Risperidone

Mechanism

Chemical and Commercial Profile

Common trade names: Risperdal, Diaforin, Arketin.
Group: Atypical antipsychotic, derived from benzisoxazoles.

Mechanism of Action

Acts as a balanced dual antagonist of serotonergic and dopaminergic receptors:

• Selective antagonist of 5-HT_2A serotonergic receptors (K_i ≈ 0.5 nM): This blockade in the nigrostriatal pathway partially prevents the development of extrapyramidal symptoms at standard therapeutic doses.
• Selective antagonist of dopamine D₂ receptors (K_i ≈ 3 nM): It exerts its pure antipsychotic action in the mesolimbic pathway.

It also has affinity for α₁ and α₂ adrenergic receptors, as well as for H₁ histaminergic receptors, but lacks affinity for muscarinic acetylcholine receptors.

Pharmacokinetics

Pharmacokinetics

• Absorption: Rapid after oral intake; 70% bioavailability. Not influenced by the presence of food.
• Metabolism: Hepatic catalyzed by the enzyme CYP2D6, through active hydroxylation that generates the biologically equivalent metabolite 9-hydroxyrisperidone (paliperidone). Together they constitute the "active antipsychotic fraction."
• Excretion: Renal (70%) and biliary/fecal (14%).
• Half-life (t_1/2): Risperidone: 3 hours (in rapid metabolizers). 9-hydroxyrisperidone: 24 hours. This allows for a single daily administration schedule.

Indicators and dose

Indications

• Schizophrenia and acute psychotic episodes.
• Short-term treatment (up to 6 weeks) of persistent aggression in patients with moderate to severe Alzheimer's dementia who do not respond to other non-pharmacological measures.
• Treatment of acute or mixed mania in bipolar type I disorder.
• Conduct disorder and aggression in children over 5 years of age with documented intellectual disability.

Dosage and Settings

• Schizophrenia: Start with 2 mg/day (divided into two doses or a single dose at night); optimal therapeutic range of 4 mg to 6 mg/day. Doses greater than 10 mg/day rarely provide additional benefit and markedly increase extrapyramidal adverse effects.
• Aggressiveness in Dementia: Extremely low doses: Start with 0.25 mg twice a day; gradually increase to a usual maximum of 1.5 mg to 2 mg/day total.
• Renal / Liver Failure: Moderate to severe (Cl_Cr < 30 ml/min): Reduce the starting dose to 0.5 mg twice daily and limit increases to 0.5 mg weekly to a safe maximum of 3 mg/day.

Security

Contraindications

• Known hypersensitivity to the compound or paliperidone.
• Active Lewy body dementia or pre-existing severe parkinsonism.

Adverse Effects (ADR)

Risk of stroke in senile dementia

In randomized clinical trials with elderly patients diagnosed with Alzheimer's dementia or vascular dementia, treatment with risperidone doubled to tripled the incidence of cerebrovascular accidents (CVA) and overall mortality compared to the placebo group. It is advisable to strictly limit the use of risperidone in this population and only as temporary rescue therapy in severe destructive aggression.

• Pronounced hyperprolactinemia: It is the atypical antipsychotic that induces greater elevations in plasma prolactin, similar to typical neuroleptics (causing galactorrhea, erectile dysfunction, menstrual irregularities and increased risk of long-term osteoporosis).
• CNS: Dose-dependent extrapyramidalism. At doses higher than 6 mg/day, D₂ blockade overcomes serotonergic compensation, significantly increasing the incidence of tremor, rigidity, and akathisia.
• Metabolic: Moderate increase in body weight, late-onset dyslipidemia.

Clinical Interactions

• Potent CYP2D6 inhibitors: Fluoxetine, paroxetine or bupropion increase plasma levels of risperidone parent, requiring close monitoring of extrapyramidal effects and an electrocardiogram.
• CYP3A4 inducers: Carbamazepine reduces the plasma concentration of the active antipsychotic fraction by 50%.

Pregnancy and Breastfeeding

FDA Category: C. Like other antipsychotics, it is associated with the risk of neonatal transient dystonias and mild motor development delay after exposure in the third trimester. Breastfeeding: Compatible with caution. The infant receives less than 4.5% of the purified maternal dose; monitor sedation, weight gain and reflex hypertonia.