Paliperidone

Atypical antipsychotic – active metabolite of risperidone

ATC code: N05AX13

Updated 12 Aug 2026 · Methodology

Indications

Schizophrenia

First line

First-line for schizophrenia per 2020 and NG178. Starting dose 6 mg once daily in the morning (OROS form – do not break), therapeutic range 3–12 mg. Long-acting injectables are the main advantage over risperidone: Xeplion (paliperidone palmitate) monthly, Trevicta every 3 months, Byannli every 6 months – convenient with adherence issues. The Huhn 2019 network meta-analysis showed efficacy comparable to risperidone; prolactin-related effects are similar.

Sources

ICD-10: F20 · ICD-11: 6A20

Marketing claims without evidence base

The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.

Stress and anxiety

Not recommended

Paliperidone is an antipsychotic, the active metabolite of risperidone. It is prescribed only for schizophrenia and schizoaffective disorder ( 2020 guidelines). For acute stress, paliperidone does not work: no clinical studies of such use exist. The drug has serious side effects: extrapyramidal symptoms (tremor, muscle stiffness), QT-interval prolongation, hyperprolactinemia, metabolic syndrome. In elderly patients with dementia, it increases mortality ( boxed warning). If paliperidone was prescribed for stress, consider seeking a second opinion.

Sources

ICD-10: F41.9 · ICD-11: 6B0Z

How to read tiers A–F

AStrong evidence – first or second line in international guidelines
BRecommended in selected cases
CStudy data contradict each other
DBenefit not proven, no documented harm
FDocumented harm, or risk without benefit

Mechanism of action

9-hydroxyrisperidone – the main active metabolite of risperidone, marketed as a separate drug. A D2 dopamine and 5-HT2A serotonin receptor antagonist. Compared with risperidone, more stable pharmacokinetics via OROS (osmotic release oral system) and long-acting injectables (Xeplion monthly, Trevicta every 3 months, Byannli every 6 months). Less CYP metabolism – suitable in hepatic disease. Predominantly renally excreted.

Safety

Boxed warning

FDA boxed warning: increased mortality in elderly patients with dementia treated with atypical antipsychotics. Not for dementia-related psychosis.

Contraindications

Paliperidone or risperidone hypersensitivity
Dementia in older adults
Parkinson's disease, Lewy body dementia
QT prolongation
Pregnancy – with caution
Lactation
Age under 12

Serious adverse effects

Neuroleptic malignant syndrome
Tardive dyskinesia
Cerebrovascular events in older adults with dementia
QT prolongation and ventricular arrhythmias
Type 2 diabetes
Thromboembolic events

Common adverse effects

Drowsiness
Hyperprolactinemia (galactorrhea, amenorrhea, sexual dysfunction)
Weight gain
Extrapyramidal disorders
Orthostatic hypotension
Tachycardia

Pregnancy: can you take Paliperidone?

T3 use carries neonatal extrapyramidal and withdrawal risk.

Breastfeeding: can you take Paliperidone?

Moderate milk concentrations. Use during lactation cautiously with monitoring of infant sedation, weight gain, and extrapyramidal symptoms.

Calculate RID Full profile on NIH LactMed ↗

Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.

Practical notes

Timing and administration

Oral OROS form is taken in the morning with food – meals raise bioavailability by 50–60%. Do not break or chew – this disrupts controlled release. Intact tablet «shell» is excreted in stool – this is normal. Long-acting injectables are given IM into deltoid or gluteal muscle. Adjust dose in renal impairment: eGFR 50–80 – max 6 mg; eGFR under 50 – max 3 mg.

Label mentions23 mentions

Verbatim lines from the interaction sections, in the language of the label

From this drug’s label

MajorCarbamazepine
«7. DRUG INTERACTIONS: Strong CYP3A4/P-glycoprotein (P-gp) inducers: It may be necessary to increase the dose of paliperidone when a strong inducer of both CYP3A4 and P-gp (e.g., carbamazepine) is…»
FDA, section 7 · Open on DailyMed
MajorRisperidone
«Uso c onc omitante de paliperidona y r i sper i dona: No se recomienda el uso de paliperidona con risperidona oral dado que paliperidona es el m eta bol it o activo de risperidona y que la…»
AEMPS, section 4.5 · Open on CIMA
Moderateantiarrítmicosclass named in the label
«Se aconseja precaución cuando se recete paliperidona junto con medicamentos que prolongan el i nt e rva l o QT, p. ej., antiarrítmicos de las clases IA (p. ej., quinidina, disopiramida) y III (p…»
AEMPS, section 4.5 · Open on CIMA
Moderateantidepresivos tricíclicosclass named in the label
«Posibilidad de que paliperidona a f ec te a otros m e di ca m e ntos: Se recomienda precaución cuando se coadministre paliperidona junto con otros medicamentos que disminuyan el umbral convulsivo (es…»
AEMPS, section 4.5 · Open on CIMA
Moderateantihistamínicosclass named in the label
«Se aconseja precaución cuando se recete paliperidona junto con medicamentos que prolongan el i nt e rva l o QT, p. ej., antiarrítmicos de las clases IA (p. ej., quinidina, disopiramida) y III (p…»
AEMPS, section 4.5 · Open on CIMA
ModerateCarbamazepine
«Posibilidad de que otros m e di c amentos a f ec ten a paliperidona: la orina sugiere que durante la administración concomitante con carbamazepina, hubo un e f ect o mínimo en el metabolismo del CYP…»
AEMPS, section 4.5 · Open on CIMA
ModerateClozapine
«Posibilidad de que paliperidona a f ec te a otros m e di ca m e ntos: Se recomienda precaución cuando se coadministre paliperidona junto con otros medicamentos que disminuyan el umbral convulsivo (es…»
AEMPS, section 4.5 · Open on CIMA
ModerateDisopyramide
«Se aconseja precaución cuando se recete paliperidona junto con medicamentos que prolongan el i nt e rva l o QT, p. ej., antiarrítmicos de las clases IA (p. ej., quinidina, disopiramida) y III (p…»
AEMPS, section 4.5 · Open on CIMA
ModerateISRSclass named in the label
«Posibilidad de que paliperidona a f ec te a otros m e di ca m e ntos: Se recomienda precaución cuando se coadministre paliperidona junto con otros medicamentos que disminuyan el umbral convulsivo (es…»
AEMPS, section 4.5 · Open on CIMA
Moderatemedicamentos que prolongan el QTclass named in the label
«Intervalo QT: Hay que tener precaución cuando se prescriba paliperidona a pacientes con enfermedad cardiovascular conocida o con antecedentes familiares de prolongación del QT, y cuando se usa a la…»
AEMPS, section 4.4 · Open on CIMA
ModerateMethylphenidate
«Discinesia tardía/síntomas extrapiramidales: Se requiere precaución en pacientes que reciben tanto psicoestimulantes (p. ej., metilfenidato) como paliperidona de forma concomitante, ya que pueden…»
AEMPS, section 4.4 · Open on CIMA
Moderateopioidesclass named in the label
«Posibilidad de que paliperidona a f ec te a otros m e di ca m e ntos: Los efectos principales de paliperidona se ejercen en el SNC (ver sección 4.8), por lo que paliperidona s e debe utilizar con…»
AEMPS, section 4.5 · Open on CIMA
ModerateQuinidine
«Se aconseja precaución cuando se recete paliperidona junto con medicamentos que prolongan el i nt e rva l o QT, p. ej., antiarrítmicos de las clases IA (p. ej., quinidina, disopiramida) y III (p…»
AEMPS, section 4.5 · Open on CIMA
ModerateRifampicin
«Posibilidad de que otros m e di c amentos a f ec ten a paliperidona: la orina sugiere que durante la administración concomitante con carbamazepina, hubo un e f ect o mínimo en el metabolismo del CYP…»
AEMPS, section 4.5 · Open on CIMA
ModerateSotalol
«Se aconseja precaución cuando se recete paliperidona junto con medicamentos que prolongan el i nt e rva l o QT, p. ej., antiarrítmicos de las clases IA (p. ej., quinidina, disopiramida) y III (p…»
AEMPS, section 4.5 · Open on CIMA
ModerateTramadol
«Posibilidad de que paliperidona a f ec te a otros m e di ca m e ntos: Se recomienda precaución cuando se coadministre paliperidona junto con otros medicamentos que disminuyan el umbral convulsivo (es…»
AEMPS, section 4.5 · Open on CIMA
CYP2D6 inhibitorsclass named in the label
«Potential for Other Drugs to Affect Paliperidone: Paliperidone is metabolized to a limited extent by CYP2D6 [see Clinical Pharmacology (12.3) ]. In an interaction study in healthy subjects in which a…»
FDA, section 7 · Open on DailyMed
Lithium
«Posibilidad de que paliperidona a f ec te a otros m e di ca m e ntos: No se han realizado estudios de interacciones entre paliperidona y el litio, pero es poco probable que s e produzca una…»
AEMPS, section 4.5 · Open on CIMA
Lithium
«Potential for Paliperidone to Affect Other Drugs: Pharmacokinetic interaction between lithium and paliperidone is unlikely.»
FDA, section 7 · Open on DailyMed
Paroxetine
«Posibilidad de que otros m e di c amentos a f ec ten a paliperidona: Los estudios in vitro indican que las enzimas CYP2D6 y CYP3A4 pueden tener una i nt e rvenc i ón mínima en el metabolismo de…»
AEMPS, section 4.5 · Open on CIMA
Paroxetine
«Potential for Other Drugs to Affect Paliperidone: Paliperidone is metabolized to a limited extent by CYP2D6 [see Clinical Pharmacology (12.3) ]. In an interaction study in healthy subjects in which a…»
FDA, section 7 · Open on DailyMed

From other drugs’ labels

MajorRisperidone
«Paliperidona: No se recomienda la administración concomitante de risperidona oral con paliperidona ya que paliperidona es el metabolito activo de risperidona y la combinación de los dos puede suponer…»
AEMPS, section 4.5 · Open on CIMA
Carbamazepine
«Fármacos que pueden disminuir los niveles plasmáticos de carbamazepina: Antipsicóticos: clozapina, haloperidol y bromperidol, olanzapina, quetiapina, risperidona, ziprasidona, aripiprazol…»
AEMPS, section 4.5 · Open on CIMA

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Frequently asked

What is Paliperidone used for?

Paliperidone is evaluated for the following indications with varying evidence strength: Schizophrenia (evidence tier A), Stress and anxiety (evidence tier F). See the full indication matrix with dosing and citations above on this page.

What are the side effects of Paliperidone?

Common side effects of Paliperidone (≥ 1 in 100): Drowsiness, Hyperprolactinemia (galactorrhea, amenorrhea, sexual dysfunction), Weight gain, Extrapyramidal disorders, Orthostatic hypotension, Tachycardia. See the Safety section for uncommon and serious reactions.

Is Paliperidone safe during pregnancy?

T3 use carries neonatal extrapyramidal and withdrawal risk.

Is Paliperidone compatible with breastfeeding?

Moderate milk concentrations. Use during lactation cautiously with monitoring of infant sedation, weight gain, and extrapyramidal symptoms.

Who should not take Paliperidone?

Paliperidone is contraindicated in: Paliperidone or risperidone hypersensitivity; Dementia in older adults; Parkinson's disease, Lewy body dementia; QT prolongation; Pregnancy – with caution. Full list in the Safety section.

Does Paliperidone carry an FDA boxed warning?

FDA boxed warning: increased mortality in elderly patients with dementia treated with atypical antipsychotics. Not for dementia-related psychosis.

Official sources

Direct links to regulator labels. Open in a new tab.

AEMPS / CIMALabel dated 06/21/2024
EMALabel dated 06/18/2020
FDA / DailyMedLabel dated 07/28/2026

Other drugs in this group

Passionflower (Passiflora incarnata, aerial parts), Phenazepam, Phenibut, Pimavanserin, Quetiapine, Alprazolam, Clobazam, Hydroxyzine