The functional role of ERK activity in esketamine's antidepressant effects.

Abstract

Esketamine has been approved for the treatment of treatment-resistant depression. However, there is an unmet clinical need to extend the duration of esketamine's action to reduce the high recurrence rate after drug withdrawal and the potential side effects of repeated esketamine use. Here, we found that increasing extracellular signal-regulated kinase (ERK) activity by pharmacologically inhibiting dual-specificity phosphatases 6 (DUSP6) had no antidepressant-like effects. However, when combined with 10 mg/kg esketamine, it extended esketamine's antidepressant-like effects from 7 days to 10 days in naïve mice. Regrettably, inhibition of DUSP6 does not exert a dose-sparing effect or an early onset on the behavioral effects of esketamine. Moreover, inhibiting ERK activity by using SL327 prevents the rapid and sustained antidepressant-like effects of esketamine, and SL327 alone has no significant effects. These results suggest that ERK-related signaling is essential for the rapid and sustained antidepressant-like effects of esketamine, and enhancement of ERK activity has the potential to prolong the antidepressant-like effects of esketamine.

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