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Ziprasidone (Geodon^®) was the fifth atypical antipsychotic to gain FDA approval. Ziprasidone is FDA approved for the treatment of schizophrenia, and the intramuscular injection form of Ziprasidone is approved for acute agitation in schizophrenic patients. "Unlabeled" uses include treatment of bipolar disorder.

Chemistry

Ziprasidone is 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, C₂₁H₂₁ClN₄OS.

chemical structure of ziprasidone

Pharmacology

Ziprasidone has a high affinity for dopamine, serotonin, and alpha adrenergic receptors and a medium affinity for histaminic receptors. Ziprasidone is somewhat unique among the "atypicals" in that it 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 is 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. Antagonism at histaminic and alpha adrenergic receptors likely explains some of the side effects of ziprasidone, such as sedation and orthostasis.

Pharmacokinetics

The elimination half-life of ziprasidone is about 7 hours. Steady state plasma concentrations are achieved within one to three days. The bioavailability of ziprasidone is about 60% when taken with food.

Metabolism

Ziprasidone is hepatically metabolized by aldehyde reductase. Minor metabolism occurs via cytochrome P450 3A4. Medication that induce (e.g carbamazepine) or inhibit (e.g. ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone. There are no known induces or inhibitors of aldehyde reductase.

Adverse Events

Ziprasidone may increase the QTc interval in some patients and may increase the risk of a type of heart arrythmia 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. When compared with Haldol the QTc effect of ziprasidone is small. Given that psychiatrists have no compunction to use IM Haldol, the use of ziprasidone should not bring any more concern. The initial fear over ziprasidone and QTc was really a question of timing and effective marketing campaigns by rival drug manufacturers. At the time the drug was going through trials there were a number of scares with drugs that effected QTc including antihistamines (Hismanal) which led to ziprasidone being painted with a broad brush.

Adverse events reported for ziprasidone include sedation, insomnia, orthostasis, akathisia and other extrapyramidal side-effects.

Recently the FDA required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and diabetes with atypical antipsychotics. Some evidence suggests that ziprasidone may not be as bad as some of the other atypical antipsychotics at causing insulin resistance and weigth gain. In fact in a trial of long term therapy with ziprasidone, overweight patients (BMI>27) actually had a mean weight loss overall. Ziprasidone is not though a weight loss drug. The weight loss reflected in this study on ziprsidone was really reflective of patients who had gained weight on other antipsychotics who were now trending back toward their baseline.

External links

Geodon - Manufacturers Website
Package Insert (PDF)

@@ Line 8: / Line 8: @@
 ==Pharmacology==
-Ziprasidone has a high affinity for dopamine, serotonin, and alpha adrenergic receptors and a medium affinity for histaminic receptors. Ziprasidone is somewhat unique among the "atypicals" in that it 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 is 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.  Antagonism at histaminic and alpha adrenergic receptors likely explains some of the side effects of ziprasidone, such as sedation and orthostasis. About 1 in 10-20 (approximately) patient titrated up to high doses of Geodon (360mg a day) will show a significant improvment in cognition. They will become more attentive, engageable and responsive - this is not an effect commonly seen with other atypical antipsychotics (Risperdal/Zyprexa). This is likely secondary to sparing of D2 at mesocortical level and may be more a result of stopping older mare "dulling" drugs and restoring equilibrium in the cortex than any specific drug effect.
+Ziprasidone has a high affinity for dopamine, serotonin, and alpha adrenergic receptors and a medium affinity for histaminic receptors. Ziprasidone is somewhat unique among the "atypicals" in that it 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 is 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.  Antagonism at histaminic and alpha adrenergic receptors likely explains some of the side effects of ziprasidone, such as sedation and orthostasis.
 ==Pharmacokinetics==
@@ Line 18: / Line 18: @@
 ==Adverse Events==
-Ziprasidone may increase the [[QTc interval]] in some patients and may increase the risk of a type of heart arrythmia 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. When compared with Haldol the QTc effect of Geodon is small. Given that psychiatrists have no compunction to use IM Haldol, the use of Geodon should not bring any more concern. The initial fear over Geodon and QTc was really a question of timing. At the time the drug was going through trials there were a number of scares with drugs that effected QTc including antihistamines (Hismanal) which led to Geodon being painted with a broad brush.
+Ziprasidone may increase the [[QTc interval]] in some patients and may increase the risk of a type of heart arrythmia 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. When compared with Haldol the QTc effect of ziprasidone is small. Given that psychiatrists have no compunction to use IM Haldol, the use of ziprasidone should not bring any more concern. The initial fear over ziprasidone and QTc was really a question of timing and effective marketing campaigns by rival drug manufacturers. At the time the drug was going through trials there were a number of scares with drugs that effected QTc including antihistamines (Hismanal) which led to ziprasidone being painted with a broad brush.
-Adverse events reported for ziprasidone include [[sedation]], [[insomnia]], [[orthostasis]], and [[extrapyramidal side-effects]].
+Adverse events reported for ziprasidone include [[sedation]], [[insomnia]], [[orthostasis]], akathisia and other [[extrapyramidal side-effects]].
-Recently the FDA required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and diabetes with atypical antipsychotics.  Some evidence suggests that ziprasidone may not be as bad as some of the other atypical antipsychotics at causing insulin resistance and weigth gain.  In fact in a trial of long term therapy with ziprasidone, overweight patients ([[BMI]]>27) actually had a mean weight loss overall. Geodon is not though a weight loss drug. The weight loss reflected in this study on Geodon was really reflective of patients who had gained weight on other antipsychotics who were now trending back toward their baseline.
+Recently the FDA required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and diabetes with atypical antipsychotics.  Some evidence suggests that ziprasidone may not be as bad as some of the other atypical antipsychotics at causing insulin resistance and weigth gain.  In fact in a trial of long term therapy with ziprasidone, overweight patients ([[BMI]]>27) actually had a mean weight loss overall. Ziprasidone is not though a weight loss drug. The weight loss reflected in this study on ziprsidone was really reflective of patients who had gained weight on other antipsychotics who were now trending back toward their baseline.
 ==External links==