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

Escitalopram attenuates S-ketamine–induced dopamine release in the nucleus accumbens, and VV147 preserves rapid antidepressant effects without increasing NAc dopamine signaling.

• Why it matters: Ketamine’s rapid antidepressant benefits are constrained by psychotomimetic effects and abuse-related reward liability, and it is unclear whether efficacy can be separated from mesolimbic dopamine activation.
• What they did: The study tested escitalopram’s impact on S-ketamine–evoked dopamine release in the nucleus accumbens, then designed VV147 by combining SERT inhibition with NMDAR antagonism and evaluated it in chronic stress depression models.
• The result: VV147 did not increase NAc dopamine signaling unlike S-ketamine, while still retaining rapid antidepressant effects in chronic stress models, suggesting a strategy to reduce dopamine-linked reward effects.

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