Ziprasidone
Ziprasidone
Generic Name
Ziprasidone
Brand Names
*Geodon*) is a second‑generation (atypical) antipsychotic widely used for schizophrenia and bipolar disorder. It offers a distinct receptor profile that translates into a favorable metabolic side‑effect profile but requires careful cardiac monitoring.
Mechanism
- Dopamine D₂ receptor antagonist (IC₅₀ ≈ 35 nM) – blocks mesolimbic and nigrostriatal pathways, reducing positive psychotic symptoms and extrapyramidal risk.
- Serotonin 5‑HT₂A receptor antagonist (IC₅₀ ≈ 36 nM) – augments dopamine release in prefrontal cortex, improving negative and cognitive symptoms.
- *Partial agonist* at 5‑HT₁A receptors, contributing to anxiolytic and antidepressant properties.
- Weak affinity for α₁‑adrenoceptors and H₁ histamine receptors—minimal sedation and orthostatic hypotension at therapeutic doses.
Pharmacokinetics
| Parameter | Typical Value (oral) | Remarks |
| Absorption | 30 % oral bioavailability; rapid peak (1–2 h). | *Sublingual* bypasses first‑pass, 70 % bioavailability. |
| Distribution | Plasma protein binding 50‑70 % (albumin and α‑1‑acid glycoprotein). | Lipid‑soluble; central nervous system penetration efficient. |
| Metabolism | Primarily hepatic via CYP3A4 (≈25 %) and CYP2D6 (≈15 %); minimal glucuronidation. | Strong CYP3A4 inhibitors (ketoconazole) or inducers (rifampin) alter exposure. |
| Elimination | Renal excretion 10‑15 % unchanged; half‑life 14‑16 h (IV), 16‑17 h (oral). | Dose adjustment not required for mild‑moderate renal impairment. |
| Drug–Drug Interactions | CYP3A4 inhibitors ↑AUC; CYP3A4 inducers ↓AUC. | Potential for QT prolongation when combined with other agents that prolong QT. |
Indications
- Schizophrenia (acute, maintenance, relapse prevention)
- Bipolar I disorder – manic or mixed episodes, prophylaxis of acute mania
- Adjunctive therapy for mood disorders when dopamine/serotonin modulation is desired
- Pediatric use (≥5 yr) is *limited*; data primarily for adults
Contraindications
- QT prolongation: absolute contraindication—history of congenital long‑QT, recent myocardial infarction, uncontrolled arrhythmia, or concurrent QT‑prolonging drugs.
- Severe hepatic impairment: reduced metabolism; monitor cautiously.
- Cardiovascular disease: caution; obtain baseline ECG.
- Pregnancy: category B—use only if benefits outweigh risks.
- Concurrent CNS depressants: additive sedation—avoid with high doses of benzodiazepines.
Dosing
| Age/Weight | Route | Initial Dose | Titration | Maintenance | Max Daily Dose |
| Adult ≥70 kg | Oral | 20 mg BID (or 50 mg SR) | Add 10 mg BID every 3–5 days | 40–80 mg BID or 50–150 mg SR | 80 mg BID / 150 mg SR |
| Adult <70 kg | Oral | 40 mg SR daily | Increase 10 mg SR weekly | 50–100 mg SR | 100 mg SR |
| Pediatric (≥5 yr) | Oral | 5 mg/kg BID | 5 mg/kg BID every 3–5 days | 10–20 mg/kg/day | 20 mg/kg/day |
| Sublingual | 10 mg/5 mg → 20 mg BID | Same titration | Same maintenance | Same max |
*Key points:*
• Switching: Perform a 2‑day overlap when switching to Ziprasidone to avoid dopamine‑depletion dyskinesia.
• Long‑acting injectable: Not available.
Adverse Effects
Common (≥5 %)
• Nausea, vomiting, dyspepsia
• Somnolence, dizziness, headache
• Weight loss or minimal weight gain
• Dry mouth, blurred vision, ocular discomfort
Serious (≤1 %)
• QT/QRS prolongation → torsades de pointes
• Neuroleptic malignant syndrome (rare)
• Hyperglycemia & impaired glucose tolerance (minimal compared with other atypicals)
• Akathisia, tardive dyskinesia (low cumulative risk)
*Note*: Metabolic profile is favorable; monitor lipids and glucose periodically, but weight monitoring remains useful.
Monitoring
- Baseline: ECG (QTc), CBC, electrolytes, liver panel, fasting glucose, lipid profile.
- During therapy:
- ECG at 2 weeks, 3 months, and thereafter if QT‑prolonging co‑medication added.
- Weight and BMI quarterly.
- Blood glucose yearly, or sooner if risk factors exist.
- Drug interactions: Re‑evaluate when introducing potent CYP3A4 inhibitors/inducers or anticholinergic agents.
Clinical Pearls
- Fast‑track weight‑control: Ziprasidone’s minimal H1 activity translates to the lowest weight‑gain risk among atypicals; ideal for patients with metabolic comorbidities.
- Sublingual advantage: Useful when oral intake is compromised (e.g., nausea, vomiting); onset ~1 h, but requires frequent dosing.
- Cardiac caution: Although QT prolongation incidence is lower than clozapine or olanzapine, any dose ≥80 mg BID demands an ECG.
- Drug interactions to remember:
- CYP3A4 inhibitors (e.g., ketoconazole, erythromycin) → increase Ziprasidone levels → risk of QT prolongation.
- CYP3A4 inducers (e.g., rifampin, carbamazepine) → decrease levels → therapeutic failure.
- Dose titration in elderly or hepatic impairment should be conservative; start at lowest effective dose.
- Therapeutic drug monitoring not routinely required; plasma levels (Cmax 20–60 ng/mL) correlate poorly with clinical response.
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• Quick Reference Table
| Parameter | Typical Value | Clinical Impact |
| QTc > 450 ms | Avoid | High arrhythmia risk |
| Weight change ≤5% | Acceptable | Metabolic safety |
| Cmax 20–60 ng/mL | No clear target | Clinical response variable |
*Use as a snapshot for rapid recall when prescribing or teaching Ziprasidone.*