Ziprasidone

Indications

• Schizophrenia in adults, for acute treatment and for maintenance, with efficacy comparable to other second-generation agents when dosed adequately.
• Acute manic or mixed episodes associated with bipolar I disorder in adults, with or without psychotic features.
• Maintenance treatment of bipolar I disorder in adults as an adjunct to lithium or valproate after an acute episode has responded.
• Intramuscular ziprasidone is approved for acute agitation in adults with schizophrenia when rapid control is needed.
• Off-label use includes treatment of psychosis in patients where weight and metabolic risk dominate the choice, and adjunctive use in bipolar depression.

Mechanism of action

• Antagonist at dopamine D2 and potent antagonist at serotonin 5-HT2A, with one of the highest 5-HT2A to D2 affinity ratios in the class.
• Partial agonism at 5-HT1A and antagonism at 5-HT2C add antidepressant and anxiolytic properties beyond dopamine blockade.
• Moderate inhibition of serotonin and norepinephrine reuptake distinguishes it pharmacologically and may support mood benefit.
• Very low histamine H1 and muscarinic affinity accounts for minimal weight gain, little sedation, and no anticholinergic burden.
• Blockade of the cardiac potassium channel underlies the dose-related QTc prolongation that limits its use in cardiac disease.

Pharmacokinetics

• Absorption is the critical issue: bioavailability roughly doubles when taken with a meal of at least 500 kcal, so fasting doses fail.
• About two thirds of clearance is by aldehyde oxidase, a pathway with few clinically relevant inhibitors, and one third by CYP3A4.
• Oral half-life is about 7 hours, which mandates twice-daily dosing, while the intramuscular half-life is 2-5 hours.
• Ziprasidone is not a meaningful CYP inhibitor or inducer, so it adds little to a complicated medication list.
• Less than 1 percent is excreted unchanged in urine and renal impairment needs no adjustment, though the IM cyclodextrin vehicle is renally cleared.

Dosing

• Schizophrenia: start 20 mg twice daily with food, then titrate at intervals of at least 2 days to a usual 40-80 mg twice daily.
• Bipolar mania: start 40 mg twice daily with food, increase to 60-80 mg twice daily on day 2, then adjust within 40-80 mg twice daily.
• The labeled maximum is 100 mg twice daily, or 200 mg/day, and doses at the low end are commonly subtherapeutic in practice.
• Intramuscular dosing is 10 mg every 2 hours or 20 mg every 4 hours, up to 40 mg/day, and for no more than 3 consecutive days.
• No adjustment is needed for renal or hepatic impairment, but avoid the intramuscular form in significant renal impairment.
• Taper over one to two weeks when discontinuing, since the short half-life makes abrupt stopping prone to rebound symptoms.

Adverse effects

• Somnolence, dizziness, akathisia, and nausea are the most common effects and are largely dose related and worse with rapid titration.
• QTc prolongation averages 10-20 ms, more than most second-generation agents, and is the reason for its cardiac contraindications.
• Weight and metabolic effects are among the lowest of the class, alongside lurasidone and aripiprazole, with essentially neutral lipids.
• Extrapyramidal symptoms and modest prolactin elevation occur, generally less than with risperidone but more than with quetiapine.
• Rare but serious events include neuroleptic malignant syndrome, drug reaction with eosinophilia and systemic symptoms, and priapism.

Monitoring

• Baseline potassium and magnesium, correcting deficits before starting, since hypokalemia and hypomagnesemia amplify QT risk.
• Baseline ECG in patients with cardiac disease, on other QT-prolonging drugs, or with a family history of sudden death or long QT.
• Discontinue if QTc exceeds 500 ms on treatment, and reassess any concurrent QT-prolonging medication before restarting.
• Standard metabolic panel of weight, blood pressure, fasting glucose or A1c, and lipids at baseline, 12 weeks, and annually.
• Confirm at every visit that the patient is actually taking doses with a substantial meal, because absorption is the usual reason for failure.

Interactions

• Contraindicated with known QT prolongation, recent myocardial infarction, uncompensated heart failure, and other QT-prolonging drugs.
• Avoid combining with dofetilide, sotalol, Class IA and III antiarrhythmics, methadone, moxifloxacin, and pentamidine.
• Strong CYP3A4 inducers such as carbamazepine reduce exposure by about 35 percent, and ketoconazole increases it by about 35 percent.
• Additive sedation with opioids, benzodiazepines, and alcohol, and additive hypotension with antihypertensive agents.
• Diuretic-induced electrolyte loss is the most common practical route to dangerous QT interaction, so review the diuretic list.

Special populations

• Pregnancy data are more limited than for olanzapine or quetiapine; third-trimester exposure risks neonatal extrapyramidal and withdrawal symptoms.
• Limited lactation data, but the low reported milk concentrations suggest breastfeeding is likely compatible with infant monitoring.
• Not approved in pediatric patients, and adolescent trials in bipolar disorder and schizophrenia failed to establish efficacy.
• In older adults consider a baseline ECG, start at the low end, and remember the dementia-related mortality warning.
• No dose adjustment for renal or hepatic impairment, though the intramuscular vehicle accumulates in renal failure.

Clinical pearls

• A 500 kcal meal is part of the prescription; taken fasting, absorption falls by about half.
• Best metabolic choice when weight matters, provided the ECG and electrolytes are clean.
• Starting at 20 mg twice daily and stopping there is a common cause of apparent nonresponse.