Esketamine modulates key psychological constructs, including deficits in mentalization and emotional inflexibility.

Esketamine facilitates cognitive flexibility, enabling patients to disengage from rigid patterns of negative thinking.

Esketamine restores emotional responsiveness and enhances emotion regulation strategies, counteracting the emotional blunting.

Esketamine may enhance mentalization capacities, potentially improving interpersonal functioning.

Esketamine’s rapid impact on psychache reduction may directly contribute to its ability to mitigate suicidal ideation.

Treatment-Resistant Depression (TRD) remains a major challenge in the management of Major Depressive Disorder (MDD). Esketamine, the S-enantiomer of ketamine and a glutamatergic modulator, has been approved by the FDA and EMA for TRD in 2019. Beyond its rapid antidepressant effects, esketamine may enhance neuroplasticity, facilitating the reconnection with emotional and cognitive processes, improving mentalization, social cognition and promoting resilience.

This prospective multicenter observational study aimed to evaluate esketamine's therapeutic impact on depressive symptoms and explore whether psychological and clinical factors—including mentalization, psychache, social cognition, suicidality, and cognitive-emotional rigidity—could predict treatment response, enabling a more personalized approach to TRD management.

Thirty-six TRD patients treated with esketamine were assessed over a six-month follow-up period using psychometric measures of depression severity, suicidality, mentalization, social cognition, psychache, and cognitive-emotional rigidity.

A significant association emerged between mentalization deficits and depressive symptoms. Specifically, patients with poor baseline mentalization abilities exhibited higher Montgomery-Åsberg Depression Rating Scale (MADRS) scores both at baseline and throughout follow-up. In contrast, greater cognitive rigidity appeared to have a protective role, potentially mitigating negative thinking and providing emotional stability, which may enhance resilience to stressors.

These findings highlight the importance of a personalized treatment approach in TRD. Esketamine may be particularly beneficial in reducing cognitive rigidity, improving mentalization, and breaking the cognitive inflexibility that contributes to sustained negative depressive thinking patterns. Further research is needed to refine patient stratification and optimize treatment strategies for individuals with TRD.

Major Depressive Disorder

Treatment-Resistant Depression

Esketamine

Mentalization

Cognitive rigidity

Psychache

© 2025 The Authors. Published by Elsevier B.V.