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Ziprasidone Stats & Data

Depressant

Geodon Zeldox Zipwell

NPS DataHub

MW412.94

FormulaC21H21ClN4OS

CAS146939-27-7

IUPAC5-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloro-1,3-dihydroindol-2-one

SMILESO=C1Cc2cc(CCN3CCN(CC3)c3nsc4ccccc34)c(Cl)cc2N1

InChIKeyMVWVFYHBGMAFLY-UHFFFAOYSA-N

Psychoactive Class Depressant

Half-Life 7–10 h oral; 2–5 h IM

Pharmacology

DrugBank

State Solid

Description

Disorders such as schizophrenia and bipolar disorder can significantly impair mood, cognition, and behavior. These mental illnesses can often be accompanied by comorbidities such as depression and substance abuse, and can significantly impact the quality of life of patients and caregivers. Luckily, several treatment options for psychotic disorders have been introduced to market since the realization of chlorpromazine's antipsychotic properties in 1952. Second generation antipsychotics (commonly referred to as atypical antipsychotics) include clozapine, quetiapine, olanzapine, aripiprazole and ziprasidone among others, and are generally thought to be as efficacious as first generation antipsychotics but differ in their adverse effect profiles. First generation antipsychotics are associated with extrapyramidal adverse effects while atypical antipsychotics are linked to weight gain, impaired glucose tolerance and metabolic syndrome. Ziprasidone is used to treat schizophrenia and bipolar disorder. It can effectively reduce the rate and time of relapses in schizophrenia, and can be used to treat manic episodes in bipolar disorder although the mechanism of action is unknown. Although ziprasidone is classified as an atypical antipsychotic, it appears to have a lower incidence of metabolic adverse effects compared to other medications in the same class.

Mechanism of Action

The effects of ziprasidone are differentiated from other antispychotics based on its preference and affinity for certain receptors. Ziprasidone binds to serotonin-2A (5-HT2A) and dopamine D2 receptors in a similar fashion to other atypical antipsychotics; however, one key difference is that ziprasidone has a higher 5-HT2A/D2 receptor affinity ratio when compared to other antipsychotics such as olanzapine, quetiapine, risperidone, and aripiprazole. Ziprasidone offers enhanced modulation of mood, notable negative symptom relief, overall cognitive improvement and reduced motor dysfunction which is linked to it's potent interaction with 5-HT2C, 5-HT1D, and 5-HT1A receptors in brain tissue. Ziprasidone can bind moderately to norepinephrine and serotonin reuptake sites which may contribute to its antidepressant and anxiolytic activity. Patient's taking ziprasidone will likely experience a lower incidence of orthostatic hypotension, cognitive disturbance, sedation, weight gain, and disruption in prolactin levels since ziprasidone has a lower affinity for histamine H1, muscarinic M1, and alpha1-adrenoceptors.

Pharmacodynamics

Ziprasidone is classified as a "second generation" or "atypical" antipsychotic and is a dopamine and 5HT2A receptor antagonist with a unique receptor binding profile. As previously mentioned, ziprasidone has a very high 5-HT2A/D2 affinity ratio, binds to multiple serotonin receptors in addition to 5-HT2A, and blocks monoamine transporters which prevents 5HT and NE reuptake. On the other hand, ziprasidone has a low affinity for muscarinic cholinergic M1, histamine H1, and alpha1-adrenergic receptors.

Metabolism

Ziprasidone is heavily metabolized in the liver with less than 5% of the drug excreted unchanged in the urine. The primary reductive pathway is catalyzed by aldehyde oxidase, while 2 other less prominent oxidative pathways are catalyzed by CYP3A4. Ziprasidone is unlikely to interact with other medications metabolized by CYP3A4 since only 1/3 of the antipsychotic is metabolized by the CYP3A4 system. There are 12 identified ziprasidone metabolites (abbreviations italicized): Ziprasidone sulfoxide, ziprasidone sulfone, (6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl)acetic acid (_OX-COOH_), OX-COOH glucuronide, 3-(piperazine-1-yl)-1,2-benzisothiazole (_BITP_), BITP sulfoxide, BITP sulfone, BITP sulfone lactam, S-Methyl-dihydro-ziprasidone, S-Methyl-dihydro-ziprasidone-sulfoxide, 6-chloro-5-(2-piperazin-1-yl-ethyl)-1,3-dihydro-indol-2-one (_OX-P_), and dihydro-ziprasidone-sulfone. As suggested by the quantity of metabolites, ziprasidone is metabolized through several different pathways. Ziprasidone is sequentially oxidized to ziprasidone sulfoxide and ziprasidone sulfone, and oxidative N-dealkylation of ziprasidone produces OX-COOH and BITP. OX-COOH undergoes phase II metabolism to yield a glucuronidated metabolite while BITP is sequentially oxidized into BITP sulfoxide, BITP sulfone, then BITP sulfone lactam.

Absorption

In the absence of food, ziprasidone's oral bioavailability is 60%, and absorption may reach 100% if ziprasidone is taken with a meal containing at least 500 kcal. The difference in bioavailability has little to do with the fat content of the food and appears to be related to the bulk of the meal since more absorption occurs the longer ziprasidone remains in the stomach.

Toxicity

The most common adverse reactions reported with ziprasidone include somnolence, respiratory tract infections, extrapyramidal symptoms, dizziness, akathisia, abnormal vision, asthenia, vomiting, headache and nausea.

Indication

In its oral form, ziprasidone is approved for the treatment of schizophrenia, as monotherapy for acute treatment of manic or mixed episodes related to bipolar I disorder, and as adjunctive therapy to lithium or valproate for maintenance treatment of bipolar I disorder. The injectable formulation is approved only for treatment of acute agitation in schizophrenia.

Half-life

The half life of ziprasidone is 6-7 hours.

Protein Binding

Ziprasidone is extensively protein bound with over 99% of the drug bound to plasma proteins, primarily albumin and alpha1-acid glycoprotein.

Elimination

Ziprasidone is extensively metabolized after oral administration with only a small amount excreted in the urine (<1%) or feces (<4%) as unchanged drug.

Volume of Distribution

The mean apparent volume of distribution of Ziprasidone is 1.5 L/kg.

Clearance

The mean apparent systemic clearance is 7.5 mL/min/kg.

Tolerance & Pharmacokinetics

drugs.wiki

Half-Life

7–10 h oral; 2–5 h IM

Addiction Potential

Low—ziprasidone is not classically reinforcing. Abrupt cessation after chronic use may precipitate relapse of underlying illness and rebound agitation; physiologic dependence is not typical. Compulsive redosing for sedation has been anecdotally reported but is uncommon.

Experience Report Analysis

Erowid

6 Reports

2001–2006 Date Range

Demographics

Gender Distribution

Reports Over Time

Real-World Dose Distribution

62K Doses

From 13 individual dose entries

Oral (n=11)

Median: 40.0mg 25th: 20.0mg 75th: 70.0mg 90th: 100.0mg

mg/kg median: 0.672 mg/kg 75th: 0.84

Form / Preparation

Most common forms and preparations reported

Read full reports on Erowid →

Harm Reduction

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Oral exposure is highly food‑dependent: ≥500 kcal meals yield near‑maximal, more reproducible AUC/Cmax; fasting or ~250 kcal meals can reduce exposure by roughly half or more, and simply increasing milligram dose does not fully compensate. This underexposure pattern drives unnecessary redosing and increases side‑effect variability. QTc prolongation with therapeutic oral dosing is typically in the low‑to‑moderate range on average, but torsades risk rises sharply with QTc ≥500 ms or large within‑person increases (≥60 ms); correct electrolytes and avoid stacking QT‑prolongers. IM ziprasidone is for acute agitation; do not inject IV. The IM product contains SBECD, which is renally cleared; use caution in significant renal impairment. Ziprasidone’s metabolism is predominantly via aldehyde oxidase with a lesser CYP3A4 contribution; thus, strong CYP3A4 inhibitors/inducers usually cause only modest level changes compared with drugs cleared mainly by CYPs. Rare but serious DRESS (drug reaction with eosinophilia and systemic symptoms) has been reported; any fever/rash/systemic symptoms in the first month warrant immediate discontinuation and evaluation. Akathisia and other EPS can occur, particularly at higher doses or when used to counter stimulant effects; paradoxical restlessness may worsen distress even as psychosis is blunted. If considering higher‑than‑label dosing or combining with QT‑prolongers, obtain a recent ECG; QTc ≥500 ms is a stop signal and ≥450–470 ms warrants caution and risk‑factor mitigation.

References

Drugs.wiki References

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