ziprasidone

General Information

Ziprasidone (brand Geodon) is a second-generation antipsychotic with minimal metabolic impact but a notable propensity for QT prolongation, indicated for schizophrenia and bipolar mania.

This profile focuses on adult schizophrenia and acute manic/mixed episodes where twice-daily dosing with food is acceptable.

The compare view and the ziprasidone evidence feed can help weigh weight neutrality, dosing logistics, and QTc risk against similarly positioned SGAs when evaluating cardiovascular monitoring or augmentation needs.

Coordinate care plans through the schizophrenia hub and bipolar disorder hub to align relapse prevention, metabolic labs, and alternative depot strategies.

Selected for patients needing weight-neutral therapy, with careful cardiac screening; adherence depends on food requirement and BID dosing.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Ziprasidone antagonizes dopamine D2 and serotonin 5-HT2 receptors while partially agonizing 5-HT1A and inhibiting serotonin/norepinephrine reuptake, supporting mood stabilization.

Moderate histamine H1 and α1 antagonism contributes to sedation and orthostasis; minimal muscarinic activity limits anticholinergic effects.

• Antagonist at dopamine D2/D3 receptors.
• Antagonist at serotonin 5-HT2A/5-HT2C/5-HT1D; partial agonist at 5-HT1A; inhibitor of serotonin and norepinephrine transporters.
• Moderate antagonist at histamine H1 and adrenergic α1 receptors.

Metabolism and Pharmacokinetics

• Oral bioavailability ~60% when taken with ≥500 calories; falls markedly if fasting.
• Greater than 99% protein bound with modest volume of distribution (~1.5 L/kg).
• Metabolized primarily by aldehyde oxidase and CYP3A4 (minor) to inactive metabolites.
• Half-life ~7 hours orally; IM half-life 2–3 hours.
• Eliminated ~59% in feces and ~20% in urine, mostly as metabolites.

Dosing and Administration

• Schizophrenia: start 20 mg twice daily with food; increase to 40 mg BID on day 3; maintenance 40–80 mg BID (max 100 mg BID).
• Bipolar mania: start 40 mg BID with food; titrate to 60–80 mg BID within several days as tolerated.
• IM agitation: 10–20 mg IM every 2–4 hours as needed (max 40 mg/day); transition to oral therapy when feasible.

Monitoring & Labs

• Baseline ECG for patients with cardiac disease, electrolyte abnormalities, or QT-active co-medications; repeat after dose increases and for symptoms (palpitations, syncope).
• Electrolytes (potassium, magnesium) when risk factors for depletion are present (diuretics, vomiting/diarrhea, eating disorders) to reduce QTc risk.
• Food adherence: confirm each dose is taken with ≥500 calories (meal planning, reminders) because fasting dosing can mimic nonresponse.
• Orthostatic vitals and sedation during titration, especially in older adults and when antihypertensives or other CNS depressants are used.
• EPS/AIMS monitoring at routine intervals (akathisia and parkinsonism can occur, particularly at higher doses).

Ziprasidone monitoring centers on QTc safety and on reliable food intake, since absorption is meal-dependent and missed-meal dosing undermines treatment.

Adverse Effects

Interactions

• Avoid coadministration with other QT-prolonging agents (e.g., class IA/III antiarrhythmics, moxifloxacin) to reduce torsades risk.
• CYP3A4 inhibitors (ketoconazole, clarithromycin) modestly raise levels—monitor QT interval and tolerability.
• CYP3A4 inducers (carbamazepine, rifampin) may lower exposure—monitor efficacy and adjust if needed.
• Additive CNS depression with alcohol, benzodiazepines, opioids.
• Caution with antihypertensives due to orthostatic hypotension.

Other Useful Information

• Instruct patients to take each dose with ≥500 calories to ensure therapeutic exposure.
• Obtain baseline ECG in patients with cardiac disease, electrolyte disturbances, or on other QT-active regimens; repeat if dose increases or symptoms arise.
• Educate patients on symptoms of arrhythmia (palpitations, syncope) and advise immediate evaluation if they occur.

References

1. GEODON (ziprasidone) prescribing information — Pfizer (2024)
2. Ziprasidone IN THE Treatment OF Acute Manic OR Mixed Episodes OF Bipolar Disorder: A Randomized, Double Blind, Placebo Controlled Trial — American Journal of Psychiatry (2003)
3. Ziprasidone IN THE Treatment OF Acute Schizophrenia: A Randomized, Double Blind, Placebo Controlled Trial — Psychopharmacology (2001)
4. Metabolic AND Endocrine Adverse Effects OF Second Generation Antipsychotics: A Systematic Review — CNS Drugs (2011)
5. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia — American Psychiatric Association (2020)Guidelineschizophreniaclinical