Ziprasidone

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Ziprasidone
Ziprasidone2D.svg
Ziprasidone3Dan.gif
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
Licence data US FDA:link
Pregnancy cat.
Legal status
Routes Oral, IM
Pharmacokinetic data
Bioavailability 60% (oral)
100% (IM)
Metabolism hepatic (aldehyde reductase)
Half-life 7 hours
Excretion Urine and feces
Identifiers
CAS number 146939-27-7 YesY
ATC code N05AE04
PubChem CID 60854
IUPHAR ligand 59
DrugBank DB00246
ChemSpider 54841 YesY
UNII 6UKA5VEJ6X YesY
KEGG D08687 YesY
ChEBI CHEBI:10119 YesY
ChEMBL CHEMBL708 YesY
Chemical data
Formula C21H21ClN4OS 
Mol. mass 412.936 g/mol
 YesY (what is this?)  (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. 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, mood disorders, anxiety, aggression, dementia, attention deficit hyperactivity disorder, obsessive compulsive disorder, autism, and post-traumatic stress disorder.

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[edit]

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.[1]

Schizophrenia[edit]

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 120mg daily and higher are required.[2]

Pharmacology[edit]

Binding profile[edit]

Ziprasidone acts as an antagonist/inverse agonist (unless otherwise noted) of the following receptors and transporters:[3][4][5][6][7]

Correspondence to clinical effects[edit]

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.[3][12] It also displays some inhibition of synaptic reuptake of serotonin and norepinephrine, though not dopamine.[3][13]

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.[14] 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.[15] 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[edit]

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. Steady state plasma concentrations are achieved within one to three days. The mean half-life ranges from two to five hours. 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%.[16][17]

Ziprasidone is hepatically metabolized by aldehyde oxidase; minor metabolism occurs via cytochrome P450 3A4 (CYP3A4).[18] Medications that induce (e.g. carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.[19][20]

Adverse effects[edit]

Ziprasidone received a black box warning due to increased mortality in elderly patients with dementia-related psychosis.[16]

Sources for the following lists of adverse effects[21][22][23][24][25]

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

Very common adverse effects (>10%)
  • Somnolence
  • Headache


Common adverse effects (1-10%)
  • Hypersalivation
  • Respiratory disorders
  • Nausea
  • Vomiting
  • Dry mouth
  • Constipation
  • Dyspepsia
  • Dizziness
  • Extrapyramidal symptoms (EPS) such as: (in a recent meta-analysis of 15 antipsychotic drugs it came 8th for extrapyramidal side effects[26])
- Tremor
- Dystonia
- Akathisia
- Parkinsonism
- Muscle rigidity
  • Rash
  • Tachycardia
  • Orthostatic hypotension
  • Diarrhea
  • Anorexia
  • Myalgia
  • Rhinitis
  • Cough
  • Anxiety
  • Abnormal vision
  • Spasmodic movement
  • Asthenia
  • Weight gain (usually less prominent than with other atypical antipsychotics, as is supported by a recent meta-analysis in which it produced the 2nd least weight gain, after haloperidol[26])


Uncommon (0.1-1%) adverse effects
  • Abnormal gait
  • Thirst
  • Palpitation
  • Hyperprolactinaemia (according to a recent meta-analysis of 15 atypical antipsychotics it produces less prolactin elevation than risperidone, paliperidone, haloperidol, sertindole and lurasidone[26])
  • Dysphagia
  • Flatulence
  • Gastritis
  • Tinnitus
  • Photophobia
  • Hepatic enzyme increased
  • Increased appetite
  • Heart rate increased
  • Rhinitis
  • Joint stiffness
  • Muscle cramps
  • Pain in extremity
  • Ataxia
  • Bradykinesia
  • Cogwheel rigidity
  • Disturbance in attention
  • Drooling
  • Dysarthria
  • Generalised tonic-clonic seizures
  • Hypokinesia
  • Hypersomnia
  • Hypoaesthesia
  • Lethargy
  • Oculogyric crisis
  • Paraesthesia
  • Tardive dyskinesia
  • Vertigo
  • Throat tightness
  • Nightmares
  • Dyspnoea
  • Sore throat
  • Dysuria
  • Urinary incontinence
  • Acne
  • Maculopapular rash
  • Rash
  • Urticaria


Rare (<0.1%) side effects
  • Drug Reaction with Eosinophilia and Systemic Symptoms
  • Chest pain
  • Feeling hot
  • Pyrexia
  • Sluggishness
  • Gastroesophageal reflux
  • Loose stools
  • Lymphopaenia
  • Ear pain
  • Positional vertigo
  • Amblyopia
  • Eye pruritus
  • Visual disturbance
  • Blood lactic dehydrogenase increased
  • Body temperature increased
  • QT interval prolongation
  • Eosinophilia
  • Hypocalcaemia
  • Liver function test abnormal
  • Increased pulse
  • Arthropathy
  • Musculoskeletal discomfort
  • Trismus
  • Akinesia
  • Paresis
  • Restless legs syndrome,
  • Torticollis
  • Anorgasmia
  • Bradyphrenia
  • Flat affect
  • Panic attack
  • Sleep walking
  • Hiccups
  • Erectile dysfunction
  • Galactorrhoea
  • Gynaecomastia
  • Priapism
  • Alopecia
  • Allergic dermatitis
  • Erythema
  • Psoriasis
  • Skin irritation
  • Swelling face
  • Papular rash
  • Neuroleptic malignant syndrome
  • Tardive dyskinesia


Ziprasidone is known to cause activation into mania in some bipolar patients.[27][28][29]

This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans.[16]

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 may not be as bad as some of the other atypical antipsychotics (namely, olanzapine (Zyprexa)) at causing insulin resistance and weight gain.[30][31][32][33] In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall; [16] According to the manufacturer insert, ziprasidone caused an average weight gain of 2.2 kg (4.8 lbs) (which is significantly lower than other atypicals–clozapine and olanzapine).

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.[34]

Discontinuation[edit]

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[35]

Synthesis[edit]

Ziprasidone synthesis: John A. Lowe, Arthur A. Nagel. Pfizer Inc. U.S. Patent 4,831,031 (1989).

References[edit]

  1. ^ "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. 
  2. ^ 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. 
  3. ^ a b c 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. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ a b PDSP certified data
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  20. ^ 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. 
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  22. ^ 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
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  32. ^ Sacher J, Mossaheb N, Spindelegger C, et al. (June 2008). "Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers". Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology 33 (7): 1633–41. doi:10.1038/sj.npp.1301541. PMID 17712347. 
  33. ^ 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. 
  34. ^ "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. 
  35. ^ 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[edit]

External links[edit]