Mechanism of Action of Risperidone
Risperidone exerts its therapeutic effects through combined antagonism of dopamine D2 and serotonin 5-HT2 receptors, with the clinical activity resulting from both the parent compound and its equipotent metabolite, 9-hydroxyrisperidone. 1
Primary Receptor Mechanisms
The FDA-approved mechanism indicates that while the exact mechanism in schizophrenia remains unknown, risperidone's therapeutic activity is proposed to be mediated through combined D2 and 5-HT2 receptor antagonism 1. This dual antagonism distinguishes risperidone from traditional antipsychotics and contributes to its atypical profile 2.
Risperidone demonstrates selective monoaminergic antagonism with high binding affinity (Ki of 0.12 to 7.3 nM) for:
- Serotonin 5-HT2 receptors 1
- Dopamine D2 receptors 1
- α1 and α2 adrenergic receptors 1
- H1 histaminergic receptors 1
The serotonin receptor affinity is approximately 200 times greater than haloperidol, while dopamine antagonistic potency is comparable to haloperidol 3.
Active Metabolite Contribution
The clinical effect results from combined concentrations of risperidone and 9-hydroxyrisperidone, which has similar pharmacological activity to the parent compound 1. Both moieties contribute equally to the antipsychotic effect, forming the active therapeutic entity 2, 3.
Secondary Receptor Activity
Risperidone acts as an antagonist at additional receptors with lower potency 1:
- Low to moderate affinity (Ki 47-253 nM): 5-HT1C, 5-HT1D, and 5-HT1A receptors 1
- Weak affinity (Ki 620-800 nM): Dopamine D1 receptors and haloperidol-sensitive sigma sites 1
- No affinity: Cholinergic muscarinic or β1/β2 adrenergic receptors 1
Clinical Implications of Mechanism
The American Academy of Sleep Medicine notes that risperidone's combined 5-HT2 and D2 antagonism contributes to efficacy in treating PTSD-related nightmares 4. The American Academy of Child and Adolescent Psychiatry indicates this mechanism underlies effectiveness in treating disruptive behavior disorders in children with intellectual disabilities 4.
Common Mechanistic Side Effects
Antagonism at receptors beyond D2 and 5-HT2 explains risperidone's characteristic adverse effects 1:
- D2 antagonism in tuberoinfundibular pathway: Hyperprolactinemia (commonly observed, particularly in children) 5
- D2 antagonism in nigrostriatal pathway: Extrapyramidal side effects (risperidone has highest risk among atypical agents) 6
- H1 antagonism: Sedation and weight gain 6
- α1 antagonism: Orthostatic hypotension 6
The American Academy of Child and Adolescent Psychiatry suggests considering alternatives like aripiprazole when prolactin elevation is a concern 5.