The atypical antipsychotic aripiprazole has a unique pharmacological profile that provides ‘adaptive’ pharmacological activity.

Depending on endogenous dopamine levels and signaling status, aripiprazole may act as a full antagonist, a moderate antagonist, or a partial agonist at dopamine D2 receptors (D2Rs), consistent with purported biased ligand pharmacology.

The efficacy of aripiprazole can be mainly attributed to this combination of partial agonism/antagonism at D2Rs and serotonin 5-HT1A receptors, together with antagonism at serotonin 5-HT2A receptors.

However, the receptor profile of the compound is much more complex, and animal models have shown that aripiprazole affects multiple cellular pathways and several cortical and subcortical neurotransmitter circuitries and has an impact on gene expression distinct from other antipsychotics.

Based on the pharmacological and functional characteristics of aripiprazole, a number of new dopaminergic biased ligands are emerging as potential candidates for the treatment of psychosis, potentially improving the ‘dopamine modulation’ features of the prototypical compound.