Psychiatry Research
July 29, 2023
Mauro Pettorruso, Roberto Guidotti, Giacomo D’andrea et al.
56 citations
Machine learning models predicted which patients with treatment-resistant depression would respond to esketamine nasal spray. In a retrospective study of 149 patients, three random forest classifiers achieved 68.53% accuracy for response at one month and 66.26% at three months, and 68.60% accuracy for remission at three months. Features such as severe anhedonia, anxious distress, mixed symptoms, and bipolarity positively predicted response and remission, while benzodiazepine use and depression severity were linked to delayed responses. The findings suggest machine learning may aid personalized treatment decisions for treatment-resistant depression.
American Journal of Geriatric Psychiatry
July 8, 2023
Giacomo D’andrea, Stefania Chiappini, Roger S. McIntyre et al.
36 citations
Esketamine nasal spray (ESK-NS) shows preliminary effectiveness for treatment-resistant depression in adults aged 65 and older, with 53.3% of participants responding (MADRS score reduced by at least 50%) and 33.33% achieving remission (MADRS below 10) after three months. Common adverse effects included dizziness (50%), dissociation (33.3%), sedation (30%), and hypertension (13.33%). Twenty percent of participants discontinued treatment. These findings, from a post-hoc analysis of 30 older adults, suggest ESK-NS can be effective but is associated with high rates of treatment-emergent adverse events, most of which did not require stopping treatment.
Frontiers in psychiatry
January 1, 2024
Matteo Di Vincenzo, Vassilis Martiadis, Bianca Della Rocca et al.
31 citations
Treatment-resistant depression (TRD) is defined as failing at least two adequate antidepressant trials. Esketamine, the S-enantiomer of ketamine, has been approved for TRD by the U.S. FDA and European Medicines Agency, but misconceptions about it persist among clinicians and patients. This review searched databases for keywords including "esketamine" and "myth" to identify false beliefs. Common myths included misunderstandings about TRD prevalence, clinical features, and predictors, as well as esketamine's treatment criteria, dissociative symptoms, addiction potential, and administration. Evidence-based facts counter these myths, showing esketamine is effective for TRD with necessary precautions, and accurate diagnosis is key to recovery.
Current neuropharmacology
January 1, 2025
Gianluca Rosso, Giacomo d'Andrea, Stefano Barlati et al.
23 citations
Among patients with treatment-resistant depression who continued esketamine nasal spray for at least six months, 76.2% responded or achieved remission. Of those who had not responded by six months, a subset improved by twelve months. Side effects occurred in 71.8% of patients at six months, decreasing to 42% at twelve months; the most common were sedation and dissociation. Only two patients stopped treatment due to tolerability issues. The findings suggest esketamine is effective and safe for mid- to long-term treatment, with a novel observation of late clinical response in some patients. Results require confirmation in larger samples and longer observation periods.
Current Neuropharmacology
October 20, 2025
Vassilis Martiadis, Fabiola Raffone, Danilo Atripaldi et al.
21 citations
A single dose of esketamine quickly reduced suicidal thoughts and depression in people with treatment-resistant depression. Preliminary evidence suggests that men and women may respond differently, indicating that personalized treatment approaches could improve results. More research is needed to confirm these gender differences, examine long-term effects, and understand the biological reasons behind them.
Psychopathology
January 1, 2024
Pietro Sarasso, Martina Billeci, Irene Ronga et al.
18 citations
Dissociative experiences from ketamine, often seen as undesirable side effects, may be essential for its antidepressant action in certain depression subtypes. The 'relaxed prior hypothesis' proposes that ketamine enhances sensitivity to bodily signals by blocking glutamate, improving short-term plasticity. Two patients with 'depersonalized depression' (Entfremdungsdepression) in a six-month esketamine program showed that induced dissociation, particularly disembodiment, could suspend ingrained patterns of feeling and behavior. This creates a window of psychological plasticity, allowing the body to regain responsiveness to emotional cues. The findings suggest esketamine's dissociative effects may be especially beneficial for those with compromised interoceptive awareness and interaffectivity.
Journal of Clinical Medicine
February 20, 2026
Vassilis Martiadis, Fabiola Raffone, Serena Testa et al.
7 citations
Intranasal esketamine provides rapid symptom relief for treatment-resistant depression when standard antidepressants fail, but its real-world effectiveness depends on organizational and multidisciplinary factors beyond pharmacology. This narrative review synthesizes clinical and real-world evidence to propose a phase-based integration framework that specifies complementary roles for psychiatry, nursing, and psychotherapy across pre-treatment assessment, induction, session delivery, post-session integration, and maintenance phases. The framework emphasizes safety, continuity of care, and patient-centred monitoring, with measurable implementation indicators. While evidence supports esketamine's efficacy in reducing depressive symptoms, anhedonia, and suicidality, prospective implementation studies are needed to evaluate clinical effectiveness, feasibility, and cost-effectiveness of the proposed multidisciplinary approach.
Frontiers in psychiatry
January 1, 2025
Miriam Olivola, Filippo Mazzoni, Barbara Tarantino et al.
7 citations
In treatment-resistant depression, esketamine—a glutamatergic modulator approved in 2019—may improve not only depressive symptoms but also key psychological factors such as mentalization, psychache, social cognition, suicidality, and cognitive-emotional rigidity. In a six-month observational study of 36 patients with treatment-resistant depressive episodes, depressive symptoms significantly decreased, as measured by the Montgomery-Åsberg Depression Rating Scale. By six months, 69% of patients achieved remission, indicating a robust and sustained response. The findings suggest esketamine may be particularly beneficial in reducing cognitive rigidity and improving mentalization, potentially breaking the inflexible thinking patterns that sustain depression. Personalized treatment approaches are emphasized.
Asian journal of psychiatry
June 1, 2026
Fabiola Raffone, Filippo Mazzoni, Arianna De Ciechi et al.
3 citations
In a six-month observational study of 90 outpatients with treatment-resistant depression receiving intranasal esketamine, those with and without comorbid borderline personality disorder showed sustained reductions in suicidal ideation, suicidal behavior, and deliberate self-harm. Improvements were significant from month one onward. Self-harm episode frequency in the borderline group dropped from a mean of 30.8 at baseline to 2.4 at six months. Baseline impulsivity correlated with self-harm and suicidal measures, but these associations weakened by six months. No serious adverse events, treatment discontinuations, or increases in suicidality occurred. Controlled studies are needed to confirm durability, especially for patients with borderline personality disorder.
Brain Sciences
February 7, 2026
Miriam Olivola, Tiziano Prodi, Giada Versaci et al.
2 citations
During intranasal esketamine treatment for treatment-resistant depression, patients describe four distinct types of dissociative experiences: sensory alteration and perceptual flow (27.8%), time suspension and chronological drift (58.3%), body and space alteration (55.6%), and psychic distance from suffering (83.3%). Most patients frame these experiences as neutral or meaningful, often linked to temporary relief from rumination and depressive distress, though a minority report transient distress or loss of control. The findings suggest dissociation functions as a transitional subjective state whose clinical relevance depends on anticipation, framing, monitoring, and integration, supporting structured psychoeducation and in-session support in esketamine programs.
The Lancet Regional Health - Europe
July 15, 2026
Vassilis Martiadis
It remains unclear whether the strong antidepressant effects of psilocybin seen in clinical trials can be replicated in routine care, because trials enroll highly selected patients, withdraw other medications, and follow strict protocols. Jungwirth et al. provide early evidence from everyday practice: among 19 adults with treatment-resistant depression treated with psilocybin under Switzerland's limited medical use framework, clinician-rated depressive symptoms decreased substantially—a reduction of about 11 points on the Montgomery–Åsberg Depression Rating Scale, with a large effect size (Hedges' g ≈ 1.4).
Open MIND
July 13, 2026
Vassilis Martiadis, Fabiola Raffone
In patients receiving routine esketamine treatment for depression, the reduction in suicidal thoughts over six months is not fully explained by concurrent improvement in depressive symptoms, suggesting a partly independent anti-suicidal effect. This pattern also holds for deliberate self-harm in the subgroup with comorbid borderline personality disorder, a population previously excluded from clinical trials. Early improvement in depression predicts later reduction in suicidal ideation, but a direct, non-mediated path remains. Change in trait impulsivity was explored as an alternative mediator of these effects.
Clinical Neuropsychopharmacology and Addiction
June 25, 2026
Luca Persico, Giacomo D’andrea, Clara Cavallotto et al.
Intranasal esketamine substantially reduced depression severity in 210 patients with treatment-resistant depression treated in routine clinical practice. Depression scores improved markedly over three months, and men showed a modest advantage over women by the end of treatment, with lower depression ratings and higher rates of response and remission. Among patients under 65 years, sex differences were small and not statistically significant; among those 65 and older, men appeared to benefit more numerically, but this difference did not hold up after statistical correction and remains uncertain. Discontinuation rates and safety outcomes were similar between sexes. The authors call for future studies to examine hormonal, vascular, inflammatory, and other factors that might explain the observed sex differences.
Psychiatry research
June 16, 2026
Filippo Mazzoni, Fabiola Raffone, Arianna De Ciechi et al.
Among 90 outpatients with treatment-resistant depression, half also had borderline personality disorder (BPD). Depressive symptoms, measured by the MADRS scale, improved substantially over six months of intranasal esketamine treatment. The BPD group showed faster early improvement, and from one month onward had higher response rates (≥50% reduction in symptoms). Remission rates at six months were similar between groups (48.9% with BPD vs. 57.8% without). Anxiety and impulsivity decreased across the whole sample, and cognitive function did not worsen. No serious adverse events or dropouts occurred. Comorbid BPD did not hinder the overall remission outcome.
Behavioral sciences (Basel, Switzerland)
May 14, 2026
Fabiola Raffone, Carlo Ignazio Cattaneo, Enrico Pessina et al.
Trauma-related autobiographical memories can become intrusive and distressing, contributing to post-traumatic stress disorder (PTSD) and depression, including treatment-resistant depression (TRD). Intranasal esketamine, an approved rapid-acting treatment for TRD, may create conditions that facilitate psychotherapeutic work on traumatic memories. This narrative review synthesizes evidence on ketamine and esketamine for PTSD and trauma symptoms, distinguishing intravenous ketamine studies, intranasal esketamine data, and combination approaches with psychotherapy.
Clinics and practice
March 13, 2026
Alessandro Guffanti, Matteo Leonardi, Natascia Brondino et al.
In three young adults (ages 20–25) with mild to moderate autism spectrum disorder and treatment-resistant depression, intranasal esketamine added to standard antidepressants reduced depressive symptoms. Two patients achieved clinical remission at six months, and one showed partial response. Suicidal ideation decreased, but mentalization and social cognition improved only mildly. Subjective quality of life rose substantially for all three. No major side effects occurred. These preliminary observations require confirmation in controlled trials.
Preprints.org
January 15, 2026
A. Guffanti, Matteo Leonardi, Natascia Brondino et al.
preprint
Intranasal Esketamine, when added to standard antidepressants, reduced depressive symptoms in three young adults with both treatment-resistant depression and autism spectrum disorder. Two patients achieved full remission and one showed partial remission over six months, with no major side effects. Suicidal thoughts decreased, but abilities related to understanding others' mental states improved only slightly. Quality of life scores rose substantially for all three patients. The authors note the small sample prevents statistical conclusions and call for larger, randomized studies.