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Background: Treatment-Resistant Depression (TRD) affects almost 30 % of patients with Major Depressive Disorder (MDD). Esketamine Nasal Spray (ESK-NS) has recently been approved for TRD in combination with a Serotonin Specific Reuptake Inhibitor/SSRI or a Serotonin-Norepinephrine Reuptake Inhibitor/SNRI. There is a lack of studies investigating the effectiveness and safety of ESK-NS in combination with other oral antidepressants., Aim: To assess the efficacy of Vortioxetine plus ESK-NS in mitigating depressive symptoms and emotional blunting, as well as its tolerability in TRD subjects, compared to the standard-of-care of SSRI/SNRI plus ESK-NS., Methods: We conducted a post-hoc analysis of the REAL-ESK study. The study included twenty TRD patients, ten subjects taking Vortioxetine as the main oral antidepressant with ESK-NS, and ten subjects taking SSRI or SNRI with ESK-NS. Psychometric assessments (Montgomery-Åsberg Depression Rating Scale/MADRS, Brief Psychiatric Rating Scale/BPRS) were conducted at baseline(T0), one month(T1), and three months after the treatment initiation(T2)., Results: The combination of Vortioxetine and ESK-NS was as effective as the standard-of-care in reducing depressive symptoms, with a higher effect size in reducing emotional blunting at T2. The safety and tolerability profile of the Vortioxetine+ESK-NS combination appeared to be better, with a lower rate of treatment-emergent adverse events., Conclusion: The combination of Vortioxetine and ESK-NS may be a valuable alternative to the standard-of-care SSRI/SNRI plus ESK-NS in TRD patients, particularly regarding the reduction of emotional blunting and potentially a better safety and tolerability profile. Further randomized controlled trials with larger sample sizes and prospective designs are needed to confirm these findings., Competing Interests: Declaration of competing interest Dr. Ileana Andriola was a speaker at Janssen sponsored conference. Dr. Antonio Vita received grant/research support and speaker/consultant fees for Angelini, Boheringer Ingelheim, Innovapharma, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Recordati, Roche, Rovi Pharma, Takeda. Dr. Bernardo Maria Dell'Osso has received lecture honoraria from Angelini, Lundbeck, Janssen, Pfizer, Neuraxpharm, Arcapharma, and Livanova. Dr. Giorgio Di Lorenzo has been a speaker and/or a consultant for Angelini, FB-Health, Janssen-Cilag, Livanova, Lundbeck, Neuraxpharm, Otsuka, and Recordati. Dr. Giovanni Martinotti has been a consultant and/or a speaker and/or has received research grants from Angelini, Doc Generici, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Recordati. The remaining authors declare that the research was conducted without any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Treatment-Resistant Depression (TRD) poses a substantial health and economic challenge, persisting as a major concern despite decades of extensive research into novel treatment modalities. The considerable heterogeneity in TRD's clinical manifestations and neurobiological bases has complicated efforts toward effective interventions. Recognizing the need for precise biomarkers to guide treatment choices in TRD, herein we introduce the SelecTool Project. This initiative focuses on developing (WorkPlane 1/WP1) and conducting preliminary validation (WorkPlane 2/WP2) of a computational tool (SelecTool) that integrates clinical data, neurophysiological (EEG) and peripheral (blood sample) biomarkers through a machine-learning framework designed to optimize TRD treatment protocols. The SelecTool project aims to enhance clinical decision-making by enabling the selection of personalized interventions. It leverages multi-modal data analysis to navigate treatment choices towards two validated therapeutic options for TRD: esketamine nasal spray (ESK-NS) and accelerated repetitive Transcranial Magnetic Stimulation (arTMS). In WP1, 100 subjects with TRD will be randomized to receive either ESK-NS or arTMS, with comprehensive evaluations encompassing neurophysiological (EEG), clinical (psychometric scales), and peripheral (blood samples) assessments both at baseline (T0) and one month post-treatment initiation (T1). WP2 will utilize the data collected in WP1 to train the SelecTool algorithm, followed by its application in a second, out-of-sample cohort of 20 TRD subjects, assigning treatments based on the tool's recommendations. Ultimately, this research seeks to revolutionize the treatment of TRD by employing advanced machine learning strategies and thorough data analysis, aimed at unraveling the complex neurobiological landscape of depression. This effort is expected to provide pivotal insights that will promote the development of more effective and individually tailored treatment strategies, thus addressing a significant void in current TRD management and potentially reducing its profound societal and economic burdens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Pettorruso, Di Lorenzo, Benatti, d’Andrea, Cavallotto, Carullo, Mancusi, Di Marco, Mammarella, D’Attilio, Barlocci, Rosa, Cocco, Padula, Bubbico, Perrucci, Guidotti, D’Andrea, Marzetti, Zoratto, Dell’Osso and Martinotti.)

Objective: People with mental illness are overrepresented throughout the criminal justice system. In Italy, the Judicial Psychiatric Hospitals are now on the edge of their closure in favor of small-scale therapeutic facilities (REMS). Therefore, when patients end their duty for criminal behaviors, their clinical management moves back to the outpatient psychiatric centers. Elevated risks of rule-violating behavior are not equally shared across the spectrum of psychiatric disorders. To broaden the research in this area, we analyzed sociodemographic, clinical, and forensic variables of a group of psychiatric patients with a history of criminal behaviors, attending an outpatient psychiatric service in Milan, focusing on substance use disorder (SUD)., Methods: This is a cross-sectional single center study, conducted from 2020. Seventy-six subjects with a history of criminal behaviors aged 18 years or older and attending an outpatient psychiatric service were included. Demographic and clinical variables collected during clinical interviews with patients were retrospectively retrieved from patients' medical records. Appropriate statistical analyses for categorical and continuous variables were conducted., Results: Data were available for 76 patients, 51.3% of them had lifetime SUD. Lifetime SUD was significantly more common in patients with long-acting injectable antipsychotics therapy, a history of more than 3 psychiatric hospitalizations, and a history of previous crimes, particularly economic crimes. Additionally, this last potential correlation was confirmed by logistic regression., Conclusions: Data emerging from this survey provide new information about offenders with lifetime SUD attending an Italian mental health service. Our preliminary results should be confirmed in larger sample sizes.

Obsessive-compulsive disorder (OCD) is a chronic disease with a prevalence in the general population of around 2%-3%, generally accompanied by a severe impairment of functioning and quality of life. A consistent subgroup of patients may not achieve adequate symptom remission with first-line treatments (i.e., cognitive behavioral therapy, selective serotonin reuptake inhibitors [SSRIs]). The most validated option for treatment-resistant cases relies on the augmentative use of antipsychotics to SSRIs, preferably of the 'second generation'. Indeed, dopamine appears to be crucially involved in OCD neuropathology due to its implication in systems relating to goal-directed behaviour and maladaptive habits. Nevertheless, the mechanism of action of antipsychotics in OCD symptom improvement is still unclear. Risperidone, aripiprazole, and haloperidol seem to be the most useful medications, whereas 'first generation' antipsychotics may be indicated in case of comorbidity with tics and/or Tourette Syndrome. Antipsychotic augmentation may be also related to side-effects, particularly in the long term (e.g., alteration in metabolic profile, sedation, extrapyramidal symptoms). The present mini-review sought to provide the most updated evidence on augmentative antipsychotic use in treatment-resistant patients with OCD, providing a road map for clinicians in daily practice and shedding light on avenues for further research., (© 2024 John Wiley & Sons Ltd.)

Introduction: Intravenous ketamine (KET-IV) and intranasal esketamine (ESK-NS) are effective in the acute treatment of Treatment-Resistant Depression (TRD). Studies comparing KET-IV and ESK-NS concerning their action, safety, and tolerability are currently lacking., Materials and Methods: We combined patients' data from two unipolar TRD cohorts that received KET-IV (n = 171) at the Canadian Rapid Treatment Center of Excellence in Toronto, Canada, or ESK-NS (n = 140) at several TRD clinics in Italy. The Quick Inventory for Depression Symptomatology-Self-Report-16/QIDS-SR16 in the KET-IV group and Montgomery-Åsberg Depression Rating Scale/MADRS in the ESK-NS group measured depressive symptoms at baseline (T0) and after the acute treatment phase (T1) (i.e., four infusions of KET-IV and eight administrations of ESK-NS). As different scales were used, the primary outcome was to compare the improvement in depression severity in the two cohorts by measuring effect sizes, response and remission rates. Finally, we compare side effects and discontinuation rates., Results: At T1, KET-IV and ESK-NS significantly reduced depressive symptoms (respectively: QIDS-SR16 mean reduction = 5.65, p < 0.001; MADRS mean reduction = 11.41, p = 0.025). KET-IV showed larger effect sizes compared to ESK-NS (1.666 vs. 1.244). KET-IV had higher response rates (36 % vs. 25 %; p = 0.042) but not superior remission rates (13 % vs. 12 %; p = 0.845) than ESK-NS at T1. Despite more reported side effects, KET-IV did not cause more discontinuations for adverse events (4.6 % vs. 2.12 %; p = 0.228) than ESK-NS., Conclusion: KET-IV showed a higher short-term antidepressant effect, whereas ESK-NS exhibited lower side effects. Both were generally well tolerated. Future head-to-head studies should consider the long-term efficacy of these treatments., Competing Interests: Declaration of competing interest Dr. Taeho Greg Rhee was supported in part by the National Institute on Aging (NIA) (#R21AG070666; R21AG078972), National Institute of Mental Health (#R21MH117438), National Institute on Drug Abuse (#R21DA057540) and Institute for Collaboration on Health, Intervention, and Policy (InCHIP) of the University of Connecticut. Dr. Rhee serves as a review committee member for Patient-Centered Outcomes Research Institute (PCORI) and Substance Abuse and Mental Health Services Administration (SAMHSA) and has received honoraria payments from PCORI and SAMHSA. Dr. Rhee has also served as a stakeholder/consultant for PCORI and received consulting fees from PCORI. Dr. Rhee serves as an advisory committee member for International Alliance of Mental Health Research Funders (IAMHRF). Dr. Rhee is currently a co-Editor-in-Chief of Mental Health Science and has received honorarium payments annually from the publisher, John Wiley & Sons, Inc. Dr. Giorgio Di Lorenzo has been a speaker and/or a consultant for Angelini, FB-Health, Janssen-Cilag, Livanova, Lundbeck, Neuraxpharm, Otsuka, and Recordati. Dr. Raffaella Zanardi has been a consultant/speaker for Baldacci and Italfarmaco. Dr. Gianluca Rosso has been a speaker and/or consultant from Angelini, Janssen, Lundbeck, Otsuka, Viatris. Dr. Ileana Andriola was a speaker at Janssen sponsored conference. Dr. Bernardo Maria Dell'Osso has received lecture honoraria from Angelini, Lundbeck, Janssen, Pfizer, Neuraxpharm, Arcapharma, and Livanova. Dr. Rosenblat is the medical director of the Braxia Scientific Corp, which provides ketamine and esketamine treatment for depression; he has received research grant support from the American Psychiatric Association, the American Society of Psychopharmacology, the Canadian Cancer Society, the Canadian Psychiatric Association, the Joseph M. West Family Memorial Fund, the Timeposters Fellowship, the University Health Network Centre for Mental Health, and the University of Toronto and speaking, consultation, or research fees from Allergan, COMPASS, Janssen, Lundbeck, and Sunovion. Dr. Giovanni Martinotti has been a consultant and/or a speaker and/or has received research grants from Angelini, Doc Generici, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Recordati. Dr. Roger McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Atai Life Sciences. Dr. Roger McIntyre is the CEO of Braxia Scientific Corp. The remaining authors declare that the research was conducted without any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Climate change is one of the main global challenges and influences various aspects of human health. Numerous studies have indeed demonstrated an association between extreme climate-related events and physical and mental health outcomes, but little is still known about the association between the perception/awareness of climate change and mental health. In accordance with the PRISMA 2020 guidelines, a search was conducted on PubMed and Scopus. The protocol was registered on PROSPERO. The included studies were original observational studies published in English, reporting the association between the perception/awareness of climate change and mental health. A total of 3018 articles were identified. A total of 10 observational studies were included. The period covered in the included studies ranged between 2012 and 2022. Climate change perception is consistently associated with adverse mental health effects across different types of estimates. In particular, the studies identified an association between a higher level of perception/awareness of climate change and depression, anxiety, eco-anxiety, stress, adjustment disorder, substance use, dysphoria, and even thoughts of suicide. Qualitative data underscore the impact on daily activities, contributing to feelings of loss and suicidal ideation. Moreover, climate change perception correlates with lower well-being and resilience. The association between awareness of climate change and mental health is a complex and still poorly explored phenomenon. The main limitations are the high heterogeneity in terms of exposure assessment and data reporting, which hinders quantitative analysis. These results show that climate change perception impacts mental health. Better understanding the phenomenon represents an opportunity to inform public health interventions that promote mental well-being.

Background: Major Depressive Disorder (MDD) with suicidal ideation, intent, or behavior is a psychiatric emergency with controversial care management. Our study describes the comprehensive treatment pathways of this population in Italian routine clinical practice., Methods: ARIANNA [NCT04463108] is an observational prospective and retrospective cohort study involving both primary data collection and secondary data extract. A total of 137 adult MDD patients with suicidality were enrolled from 24 Italian care sites and followed for 90 days. Other than the description of treatment patterns, the impact of treatment on depressive symptoms and suicidality, the burden on the patient's and caregiver's quality of life, healthcare resource utilization and costs were described., Results: Of the 133 eligible patients, 68.4% were female, and the median age was 47. Approximately half of the study population had a current severe major depressive episode. Treatment strategies at the time of active suicidal ideation with intent definition/confirmation (t0) were heterogeneous, increasing in complexity during observation. According to the MADRS, patients with remission at t0+1 day were 2.6%, with the mean total score decreasing from 37.2 at t0 to 32.3., Limitations: The study sites were not randomly selected., Conclusions: To the best of our knowledge, this is the first cohort study that prospectively describes the characteristics of patients with MDD and suicide risk in Italy, and how they are treated in clinical practice. The study confirms this is a difficult-to-treat population. In addition, a lack of rapid, effective treatment for reducing depressive symptoms and suicidality is observed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. Pompili took part in advisory boards and educational activities on intranasal esketamine, receiving occasional fees for consultations or lectures by Janssen, which are unrelated to this article. In the last 2 years, he has received lectures or advisory board honoraria or engaged in clinical trial activities with Angelini, Lundbeck, Janssen, Pfizer, MSD, and Recordati. B.M. Dell'Osso received lecture honoraria from Angelini, Lundbeck, Janssen, Pfizer, Neuraxpharm, Arcapharma, and Livanova. G. Rosso received speaker/consultant fees for Angelini, Innova Pharma, Janssen, Lundbeck and Otsuka. D. Delmonte was employed by Janssen-Cilag SpA. M. Adami was employed by Janssen-Cilag SpA. G. Ascione was employed by Janssen-Cilag SpA. C. Sansone was employed by Janssen-Cilag SpA. L. Simoni was employed by Medineos SURL (IQVIA Ltd.). R. Cipelli was employed by IQVIA solutions SRL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)