Ziprasidone

Ziprasidone (marketed as Geodon, Zeldox by Pfizer) was the fifth atypical antipsychotic to gain FDA approval (February 2001). In the United States, Ziprasidone is Food and Drug Administration (FDA) approved for the treatment of schizophrenia, and the intramuscular injection form of ziprasidone is approved for acute agitation in schizophrenic patients. Ziprasidone has also received approval for acute treatment of mania and mixed states associated with bipolar disorder. The brand name Geodon has been suggested to bring to mind the phrase 'down (don) to earth (geo)' referring to the goals of the medication.

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.

Geodon was one of four drugs which Pfizer in 2009 pleaded guilty to misbranding "with the intent to defraud or mislead". Pfizer agreed to pay $2.3 billion (£1.4 billion) in settlement, and entered a corporate integrity agreement. Pfizer was found to have illegally promoted four of its drugs for use in conditions that had not been approved by the FDA.

Pharmacology
Ziprasidone possesses affinity for and acts at the following receptors and transporters: Ziprasidone has a high affinity for dopamine, serotonin, and alpha-adrenergic receptors and a moderate affinity for histamine receptors, where it is believed to act as an antagonist. Ziprasidone also displays some inhibition of synaptic reuptake of serotonin and norepinephrine, although the clinical significance of this is unknown. The mechanism of action of ziprasidone is unknown. However it has been theorized that its antipsychotic activity is mediated primarily by antagonism at dopamine receptors, specifically D2. Serotonin antagonism may also play a role in the effectiveness of ziprasidone, but the significance of 5-HT2A antagonism is debated among researchers. Ziprasidone has perhaps the most selective affinity for 5-HT2A receptors relative to D2 and 5-HT2C receptors of any neuroleptic. Antagonism at histaminic and alpha adrenergic receptors likely explains some of the side effects of ziprasidone, such as sedation and orthostasis.
 * D2 Antagonist (Ki = 4.8 nM)
 * D3 Antagonist (Ki = 7.2 nM)
 * 5-HT1A Agonist (Ki = 3.4 nM)
 * 5-HT1D Antagonist (Ki = 2.3 nM)
 * 5-HT2A Antagonist/Inverse Agonist (Ki = 0.4 nM)
 * 5-HT2C (Ki = 1.3 nM)
 * NET
 * SERT
 * H1 Antagonist (Ki = 47 nM)
 * α1-adrenergic Antagonist (Ki = 10 nM)
 * mACh (IC50 >1000 nM) [negligible affinity]

Pharmacokinetics
The systemic bioavailability of ziprasidone administered intramuscularly is 100%, or 60%, 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. It also slightly increases the QTc interval in some patients and increases the risk of a potentially lethal type of heart arrhythmia known as torsades de pointes. Ziprasidone should be used cautiously in patients taking other medications likely to interact with ziprasidone or increase the QTc interval.

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.

Adverse events reported for ziprasidone include severe chest pains, impaired erectile function and stimulation, sedation, insomnia, orthostasis, life-threatening neuroleptic malignant syndrome, akathisia, and the development of permanent neurological disorder tardive dyskinesia. Rarely, temporary speech disorders may result.

Recently, the FDA required the manufacturers of some atypical antipsychotics 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. Ziprasidone, though, is not a weight loss drug. The weight loss reflected in this study on ziprasidone was really reflective of patients who had gained weight on other antipsychotics who were now trending back toward their baseline. 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).

Discontinuation
Ziprasidone should be discontinued gradually, with careful consideration from the prescribing doctor, to avoid withdrawal symptoms or relapse. Withdrawal may become even more difficult after failed attempts.

The British National Formulary recommends a gradual withdrawal when discontinuing anti-psychotic treatment to avoid acute withdrawal syndrome or rapid relapse. Due to compensatory changes at dopamine, serotonin, adrenergic and histamine receptor sites in the central nervous system, withdrawal symptoms can occur during abrupt or over-rapid reduction in dosage. Withdrawal symptoms reported to occur after discontinuation of antipsychotics include nausea, emesis, lightheadedness, diaphoresis, dyskinesia, orthostasis, tachycardia, nervousness, dizziness, headache, excessive non-stop crying, and anxiety. The present evidence suggests that these symptoms affect a small number of susceptible individuals treated with antipsychotics. Complicated and long-lasting rebound insomnia symptoms can also occur after withdrawing from antipsychotics.

Overdose
Ziprasidone doses as large as 3,240 mg have been "survived without sequelae." The most common effects reported by Pfizer include extrapyramidal reactions, somnolence, tremor, and anxiety.