Considerations for Augmenting Aripiprazole Long-Acting Injectables with Other Antipsychotics: A Mini-Review

Aripiprazole is a third-generation antipsychotic, approved in 2002, notable for its partial agonism of the Dopamine D2 receptor and lower risk of metabolic and extrapyramidal adverse effects. It is available in a long-acting injectable formulation, which is very useful for maintaining medication compliance, which is crucial for preventing recurrent psychotic episodes in patients. Additionally, the aripiprazole long-acting injectable is frequently combined with other antipsychotic medications in acute settings to manage refractory symptoms. However, there is limited literature regarding the psychopharmacology, efficacy, and adverse effect profiles of augmenting aripiprazole long-acting injectable with other antipsychotic medications. This narrative review intends to synthesize the existing literature on aripiprazole, its comparative affinity to the dopamine D2 receptor versus other antipsychotics, and the efficacy and side effect profiles of combining aripiprazole with other antipsychotics in the context of acute inpatient treatment for psychosis. Current literature on K_i values indicates that fluphenazine, pimozide, thiothixene, trifluoperazine, and perphenazine bind more strongly to dopamine D2 receptors than aripiprazole. However, there is a knowledge gap regarding antipsychotic polypharmacy with aripiprazole and these first generation antipsychotics, limiting the discussion of these drug combinations to theory. Additionally, the muscarinic effects of aripiprazole suggest the possibility of augmentation with clozapine or xanomeline-trospium, albeit the peer-reviewed literature on this was also limited. Overall, it is difficult to draw conclusions regarding best clinical practices for these scenarios, as the existing literature is contradictory. Nonetheless, the application of the dopamine and muscarinic pathway theories for schizophrenia opens venues for future research and consideration.