The functional role of ERK activity in esketamine's antidepressant effects.
Peng Zhang, Mengyu Wu, Keke Zhang, Jiajing He, Xingxing Liu, Hongxing Zhang, Ankang Hu, Zhou Wu
Pharmacology, biochemistry, and behavior July 26, 2026 DOI: 10.1016/j.pbb.2026.174248 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Naïve mice |
| Interventions | Esketamine SL327 |
| Dose | 10 mg/kg esketamine |
| Topics | Depression Esketamine |
| Keywords | Bdnf-trkb signaling pathway Erk activity Nmda receptor |
| Key points | Inhibiting DUSP6 to increase ERK activity had no antidepressant-like effects alone, but combined with 10 mg/kg esketamine extended its antidepressant-like effects from 7 to 10 days in naïve mice. Inhibiting ERK with SL327 prevented esketamine's rapid and sustained effects, suggesting ERK signaling is essential for these 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.
Comparable studies
Other preclinical and animal studies on esketamine for depression, most cited first.