Ziprasidone (Geodon)

SGA • Last reviewed 2025-09-23

General information

Ziprasidone is a second-generation antipsychotic approved for schizophrenia and acute manic or mixed episodes (as monotherapy or adjunct to lithium/valproate). Intramuscular (IM) formulation is approved for acute agitation in schizophrenia. It was approved in 2001 and is known for a relatively neutral weight profile but carries QT prolongation warnings.

Oral ziprasidone is available as capsules (20, 40, 60, 80 mg) and must be taken twice daily with food (at least 500 calories) to ensure adequate absorption. Initial dosing for schizophrenia is 20 mg twice daily, titrated to 80 mg twice daily. For bipolar mania, start 40 mg twice daily on day 1, increase to 60-80 mg twice daily thereafter. IM formulation (10-20 mg) is used for rapid control of agitation (maximum 40 mg/day IM).

Ziprasidone antagonizes D2 and 5-HT2A receptors and is a partial agonist at 5-HT1A receptors. It also inhibits serotonin and norepinephrine reuptake, which may contribute to mood effects.

The drug is primarily metabolized via aldehyde oxidase and, to a lesser extent, CYP3A4. Oral elimination half-life is ~7 hours. IM administration avoids first-pass metabolism and has faster onset.

Dosing & administration

Schizophrenia: initiate 20 mg twice daily with food; titrate to 40-80 mg twice daily (maximum 160 mg/day).

Bipolar mania: start 40 mg twice daily; increase to 60-80 mg twice daily on day 2 depending on response.

IM: 10-20 mg up to every 2 hours; maximum 40 mg/day for acute agitation.

Renal impairment: no formal adjustment but caution due to limited data; hepatic impairment minimal effect.

Dose considerations

Food requirement: Take with ≥500 calorie meal to ensure ~2-fold higher bioavailability.
QT prolongation: Avoid doses >160 mg/day and monitor in patients with cardiac disease.
IM to oral transition: Begin oral dosing as soon as clinically feasible; overlap not required.
CYP3A4 inhibitors: Minimal effect but monitor if strong inhibitor used.

Mechanism of action

Ziprasidone antagonizes D2 receptors reducing positive symptoms and 5-HT2A receptors improving negative symptoms and EPS profile.

It partially agonizes 5-HT1A receptors and inhibits serotonin/norepinephrine reuptake, which may aid mood stabilization and anxiety reduction.

D2 Ki ~3.9 nM, 5-HT2A Ki ~0.4 nM.
Inhibits SERT and NET (Ki ~0.8 and 18 nM respectively).
Moderate affinity for H1 receptors leading to modest sedation; minimal muscarinic affinity.

Metabolism & pharmacokinetics

Oral bioavailability increases twofold with food; advise taking with meals.

Peak plasma concentration occurs 6-8 hours post-dose; half-life ~7 hours; steady state achieved within 3 days.

Tmax: 6-8 h
Half-life: ~7 h
Food effect: Cmax and AUC increase ~2-fold with 500-calorie meal

Drug interactions

Avoid combination with other QT-prolonging agents (e.g., class IA/III antiarrhythmics) due to additive risk.

CYP3A4 inhibitors modestly increase exposure; usually not clinically significant but monitor.

Strong CYP3A4 inducers (carbamazepine) may reduce levels; limited data but monitor efficacy.

Mechanism	Agents / factors	Management
QT prolongation	Amiodarone, haloperidol, methadone	Avoid combination; if unavoidable, baseline and follow-up ECG.
Enzyme induction	Carbamazepine, rifampin	Monitor clinical response; adjust antipsychotic therapy if relapse occurs.
Hypotension	Antihypertensives	Monitor blood pressure during titration.

Monitoring & safety checks

ECG (QTc)
Baseline for patients with cardiac risk, repeat after dose increases • Boxed warning for QT prolongation.
Weight, metabolic labs
Baseline and periodically • Generally weight-neutral but monitor per guidelines.
EPS/akathisia
Each visit • Akathisia and dystonia may occur especially early.

Advise consistent food intake with each dose.

Consider evening dosing to minimize daytime sedation.

Discontinuation guidance

Taper over 1-2 weeks to reduce relapse risk; withdrawal symptoms are uncommon.

Monitor for rebound psychosis or mania within 1 week.

Special populations

Pregnancy: limited data; use only if benefits justify risks; neonatal EPS/withdrawal possible.

Older adults: start at 20 mg BID; monitor for orthostasis and QT prolongation.

Renal impairment: no adjustment but exercise caution in severe renal disease due to limited data.

Adverse effects

Common: somnolence, dizziness, akathisia, nausea.

Metabolic profile favorable (minimal weight gain); hyperprolactinemia uncommon.

Serious: QT prolongation, DRESS (rare but reported), neuroleptic malignant syndrome.

References

GEODON (ziprasidone) prescribing information — Pfizer (2024)
Ziprasidone in bipolar disorder — Current Opinion in Psychiatry (2007) DOI: 10.1097/YCO.0b013e3282f2f560
Safety and effectiveness of ziprasidone — Journal of Psychopharmacology (2015) DOI: 10.1177/0269881114566335

Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.