Intranasal esketamine has been available for treatment-resistant depression (TRD) since 2019, but the trials that led to its approval answer only some of the questions prescribers face. About 97% of trial participants had failed only one or two antidepressant classes, and patients with bipolar disorder, psychosis, obsessive–compulsive disorder, four personality disorders, moderate-to-severe...
Frontiers in PsychiatrySeptember 15, 2026Serena Chiara Civardi, Filippo Besana, Federico Durbano et al.
Background Treatment-resistant depression (TRD) is a major clinical challenge, with many patients failing to respond to conventional antidepressants. Psychedelic compounds such as psilocybin and ayahuasca have recently gained attention as potential rapid-acting therapies. Beyond their neurobiological effects, methodological, ethical, and real-world applicability concerns are critical for...
Psychiatry InternationalSeptember 10, 2026Tommaso Barlattani, Giorgio Sernia, Chiara D’Amelio et al.
Background: Evidence for repeated intranasal esketamine in obsessive–compulsive disorder (OCD) remains preliminary, particularly when OCD co-occurs with treatment-resistant depression (TRD). Methods: We report a 58-year-old woman treated with intranasal esketamine in routine clinical care for TRD; change in obsessive–compulsive symptoms was followed as a secondary observational outcome. Her...
Background/context: Anxiety disorders are common in community mental health services and are frequently maintained by worry, rumination, threat monitoring, reassurance seeking, avoidance, and maladaptive attempts to control internal experience. Aim/objective: This perspective chapter examines Detached Mindfulness as a metacognitive technique for anxiety disorders and discusses its clinical...
In acute trials of intravenous and intranasal ketamine/esketamine, the rapid anti-suicidal effect appears to be at least partly independent of the overall antidepressant response. That question has, to our knowledge, never been examined in a real-world esketamine cohort followed for six months, nor in a sample enriched for comorbid borderline personality disorder (BPD), a population excluded...
Background: Intranasal esketamine (ESK-NS) is an effective treatment for treatment-resistant depression (TRD), but whether antidepressant outcomes differ by sex and age remains insufficiently explored. Methods: This secondary analysis of the REAL-ESK study included 210 patients with TRD treated with ESK-NS in routine clinical practice and assessed at baseline (T0), one month (T1), and three...
Borderline personality disorder (BPD) often occurs alongside treatment-resistant depression (TRD), but the impact of BPD on real-world outcomes with intranasal esketamine is unclear. Consecutive TRD outpatients initiating intranasal esketamine treatment at four Italian centres between 1 September 2024 and 30 September 2025 were enrolled in the study (n = 90): 45 with comorbid BPD and 45 without...
Suicidal ideation and deliberate self-harm are frequent and persistent in treatment-resistant depression (TRD), particularly when comorbid borderline personality disorder (BPD) is present. Real-world evidence on antisuicidal outcomes during intranasal esketamine in this population remains limited. In this multicentre prospective observational study, 90 outpatients with TRD received intranasal...
Introduction Treatment-resistant depression (TRD) is a severe condition associated with high suicide risk and limited response to conventional antidepressants. Intranasal esketamine has shown rapid efficacy in reducing depressive symptoms and suicidal ideation. Objectives This observational study assessed the real-world effectiveness of esketamine in reducing suicidal ideation, self-harm...
Trauma-related autobiographical memories can manifest as involuntary, vivid, emotionally charged intrusions that perpetuate avoidance, negative emotions, and functional impairment. While these memories are central to post-traumatic stress disorder (PTSD), they also occur across diagnoses and are often reported in depressive disorders, including treatment-resistant depression (TRD). Although...
Background/Objectives: Intranasal esketamine has emerged as an effective treatment for patients with treatment-resistant depression (TRD), providing rapid symptom relief when conventional antidepressant strategies fail. While its pharmacological efficacy has been demonstrated in randomized controlled trials, less attention has been paid to the organizational, relational, and multidisciplinary...
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...
BACKGROUND: Treatment-resistant depression (TRD) affects approximately one-third of patients with major depressive disorder and represents a critical clinical challenge. Esketamine (S-ketamine, Spravato), approved by FDA and EMA since 2019, and psychedelic-assisted therapies (psilocybin, MDMA) share a pharmacological feature unique among approved psychiatric treatments: they induce altered...
Esketamine rapidly improved suicidality and depression in TRD, with preliminary evidence suggesting gender-specific responses, and highlighting the importance of tailored interventions to maximize outcomes. Further research is needed to confirm these differences, explore the long-term effects, and understand the underlying mechanisms.
INTRODUCTION Anhedonia, defined as the diminished ability to experience or anticipate pleasure, is a core symptom of major depressive disorder (MDD) and bipolar depression (BD), and associated with depression severity, suicidality and poor treatment outcomes. Conventional antidepressants demonstrate limited efficacy against anhedonia. Esketamine nasal spray (ESK-NS) - a novel NMDA receptor...
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,...
Dissociative experiences are considered undesirable ketamine's adverse events. However, they might be crucial for ketamine's antidepressant effects, at least in some depression subtypes. Current understandings of ketamine's therapeutic potentials converge on the so-called "relaxed prior hypothesis," suggesting that glutamatergic blockage up-weights bottom-up surprising somatosensory/affective...