iloperidone

General Information

Iloperidone (brand Fanapt) is a second-generation antipsychotic approved in 2009 for adult schizophrenia and is often considered when patients need a lower-EPS option.

Potent antagonism at adrenergic α1 receptors necessitates a structured titration schedule to mitigate orthostatic hypotension, syncope, and tachycardia.

Tablet strengths from 1 mg to 12 mg enable fine-tuned dosing; therapy must restart at 1 mg twice daily if treatment is interrupted for three or more consecutive days.

The compare tool, the evidence library, and the Schizophrenia hub support side-by-side review of low-EPS alternatives and follow-up planning.

Use is tempered by slow titration and QTc warnings, yet iloperidone can be useful when other SGAs cause EPS or metabolic burden.

Mechanism of Action

Refer to the Glossary entry on Neurotransmitters for background on receptor systems involved in serious mental illness.

Antagonism at dopamine D2/D3 and serotonin 5-HT2A receptors delivers antipsychotic efficacy with a comparatively low EPS profile.

High affinity for α1-adrenergic receptors underlies orthostatic hypotension and reflex tachycardia, while 5-HT6/5-HT7 antagonism may support cognitive effects.

• Ki ≈0.3 nM at α1 receptors and ≈1.5 nM at 5-HT2A receptors.
• D2/D3 antagonism (Ki ≈4 nM) provides antipsychotic effect.
• Minimal muscarinic and histaminergic activity limits anticholinergic side effects.

Metabolism and Pharmacokinetics

• Oral bioavailability ~96% with peak concentrations 2–4 hours after dosing; active metabolites P88 and P95 contribute to activity.
• Metabolized via CYP2D6 and CYP3A4; elimination half-life averages 18 hours in extensive metabolizers and ~23 hours in poor metabolizers.
• Roughly 45% of drug-related material is recovered in urine and 50% in feces; protein binding ~95%.
• Steady state is achieved within 3–4 days; hepatic or renal impairment warrants slower titration and close monitoring.

Dosing and Administration

• Titrate: Day 1 1 mg BID → Day 2 2 mg BID → Day 3 4 mg BID → Day 4 6 mg BID → Day 5 8 mg BID; maintenance target 6–12 mg BID (12–24 mg/day).
• Target and maximum doses are typically reduced by 50% in CYP2D6 poor metabolizers or when co-administered with strong CYP2D6 inhibitors (fluoxetine, paroxetine).
• Dose reductions (often ~50%) are commonly used with strong CYP3A4 inhibitors (ketoconazole, clarithromycin), with attention to QTc. Strong CYP3A4 inducers (carbamazepine, rifampin) can markedly reduce exposure and are generally avoided.
• If therapy is interrupted for ≥3 consecutive days, titration is typically restarted at 1 mg twice daily to reduce orthostatic events.

Adverse Effects

Interactions

• Strong CYP2D6 inhibitors or poor metabolizer status often require halving the iloperidone dose.
• Strong CYP3A4 inhibitors elevate exposure—dose reduction by ~50% is common, with QTc monitoring often considered.
• Strong CYP3A4 inducers can markedly reduce serum levels and are generally avoided due to potential loss of efficacy.
• Additive QTc prolongation with drugs such as amiodarone, sotalol, or methadone; ECG monitoring is often considered or alternatives may be preferred.
• Concomitant antihypertensives, alcohol, or CNS depressants may potentiate hypotension and sedation.

Other Useful Information

• Orthostatic vitals are often checked at baseline, during titration, and after dose increases.
• Patient education often includes restarting titration if therapy is interrupted and reporting presyncope or palpitations.
• Routine metabolic monitoring is continued even though average weight gain is limited overall.

References

1. FANAPT (iloperidone) prescribing information — DailyMed (2024)
2. Efficacy and safety of iloperidone in acute schizophrenia — Schizophrenia Research (2008)
3. Iloperidone IN THE Treatment OF Schizophrenia: AN Evidence Based Review OF ITS Place IN Therapy — Core Evidence (2016)
4. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia — American Psychiatric Association (2020)Guidelineschizophreniaclinical
5. Iloperidone FOR Schizophrenia: Updated Systematic Review AND Meta Analysis — International Journal of Neuropsychopharmacology (2019)