Mechanism of Action for Risperdal (Risperidone)
Risperidone's therapeutic activity is mediated through combined antagonism of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptors, though the precise mechanism in treating schizophrenia remains incompletely understood. 1
Primary Receptor Activity
Risperidone acts as a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1 histaminergic receptors. 1
The clinical effect results from combined concentrations of risperidone and its major active metabolite, 9-hydroxyrisperidone, which has similar pharmacological activity to the parent compound. 1
The potent central antagonism of both 5-HT2 and D2 receptors distinguishes risperidone from traditional antipsychotics and contributes to its atypical profile. 2
Secondary Receptor Interactions
Risperidone has low to moderate affinity (Ki of 47 to 253 nM) for serotonin 5HT1C, 5HT1D, and 5HT1A receptors. 1
It demonstrates weak affinity (Ki of 620 to 800 nM) for dopamine D1 receptors and haloperidol-sensitive sigma sites. 1
Risperidone has no affinity for cholinergic muscarinic or β1 and β2 adrenergic receptors when tested at concentrations >10-5 M. 1
The significant α-noradrenergic antagonism contributes to its effectiveness in treating various types of hallucinations. 3
Clinical Implications of Mechanism
The combination of D2 and 5HT2 antagonism explains risperidone's superior efficacy against both positive and negative symptoms of schizophrenia compared to conventional antipsychotics. 4
Antagonism at receptors other than D2 and 5HT2 may explain additional therapeutic effects and side effects of risperidone. 1
The balanced serotonin-dopamine antagonism results in decreased occurrence of extrapyramidal side effects compared to traditional neuroleptics, though risperidone appears more likely to produce extrapyramidal symptoms than other atypical agents. 5, 4
The H1 histaminergic receptor antagonism contributes to sedation and somnolence, while α1 adrenergic antagonism can cause orthostatic hypotension. 5
The mechanism does not appear to be fundamentally altered by intellectual disability, though children with intellectual developmental disorder may show increased sensitivity to side effects. 5