paliperidone

General Information

Paliperidone (brand Invega) is the active metabolite of risperidone, delivered as extended-release tablets and long-acting injectable palmitate formulations for schizophrenia and schizoaffective disorder.

Paliperidone mechanism of action centers on dopamine D2 and serotonin 5-HT2A antagonism, mirroring risperidone while adding α1/α2 and H1 blockade that supports negative-symptom targeting.

This profile focuses on oral ER use and palmitate LAIs (Sustenna, Trinza, Hafyera) for adherence support.

Review cross-titration nuances alongside the Risperidone profile since the agents share metabolic pathways and prolactin considerations.

The contrast view and the Paliperidone evidence feed can help contextualize switches and depot escalation planning.

Steady plasma levels and LAI options make paliperidone central to relapse prevention; prolactin elevation and weight gain require monitoring.

Mechanism of Action

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

Paliperidone mechanism of action antagonizes dopamine D2 and serotonin 5-HT2A receptors, mirroring risperidone’s profile with additional α1, α2, and H1 antagonism for negative-symptom coverage.

Minimal muscarinic activity yields low anticholinergic burden.

• Antagonist at dopamine D2 receptors.
• Antagonist at serotonin 5-HT2A/5-HT2C/5-HT7 receptors.
• Antagonist at adrenergic α1/α2 and histamine H1 receptors.
• Minimal muscarinic receptor affinity.

Metabolism and Pharmacokinetics

• Paliperidone pharmacokinetics leverage the OROS extended-release system; once-daily ER tablets reach peak levels ~24 hours post-dose and food increases exposure by ~60%.
• Approximately 74% protein bound; volume of distribution ~487 L.
• Minimal hepatic metabolism; primarily renally excreted unchanged (~59%).
• Oral paliperidone half-life averages ~23 hours, while paliperidone palmitate LAIs exhibit apparent half-lives spanning 25–139 days depending on PP1M/PP3M/PP6M interval.
• Eliminated largely in urine with minor fecal excretion.

Dosing and Administration

• Paliperidone extended-release tablets: start 6 mg once daily; adjust 3–12 mg/day (max 12 mg/day; adolescents start at 3 mg daily).
• Schizoaffective disorder: initiate 6 mg once daily; adjust 3–12 mg/day as monotherapy or adjunct (max 12 mg/day).
• Renal impairment: reduce starting dose to 3 mg (CrCl 50–79) or 1.5 mg (CrCl 10–49); avoid if CrCl <10.
• Invega Sustenna: loading 234 mg (day 1 deltoid) and 156 mg (day 8 deltoid) then 39–234 mg monthly (max 234 mg monthly).
• Invega Trinza: eligible after ≥4 months on Sustenna; dose conversion based on last Sustenna dose (e.g., 117 mg → 410 mg quarterly; max 819 mg quarterly).
• Invega Hafyera: eligible after stability on Trinza; 1,092 mg or 1,560 mg every 6 months (max 1,560 mg every 6 months).

Adverse Effects

Interactions

• Strong CYP3A4 or P-gp inducers (carbamazepine, rifampin, St. John’s wort) decrease exposure; avoidance or closer monitoring is often used.
• Strong P-gp inhibitors (clarithromycin, verapamil) may increase exposure; monitoring for adverse effects is typical.
• Concurrent risperidone elevates paliperidone levels; overlap may require dose adjustment.
• Additive CNS depression with alcohol, benzodiazepines, opioids.
• May antagonize dopaminergic agents; paliperidone is often avoided in Parkinson’s disease when possible.

Other Useful Information

• Renal function strongly influences dosing; creatinine clearance is typically assessed at baseline and rechecked periodically.
• Counseling often covers prolactin-related symptoms and fertility concerns.
• Routine metabolic monitoring remains standard despite moderate weight gain risk.
• Manufacturer algorithms are typically used, and oral tolerability is commonly confirmed before LAI initiation.
• Adherence planning is especially important when transitioning from oral to LAI regimens.
• The LAI Navigator can support Sustenna/Trinza/Hafyera planning, alongside the Risperidone profile for cross-titration context and the bipolar disorder hub for schizoaffective mood strategies.

References

1. INVEGA ER prescribing information — DailyMed / Janssen Pharmaceuticals (2025)
2. INVEGA SUSTENNA prescribing information — DailyMed / Janssen Pharmaceuticals (2025)
3. INVEGA TRINZA (paliperidone palmitate) prescribing information — DailyMed / Janssen Pharmaceuticals (2025)
4. INVEGA HAFYERA (paliperidone palmitate) prescribing information — DailyMed / Janssen Pharmaceuticals (2025)
5. Efficacy, Safety AND Early Response OF Paliperidone Extended Release Tablets — Schizophrenia Research (2007)
6. Paliperidone palmitate maintenance treatment in delaying time to relapse in patients with schizophrenia — Schizophrenia Research (2010)
7. Savitz2016 Paliperidone Pp3m