Treatment-Resistant Depression (TRD) represents a major clinical challenge in the management of Major Depressive Disorder (MDD). It is commonly defined by the failure to achieve an adequate therapeutic response following at least two distinct antidepressant treatments, each administered at appropriate dosages and for a sufficient duration (1). Although conventional antidepressants typically require several weeks to exert measurable effects, early symptomatic improvement may emerge within the first two weeks of treatment and has been consistently associated with a higher likelihood of achieving remission (2, 3). Conversely, a suboptimal early response—often defined as less than a 20% reduction in symptom severity after two to four weeks—frequently prompts treatment modifications, such as dose escalation or switching strategies (4). Despite these interventions, approximately 20% of patients with depression remain unresponsive to standard pharmacological approaches (5).

To date, electroconvulsive therapy (ECT) remains the gold standard for the treatment of TRD, particularly in the presence of severe, life-threatening symptoms, high suicidal risk, or psychotic features (6). However, its use is often limited by reduced accessibility, logistical constraints, and persistent social stigma (7). In response to these limitations, alternative therapeutic strategies have been developed, including neuromodulation techniques such as repetitive transcranial magnetic stimulation (rTMS) and novel pharmacological approaches, most notably intranasal esketamine (8, 9).

Esketamine, the S-enantiomer of ketamine, has demonstrated significant efficacy in the treatment of TRD, when administered in combination with SSRIs or SNRIs (10). Following positive results from multiple randomized clinical trials, esketamine has received regulatory approval from both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of TRD (11–14). Pharmacodynamically, esketamine acts as a non-competitive antagonist of the N-methyl-D- aspartate (NMDA) receptor, leading to modulation of glutamatergic neurotransmission (14, 15).

The tolerability and safety profile of intranasal esketamine have been extensively evaluated in both controlled trials and real-world clinical settings (14, 16, 17). The most frequently reported adverse effects include transient dissociative symptoms, such as alterations in body perception, depersonalization, and derealization (18), as well as mild and short-lived events including hypertension, nausea, dizziness, vertigo, sedation, hypoesthesia, and anxiety (18, 19). Notably, older adults appear to be more susceptible to dizziness and sedation (17).

Several neurobiological mechanisms have been proposed to account for the rapid antidepressant and antisuicidal effects of esketamine, although these pathways are not yet fully elucidated. Consistent evidence indicates a rapid reduction in suicidal ideation and depressive symptoms following treatment initiation (20), while full symptomatic remission may require up to three months of continued administration (14). One of the most widely supported mechanisms underlying esketamine’s clinical efficacy involves the enhancement of neuroplasticity, particularly through activation of the mammalian target of rapamycin (mTOR) and brain- derived neurotrophic factor (BDNF) signaling pathways. The enhancement of neuroplasticity may support the reorganization and reconnection of cognitive and emotional networks, thereby increasing psychological resilience and enabling patients to engage more effectively in psychotherapeutic and psychosocial interventions, with potential benefits for long-term functional recovery.

Recent narrative syntheses have emphasized the relevance of these strategies in moving beyond purely symptom-based paradigms toward mechanism-informed and personalized treatment models in TRD (21).

Moreover, significant improvements in anhedonic symptoms have been shown, supporting the view that esketamine acts on clinically relevant domains beyond core depressive severity. In line with these observations, REAL-ESK findings support the effectiveness of intranasal esketamine in patients with treatment-resistant bipolar depression (TRBD), with sustained clinical benefits over time, with a favorable tolerability profile and, notably, with a low risk of manic switch.

Despite its therapeutic potential, esketamine treatment also presents relevant limitations, including logistical challenges related to in-clinic administration, prescribing and monitoring requirements, and the persistence of social stigma surrounding both the drug and psychiatric interventions more broadly (7, 14, 16). Addressing these barriers is essential to ensure broader accessibility, adherence, and integration into routine clinical care. Beyond symptom severity, dimensions such as psychache, mentalization/social cognition, and cognitive-emotional rigidity may sustain distress and suicidal risk and may be clinically relevant targets of change. We therefore examined longitudinal changes in these domains over six months of intranasal esketamine treatment in patients with TRD/TRD-B.

The present findings align with and extend a growing body of literature advocating for a shift from a purely symptom-centered model of treatment response toward a more personalized, mechanism- informed understanding of recovery in TRD. Emerging evidence suggests that improvements in psychological pain, cognitive flexibility, and higher-order reflective capacities may represent clinically meaningful processes that precede or accompany symptomatic remission, rather than mere epiphenomena of mood improvement. Within this perspective, our results indicate that esketamine’s therapeutic effects may be at least partly mediated by its impact on transdiagnostic psychological dimensions.

In particular, the marked reduction in psychache observed in our cohort supports contemporary models conceptualizing suicidal ideation and persistent distress as driven by intolerable subjective suffering rather than by depressive symptom severity alone (30). Moreover, the observed reductions in cognitive and emotional rigidity provide further support for the hypothesis that esketamine promotes psychological flexibility through neuroplastic mechanisms. Cognitive rigidity—characterized by perseverative negative thinking and impaired adaptive control—and emotional rigidity—marked by restricted affective responsiveness—are increasingly recognized as core features of treatment resistance across mood disorders. Their improvement over time in the present study suggests that esketamine may facilitate a loosening of maladaptive cognitive–emotional patterns, creating a window of opportunity for psychological reorganization and engagement in psychotherapeutic processes.

In the present study, a progressive improvement in clinical outcomes was observed over a six-month course of intranasal esketamine treatment, with remission rates showing a consistent upward trajectory across follow-up assessments. With regard to depressive symptomatology, our results confirm esketamine’s potential to induce both rapid and sustained antidepressant effects, in line with previous evidence (11, 13, 20, 31). Beyond symptom improvement, esketamine administration was associated with significant reductions in suicidal ideation and psychological distress, as reflected by both C-SSRS and PSA scores. However, the high prevalence of comorbid personality disorders in our cohort suggests that residual psychological suffering may persist despite symptomatic improvement, underscoring the need for integrative therapeutic strategies in which pharmacological stabilization facilitates engagement in psychotherapeutic interventions aimed at addressing enduring maladaptive emotional and cognitive patterns.

Beyond its well-established rapid effects on depressive symptoms and suicidal ideation (11, 13, 20, 31), our findings further suggest that esketamine modulates several key psychological dimensions— including mentalization deficits, cognitive and emotional rigidity, psychache, and social cognition— that are increasingly recognized as central to the persistence of depressive pathology and suicidal risk (32–44). In this context, the progressive increase in RMET scores observed over time indicates enhanced emotion recognition and social inference abilities, in line with prior literature describing depressive patients’ biases toward negative affective cues and difficulties in decoding positive emotional expressions (33–35).

Similarly, the progressive enhancement in reflective functioning (RFQ-8 scores), although variability acrosstime points, highlights incremental gains in mentalization abilities. As impaired mentalization is a well- acknowledged vulnerability factor in both depression and personality disorders (33), even minor improvements may yield significant benefits in emotional regulation and resilience. These findings emphasize the importance of evaluating reflective functioning as a dynamic target within the management of TRD A particularly innovative finding of this study concerns the reduction in cognitive and emotional rigidity, a core transdiagnostic dimensions across mood disorders. Cognitive rigidity, characterized by persistent negative rumination and impairments in executive functioning, and emotional rigidity, marked by a limited affective range and amplified sensitivity to negative stimuli, and that contributes to feelings of hopelessness and social isolation, are both well-documented correlates of major depressive disorder. Their observed reduction supports the hypothesis that esketamine enanhces cognitive and affective flexibility through neuroplastic mechanisms, thereby promoting adaptive coping and resilience (36–44). This interpretation aligns with contemporary models of depression that underscore deficits in flexibility, both emotional and cognitive, as core dimensions of the disorder.

The enhancement of mentalization observed in our study may, in part, mirror the overall reduction of depressive symptoms, a phenomenon that has been documented across various treatment approaches, such as SSRIs, SNRIs, and ECT (2, 4, 7, 37). Nevertheless, certain features suggest that esketamine exerts specific effects beyond those of conventional monoaminergic antidepressants. Converging lines of evidence indicate that esketamine’s modulation of glutamatergic neurotransmission via NMDA receptor antagonism leads to increased synaptic plasticity and BDNF release (14, 15, 45, 46). These neurobiological mechanisms are critically implicated not only in mood improvement but also in higher cognitive and social functions, including mentalization. Moreover, unlike SSRIs and SNRIs, which typically requiree several weeks to produce measurable changes in cognitive-emotional processing, esketamine produces rapid symptomatic relief within hours to days, potentially allowing earlier re-engagement with mentalization and relational processes, otherwise hindered during extended depressive episodes.

Preliminary evidence further supportt that esketamine enhances cognitive flexibility and reduces maladaptive rumination, creating a “window of opportunity” for psychological reorganization and integration (14, 37). The transient dissociative experience induced by esketamine may, in some patients, facilitate metacognitive distancing from distressing cognitions, indirectly supporting reflective functioning (8, 14, 18, 19).

Particularly noteworthy is the observed reduction in psychache, a deeply aversive emotional experience strongly linked suicidality. Consistent with Shneidman’s model, which conceptualizes suicide as the consequence of intolerable psychological pain rather than mental illness per se (20, 32), our results suggest that esketamine may alleviate this core affective suffering, thus reducing suicidal ideation through a distinct therapeutic mechanism. From a neurobiological perspective, this effect likely reflects enhanced neuroplasticity mediated by NMDA receptor antagonism and downstream modulation of mTOR and BDNF pathways. This plasticity may facilitate the reconnection of disrupted emotional and cognitive networks, enabling therapeutic engagement and behavioral change. Furthermore, esketamine’s modulation of limbic-prefrontal circuits may underpin its effects on emotional regulation and cognitive control (14, 15, 37, 45, 46).

To illustrate this complex interplay of mechanisms, Figure 10 presents a conceptual model of esketamine’s therapeutic trajectory beginning with neuroplastic changes that lead to rapid symptom relief, followed by progressive improvements in mentalization, cognitive and emotional flexibility, and reductions in psychache. These processes collectively enhanced social cognition, allowing individuals to re-engage with social environments in more accurate and emotionally attuned ways. Ultimately, these psychological and symptomatic improvements converge toward functional recovery and the resilience (see Figure 11). This integrative model supports a paradigm shift toward a personalized approach to TRD and TRD-B wherein pharmacological innovation is complemented by psychological and neurocognitive interventions (8, 10, 14, 31). Rather than focusing solely on symptom suppression, treatment strategies should aim to restore psychological flexibility, reflective functioning, and emotional connectedness—core dimensions of human functioning that are often disrupted in severe depression (37, 40, 44).

Our findings should be interpreted in light of several limitations. Firs, the limited sample size may have reduced the statistical power of the analyses. To address this issue, we applied non-parametric methods (Wilcoxon signed-rank test and McNemar’s test), which are less sensitive to non-normal distribution, and used the Benjamini–Hochberg procedure to control for multiple comparison. These methodological selections were made to enhance robustness, despite the restricted cohort size. Second, the inclusion of a wide range of psychometric measures and single-item analyses provide a comprehensive characterization of esketamine’s effects but concurrently increased the likehood of type I errors. To ensure interpretative reliability, we focused primarily on findings that remained significant after the correction for multiple testing, thereby prioritizing the most dependable findings. Third, missing data were managed through complete-case analysis. Although the overall incidence of missing data was minimal and randomly distributed, this approach may have slightly reduced the effective sample size for some analyses. In addition, exploratory correlations between baseline characteristics and treatment outcomes should be interpreted with caution. These analyses were designed to generate hypotheses for prospective investigations rather than to yield definitive evidence, given the limited statistical power and potential confounders involved. The naturalistic, observational design of the study may limit the generalizability of the results. The absence of a control group, such as a placebo or active comparator, precludes definitive attribution of the observed effects to esketamine rather than to non-specific contextual or psychological factors. Moreover, the repeated administration of psychometric measures at multiple time points may have introduced test-retest effects, potentially affecting participants’ responses over time. Finally, recruitment from specialized tertiary psychiatric centers may introduce selection bias, thereby limiting the external validity of the findings to broader TRD- TRD-B populations, including those managed in primary care or community mental health settings. Another consideration is the presence of two participants with a past diagnosis of bipolar disorder. However, given their predominantly depressive clinical trajectory over the past decade, the absence of manic or hypomanic episodes, and their similarity to the rest of the sample, their inclusion is unlikely to have materially affected the overall results or their interpretation.

Future investigations should therefore aim to include larger, more heterogeneous, multisite, and demographically different sample. This approach would facilitate more robust modeling of treatment trajectories and the identification of reliable clinical and sociodemographic predictors of esketamine response. Randomized controlled trials integrating both biological and psychological outcome are essential to confirm and extend the current findings and to further elucidate the multidimensional mechanisms underlying esketamine’s therapeutic effects. Addressing these limitations will ultimately enhance the comprehension of esketamine’s efficacy and safety, contributing to the development of more personalized treatment strategies for patients with resistant depressive episode.

This study provides a novel and integrative contribution on esketamine’s antidepressant effects in patients with TRD and TRD-B, The observed reductions in cognitive and emotional rigidity, together with improvements in psychache, support the hypothesis that esketamine enhances adaptive coping and resilience through neuroplastic mechanisms. In summary, esketamine may act not only as a rapid antidepressant but also as a catalyst for deeper psychological change, enabling patients to move beyond symptomatic improvement toward a more sustainable and meaningful recovery. Future investigations should further explore the interplay between esketamine’s neurobiological, cognitive, and affective effects, in order to optimize its integration within comprehensive, recovery-oriented treatment strategies for TRD and TRD-B.