Risperidone

Indications

• Schizophrenia in adults and in adolescents ages 13-17, both acutely and for maintenance, with long-acting injectables approved for maintenance therapy.
• Acute manic or mixed episodes of bipolar I disorder in patients ages 10-17 and in adults, as monotherapy or as adjunct to lithium or valproate in adults.
• Irritability associated with autistic disorder, including aggression, deliberate self-injury, and temper tantrums, in children ages 5-16.
• Risperdal Consta is also approved as monotherapy or adjunct to lithium or valproate for maintenance treatment of bipolar I disorder in adults.
• Off-label uses include Tourette's disorder, treatment-resistant depression augmentation, and short-term management of agitation in delirium.

Mechanism of action

• Potent antagonist at dopamine D2 receptors, giving reliable antipsychotic efficacy but a steep dose-dependent rise in extrapyramidal symptoms.
• Even more potent 5-HT2A antagonism, which softens striatal D2 blockade at low doses and contributes to effect on negative symptoms.
• Strong alpha-1 and alpha-2 adrenergic blockade produces orthostatic hypotension, dizziness, and reflex tachycardia during titration.
• Tuberoinfundibular D2 blockade raises prolactin more than any other second-generation agent except paliperidone, its own active metabolite.
• Moderate histamine H1 affinity gives sedation and appetite stimulation, but muscarinic affinity is negligible.

Pharmacokinetics

• Well absorbed orally with about 70 percent bioavailability, unaffected by food, and available as tablet, orally disintegrating tablet, and solution.
• CYP2D6 converts risperidone to 9-hydroxyrisperidone, which is paliperidone and is equally active, so the two drugs share a pharmacology.
• Half-life is about 3 hours for parent drug but roughly 20 hours for the active moiety, extending to 24 hours in CYP2D6 poor metabolizers.
• Renal clearance dominates for the active metabolite, so creatinine clearance below 30 mL/min roughly doubles exposure.
• Steady state is reached in about 5 days on oral dosing but takes 4-6 weeks for the long-acting injectable formulations.

Dosing

• Schizophrenia in adults: start 2 mg/day PO, increase to 4 mg on day 2, target 4-8 mg/day, with a labeled maximum of 16 mg/day.
• Efficacy plateaus near 6 mg/day while extrapyramidal symptoms climb steeply above it, so most patients should stay at or below that dose.
• Adolescents with schizophrenia start 0.5 mg/day and target 3 mg/day; autism-related irritability starts at 0.25-0.5 mg/day by body weight.
• Risperdal Consta is 12.5-50 mg IM every 2 weeks with 3 weeks of oral overlap; Uzedy is subcutaneous monthly or every 2 months without overlap.
• In renal or hepatic impairment start 0.5 mg twice daily and titrate in 0.5 mg increments no faster than weekly above 1.5 mg twice daily.
• Taper over weeks when stopping, since the short parent half-life makes abrupt discontinuation prone to rebound psychosis and cholinergic rebound.

Adverse effects

• Hyperprolactinemia is near universal at higher doses, causing amenorrhea, galactorrhea, gynecomastia, sexual dysfunction, and bone density loss.
• Extrapyramidal symptoms including akathisia, parkinsonism, and dystonia rise sharply above 6 mg/day and often require a dose reduction.
• Weight gain is moderate at roughly 2-4 kg over the first months, with intermediate risk of dyslipidemia and glucose dysregulation.
• Sedation, orthostatic hypotension, dizziness, and tachycardia are common early and are the main reason for slow initial titration.
• Tardive dyskinesia, neuroleptic malignant syndrome, and rare priapism from alpha blockade are the serious events that change prescribing.

Monitoring

• Weight, BMI, and blood pressure at baseline and each visit early on, with fasting glucose or A1c and lipids at baseline, 12 weeks, and annually.
• Check a prolactin level whenever amenorrhea, galactorrhea, gynecomastia, or sexual dysfunction appears, rather than screening everyone.
• AIMS at baseline and every 6-12 months, more often in older adults, women, and anyone with a history of extrapyramidal reactions.
• Orthostatic vital signs during titration and after any dose increase, especially in older or volume-depleted patients.
• Consider bone density assessment in patients with prolonged hyperprolactinemia and amenorrhea or hypogonadism.

Interactions

• CYP2D6 inhibitors such as fluoxetine, paroxetine, and bupropion raise the active moiety substantially and may require a dose reduction.
• Carbamazepine and other strong inducers can cut the active moiety by half; increase the dose and reverse the change when the inducer stops.
• Additive hypotension with antihypertensives and additive sedation with benzodiazepines, opioids, alcohol, and other CNS depressants.
• Risperidone antagonizes levodopa and other dopamine agonists, making it a poor choice in Parkinson disease psychosis.
• QT prolongation is modest but additive with other QT-prolonging drugs and with electrolyte depletion from diuretics.

Special populations

• Third-trimester exposure carries risk of neonatal extrapyramidal and withdrawal symptoms; the National Pregnancy Registry tracks outcomes.
• Excreted into breast milk at low relative infant dose, so breastfeeding is generally acceptable with monitoring for infant sedation.
• Approved from age 5 for autism-related irritability, where weight gain, sedation, and prolactin elevation are more pronounced than in adults.
• In older adults start at 0.25-0.5 mg/day and titrate slowly given fall risk, orthostasis, and the dementia mortality warning.
• Reduce the starting dose and titration rate in renal impairment with creatinine clearance under 30 mL/min and in hepatic impairment.

Clinical pearls

• Above 6 mg/day you buy extrapyramidal symptoms, not efficacy; go up only with clear evidence of benefit.
• Any new amenorrhea or galactorrhea should trigger a prolactin level and a switch, not reassurance.
• Risperidone is a prodrug for paliperidone, so a paliperidone switch is a formulation change.