Mentalization and Emotional-Cognitive Rigidity as predictors of esketamine's effects on Treatment-Resistant Depression: Findings from a prospective observational study.
M. Olivola, Filippo Mazzoni, Barbara Tarantino, A. Guffanti, M. Marcatili, F.l. Motta, R. Cornaggia, V. Martiadis, Tiziano Prodi, P. Politi, N. Brondino, G. Martinotti, Massimo Clerici, B. Dell'Osso
Journal of Affective Disorders September 1, 2025 DOI: 10.1016/j.jad.2025.120231 via Semantic Scholar
Summary
A six-month observational study of 36 patients with treatment-resistant depression found that those with poor mentalization abilities at the start had more severe depressive symptoms throughout treatment with esketamine. Greater cognitive rigidity appeared protective, possibly by stabilizing emotions and reducing negative thinking. The findings suggest esketamine may help break cognitive inflexibility and improve mentalization, supporting a personalized approach to treatment-resistant depression.
Study at a glance
| Characteristics | Prospective multicenter observational study Peer reviewed |
|---|---|
| Sample size | 36 |
| Population | Treatment-resistant depression patients |
| Keywords | Medicine Psychology |
| Citations | 8 |
| Key finding | Patients with poor baseline mentalization abilities had higher depression severity scores throughout six months of esketamine treatment, while greater cognitive rigidity appeared protective. |
Abstract
INTRODUCTION 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. OBJECTIVE 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.