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">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.
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 120mg daily and higher are required.
Pharmacology
Binding profile
Ziprasidone acts as an antagonist/inverse agonist (unless otherwise noted) of the following receptors and transporters:
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 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. 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%.
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.
Adverse effects
Ziprasidone received a black box warning due to increased mortality in elderly patients with dementia-related psychosis.
Sources for the following lists of adverse effects
Note: The percentages given are incidences of respective adverse effects.
Ziprasidone is known to cause activation into mania in some bipolar patients.
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 may not be as bad as some of the other atypical antipsychotics (namely, olanzapine (Zyprexa)) at causing insulin resistance and weight gain. 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 atypicalsâ€"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.
Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.
Synthesis
References
Further reading
- David Taylor (2006). Schizophrenia In Focus. Pharmaceutical Press. p. 123. ISBN 978-0-85369-607-0. Retrieved 13 May 2012.Â
External links
- Geodon manufacturer's website
- Geodon Package Insert