Paliperidone (Invega)
SGA • Last reviewed 2025-09-23
General information
Paliperidone (9-hydroxyrisperidone) is the primary active metabolite of risperidone and is approved for schizophrenia (adults and adolescents) and schizoaffective disorder (as monotherapy or adjunct to mood stabilizers/antidepressants). Extended-release oral tablets employing osmotic-controlled release oral delivery system (OROS) technology were approved in 2006, offering once-daily dosing without cross-titration. Paliperidone serves as the oral anchor for long-acting injectable paliperidone palmitate formulations (Invega Sustenna, Trinza, Hafyera).
Tablets are available in 1.5, 3, 6, 9, and 12 mg strengths. The recommended starting dose for schizophrenia is 6 mg once daily in the morning, taken with or without food but consistently. Dose adjustments are based on response and tolerability, with an effective range of 3-12 mg/day. For schizoaffective disorder the suggested target is 6-12 mg/day; adjunctive therapy with mood stabilizers or antidepressants does not require paliperidone dose changes. Renal impairment requires significant dose reductions because the drug is primarily renally cleared.
Paliperidone is a potent antagonist at dopamine D2 and serotonin 5-HT2A receptors with additional antagonism at alpha1, alpha2, and H1 receptors. Compared with risperidone it has minimal hepatic metabolism and lower potential for drug-drug interactions but similar prolactin elevation and extrapyramidal risk at higher doses. The absence of muscarinic affinity reduces anticholinergic adverse events.
Pharmacokinetic properties reflect the OROS delivery system: absorption begins within the stomach and continues through the colon, producing a smooth plasma concentration-time curve. Peak levels occur about 24 hours after dosing and the terminal half-life is ~23 hours, supporting once-daily use. Approximately 59% of a dose is excreted unchanged in urine, and exposure increases 1.5-3 fold in moderate-to-severe renal impairment; hepatic impairment has minimal impact because metabolism is limited.
Dosing & administration
Schizophrenia: 6 mg once daily in the morning; adjust every 4-5 days by 3 mg increments within the 3-12 mg/day range.
Schizoaffective disorder: 6-12 mg once daily; can be combined with lithium, valproate, or antidepressants without dosage change.
Renal impairment (CrCl 50-80 mL/min): start 3 mg once daily, maximum 6 mg; CrCl 10-49 mL/min start 1.5 mg once daily, maximum 3 mg.
No dosage adjustment is needed for mild-to-moderate hepatic impairment.
Dose adjustments
- Normal renal function
- Start 6 mg QAM; titrate 3-12 mg/day.
- CrCl 50-80 mL/min
- Start 3 mg QAM; do not exceed 6 mg/day.
- CrCl 10-49 mL/min
- Start 1.5 mg QAM; maximum 3 mg/day; XR tablets not recommended if CrCl <10 mL/min.
- Transition to LAI
- Establish tolerability with oral paliperidone or risperidone before initiating paliperidone palmitate injections.
Mechanism of action
Paliperidone blocks D2 receptors in the mesolimbic pathway, reducing positive symptoms, while 5-HT2A antagonism restores dopaminergic tone in the nigrostriatal pathway, limiting EPS compared with pure D2 blockade.
High affinity for 5-HT7 receptors may contribute to procognitive and mood-stabilizing effects suggested in schizoaffective disorder trials. Alpha1 antagonism accounts for orthostatic hypotension, and H1 antagonism yields moderate weight gain and sedation; lack of muscarinic binding minimizes anticholinergic burden.
- D2 Ki about 2.8 nM with high receptor occupancy at therapeutic doses.
- 5-HT2A Ki about 0.8 nM, promoting dopamine release in striatum.
- Negligible affinity for muscarinic receptors.
Metabolism & pharmacokinetics
Following oral dosing the OROS system delivers paliperidone gradually; Tmax occurs around 24 hours and steady state is reached in 4-5 days. Food modestly increases Cmax (about 60%) and AUC (about 50%) but the effect is not clinically significant; consistent administration is preferred.
Because renal elimination dominates, exposure increases substantially with declining creatinine clearance. Hemodialysis removes little drug; use is not recommended in end-stage renal disease. Minimal CYP involvement reduces interaction potential compared with risperidone.
- Absolute oral bioavailability
- About 28%
- Tmax
- About 24 h (median)
- Terminal half-life
- About 23 h
- Renal excretion
- About 59% unchanged in urine
Drug interactions
Coadministration with strong CYP3A4 or P-gp inducers (carbamazepine) decreases paliperidone concentrations by roughly one third; monitor and consider dose increase.
Paliperidone may enhance QT prolongation when combined with other QT-prolonging drugs; avoid combinations with class IA or III antiarrhythmics if possible.
Orthostatic hypotension risk increases with antihypertensives due to additive alpha1 blockade.
| Mechanism | Agents / factors | Management |
|---|---|---|
| Induction of P-gp/CYP3A4 | Carbamazepine, rifampin | Monitor efficacy; dosage increase may be needed or switch to a non-inducing agent. |
| Additive QT prolongation | Class IA/III antiarrhythmics, fluoroquinolones | Obtain baseline ECG when risk factors present; correct electrolytes. |
| Additive hypotension | Antihypertensives, alpha-blockers | Monitor blood pressure during initiation and dose adjustments. |
Monitoring & safety checks
Renal function (serum creatinine, eGFR)
Baseline and at least annually • Dosing depends on renal clearance.
Prolactin-related symptoms
Each visit • Paliperidone raises prolactin leading to galactorrhea, menstrual changes, or sexual dysfunction.
Weight, BMI, fasting lipids and glucose
Baseline, 12 weeks, annually • Moderate metabolic risk similar to risperidone.
EPS assessment (AIMS or SAS)
Baseline and periodically • Dose-related extrapyramidal symptoms can occur.
Counsel patients about the OROS shell appearing in stool; reassure that drug release is complete.
Because paliperidone elevates prolactin more than some SGAs, proactively inquire about sexual and menstrual side effects.
Discontinuation guidance
When feasible taper paliperidone over 1-2 weeks to reduce relapse risk; abrupt stop can precipitate rebound psychosis or mood symptoms, especially in schizoaffective disorder.
Transition to long-acting injection should overlap with oral dosing until the first injection reaches steady release (for example continue oral medication for one week after the first Sustenna dose if clinically indicated).
Special populations
Renal impairment: reduce starting and maximum doses per creatinine clearance; avoid XR tablets if CrCl under 10 mL/min because of limited data.
Hepatic impairment: mild-to-moderate impairment does not require adjustment, but monitor for orthostasis in cirrhosis.
Pregnancy: third-trimester exposure associated with neonatal EPS or withdrawal; weigh maternal benefit versus fetal risk and monitor neonates.
Older adults: greater sensitivity to orthostatic hypotension and QT prolongation; start at lower end of dosing range.
Adverse effects
Common: akathisia, tremor, somnolence, orthostatic hypotension, weight gain.
Endocrine: prolactin elevation leading to galactorrhea, gynecomastia, amenorrhea.
Serious: neuroleptic malignant syndrome, tardive dyskinesia, QT prolongation in susceptible patients.
LAI availability
Clozapine does not have an FDA-approved long-acting injectable formulation. Related LAI options for the treatment class are listed below.
References
- INVEGA (paliperidone) extended-release tablets prescribing information — DailyMed / Janssen Pharmaceuticals (2025)
- Efficacy, safety and early response of paliperidone extended-release tablets — Schizophrenia Research (2007) DOI: 10.1016/j.schres.2007.03.003
- A critical appraisal of paliperidone long-acting injection in schizoaffective disorder — Therapeutics and Clinical Risk Management (2016) DOI: 10.2147/TCRM.S81581
Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.