Serotonin Reuptake Inhibition Reduces NMDAR-Associated Reward Liability Without Compromising Rapid Antidepressant Efficacy

Ketamine has changed the treatment landscape for depression by providing rapid antidepressant effects, yet its clinical utility remains limited by psychotomimetic effects and abuse potential. It remains unclear whether rapid antidepressant efficacy can be dissociated from mesolimbic dopamine activation and its associated reward-related effects. Here, we show that the serotonin reuptake inhibitor escitalopram, by enhancing serotonergic signaling, attenuates S-ketamine-induced dopamine (DA) release in the nucleus accumbens (NAc). Inspired by this finding, we designed and evaluated VV147 by incorporating SERT inhibition into NMDAR antagonism to reduce the reward-related liability of NMDAR blockade. Unlike S-ketamine, VV147 did not increase NAc dopamine signaling but retained rapid antidepressant effects in chronic stress models of depression. Together, these findings suggest a potential dissociation between rapid antidepressant efficacy and acute dopamine activation, providing a possible strategy for developing rapid-acting antidepressants with reduced dopamine-related reward effects.