Personalizing esketamine treatment in TRD and TRBD: the role of mentalization, cognitive rigidity, psychache, and suicidality.
Miriam Olivola, Filippo Mazzoni, Barbara Tarantino, Alessandro Guffanti, Matteo Marcatili, Monica Macellaro, Nicolaja Girone, Vassilis Martiadis, Fabiola Raffone, Tiziano Prodi, Natascia Brondino, Giovanni Martinotti, Massimo Clerici, Roberta Anniverno, Bernardo Dell'Osso
Frontiers in Psychiatry 2025 DOI: 10.3389/fpsyt.2025.1736114 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Prospective multicenter observational study Peer reviewed |
|---|---|
| Sample size | 36 |
| Population | Treatment-resistant depressive episode patients (including TRD and TRB) |
| Intervention | Esketamine |
| Duration | Six-month follow-up |
| Topics | Depression Esketamine Ketamine |
| Keywords | Cognitive rigidity Mentalization Psychache |
| Citations | 7 |
| Key findings | Esketamine treatment led to significant improvement in depressive symptoms and key psychological domains, with 69% of patients achieving remission by six months. |
Abstract
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, was 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 and social cognition, and promoting resilience. This prospective multicenter observational study aimed to evaluate esketamine's therapeutic impact on both depressive symptoms and key psychological factors-including mentalization, psychache, social cognition, suicidality, and cognitive-emotional rigidity-that could predict treatment response and enable a more personalized approach to TRD and TRBD management. Thirty-six treatment-resistant depressive episode patients, including TRD and TRB, 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 improvement in depressive symptoms was observed, as indicated by a reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) scores over time. Moreover, improvement was observed in different key psychological domains, such as mentalization, psychache, social cognition, suicidality, and cognitive-emotional rigidity. By six months, 69% of patients achieved remission, confirming a robust and sustained therapeutic response. These findings highlight the importance of a personalized treatment approach in treatment- resistant depressive episode patients. 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 treatment-resistant depressive episode patients.
Comparable studies
Other observational and cohort studies on esketamine for depression, most cited first.
Citations in the library
Cited by 4
- Esketamine in treatment-resistant depression with and without comorbid borderline personality disorder: A real-world longitudinal study of suicidal ideation and self-harm. Asian Journal of Psychiatry June 1, 2026
- Ketamine as a potential cognitive enhancer in neurological disorders: evidence from preclinical and clinical studies Frontiers in Neurology March 30, 2026
- (Es)ketamine in functional neurological disorder: a systematic review Frontiers in Psychiatry July 20, 2026
- The neurobiological synergy of transcranial magnetic stimulation and mindfulness-based interventions in treatment-resistant depression: a narrative review. Frontiers in Psychiatry 2026
Cites 10
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression The Journal of Clinical Psychiatry April 20, 2020
- Long-Term Safety and Maintenance of Response With Esketamine Nasal Spray in Participants With Treatment-Resistant Depression: Interim Results of the SUSTAIN-3 Study Neuropsychopharmacology May 12, 2023
- Treating bipolar depression with esketamine: Safety and effectiveness data from a naturalistic multicentric study on esketamine in bipolar versus unipolar treatment‐resistant depression Bipolar Disorders January 13, 2023
and 5 more in the library