Arketamine appears to be more effective as a rapid-acting antidepressant than esketamine in preclinical research.
In rodent studies, esketamine produced hyperlocomotion, prepulse inhibition deficits, and rewarding effects, while arketamine did not, in accordance with its lower potency as an NMDA receptor antagonist and dopamine reuptake inhibitor. As such, arketamine may have a lower propensity for producing psychotomimetic effects and a lower abuse potential in addition to superior antidepressant efficacy.
A study conducted in mice found that ketamine's antidepressant activity is not caused by ketamine inhibiting NMDAR, but rather by sustained activation of a different glutamate receptor, the AMPA receptor, by a metabolite, (2R,6R)-hydroxynorketamine; as of 2017 it was unknown if this was happening in humans. Arketamine is an AMPA receptor agonist.
Paradoxically, arketamine shows greater and longer-lasting rapid antidepressant effects in animal models of depression relative to esketamine. It has been suggested that this may be due to the possibility of different activities of arketamine and esketamine and their respective metabolites at the α-nicotinic receptor, as norketamine and hydroxynorketamine are potent antagonists of this receptor and markers of potential rapid antidepressant effects (specifically, increased mammalian target of rapamycin function) correlate closely with their affinity for it. The picture is unclear however, and other mechanisms have also been implicated.