Antipsychotics: The Essentials Module 2 Mechanism of Action of Aripiprazole Flavio Guzmán, MD

Aripiprazole is a partial agonist that acts on mesolimbic and mesocortical dopamine pathways.

What is an partial agonist?

Aripiprazole as partial agonist

Partial agonism in the mesolimbic pathway

Dopamine Activity in Healthy Individuals Dopaminergic neurotransmission Maximal Activity Normal Activity Basal Activity log [drug] Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:488-501.

Schizophrenia: overactivity of the mesolimbic pathway Dopaminergic neurotransmission Maximal Activity Schizophrenia Basal Activity log [drug] Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:488-501.

Aripiprazole therapy Dotted sigmoidal line: actions of partial agonist in the presence of endogenous concentrations of dopamine. Dopaminergic neurotransmission Maximal Activity Schizophrenia Basal Activity log [drug] Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:488-501.

Partial agonism in the mesocortical pathway

Dopamine Activity in Normal Circumstances Dopaminergic neurotransmission Maximal Activity Normal Activity Basal Activity log [drug] Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:488-501.

Dopamine System in Schizophrenia Maximal Activity Normal Activity Schizophrenia Basal Activity log [drug] Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:488-501.

Aripiprazole Therapy Dopaminergic neurotransmission Maximal Activity Normal Activity Schizophrenia Basal Activity log [drug] Courtesy of Richard Mailman, modified from Mailman RB, Murthy V. Current pharmaceutical design 2010;16:488-501.

Aripiprazole effects on other dopamine pathways Tuberoinfundibular Pathway Nigrostriatal Pathway Less risk of hyperprolactinemia Less risk of EPS

Other pharmacological properties

Key Points Aripiprazole is a partial agonist at D2 receptors. It may act as an antipsychotic by: Lowering dopaminergic neurotransmission in the mesolimbic pathway. Enhancing dopaminergic activity in the mesocortical pathway. It has a lower risk of EPS and hyperprolactinemia than other antipsychotics