|Systematic (IUPAC) name|
|Licence data||US FDA:|
|Pregnancy cat.||B3 (AU) C (US)|
|Legal status||Prescription Only (S4) (AU) ℞-only (US)|
|Metabolism||hepatic (aldehyde reductase)|
|Excretion||Urine and feces|
|Mol. mass||412.936 g/mol|
| (what is this?)
Ziprasidone (marketed as Geodon, Zeldox by Pfizer) 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.
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.
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 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.
Note: The percentages given are incidences of respective adverse effects.
- Very common adverse effects (>10%)
- Common adverse effects (1-10%)
- Respiratory disorders
- Dry mouth
- Extrapyramidal symptoms (EPS) such as: (in a recent meta-analysis of 15 antipsychotic drugs it came 8th for extrapyramidal side effects)
- - Tremor
- - Dystonia
- - Akathisia
- - Parkinsonism
- - Muscle rigidity
- Orthostatic hypotension
- Abnormal vision
- Spasmodic movement
- 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)
- Uncommon (0.1-1%) adverse effects
- Abnormal gait
- Hyperprolactinaemia (according to a recent meta-analysis of 15 atypical antipsychotics it produces less prolactin elevation than risperidone, paliperidone, haloperidol, sertindole and lurasidone)
- Hepatic enzyme increased
- Increased appetite
- Heart rate increased
- Joint stiffness
- Muscle cramps
- Pain in extremity
- Cogwheel rigidity
- Disturbance in attention
- Generalised tonic-clonic seizures
- Oculogyric crisis
- Tardive dyskinesia
- Throat tightness
- Sore throat
- Urinary incontinence
- Maculopapular rash
- Rare (<0.1%) side effects
- Chest pain
- Feeling hot
- Gastroesophageal reflux
- Loose stools
- Ear pain
- Positional vertigo
- Eye pruritus
- Visual disturbance
- Blood lactic dehydrogenase increased
- Body temperature increased
- QT interval prolongation
- Liver function test abnormal
- Increased pulse
- Musculoskeletal discomfort
- Restless legs syndrome,
- Flat affect
- Panic attack
- Sleep walking
- Erectile dysfunction
- Allergic dermatitis
- Skin irritation
- Swelling face
- Papular rash
- Neuroleptic malignant syndrome
- Tardive dyskinesia
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;  however, a common side-affect of the drug is nausea and anorexia. 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).
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.
Support groups such as The Icarus Project and other online forums provide resources and social support for those attempting to discontinue antipsychotics and other psychiatric medications. Withdrawal symptoms reported to occur after discontinuation of antipsychotics include nausea, emesis, lightheadedness, diaphoresis, dyskinesia, orthostatic hypotension, tachycardia, nervousness, dizziness, headache, excessive non-stop crying, and anxiety. Some have argued that additional somatic and psychiatric symptoms associated with dopaminergic super-sensitivity, including dyskinesia and acute psychosis, are common features of withdrawal in individuals treated with neuroleptics. This has led some to suggest that the withdrawal process might itself be schizo-mimetic, producing schizophrenia-like symptoms even in previously healthy patients, indicating a possible pharmacological origin of mental illness in a yet unknown percentage of patients currently and previously treated with antipsychotics. This question is unresolved, and remains a highly controversial issue among professionals in the medical and mental health communities, as well the public. Complicated and long-lasting rebound insomnia symptoms can also occur after withdrawing from antipsychotics.
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