Connected speech elicited by picture-description tasks offers a sensitive, non-invasive window into psychopathology and is increasingly relevant for digital health applications. In psychotic disorders, narrative disorganization and prosodic abnormalities have been linked to illness severity and functional outcome. This study examined whether acoustic speech markers can serve as objective, scalable biomarkers of psychosis. We enrolled 28 adults (18–65 years) with DSM-5 psychotic disorders (PD) and 15 healthy controls (HC) who completed the Boston Diagnostic Aphasia Examination “Cookie Theft” picture description. Major neurological disease, aphasia, intellectual disability, acute substance intoxication, and comorbid major depressive disorder were exclusion criteria. Acoustic features included mean and variability of pitch, spectral centroid and bandwidth, root mean square (RMS) energy, Mel-frequency cepstral coefficients (MFCCs), and gammatone filterbank metrics. Three machine learning (ML) approaches have been applied to classify PD and HC, namely support vector machine (SVM), Logistic regression, and decision tree. The SVM classifier achieved the best performance reaching an area under the curve of the receiver operating curve (ROC-AUC) of 0.95. If replicated in larger samples, this approach may function as a practical digital biomarker to complement clinical scales for early detection, individualized prognosis, and longitudinal treatment monitoring.

BACKGROUND AND AIM:Childhood trauma is a major transdiagnostic risk factor for mood disorders, whereas resilience may mitigate its long-term impact, yet their domain-specific interplay remains poorly defined. This study examined the multidimensional associations between childhood trauma and resilience in major depressive disorder, bipolar disorder, and healthy controls. We tested whether specific trauma subtypes differentially predict distinct resilience domains across diagnostic groups. METHODS:In this cross-sectional study, the final analytic sample comprised 300 participants: 100 healthy controls, 116 individuals with unipolar depression, and 84 individuals with bipolar disorder. Childhood trauma was assessed using the Childhood Trauma Questionnaire, and resilience was measured with the Connor-Davidson Resilience Scale, enabling domain-specific analyses of resilience profiles. RESULTS:Patients with mood disorders showed significantly lower resilience and higher childhood trauma exposure than healthy controls, with no differences between unipolar and bipolar disorder. All resilience domains except Spiritual Influences were reduced in patients. PCA-derived dimensions of resilience and childhood trauma robustly distinguished patients from controls but failed to separate unipolar from bipolar disorder, indicating shared latent vulnerability patterns. Correlation analyses showed inverse associations between childhood trauma and resilience in healthy controls and unipolar depression, but not in bipolar disorder. Across the full sample and within patients only, emotional neglect emerged as the strongest and most consistent independent association with reduced resilience, particularly affecting perceived control, personal competence, positive acceptance of change, and spiritual influences. CONCLUSION:A careful assessment of developmental history, including subtle forms of childhood trauma such as emotional neglect, is essential for understanding resilience differences in mood disorders. Identifying these vulnerabilities may help reveal compromised resilience domains and guide more personalized, resilience-oriented interventions.

Introduction Ketamine, initially developed as an anesthetic and now increasingly prescribed for treatment-resistant depression, is also widely misused in recreational contexts. Chronic ketamine use, often leading to dependence, has been associated with severe physical complications, including ulcerative cystitis and gastrointestinal dysfunction, as well as cognitive, affective, and psychotic disturbances. Despite the growing clinical and public health relevance of ketamine misuse, the evidence on effective treatment approaches remains fragmented. Methods A systematic review was conducted in accordance with PRISMA guidelines. We searched three literature databases (PubMed, Scopus, and Web of Science) from inception to April 2025. Original studies in English reporting clinical interventions for ketamine misuse were included. Data were extracted on sociodemographic and clinical characteristics, patterns of use, comorbidities, management strategies, and outcomes.. Results From 3183 records screened, 73 studies met the inclusion criteria, including 5 controlled clinical studies, 15 observational studies, 15 case series, and 38 case reports. Findings highlighted that management of ketamine misuse is heterogeneous and often based on evidence taken from either case reports or small series. Approaches included symptomatic medical care, psychotherapeutic interventions (e.g., motivational interviewing, cognitive-behavioral therapy, occupational therapy), and pharmacological treatments such as benzodiazepines, SSRIs, naltrexone, lamotrigine, and gabapentinoids, with varying degrees of effectiveness. Multidisciplinary strategies addressing both psychiatric and somatic complications, including “K-bladder” and “K-cramps”, emerged as an essential component of the treatment/management package. Overall, the high rates of relapse into ketamine misuse and the limited length of follow-up may have reduced the strength of available evidence. Conclusions Current management of ketamine misuse relies mainly on supportive care, psychotherapy, and off-label pharmacological options, but robust evidence on efficacy is lacking. There is an urgent need for controlled studies and standardized treatment protocols. Integrated, multidisciplinary, models appear most promising in addressing the complex medical and psychiatric consequences of ketamine misuse.

BACKGROUND AND AIM:Seasonal changes, particularly increased daylight exposure, are known to influence dopamine transporter (DAT) availability, potentially affecting mood disorders such as major depressive disorder (MDD). This study aimed to evaluate seasonal variations in the striatum using ¹²³I-FP-CIT SPECT in patients with MDD, and examine associations with specific psychopathological symptoms. METHODS:In this retrospective study, DAT SPECT scans from 85 patients with MDD were analyzed according to the season of imaging-fall-winter (FW) or spring-summer (SS). Psychometric assessments included the Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), Snaith-Hamilton Pleasure Scale (SHAPS), and Depression Retardation Rating Scale (DRRS). RESULTS:No overall differences in DAT availability were observed between FW and SS. However, anhedonia levels were higher in FW (p = 0.050). Patients with severe depression (HAMD ≥ 25) showed lower DAT availability in the left putamen, especially during SS (p = 0.014). Patients with marked psychomotor retardation (DRRS ≥ 18) exhibited reduced DAT availability in the left putamen (p = 0.002), with further reductions across all striatal regions during SS. Patients with suicidal ideation showed decreased DAT in the right (p = 0.029) and left putamen (p = 0.015). A negative correlation was found between DRRS scores and left putamen DAT availability (p = 0.034). CONCLUSION:Reduced DAT availability is associated with key depressive symptoms, notably psychomotor retardation and suicidal ideation. Seasonal effects, especially in the SS period, may exacerbate dopaminergic dysregulation. These findings support integrating seasonal and neurobiological factors in the assessment and management of severe MDD.

IntroductionLorlatinib is a third-generation tyrosine kinase inhibitor approved for the first-line treatment of ALK-positive metastatic non-small cell lung cancer, frequently associated with psychiatric adverse events.MethodThis study presents the clinical case of a patient who was successfully treated with low-dose trazodone for lorlatinib-induced psychiatric symptoms. In addition, an overview of the existing literature on the management of psychiatric adverse events (AEs) associated with ALK inhibitors is provided.Results and conclusionsBased on the evidence presented and the preliminary outcomes observed in the reported case, this study aims to outline a management strategy for lorlatinib-related psychiatric complications.

Alcohol Use Disorder (AUD) is a frequent and often treatment-resistant condition, with high relapse rates and frequent psychiatric comorbidities. In this randomized, double-blind pilot trial, 38 patients with AUD were assigned to receive either active anodal transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex or sham stimulation, in addition to standard care. The protocol consisted of 1 mA for 20 min per session, followed by maintenance stimulation over a 12-week period. The preregistered confirmatory outcomes were changes in craving severity assessed by the Brief Substance Craving Scale (BSCS) and a visual analog scale (VAS). Active tDCS did not demonstrate superiority over sham stimulation on these registered craving outcomes. However, exploratory analyses suggested possible differential effects of active tDCS on specific clinical dimensions, including reward-related craving and depressive symptoms. In particular, active stimulation was associated with greater improvement in reward craving and depressive symptomatology at selected follow-up timepoints compared with sham stimulation. These findings should be interpreted as preliminary and hypothesis-generating, given the pilot design, limited sample size, and exploratory nature of these outcomes. No major adverse effects were observed, and treatment was generally well tolerated. Overall, this pilot trial suggests that prefrontal tDCS may warrant further investigation as a potential adjunctive intervention targeting reward-related craving and mood symptoms in AUD.

INTRODUCTION:Real-world evidence on desvenlafaxine effectiveness and tolerability in Major Depressive Disorder (MDD) remains limited, particularly in clinically heterogeneous populations. This multicentre observational study evaluated the real-world effectiveness and tolerability of desvenlafaxine, focusing on depressive and anxiety symptoms, response, remission, and side-effects burden. METHODS:This multicentre prospective observational study included 197 outpatients with DSM-5-TR Major Depressive Episode initiating desvenlafaxine. Assessments were conducted at baseline (T0), one month (T1), and three months (T2). Depressive symptoms (MADRS) were the primary outcome; anxiety (HAM-A), manic symptoms (YMRS), and tolerability (ASEC) were secondary outcomes. Response was defined as ≥50% MADRS reduction and remission as MADRS <10. RESULTS:Participants (mean age 46.1 ± 14.6 years; 55.3% female) showed clinically relevant baseline severity (MADRS 30.8 ± 7.3). MADRS scores decreased significantly over time in both unadjusted and adjusted models (both p < 0.005), with greater reductions at T2. A significant time × dose association was observed at T1 (p = 0.013), although no dose-related difference persisted at T2; prior hospitalisation was associated with attenuated improvement (p < 0.005). Anxiety symptoms improved significantly across follow-up (p < 0.005). Response and remission rates increased markedly from T1 to T2 (response: 12.4% to 66.7%; remission: 3.9% to 32.6%; both p < 0.005). Overall side-effect burden decreased significantly (p < 0.005), with reduced prevalence of most adverse events. Mean YMRS scores remained low throughout follow-up, with no clinically meaningful increase from baseline. CONCLUSIONS:In this multicentre real-world cohort, desvenlafaxine was associated with substantial improvements in depressive and anxiety symptoms, increasing response and remission rates, favourable tolerability. These findings support desvenlafaxine as an effective and well-tolerated treatment option in routine clinical practice.

Background: Dual disorders (DDs) describe the coexistence of substance use disorder (SUD) and another mental health condition, commonly within psychotic and affective categories. These conditions represent a significant challenge in clinical management due to their bidirectional interactions and complexity. This study aims to evaluate the efficacy and safety of quetiapine, a second-generation antipsychotic, in patients with schizophrenia spectrum disorders and comorbid substance use disorders. Methods: A total of 28 participants with schizophrenia spectrum disorder and comorbid SUD underwent psychometric evaluations at baseline (T0), one month (T1) and three months post-initiation of quetiapine treatment (T2), administered at a mean dosage of 165 mg/day. Key outcome measures included psychopathological burden (PANSS), aggressivity (MOAS), substance craving (VAS Craving), and quality of life (Q-LES-Q-SF scales). Results: Quetiapine demonstrated significant reductions in psychopathological symptoms, with decreased PANSS total scores (p < 0.001). Positive symptoms (p < 0.001), negative symptoms (p = 0.002), substance craving (p = 0.001), and aggressivity (p = 0.006) also showed notable reductions. Quality of life significantly improved across Q-LES-Q-SF scores (p < 0.001). Quetiapine was well-tolerated, with no dropouts related to drug-induced side effects. Conclusions: This study provides preliminary evidence supporting the efficacy and safety of quetiapine in individuals with dual disorders. Improvements in psychopathology, substance craving, and quality of life underscore the importance of integrating tailored and comprehensive treatment strategies to address the multifaceted challenges of this challenging population.

Background: Approximately 20–30% of ultra-high risk (UHR) individuals transition to psychosis within 2–3 years. Neurobiological markers predicting conversion remain critical for precision prevention strategies. Objective: To systematically identify and evaluate structural and functional neuroimaging biomarkers at UHR baseline that predict subsequent conversion to psychosis. Methods: Following PRISMA 2020 guidelines, we searched five databases from January 2000 to February 2025. Two independent reviewers screened studies and assessed quality using the Newcastle–Ottawa Scale. Eligible studies examined baseline neuroimaging measures (structural MRI, functional MRI, diffusion tensor imaging, magnetic resonance spectroscopy) as predictors of psychosis conversion in UHR cohorts. Results: Twenty-five studies comprising 2436 UHR individuals (627 converters, 25.7%) were included (80.0% high quality). Reduced baseline gray matter volume in medial temporal structures (hippocampus: Cohen’s d = −0.45 to −0.68; parahippocampal gyrus: d = −0.52 to −0.71) and prefrontal cortex (d = −0.41 to −0.68) consistently predicted conversion. Progressive gray matter loss in superior temporal gyrus distinguished converters (d = −0.72). Reduced prefrontal–temporal functional connectivity predicted conversion (AUC = 0.73–0.82). Compromised white matter integrity in uncinate fasciculus (fractional anisotropy: d = −0.47 to −0.71) and superior longitudinal fasciculus predicted transition. Elevated striatal glutamate predicted conversion (d = 0.52–0.76). Thalamocortical dysconnectivity showed large effects (Hedges’ g = 0.66–0.88). Multimodal imaging models achieved 78–85% classification accuracy. Conclusions: Neuroimaging biomarkers, particularly medial temporal and prefrontal structural alterations, functional dysconnectivity, and white matter abnormalities, demonstrate moderate-to-large effect sizes in predicting UHR conversion. Multimodal approaches combining structural, functional, and neurochemical measures show promise for individualized risk prediction and early intervention targeting in precision prevention strategies.

Clinical trials investigating psychedelic compounds for depression and anxiety-related disorders are yielding promising preliminary results. Psychedelics produce profound alterations in brain function—such as suppression of the default mode network and thalamocortical dysregulation—leading to intense subjective experiences including ego dissolution and mystical-type states. While often described as meaningful or therapeutic, these effects can also be unpredictable or distressing. Because of these effects, which require labor-intensive, potentially cost-challenging preparation, administration, integration sessions, and exclude individuals with psychiatric vulnerabilities (e.g., bipolar disorder, borderline personality disorder, schizophrenia), questions remain about their real-world scalability. Consequently, there is growing interest in the possibility of dissociating the therapeutic benefits of psychedelics from their consciousness-altering effects. In this perspective, we examine emerging clinical and preclinical evidence investigating this scientifically timely and pressing question. Pharmacological strategies such as serotonin 2A receptor (5-HT2AR) antagonism and the development of “biased” psychedelic analogues or psychedelic-inspired compounds with reduced or null psychedelic potential may represent potential routes through which therapeutic efficacy may be retained even in the absence of psychedelic experiences. Current preclinical data suggest that downstream molecular and network-level mechanisms may mediate therapeutic effects independently of 5-HT2AR-driven subjective states. Whether these mechanisms can fully substitute for the experiential component of psychedelic therapy remains to be determined. Nonetheless, confirming this dissociation could mark a turning point in psychopharmacology, enabling the development of next-generation psychedelic-inspired treatments that may be more scalable, accessible, and appropriate for a broader range of psychiatric populations.

INTRODUCTION:Treatment-resistant depression (TRD) is a heterogeneous condition in which symptoms such as anhedonia, rumination, and anxiety contribute to persistent disability. Esketamine nasal spray (ESK-NS), accelerated repetitive transcranial magnetic stimulation (arTMS), and adjunctive brexpiprazole represent novel therapeutic options with distinct mechanisms, though their domain-specific effects in real-world settings remain unclear. OBJECTIVES:To compare short-term changes in depressive severity across ESK-NS, arTMS, and brexpiprazole, and to explore treatment-related effects on anhedonia, rumination, anxiety, and item-level depressive symptoms. MATERIALS AND METHODS:One hundred and one individuals with TRD were enrolled in a prospective, naturalistic, three-arm study and treated with ESK-NS, arTMS (accelerated left DLPFC protocol), or brexpiprazole augmentation (1-2 mg/day). Assessments were conducted at baseline and after one month. RESULTS:All treatments produced significant reductions in overall depressive severity and anhedonia. Rumination showed a significant time-by-treatment interaction, with greater improvement under brexpiprazole. Item-level analyses suggested partially distinct profiles, with brexpiprazole preferentially improving pessimistic and ruminative symptoms, ESK-NS enhancing affective responsiveness and cognitive symptoms, and both ESK-NS and arTMS contributing to anxiolysis. CONCLUSIONS:In routine clinical practice, ESK-NS, arTMS, and brexpiprazole were associated with short-term improvement in TRD, with exploratory signals of partially distinct symptom-domain profiles. These findings support the value of dimensional assessment in TRD and warrant confirmation in randomized studies with longer follow-up.

Idiosyncratic patterns of brain activity, often referred to as functional "brain fingerprints", capture the unique organization of an individual's brain dynamics and may serve as markers of brain dysfunction. Here, we tested the hypothesis that external perturbation may steer brain activities into individualized trajectories that facilitate identification. Twelve healthy participants received single-pulse transcranial magnetic stimulation (TMS) to the left primary motor cortex (M1) at 120% of their resting motor threshold (RMT), while 64-channel EEG recorded cortical responses to TMS. Single TMS pulse transiently increased idiosyncrasy in both, local and network-level brain dynamics, relative to baseline. Within-subject stability increased in time-frequency power envelopes, inter-trial phase clustering, and imaginary part of coherency, the latter reflecting functional connectivity. These effects were strongest in the beta frequency band and in regions surrounding the stimulation site. Together, these results show that single-pulse TMS reliably amplifies individual brain fingerprints, offering a stimulation-based method for probing subject-specific brain dynamics and potentially strengthen the sensitivity and robustness of fingerprinting metrics in clinical and personalized neuromodulation contexts.

Beyond specific training in Digital Mental Health (DMH)/Digital Psychiatry (DP), mental health professionals (MHp) should own basic digital abilities and competences and a general openness to integrating technology into both clinical practice and daily life. These digital drivers have not been adequately investigated among MHp in Italy. As part of the DIGIT-PSY project, a multicenter observational study was conducted using the EUSurvey® platform. From May to September 2023, a cohort of multiprofessional MHp from 27 Italian university centers was surveyed to assess digital literacy (DHL), readiness (TR) and acceptability (ATiPP). The main aim was identifying whether these digitally-derived variables could influence the level of digitalization proneness in MH care. Overall, 60

Bipolar disorder (BD) follows a neuro-progressive trajectory, yet current clinical staging models lack robust biological markers. Based on recent evidence, we hypothesized that BD stages are associated with alterations in the functional architecture of the Triple Network Model. We analyzed resting-state fMRI data from 123 individuals spanning five clinically defined BD stages. Using a hierarchical approach, we investigated how functional connectivity features characterize these stages, transitioning from coarse- to fine-grained analyses in both clinical classification (binary early-versus-late grouping to five-stage discrimination) and connectivity metrics (mean and standard deviation of connectivity to topological dynamic features). First, low-level functional connectivity features, combined with gene expression data, discriminated early- from late-stage illness, reaching higher performance than unimodal approaches. Next, evaluating the full staging spectrum revealed a non-linear trajectory in whole-brain connection density, which was lower at each successive stage from 0 to 3 but unexpectedly higher at stage 4. Network topology analysis contextualized this finding, revealing a reorganization of functional hubs in the final stage. Specifically, three hubs within the Salience Network exhibited decreased centrality despite the overall increase in connection density. This shift corresponded to a loss of temporal synchronization between these hubs and default-mode hubs, an axis of communication mediated by the salience network that is known to be important in healthy subjects and disrupted in psychiatric disorders. Overall, our findings suggest that late-stage BD is characterized by a subtle but significant reorganization of brain architecture, accompanied by alterations in the dynamics of the salience network which loses its coordinating role.

OBJECTIVES:Dopamine plays a central role in mediating addictive disorders (ADs), encompassing both substance-related and behavioral conditions. Some neurobiological alterations reflect trait-like vulnerability, while others are state-dependent, arising from intoxication and withdrawal. In this study, we examined striatal dopamine transporter (DAT) availability in individuals with alcohol use disorder (AUD) and gambling disorders (GD) to disentangle core mechanisms underlying addiction. METHODS:The study involved individuals with AUD (n = 14), GD (n = 14), and healthy controls (HC; n = 25). DAT binding in the bilateral caudate and putamen was assessed using single-photon emission computed tomography (SPECT) with the radiotracer 123I-FP-CIT. ADs participants underwent evaluation for addiction-specific and general psychopathological symptom severity. RESULTS:In the caudate, individuals with AUD showed higher DAT availability compared to those with GD (d = 2.234) and HC (d = 1.368). No lateralization effects were observed in any of the models. Across all ADs, DAT availability in the left putamen was significantly associated with the duration of abstinence over the past four weeks (rho = 0.444), after covarying for depression and irrespective of the diagnostic group. CONCLUSIONS:Our findings support a DAT-mediated involvement in core neurobiological processes underlying both substance-related and behavioral addictions. We propose that, in ADs, a predisposing striatal DAT deficiency may coexist with alcohol-induced upregulations (substance-specific) and with dynamic, time-sensitive fluctuations related to withdrawal processes (non-specific, addiction-related). Although a small sample size limits the generalizability of this study, these results may stimulate further research toward developing targeted therapeutic interventions.

Background: Patients affected by schizophrenia often experience a poor quality of life. Antipsychotics currently used reduce treatment compliance because of their side effects and their high non-responder rate. Antipsychotic polytherapy, also with Long-acting injectables (LAI) formulation, may increase the efficacy in refractory and non-compliant patients. This systematic review examines the coadministration of clozapine and aripiprazole LAI, studying its efficacy, tolerability and side-effects. Methods: The research was conducted on 6 August 2025, using PubMed, Scopus and Web of Science. The query search tool used was “aripiprazole AND clozapine AND (Long acting OR injectable OR LAI OR combination)”. Only original papers written in English were considered; animal research, in vitro experiments, also studies not specifying the formulation of aripiprazole were excluded. Results: Our research produced 1637 records. Removing repeated, not written in English and off topic articles, six papers were selected for qualitative synthesis. Conclusions: Available evidence on the combined use of clozapine and long-acting injectable aripiprazole is limited and largely derived from small observational studies. The reviewed reports describe recurring clinical observations suggesting that this strategy may be applicable in selected patients with treatment-resistant schizophrenia, particularly in the presence of poor adherence or clozapine-related tolerability concerns. Reported outcomes include symptom stabilization, improved adherence, and possible benefits on residual symptoms and clozapine-related adverse effects. Nonetheless, the low certainty of the evidence prevents firm conclusions regarding efficacy and safety, highlighting the need for further prospective controlled studies.

BACKGROUND:Depression is a leading global health concern and is projected to become one of the major contributors to the global burden of disease in the coming decades. Increasing evidence highlights the role of social determinants-including socioeconomic conditions, social relationships, life stressors, discrimination, and environmental influences-in shaping the risk and clinical expression of depressive disorders. This study aimed to investigate social determinants associated with the presence and severity of depressive symptoms in Italian general population. METHODS:A cross-sectional survey was conducted among 1,036 adults from the Italian general population, recruited through personal networks and online platforms using snowball sampling. Participants completed a structured questionnaire assessing sociodemographic characteristics, social support, stressful life events, quality of life, minority stress experiences, social media use, environmental and societal concerns, substance use, and mental health symptoms. Comparative analyses were performed between individuals reporting a clinician-diagnosed depressive disorder (n = 143; 13.8%) and those without a diagnosis (n = 893). RESULTS:Participants with a depressive disorder reported significantly higher exposure to multiple adverse social determinants. They were more likely to experience stressful life events, reduced perceived social support, poorer quality of life, minority stress, and negative psychosocial effects related to social media use. Concerns regarding broader socio-environmental issues, including political instability and climate change, were also more prevalent in the diagnosed group. These social vulnerabilities were accompanied by greater severity of depressive symptoms, anxiety-related manifestations, impulse-control difficulties, aggressive behaviors, and the use of substances as a coping strategy (all p ⩽ .003). CONCLUSIONS:The findings support social determinants framework for understanding depression, highlighting the contribution of social adversity, environmental stressors, and relational factors to the development and severity of depressive symptoms. Population-based surveys can help identify vulnerable groups and inform preventive strategies and public health interventions aimed at addressing the social conditions that contribute to depression.

Cannabis use has been associated with persistent perceptual disturbances, but systematic clinical characterization remains limited, particularly regarding multimodal sensory involvement. To characterize persistent perceptual disturbances following cannabis use, focusing on symptom profiles, temporal patterns, and clinical features. This exploratory observational study was conducted across the Valle d'Aosta and Piemonte regions of Italy between 2020 and 2025. We characterized 13 patients with persistent visual/auditory symptoms following cannabis exposure through comprehensive clinical assessment, neurological examination, neuroimaging, and standardized questionnaires. Given the small sample size, analysis focused on clinical characterization rather than statistical inference. Thirteen patients (10 males, mean age 24.3 ± 4.1 years) had used natural cannabis (69.2%) or synthetic cannabinoids (30.8%). Visual snow was universal (100%), with high rates of trailing phenomena (92.3%), halos (84.6%), and color changes (76.9%). A novel finding was the presence of auditory hypersensitivity in 61.5% of patients. Symptoms emerged at a mean of 3.2 ± 2.4 weeks following cannabis cessation. All neurological investigations were normal. Comorbid anxiety disorders were present in 84.6% of patients; functional impairment was severe in 30.8%, moderate in 46.2%, and mild in 23.1%. This exploratory study describes persistent multimodal sensory disturbances in patients after cannabis exposure. Consistent visual snow, frequent auditory hypersensitivity, and normal neurological investigations suggest a distinct phenotype warranting systematic investigation. While preliminary and requiring validation in larger samples, these findings highlight a potentially underrecognized cannabis complication meriting clinical attention.

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 months (T2). The primary outcome was change in Montgomery–Åsberg Depression Rating Scale (MADRS) scores. Repeated-measures ANOVA tested Time and Time × Sex effects, with post-hoc contrasts corrected using the Holm procedure. Response and remission at T2 were compared by sex. Exploratory analyses stratified patients by age (<65 vs. ≥65 years). Results: MADRS scores decreased markedly over time (Time: F = 340.707, p < 0.005), with a significant Time × Sex interaction (F = 3.283, p = 0.043). At T2, men had lower MADRS scores than women (Δ = −3.95, Holm p = 0.023) and showed higher response and remission rates. In age-stratified analyses, sex differences were small and non-significant among participants <65 years. In those ≥65 years, the T2 contrast numerically favored men, but did not reach significance in post-hoc Holm’s correction and should be considered exploratory. Safety outcomes and discontinuation rates were broadly comparable between sexes. Conclusions: ESK-NS was associated with substantial antidepressant improvement in a real-world TRD cohort. Findings suggest a modest overall male advantage, while age-stratified patterns remain exploratory. Endocrine, vascular, inflammatory, pharmacokinetic, and treatment-context factors should be investigated in prospective studies.