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| Trade names | Geodon, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a699062 |
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| Routes of administration | By mouth,intramuscular injection (IM) |
| Drug class | Atypical antipsychotic |
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| Bioavailability | 60% (oral)[4] 100% (IM) |
| Metabolism | Liver (aldehyde reductase) |
| Eliminationhalf-life | 7 to 10 hours[5] |
| Excretion | Urine and feces |
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| ECHA InfoCard | 100.106.954 |
| Chemical and physical data | |
| Formula | C21H21ClN4OS |
| Molar mass | 412.94 g·mol−1 |
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Ziprasidone, sold under the brand nameGeodon among others, is anatypical antipsychotic used to treatschizophrenia andbipolar disorder.[6] It may be usedby mouth and byinjection into a muscle (IM).[6] The intramuscular form may be used for acuteagitation in people with schizophrenia.[6]
Common side effects includetremors,tics,dizziness,dry mouth,restlessness,nausea, and mildsedation.[7][8] Although it can also causeweight gain, the risk is much lower than for other atypical antipsychotics.[9] How it works is not entirely clear but is believed to involve effects onserotonin anddopamine in thebrain.[6]
Ziprasidone was approved for medical use in the United States in 2001.[6] The pills are made up of the hydrochloride salt, ziprasidone hydrochloride. The intramuscular form is themesylate, ziprasidone mesylate trihydrate, and is provided as alyophilized powder. In 2020, it was the 282nd most commonly prescribed medication in the United States, with more than 1 million prescriptions.[10][11]
Ziprasidone is approved by the USFood and Drug Administration (FDA) for the treatment ofschizophrenia as well as acutemania andmixed states associated withbipolar disorder. Its intramuscular injection form is approved for acute agitation in schizophrenic patients for whom treatment with just ziprasidone is appropriate.[12]
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 thanlurasidone andiloperidone, approximately as effective aschlorpromazine andasenapine, and 9–13% less effective thanhaloperidol,quetiapine, andaripiprazole.[13] Ziprasidone is effective in the treatment of schizophrenia, though evidence from the CATIE trials suggests it is less effective thanolanzapine, and equally as effective compared toquetiapine. There are higher discontinuation rates for lower doses of ziprasidone, which are also less effective than higher doses.[14]
Ziprasidone (and all other second generation antipsychotics (SGAs)) received aboxed warning in the US due to increased mortality in elderly people withdementia-relatedpsychosis.[3]
Sleepiness and headache are very common adverse effects (>10%).[7][8]
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[9]), rashes, fast heart beats, blood pressure falling when standing up quickly, muscle pain, weakness, twitches, dizziness, and anxiety.[7][8]Extrapyramidal symptoms are also common and include tremor,dystonia (sustained or repetitive muscle contractions),akathisia (the feeling of a need to be in motion),parkinsonism, and muscle rigidity; in a 2013 meta-analysis of 15 antipsychotic drugs, ziprasidone ranked 8th for such side effects.[15]
Ziprasidone is known to trigger mania in some bipolar patients.[16][17][18]
This medication can cause birth defects, according to animal studies, although this side effect has not been confirmed in humans.[3]
Recently, the FDA required the manufacturers of some atypical antipsychotics to include a warning about the risk ofhyperglycemia andType II diabetes with atypical antipsychotics. Some evidence suggests that ziprasidone does not causeinsulin resistance to the degree of other atypical antipsychotics, such asolanzapine. Weight gain is also less of a concern with ziprasidone compared to other atypical antipsychotics.[19][20][21][22] In fact, in a trial of long term therapy with ziprasidone, overweight patients (BMI > 27) actually had a mean weight loss overall.[3] According to the manufacturer insert, ziprasidone caused an average weight gain of 2.2 kg (4.8 lbs), which is significantly lower than other atypical antipsychotics, making this medication better for patients that are concerned about their weight.In December 2014, the FDA warned that ziprasidone could cause a potentially fatal skin reaction,Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), although this was believed to occur only rarely.[23]
TheBritish National Formulary recommends a gradual withdrawal whendiscontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[24] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[25] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[25] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[25] Symptoms generally resolve after a short period of time.[25]
There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[26] It may also result in reoccurrence of the condition that is being treated.[27] Rarelytardive dyskinesia can occur when the medication is stopped.[25]
| Site | Ki (nM) | Action | Ref | |
|---|---|---|---|---|
| SERTTooltip Serotonin transporter | 112 | Blocker | [28] | |
| NETTooltip Norepinephrine transporter | 44 | Blocker | [28] | |
| DATTooltip Dopamine transporter | 10000+ | ND | [28] | |
| 5-HT1A | 2.5–76 | Partial agonist | [29][30][31] | |
| 5-HT1B | 0.99–4.0 | Partial agonist | [30][28] | |
| 5-HT1D | 5.1–9.0 | Partial agonist | [30][28] | |
| 5-HT1E | 360–1279 | ND | [30][28] | |
| 5-HT2A | 0.08–1.4 | Antagonist | [32][29][30] | |
| 5-HT2B | 27.2 | Antagonist | [28] | |
| 5-HT2C | 0.72–13 | Antagonist | [29] | |
| 5-HT3 | 10000+ | ND | [28] | |
| 5-HT5A | 291 | ND | [28] | |
| 5-HT6 | 61–76 | Antagonist | [31][29] | |
| 5-HT7 | 6.0–9.3 | Antagonist | [28][31][29] | |
| α1A | 18 | Antagonist | [28][31] | |
| α1B | 9.0 | Antagonist | [28] | |
| α2A | 160 | Antagonist | [28][30][31] | |
| α2B | 48 | Antagonist | [28][30][31] | |
| α2C | 59–77 | Antagonist | [28][30][31] | |
| β1 | 2570+ | ND | [30][28] | |
| β2 | 10000+ | ND | [30][28] | |
| D1 | 30–130 | ND | [28][29] | |
| D2 | 4.8 | Antagonist | [33][29][31] | |
| D2L | 4.6 | Antagonist | [30][34] | |
| D2S | 4.2 | Antagonist | [30] | |
| D3 | 7.2 | Antagonist | [33][29][30] | |
| D4 | 0.8–105 | Antagonist | [33][29][28] | |
| D4.2 | 28–39 | Antagonist | [34] | |
| D4.4 | 14.9 | Antagonist | [35] | |
| D5 | 152 | ND | [28] | |
| H1 | 15–130 | Antagonist | [30][29][28] | |
| H2 | 3500+ | ND | [28] | |
| H3 | 10000+ | ND | [28] | |
| H4 | 10000+ | ND | [28] | |
| M1 | 300+ | ND | [36][28][29] | |
| M2 | 3000+ | ND | [36][28] | |
| M3 | 1300+ | ND | [36][31][28] | |
| M4 | 1600+ | ND | [36][28] | |
| M5 | 1600+ | ND | [36][28] | |
| σ1 | 110 | ND | [30] | |
| σ2 | ND | ND | ND | |
| Opioid | 1000+ | ND | [30] | |
| nAChTooltip Nicotinic acetylcholine receptor | 10000+ | ND | [28] | |
| NMDA (PCP) | 10000+ | ND | [28] | |
| VDCCTooltip Voltage-dependent calcium channel | 10000+ | ND | [28][30] | |
| VGSCTooltip Voltage-gated sodium channel | 2620 | ND | [30] | |
| hERGTooltip Human Ether-à-go-go-Related Gene | 169 | Blocker | [37] | |
| Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except H3 (guinea pig), σ1 (guinea pig), opioid (rodent),NMDA/PCP (rat),VDCC, andVGSC.[28] | ||||
Ziprasidone mostlyaffects the receptors ofdopamine (D2),serotonin (5-HT2A, partially5-HT1A,5-HT2C, and5-HT1D)[4][38][39] andepinephrine/norepinephrine (α1) to a high degree, while ofhistamine (H1) - moderately.[40][41] It also somewhatinhibitsreuptake ofserotonin andnorepinephrine, though notdopamine.[40][42]
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.[43] 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.;[44] however, its effects on the 5-HT1A receptor may be limited as a study[45] found ziprasidone would likely "produce detectable occupancy [of 5-HT1A 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 α1-adrenergic receptor likely in part explains some of its side effects, such asorthostatic hypotension. Unlike many other antipsychotics, ziprasidone has no significant affinity for the mACh receptors, and as such lacks anyanticholinergic side effects. Like most other antipsychotics, ziprasidone is sedating due primarily to serotonin and dopamine blockade.[46][47]
The systemicbioavailability of ziprasidone is 100% when administered intramuscularly and 60% when administered orally without food.[4]
After a single dose intramuscular administration, the peak serum concentration typically occurs at about 60 minutes after the dose is administered, or earlier.[48] 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.[3][49]
Ziprasidone is hepatically metabolized byaldehyde oxidase; minor metabolism occurs viacytochrome P450 3A4 (CYP3A4).[50] Medications that induce (e.g.carbamazepine) or inhibit (e.g.ketoconazole) CYP3A4 have been shown to decrease and increase, respectively, blood levels of ziprasidone.[51][52]
Its biological half-life time is 10 hours at doses of 80–120 milligrams.[5]
Ziprasidone is chemically similar torisperidone,[53] of which it is astructural analogue.[54]It was first synthesized in 1987 at thePfizer central research campus inGroton, Connecticut.[55]
Phase I trials started in 1995.[56] In 1998 ziprasidone was approved in Sweden.[57][58] After the FDA raised concerns aboutlong QT syndrome, more clinical trials were conducted and submitted to the FDA, which approved the drug on February 5, 2001.[56][59][60]
In September 2009, theU.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.[61]
In the US, Geodon is marketed byViatris afterUpjohn was spun off fromPfizer.[62][63][64]
Ziprasidone has been studied in and reported to be effective in the treatment ofborderline personality disorder, but findings are mixed.[65][66][67][68]
{{cite journal}}: CS1 maint: overridden setting (link){{cite journal}}: CS1 maint: overridden setting (link){{cite journal}}: CS1 maint: overridden setting (link){{cite journal}}: CS1 maint: overridden setting (link)Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.
{{cite journal}}: CS1 maint: overridden setting (link){{cite journal}}: CS1 maint: overridden setting (link){{cite journal}}: CS1 maint: overridden setting (link){{cite journal}}: CS1 maint: overridden setting (link)Ziprasidone. This atypical antipsychotic has an affinity with serotonin 5HT2A, 5HT1B, and dopamine D2 receptors [31]. Ziprasidone at a daily dose of 80 mg for the treatment of BPD patients proved to be effective in the control of anger, paranoid ideation, impulsivity, and emotional instability, but not for anxiety and depressive symptoms [62]. The use of ziprasidone (daily dose range of 40–160 mg) could be considered for managing acute cases of BPD, considering the reported improvements of suicidal and self-injurious risk, hostility and aggression, impulse control, and severe anxious depressive symptoms [63].
