Geodon | Pharmacology Mentor

Generic Name

Ziprasidone

Mechanism

Ziprasidone is a second‑generation antipsychotic.
Binding profile:
*High affinity* for dopamine D₂ and serotonin 5‑HT₂A receptors → reduces psychotic symptoms.
*Partial agonist* at 5‑HT₁A receptors → contributes to anxiolytic and antidepressant effects.
*Low affinity* for histamine H₁, muscarinic M₁/M₃, and adrenergic α₁ receptors → minimal sedation and anticholinergic burden.
Neurochemical impact: D₂ blockade in the mesolimbic pathway dampens positive symptoms; 5‑HT₂A blockade modulates negative and cognitive symptoms.
Cardiac effect: Inhibits HERG potassium channels → can prolong QTc interval.

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Pharmacokinetics

Absorption: Bioavailability ~9 % (oral); significantly reduced by food (fatty meals).
Distribution: Highly protein‑bound (~95 %); crosses the blood‑brain barrier.
Metabolism: Predominantly hepatic via CYP3A4; minor CYP2D6 contribution.
Elimination: Renal excretion of unchanged drug & metabolites; half‑life ~7–12 h (oral).
Drug interactions:
Strong CYP3A4 inhibitors ↑ plasma levels (e.g., ketoconazole) → ↑ QTc risk.
CYP3A4 inducers ↓ exposure (e.g., rifampin, carbamazepine).
Concomitant drugs capable of prolonging QTc (e.g., amiodarone) should be avoided or monitored.

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Indications

Schizophrenia (acute and maintenance).
Bipolar Disorder (acute mania).
Adjunctive therapy in treatment‑resistant schizophrenia (per FDA guidance).

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Contraindications

Contraindicated in patients with:
Known hypersensitivity to ziprasidone.
Baseline QTc > 460 ms (men) / > 470 ms (women).
Severe hepatic impairment.
Warnings:
QTc prolongation & torsades de pointes, especially with electrolyte disturbances, bradycardia, or concomitant QT‑prolonging drugs.
Falls/orthostatic hypotension in elderly.
Weight‑neutral: still monitor metabolic parameters.

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Dosing

Condition	Initial Dose	Titration	Maintenance	Notes
Schizophrenia	20 mg PO BID (fasting)	+20 mg/day increments up to 80 mg BID	50–80 mg BID (total 100–160 mg/day)	Avoid food within 1 h prior to ingestion.
Bipolar Mania	20 mg PO BID	+20 mg/day up to 80 mg BID	60–80 mg BID	Rapid titration may precipitate mania; monitor mood.

• Intravenous: 2 mg/kg over 5 min, then 1 mg/kg/12 h. Not first‑line for chronic use.
• Swallowing difficulties: Chewable tablets or oral solution; avoid crushing.

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Adverse Effects

Common (≥10 %)
• Akathisia, dystonia (rare).
• Extrapyramidal symptoms (≤5 %).
• Metabolic: weight gain, dyslipidemia (low‑)
• Dry mouth, constipation, constipation → monitor GI motility.

Serious (≤1 %)
• QTc prolongation → torsades de pointes.
• Neuroleptic malignant syndrome (rare).
• Severe agitation, lability.
• Hepatic dysfunction → AST/ALT rise.

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Monitoring

Parameter	Frequency	Target
QTc	Baseline → 1 wk → 4 wk → every 3 mo (if stable)	< 460 ms (M)/470 ms (F); < 500 ms acceptable with close surveillance
Lipid profile, fasting glucose	Baseline → every 3 mo	< 200 mg/dL
Weight & BMI	Baseline → every 3 mo	maintain < 30 kg/m²
LFTs	Baseline → every 3 mo	< two‑fold ULN
ECG (if QTc ≥ 460 ms)	Repeat 1 wk	Evaluate need to discontinue or adjust

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Clinical Pearls

Take with an empty stomach – a fatty meal can cut bioavailability by >50 %. Consider administering in the morning uncoupled from meals.
Avoid nocturnal dosing – peak dose at night → increased risk of nocturnal QTc prolongation.
Monitor electrolytes – K⁺ < 3.5 mEq/L, Mg²⁺ < 1.5 mEq/L augment torsades risk.
Switching from other antipsychotics: hold previous D₂ blocker for 4–5 half‑lives to prevent neuroleptic syndrome.
High‑yield ECOG: Ziprasidone is unique among atypicals for its minimal metabolic effects yet significant QTc liability – a classic “protect ketosis, risk arrhythmia” scenario.
Pediatric use: FDA approved for ≤ 18 y with schizophrenia; dose starts 5 mg PO BID and titrates to ≤ 30 mg BID.
Pregnancy: Category C – weigh psychiatric stability against fetal QTc prolongation risk; counsel patient.

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