Aripiprazole is the first of the next-generation atypical antipsychotic drugs. It has been called a 'Goldilocks-like' drug, as it is a partial agonist — meaning it shows not too much agonist and not too much antagonist properties — in contrast to the existing dopamine antagonist treatments. Aripiprazole has been shown in some studies to be as effective as current antipsychotics, such as haloperidol, and have fewer side effects, but how the partial agonism could explain the range of activities of the drug was not fully known.

To clarify this, Milinoff and colleagues looked at the interactions of the drug with the recombinant human dopamine D2 receptor, D2L. Their studies, published in the Journal of Pharmacology and Experimental Therapeutics, report that aripiprazole showed characteristics of a partial agonist in binding-affinity and cyclic-AMP-accumulation studies. Also, partial receptor inactivation reduced the maximum effect of aripiprazole on inhibition of cAMP accumulation at concentrations that did not alter the effect of the agonist dopamine, and increasing concentrations of aripiprazole blocked the action of dopamine equal to the agonist effect of aripiprazole alone. Finally, the efficacy of aripiprazole differed to that of dopamine, depending on the density of D2L receptors; and modulating the density of receptors affected the action of aripiprazole — aripiprazole behaved like an agonist in the presence of a receptor reserve for dopamine, but in its absence behaved like an antagonist.

So, the authors conclude that this, and previous studies (showing the partial agonism of 5-hydroxytryptamine (5-HT)1A serotonin receptors and antagonism of 5-HT2A serotonin receptors), support the model that aripiprazole belongs to a class of treatments known as dopamine–serotonin system stabilizers (DSSs). This partial-agonist activity of aripiprazole at D2 receptors, the authors say, could explain the observed unique activity and the sustained efficacy of the drug.