Ziprasidone - Drug Monograph

Introduction

Ziprasidone is an atypical antipsychotic medication belonging to the benzisothiazolyl piperazine class. Approved by the FDA in 2001, it represents an important therapeutic option in the management of psychotic disorders with a distinct pharmacological profile that offers both efficacy and a favorable metabolic side effect profile compared to some other antipsychotics.

Mechanism of Action

Ziprasidone exerts its therapeutic effects through potent antagonism of dopamine D2 and serotonin 5-HT2A receptors. Its unique receptor binding profile includes:

• High affinity for serotonin 5-HT1A/1B/1D/2A/2C receptors
• Moderate affinity for dopamine D2/D3 receptors
• Significant activity as a serotonin and norepinephrine reuptake inhibitor
• Minimal affinity for muscarinic cholinergic receptors

This combination provides antipsychotic efficacy while potentially reducing extrapyramidal symptoms and offering mood-stabilizing properties.

Indications

• Treatment of schizophrenia in adults
• Acute treatment of manic or mixed episodes associated with bipolar I disorder (as monotherapy)
• Maintenance treatment of bipolar I disorder (as adjunct to lithium or valproate)
• Acute agitation in schizophrenia (intramuscular formulation)

• Bipolar depression
• Treatment-resistant depression (adjunctive therapy)
• Behavioral symptoms in dementia (with caution)

Dosage and Administration

• Initial dose: 20 mg twice daily with food
• Titration: Increase to 60-80 mg twice daily based on response and tolerance
• Maximum recommended dose: 200 mg daily (100 mg twice daily)

• Acute agitation: 10-20 mg every 2 hours as needed
• Maximum: 40 mg daily

• Renal impairment: No dosage adjustment required
• Hepatic impairment: Use with caution; no specific dosage recommendation
• Elderly: Consider lower starting doses (20 mg daily)
• Pediatrics: Not recommended for children under 18 years

Pharmacokinetics

• Oral bioavailability: ~60% with food
• Tmax: 6-8 hours (oral); 1 hour (IM)
• Food increases absorption by approximately 100%

• Protein binding: >99%
• Vd: 1.5 L/kg
• Crosses blood-brain barrier and placenta

• Primarily hepatic via aldehyde oxidase and CYP3A4
• Three major metabolites (none pharmacologically active)

• Half-life: 7 hours (oral); 2-5 hours (IM)
• Excretion: Feces (66%) and urine (20%)
• Clearance: 7.5 mL/min/kg

Contraindications

• Known hypersensitivity to ziprasidone
• History of prolonged QT interval or congenital long QT syndrome
• Recent acute myocardial infarction
• uncompensated heart failure
• Concomitant use with other drugs known to prolong QT interval
• Patients with history of neuroleptic malignant syndrome

Warnings and Precautions

• Increased mortality in elderly patients with dementia-related psychosis

• QT prolongation: Requires baseline and periodic ECG monitoring
• Orthostatic hypotension: Particularly during initial titration

• Extrapyramidal symptoms
• Tardive dyskinesia
• Neuroleptic malignant syndrome

• Hyperglycemia and diabetes mellitus
• Dyslipidemia (minimal effect compared to other antipsychotics)
• Weight gain (generally modest)

• Seizures
• Dysphagia
• Cognitive and motor impairment

Drug Interactions

• QT-prolonging drugs: Class IA/III antiarrhythmics, macrolides, fluoroquinolones
• CYP3A4 inhibitors: Ketoconazole, clarithromycin (increase ziprasidone levels)
• CYP3A4 inducers: Carbamazepine, rifampin (decrease ziprasidone levels)
• Antihypertensive agents: Additive hypotensive effects

• Lithium: Increased risk of extrapyramidal symptoms
• Dopamine agonists: Antagonistic effects

Adverse Effects

• Somnolence (14%)
• Nausea (10%)
• Constipation (8%)
• Dizziness (8%)
• Akathisia (8%)

• QT prolongation (0.06%)
• Neuroleptic malignant syndrome
• Tardive dyskinesia
• Seizures
• Pancreatitis
• Priapism

• Weight gain: Average 1.4 kg after 1 year
• Minimal effects on glucose and lipids compared to other atypical antipsychotics

Monitoring Parameters

• Complete medical and psychiatric history
• ECG (QTc interval)
• Weight, height, BMI
• Fasting blood glucose and lipid profile
• Blood pressure (standing and sitting)

• ECG: At baseline, following dose changes, and periodically
• Metabolic parameters: Every 3 months first year, then annually
• Extrapyramidal symptoms: At each visit
• Therapeutic response and side effects

• Not routinely required
• Therapeutic range: 50-200 ng/mL

Patient Education

• Take with food containing at least 500 calories
• Do not abruptly discontinue medication
• Avoid alcohol and other CNS depressants
• Rise slowly from sitting/lying position
• Report any unusual movements, fever, or muscle rigidity
• Notify all healthcare providers about ziprasidone use
• Use effective contraception if sexually active

• Fainting or dizziness
• Irregular heartbeat
• High fever or muscle stiffness
• Difficulty swallowing
• Persistent nausea/vomiting
• Thoughts of self-harm

• Regular exercise and balanced diet to manage weight
• Caution when driving or operating machinery
• Regular medical follow-up appointments

References

1. FDA Prescribing Information: Geodon (ziprasidone hydrochloride) 2. Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. Cambridge University Press; 2013 3. Leucht S, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia. Lancet. 2013;382(9896):951-962 4. Miceli JJ, et al. The pharmacokinetics of ziprasidone in healthy volunteers. Br J Clin Pharmacol. 2000;49 Suppl 1:5S-13S 5. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Schizophrenia. 3rd ed. 2020 6. Kane JM, et al. Efficacy and safety of ziprasidone in the treatment of schizophrenia. J Clin Psychiatry. 2003;64(3):245-253 7. Caccia S. Safety and pharmacokinetics of atypical antipsychotics in children and adolescents. Paediatr Drugs. 2013;15(3):217-233