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Author: Flavio Guzman, MD

Psychiatrist
Pharmacology Department
University of Mendoza
Argentina

As with other drugs in psychopharmacology, the mechanism of action of aripiprazole in

schizophrenia has not been fully elucidated.

From a pharmacological perspective, aripiprazole is different to other antipsychotic agents, as it is the

only approved antipsychotic that reduces dopaminergic neurotransmission through D2 partial
agonism, not D2 antagonism.

The following presentation discusses current thinking on the mechanism of action of aripiprazole
(scroll down to see a summary with images).

This image depicts aripiprazole binding to three different receptors: D2, 5HT1A, 5HT2A

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 What are the implications of D2 partial agonism? Aripiprazole binds to the D2 receptor with
the same affinity than dopamine, but has a lower intrinsic efficacy, so the response it
triggers is lower than dopamine but higher than an antagonist.

Aripiprazole as partial agonist: note that the signal is lower than dopamine but higher than an
antagonist

As partial agonist at D2 receptors, it modulates neurotransmission in dopaminergic

pathways (mainly mesolimbic and mesocortical pathway).
According to the dopamine theory of schizophrenia, overactivity of the mesolimbic
pathway may trigger positive symptoms (hallucinations, delusions).

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 Positive symptoms of schizophrenia might be the result of an overactivation of the mesolimbic
pathway.

Aripiprazole might decrease activity in the mesolimbic pathway through partial D2

agonism, which would in turn reduce positive symptoms.

Aripiprazole reduces dopaminergic activity in the mesolimbic pathway through partial D2 agonism.

The dopamine theory of negative and cognitive symptoms suggests that there is a
hypofunction of dopaminergic neurotransmission in the mesocortical pathway.

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Dopaminergic activity in the mesocortical pathway is thought to be reduced in schizophrenia

One postulated mechanism of action of aripiprazole in schizophrenia is the ability of the

drug to increase dopaminergic activity from a subnormal level to normal activity in the
mesocortical pathway.

Partial D2 agonism might increase dopaminergic activity in the mesocortical pathway.

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