What is the mechanism of action (MOA) of Risperidone (risperidone)?

Mechanism of Action of Risperidone

Risperidone is a selective monoaminergic antagonist with high affinity for serotonin Type 2 (5HT2) and dopamine Type 2 (D2) receptors, as well as α1 and α2 adrenergic and H1 histaminergic receptors. 1

Primary Receptor Activity

• Risperidone demonstrates significant antagonism at multiple receptor sites with varying affinities:

  • High affinity (Ki of 0.12 to 7.3 nM) for serotonin 5-HT2 receptors 1
  • High affinity for dopamine D2 receptors 1
  • High affinity for α1 and α2 adrenergic receptors 1
  • High affinity for H1 histaminergic receptors 1

• The serotonin antagonism of risperidone is approximately 200 times greater than that of conventional antipsychotics like haloperidol, while its dopamine antagonistic potency is comparable 2

Secondary Receptor Activity

• Risperidone exhibits lower affinity for additional receptors:
  • Low to moderate affinity (Ki of 47 to 253 nM) for serotonin 5HT1C, 5HT1D, and 5HT1A receptors 1
  • Weak affinity (Ki of 620 to 800 nM) for dopamine D1 and haloperidol-sensitive sigma sites 1
  • No significant affinity for cholinergic muscarinic or β1 and β2 adrenergic receptors 1

Active Metabolite

• Risperidone is extensively metabolized in the liver through hydroxylation to 9-hydroxyrisperidone by the enzyme CYP 2D6 1
• 9-hydroxyrisperidone has similar pharmacological activity to the parent compound 1, 2
• The clinical effect of risperidone results from the combined concentrations of both risperidone and 9-hydroxyrisperidone 1

Unique Pharmacological Profile

• Risperidone possesses a unique balance of serotonin and dopamine antagonism, with its affinity for 5-HT2A receptors being significantly greater than its affinity for D2 receptors 3
• This distinctive receptor profile is thought to contribute to its efficacy for both positive and negative symptoms of schizophrenia 3, 4
• The relatively low incidence of extrapyramidal symptoms at therapeutic doses may reflect preferential action on mesolimbic rather than nigrostriatal dopaminergic pathways 4

Clinical Applications Based on MOA

• The combined 5-HT2 and D2 antagonism is believed to contribute to risperidone's efficacy in:
  • Schizophrenia (positive and negative symptoms) 3, 4
  • Irritability associated with autistic disorder 5
  • PTSD-related nightmares 6
  • Disruptive behavior disorders in children with intellectual disabilities 6

Pharmacokinetic Considerations

• Risperidone is well absorbed with an absolute oral bioavailability of approximately 70% 1
• Peak plasma concentrations occur about 1 hour after oral administration 1, 7
• The drug demonstrates dose-proportional pharmacokinetics within the therapeutic range 1, 7
• Food does not significantly affect the rate or extent of absorption 1

While the exact mechanism of action in specific disorders is not fully understood, the therapeutic effects of risperidone are believed to result primarily from its combined antagonism of serotonin 5-HT2 and dopamine D2 receptors, with contributions from its actions at other receptor sites.