5-HT6 receptor (Ki = 61 nM)
- 5-HT7 receptor (Ki = 6 nM)
- D1 receptor (Ki = 30 nM)
- D2 receptor (Ki = 6.8 nM)
- D3 receptor (Ki = 7.2 nM)
- α1A-adrenergic receptor (Ki = 18 nM)
- α2A-adrenergic receptor (Ki = 160 nM)
- H1 receptor (Ki = 63 nM)
- 5-HT transporter (Ki = 53 nM) (inhibitor)
- NE transporter (Ki = 48 nM) (inhibitor)
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. It also displays some inhibition of synaptic reuptake of serotonin and norepinephrine, though not dopamine.
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. 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. 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.
After a single dose intramuscular administration, the peak serum concentration typically occurs at about 60 minutes after the dose is administered, or earlier. 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 is hepatically metabolized by aldehyde oxidase; minor metabolism occurs via cytochrome P450 3A4 (CYP3A4). Medications that induce (e.g. carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.
It's biological half-life time is 6–7 hours and reaching the steady-state plasma levels within 1–3 days.
Society and culture
In September 2009, the U.S. Justice Department announced that Pfizer had been ordered to pay an historic fine of $2.3 billion as a penalty for fraudulent marketing of several drugs, including Geodon. Pfizer had illegally promoted Geodon and caused false claims to be submitted 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.
Ziprasidone was first synthesized on the Pfizer central research campus in Groton,Connecticut. Phase I trials started in 1995. In 1998 ziprasidone was approved in Sweden. After the FDA raised concerns about long QT syndrome,more clinical trials were conducted and submitted to the FDA, which approved the drug in 2001.
- "Geodon". Drugs.com. Retrieved June 4, 2015.
- Poole, Jerod. "Geodon Approved Uses". CrazyMeds. Retrieved June 19, 2015.
- "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.
- 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. PMID 19375893.
- 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.
- "Geodon Prescribing Information" (PDF). Pfizer, Inc. Retrieved 2009-01-26.
- "Product Information: Zeldox IM (ziprasidone mesilate)". Australia Therapeutic Goods Adminsitration. February 24, 2016.
- "Product Information: Zeldox (ziprasidone hydrochloride)". Australia Therapeutic Goods Adminsitration. February 24, 2016.
- FDA Psychopharmacological Drugs Advisory Committee (July 19, 2000). "Briefing Document for Zeldoz Capsules" (PDF). FDA.
- Leucht, S; 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- "FDA Drug Safety Communication: FDA reporting mental health drug ziprasidone (Geodon) associated with rare but potentially fatal skin reactions". FDA. December 11, 2014. Retrieved December 12, 2014.
- Läkemedelsverket. "Zeldox (ziprasidon) - Läkemedelsverket / Medical Products Agency". lakemedelsverket.se. Retrieved October 17, 2016.
- Kay, Jerald; First, Michael B.; Lieberman, Jeffrey A. (March 30, 2015). "Psychiatry, 2 Volume Set". John Wiley & Sons. Retrieved October 6, 2016 – via Google Books.
- Kay, Jerald; First, Michael B.; Lieberman, Jeffrey A. (March 30, 2015). "Psychiatry, 2 Volume Set". John Wiley & Sons. Retrieved October 6, 2016 – via Google Books.
- Meltzer, H. Y. (August 1, 1999). "The role of serotonin in antipsychotic drug action". Neuropsychopharmacology. 21 (2 Suppl): 106S–115S. doi:10.1016/S0893-133X(99)00046-9. Retrieved October 16, 2016 – via PubMed.
- M.D, Edited by Terence A. Ketter (April 9, 2015). "Advances in Treatment of Bipolar Disorders". American Psychiatric Pub. Retrieved October 6, 2016 – via Google Books.
- Yatham, Lakshmi N.; Kusumakar, Vivek (August 21, 2013). "Bipolar Disorder: A Clinician's Guide to Treatment Management". Routledge. Retrieved October 6, 2016 – via Google Books.
- Akiskal, Hagop S.; Tohen, Mauricio (March 23, 2011). "Bipolar Psychopharmacotherapy: Caring for the Patient". John Wiley & Sons. Retrieved October 6, 2016 – via Google Books.
- Tanyeri, Pelin; Buyukokuroglu, Mehmet Emin; Mutlu, Oguz; Ulak, Güner; Akar, Füruzan Yildiz; Celikyurt, Ipek Komsuoglu; Erden, Bekir Faruk (November 1, 2015). "Effects of ziprasidone, SCH23390 and SB277011 on spatial memory in the Morris water maze test in naive and MK-801 treated mice". Pharmacol. Biochem. Behav. 138: 142–147. doi:10.1016/j.pbb.2015.09.014. Retrieved October 16, 2016 – via PubMed.
- Meltzer, Herbert Y.; Sumiyoshi, Tomiki (December 16, 2008). "Does stimulation of 5-HT(1A) receptors improve cognition in schizophrenia?". Behav. Brain Res. 195 (1): 98–102. doi:10.1016/j.bbr.2008.05.016. PMID 18707769. Retrieved October 18, 2016 – via PubMed.
- Harvey, Philip D. (January 1, 2003). "Ziprasidone and cognition: the evolving story". J Clin Psychiatry. 64 Suppl 19: 33–39. PMID 14728088. Retrieved October 18, 2016 – via PubMed.
- Hagop S. Akiskal; Mauricio Tohen (June 24, 2011). Bipolar Psychopharmacotherapy: Caring for the Patient. John Wiley & Sons. p. 209. ISBN 978-1-119-95664-8. Retrieved May 13, 2012.
- 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.
- 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.
- "PDSP Database – UNC". Retrieved February 2, 2016.
- 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.
- 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.
- Roland Seifert; Thomas Wieland; Raimund Mannhold; Hugo Kubinyi; Gerd Folkers (July 17, 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 May 13, 2012.
- 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.
- 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.
- 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.
- 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 May 13, 2012.
- Alan F. Schatzberg; Charles B. Nemeroff (February 10, 2006). Essentials of Clinical Psychopharmacology. American Psychiatric Pub. p. 297. ISBN 978-1-58562-243-6. Retrieved May 13, 2012.
- Monti JM (March 2010). "Serotonin 5-HT(2A) receptor antagonists in the treatment of insomnia: present status and future prospects.". Drugs Today. doi:10.1358/dot.2010.46.3.1437247. PMID 20467592.
- Salmi P, Ahlenius S (April 2000). "Sedative effects of the dopamine D1 receptor agonist A 68930 on rat open-field behavior.". Neuroreport. PMID 10817605.
- "Ziprasidone (Professional Patient Advice)". Drugs.com. Retrieved 2016-02-02.
- 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.
- 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.
- 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 . PMID 10771457.
- 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 . PMID 10771458.
- "Justice Department Announces Largest Health Care Fraud Settlement in Its History". justice.gov. Retrieved October 6, 2016.
- "Approval Package For: Application Number 20-919" (PDF). FDA Center For Drug Evaluation And Research. May 26, 1998.
- "First Approval For Pfizer's Zeldoxs". The Pharma Letter. Retrieved October 15, 2016.
- Letter, The Pharma. "Pfizer's Zeldox approvable in USA – Pharmaceutical industry news". thepharmaletter.com. Retrieved October 15, 2016.
- "FDA Background On ZeldoxTM (ziprasidone hydrochloride capsules) Pfizer, Inc. PsychoPharmacological Drugs Advisory Committee" (PDF). FDA. July 19, 2000.
- Inc, Pfizer. "Pfizer to Launch Zeldox in 9 European Union Countries Beginning Next Month". prnewswire.com. Retrieved October 16, 2016.