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, 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. Objective: 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. Methods: 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. Results: 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. Conclusions: 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.

Background/Objectives: In the past two decades, significant advancements in neuromodulation techniques have occurred, such as transcranial magnetic stimulation (TMS) for treatment-resistant depression (TRD). According to the assumption that repeated stimulation within a condensed timeframe can yield sustained efficacy, an accelerated protocol may be more effective in reducing time to response. With those premises, this study aimed to evaluate a sample of TRD patients treated with standard repetitive TMS (rTMS) and accelerated rTMS (arTMS). Methods: Nine subjects were treated with standard rTMS and 19 with arTMS. Psychometric assessment was made at the baseline and one week, one month, and three months after the treatment. A linear mixed-effect regression was performed along with other appropriate statistical analyses. Results: A significant improvement over time was observed for both depressive and cognitive symptoms. Moreover, considering the reduction in the Montgomery–Asberg Depression Rating Scale scores, a better treatment response was observed in subjects treated with arTMS (p < 0.05). Conclusions: Our findings showed a significant difference between the two protocols in terms of clinical response. Although further studies are needed to confirm the superiority of arTMS, the better cost-effectiveness of this technique should be considered.

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.

Background/Objectives: Esketamine-related dissociation is a transient, pharmacologically induced altered state that differs from the trait-like pathological dissociation typically observed in trauma-related conditions. While most studies have quantified these effects using the Clinician-Administered Dissociative States Scale (CADSS), patients’ subjective phenomenology and meaning-making remain underexplored. This qualitative exploratory study investigated how patients narrate, interpret, and integrate dissociative experiences occurring during intranasal esketamine treatment for treatment-resistant depression (TRD). Methods: We conducted semi-structured interviews with 36 adults with TRD who were receiving intranasal esketamine in outpatient settings in Northern Italy (2022–2024). Interviews focused on the most salient dissociative experiences during treatment. Transcripts were anonymized and analyzed using inductive thematic analysis. Two researchers coded the data independently; discrepancies were resolved by consensus, and recruitment continued until thematic saturation was reached. Results: Four experiential domains emerged: sensory alteration and perceptual flow (10/36, 27.8%), time suspension and chronological drift (21/36, 58.3%), body and space alteration (20/36, 55.6%), and psychic distance from suffering (30/36, 83.3%). While a minority described transient distress or loss of control, most narratives framed dissociation as neutral or subjectively meaningful, often associated with a temporary reduction in ruminative self-focus and depressive distress. Conclusions: A narrative, phenomenological lens complements quantitative research by clarifying what esketamine-induced dissociation feels like to patients and how it is appraised in context. The findings do not imply a causal or mediating role in antidepressant efficacy. Rather, they suggest that dissociation functions as a transitional subjective state, the clinical relevance of which depends on anticipation, framing, monitoring, and integration. These results support the use of structured psychoeducation, in-session support, and post-session integration within real-world esketamine programs.

During the COVID-19 pandemic, a significant rise in mental health issues was observed. Particularly, children and adolescents have shown a higher risk of developing mental disorders than adults. This study aimed to describe the evolving features of the requests for psychiatric emergency interventions during the COVID-19 pandemic in young people. We conducted a cross-sectional study comparing the number, characteristics, and symptoms of people aged between 12 and 18 years old attending one Emergency Department (ED) for psychiatric issues, considering three different periods: T0 (8 March 2019–7 March 2020), T1 (8 March 2020–7 March 2021), and T2 (8 March 2021–7 March 2022). Total admissions were 220: 99 (45%) during T0, 40 (18.1%) for T1, and 81 (36.8%) for T2 (P < 0.001). A significant decrease in the mean age from T0 to T1 was found (P < 0.01). Admissions for psychomotor agitation decreased, while admission due to anxiety disorder and nonsuicidal self-injury raised significantly (P < 0.05), as for first psychiatric presentation (P < 0.01). Regarding substance use, a significant reduction was observed (P < 0.05). The rates of eating disorders (P < 0.001) and early insomnia (P < 0.01) increased from T0. These findings highlight the worsening of psychiatric symptoms in the young population during the COVID-19 pandemic.

Background: Brexpiprazole, a third-generation antipsychotic with partial dopamine D2/D3 and serotonin 5-HT1A agonist properties, has emerged as a promising therapeutic option for patients with schizophrenia, including those with comorbid substance use disorders (SUDs). Managing psychosis in the presence of substance use represents a major clinical challenge, often associated with poorer outcomes, reduced adherence, and increased relapse risk. Methods: This narrative review(non-systematic) synthesizes evidence from randomized controlled trials, observational real-world studies, and expert consensus reports published between 2020 and 2026. The literature was examined to evaluate the pharmacological mechanisms, clinical efficacy, safety, and practical use of brexpiprazole in psychotic disorders, with particular attention to populations with comorbid substance use disorders. As a narrative review, this work does not employ systematic search protocols or quality appraisal tools; findings should be interpreted with this methodological limitation in mind. Results: Available evidence suggests that brexpiprazole can meaningfully reduce both positive and negative symptoms of psychosis, while also demonstrating beneficial effects on substance craving and functional outcomes in patients with dual diagnoses. Across randomized and real-world studies, brexpiprazole shows a favorable tolerability profile, characterized by minimal activation, low sedation, reduced risk of extrapyramidal symptoms, and limited cardiometabolic burden. These properties support its use in complex clinical populations requiring long-term treatment and polypharmacological management. Clinical Implications and Decision-Making: Based on the available evidence, brexpiprazole may be particularly suitable for: (1) patients with prominent negative symptoms requiring improvement in motivation and social functioning; (2) individuals with comorbid substance use disorders, particularly stimulant use, where dopaminergic modulation may address both psychotic symptoms and craving; (3) patients who have experienced significant metabolic or motor side effects with other antipsychotics; (4) individuals requiring cognitive preservation or enhancement. However, clinicians should consider that most evidence derives from relatively short-term studies with selected populations, and long-term real-world effectiveness data remain limited. Treatment decisions should be individualized based on symptom profile, comorbidity burden, prior medication responses, and patient preferences. Conclusions: Brexpiprazole represents a clinically valuable option for the management of psychosis, particularly in patients with comorbid substance use disorders. Its balanced pharmacological profile, combined with consistent efficacy and good tolerability, supports its role in integrated, long-term treatment strategies for complex and dual-diagnosis populations.