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Ziprasidone, sold under the brand name Geodon among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder.
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Ziprasidone was approved for medical use in the United States in 2001.
Medical uses
thumb|250px|Ziprasidon Krka brand medicine.
Ziprasidone is approved by the US 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.
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. 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.
Adverse effects
Ziprasidone (and all other second generation antipsychotics (SGAs)) received a boxed warning in the US due to increased mortality in elderly people with dementia-related psychosis.
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.
Ziprasidone is known to trigger 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. In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall.
Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
|-
! Site !! K<sub>i</sub> (nM) !! Action !! Ref
|-
| || 112 || Blocker ||
|-
| 5-HT<sub>1B</sub> || 0.99–4.0 || Partial agonist ||
|-
| D<sub>2S</sub> || 4.2 || Antagonist ||
|-
| D<sub>5</sub> || 152 || ||
|- class="sortbottom"
| colspan="5" style="width: 1px;" | Values are K<sub>i</sub> (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except H<sub>3</sub> (guinea pig), σ<sub>1</sub> (guinea pig), opioid (rodent), / (rat), , and . and epinephrine/norepinephrine (α<sub>1</sub>) to a high degree, while of histamine (H<sub>1</sub>) - moderately. It also somewhat inhibits 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 D<sub>2</sub>. Blockade of the 5-HT<sub>2A</sub> 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-HT<sub>2A</sub> and 5-HT<sub>2C</sub> and activation of 5-HT<sub>1A</sub> as well as inhibition of the reuptake of serotonin and norepinephrine may all contribute to its ability to alleviate negative symptoms.; however, its effects on the 5-HT<sub>1A</sub> receptor may be limited as a study found ziprasidone would likely "produce detectable occupancy [of 5-HT<sub>1A</sub> 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 α<sub>1</sub>-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.
It has also been identified as a potent vesicular monoamine transporter 2 (VMAT2) inhibitor ( = 15nM).
Pharmacokinetics
The systemic bioavailability of ziprasidone is 100% when administered intramuscularly and 60% when administered orally without food. 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.
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.
Its biological half-life time is 10 hours at doses of 80–120 milligrams. of which it is a structural analogue.
It was first synthesized in 1987 at 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 on February 5, 2001.
Society and culture
Lawsuit
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.
Brand names
In the US, Geodon is marketed by Viatris after Upjohn was spun off from Pfizer.
Research
Ziprasidone has been studied in and reported to be effective in the treatment of borderline personality disorder, but findings are mixed.