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Introduction: Persistent depressive episodes and subsyndromic depressive symptoms frequently characterize mood alterations in bipolar disorder (BD) and negatively influence quality of life and suicide risk. BD patients with predominant depressive episodes generally show significantly higher treatment resistance rates. Although not specifically approved in Italy for bipolar depression, recently published observational data suggest that the cariprazine add-on may be a potential effective short-term treatment for resistant bipolar depression. Nevertheless data on long-term cariprazine treatment are lacking. Objectives: This study evaluated the efficacy and safety of long-term cariprazine augmentation in patients suffering from treatment-resistant bipolar depression. Methods: 30 resistant bipolar depressed patients, whose resistance was defined according to The CINP Guidelines on the Definition and Evidence-Based Interventions for Treatment-Resistant Bipolar Disorder, were treated with cariprazine 1,5 -3 mg flexible dose for 4 weeks, added to previous mood stabilizing and/or antidepressant treatment. Psychopathology at time 0 and at 4, 8, 12, 16, 20, 24 weeks of treatment was evaluated using the Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HARS), the Young Mania Rating Scale (YMRS) and the Bipolar Depression Rating Scale (BDRS); safety and tolerability was measured by the UKU Side Effect Rating Scale. The drop-out rate was assessed throughout the study duration. Results: Cariprazine add-on was effective in the study sample but only during the first 4 weeks of treatment. Improvement in depression scores started from the first week, reaching about 40% mean HDRS score reduction at T4; a moderate ulterior decrease (-15%) was reached at T24 but was accompanied by a significant drop-out rate; anxiety symptoms improved (mean HARS score reduction 37% at T4) mainly during the first 4 weeks. The treatment was generally well tolerated. From week 4 to 24 we observed a near 70% drop-out rate (18 total drop-outs) with maximum drop-outs between weeks 4-8 (n=7) and 18-24 (n=7). Discontinuation causes were inefficacy (5/18); clinical worsening (10/18); side effects (3/18); hypomanic shift (2/18). Conclusions: Despite the relatively small population examined and the observational design, our results suggest that cariprazine may represent an effective and safe short-term enhancement strategy in resistant bipolar depression. Long-term treatment, in this sample, did not lead to significant improvements and was burdened by a high drop-out rate, mainly due to inefficacy/clinical worsening. Further studies on larger samples are needed to confirm these preliminary findings, both in short-term and in longer observations. Disclosure of Interest: None Declared [ABSTRACT FROM AUTHOR]

Introduction: Anxiety disorders are one of the most common mental illnesses, and a consistent increase was observed after the COVID-19 pandemic. Mindfulness refers to a process that leads to a mental state characterized by nonjudgmental awareness of the present experience. Mindfulness can be considered both a skill and a practice. The stronger is the ability to adopt a mindful state, the less suffering one will experience. While Mindfulness-based Psychotherapies have shown efficacy in their treatment, they have not yet been thoroughly studied in Italian public mental health services. In Detached Mindfulness, negative thoughts are acknowledged and avoided by turning them into actions using a standardized, time-limited, metacognitive intervention. Objectives: The purpose of this study is to examine the efficacy and cost-effectiveness of Detachment Mindfulness for twelve patients with Generalized Anxiety Disorder (GAD) not being treated pharmacologically. Methods: We enrolled 12 patients diagnosed with GAD according to DSM-V in an 8-session program of Detached Mindfulness Psychotherapy (once a week). The Generalized Anxiety Disorder - 7 Scale (GAD-7) and the Kellner Symptom Questionnaire (SQ) were used to assess anxiety symptoms at baseline (T0), after 4 sessions (T1), and at the end of treatment (T2). The Client Satisfaction Questionnaire (CSQ-8) was used to assess treatment satisfaction. Results: The GAD-7 score showed consistent reductions in generalized anxiety symptoms after Detached Mindfulness treatment (mean decrease of -42% at the end of the program). As measured by SQ, patients also reported improvement in physical well-being, relaxation, and somatic symptoms significantly respect to baseline. As for treatment satisfaction, ten out of twelve patients rated their treatment as satisfactory. As reported by patients, mindfulness can become a powerful and effective means to relate to one's own internal experiences such as anxiety or fear, learning to recognize them, staying with them and avoiding their consequences. Conclusions: These results showed that detached mindfulness was an effective and cost-effective intervention for GAD, given the short amount of time it requires and the ease with which it can be implemented. For its extensive use in the public mental health system to be further supported, studies on larger populations are needed. Disclosure of Interest: None Declared [ABSTRACT FROM AUTHOR]

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.)

Obsessive-compulsive disorder (OCD) is a common and debilitating psychiatric disorder with an approximate incidence of 2.5% in the general population. Serotonin reuptake inhibitors (SRIs) are considered the first line of pharmacological treatment but up to 50% of patients fail to achieve clinical remission or response. Atypical antipsychotics are one of the most common augmentation strategies in OCD treatment resistant patients. Brexpiprazole, a novel atypical antipsychotic with dopamine partial agonism action, has never been studied in addition to SRIs treatment in OCD resistant patients. This study retrospectively investigated the safety and efficacy of a 12 week brexpiprazole augmentation trial in 34 OCD resistant patients. SRI treatment resistance was defined as failing to improve the YBOCS total score by more than 25% from the beginning of the SRI trial. Brexpiprazole augmentation response was defined as at least a 25% improvement in the YBOCS total score. At the end of the study, 17 patients (50.0%) met the response criteria of ≥25% improvement in YBOCS total score vs. baseline. No safety issues were raised throughout the observation period. A total of 19 patients (55.9%) reported adverse experiences, generally mild and not requiring medical intervention. This is the first study to examine the safety and efficacy of brexpiprazole augmentation in resistant OCD patients. Our findings show that brexpiprazole may be a promising and well-tolerated augmentation strategy for SRI-resistant OCD patients. However, further research in larger populations is needed to confirm these results and investigate the long-term safety and tolerability of brexpiprazole in OCD patients.

Obesity and weight gain represent a challenging issue in people suffering from schizophrenia and other severe mental illnesses (SMI). Most of clinical guidelines for the management of overweight and obesity in people with SMI share a stepwise approach starting with more conservative interventions, with diet, physical activity, lifestyle coaching and behavioral modifications. The aim of this study was to evaluate the effectiveness of a group weight management program in a real-world outpatient Italian setting. Data from 100 patients diagnosed with schizophrenia or bipolar disorder, undergone to a group metabolic management program, were analyzed through a 12 months follow-up. The main body weight (kgs) decreased from 98.01±18.30 at baseline to 93.29±17.36 (p>0.001) at 6 months to 90.35±17.90 at 12 months. Parallel statistically significant decreases were found for BMI, waist circumference, glycaemia and systolic blood pressure. After patients' segmentation into normal-weight, overweight and obese at baseline, the significant of the decrease emerged only between baseline and the 6-month endpoint, thus suggesting that the program was successful in the short-term. Notwithstanding the limitations of the study, the 12-month intervention evaluated demonstrated feasibility and a high retention rate. This allowed a relevant weight reduction during the first six months, followed by durable maintenance until the end of the study. Current NICE recommendation guidance indicates that people with SMI, particularly those on antipsychotic treatment, should be provided with integrated nutrition and exercise programmes by their healthcare professional. Future research should focus on the effectiveness and cost-effectiveness of this kind of interventions and their reliability in the different real-world healthcare settings.

Introduction: Eating Disorders (EDs) affect individuals globally and are associated with significant physical and mental health challenges. However, access to adequate treatment is often hindered by societal stigma, limited awareness, and resource constraints., Methods: The project aims to utilize the power of Artificial Intelligence (AI), particularly Machine Learning (ML) and Deep Learning (DL), to improve EDs diagnosis and treatment. The Master Data Plan (MDP) will collect and analyze data from diverse sources, utilize AI algorithms for risk factor identificat io n, treatment planning, and relapse prediction, and provide a patient-facing chatbot for information and support. This platform will integrate patient data, support healthcare professionals, and empower patients, thereby enhancing care accessibility, personalizing treatment plans, and optimizing care pathways. Robust data governance measures will ensure ethical and secure data management., Results: Anticipated outcomes include enhanced care accessibility and efficiency, personalized treatment plans leading to improved patient outcomes, reduced waiting lists, heightened patient engagement, and increased awareness of EDs with improved resource allocation., Discussion: This project signifies a pivotal shift towards data-driven, patient-centered ED care in Italy. By integrat ing AI and promoting collaboration, it seeks to redefine mental healthcare standards and foster better well- being among individuals with EDs., 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 authors 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 Monaco, Vignapiano, Piacente, Pagano, Mancuso, Steardo, Marenna, Farina, Petrillo, Leo, Ferrara, Palermo, Martiadis, Solmi, Monteleone, Fasano and Corrivetti.)

Background: A significant number of young individuals are readmitted one or more times shortly after their first episode of psychosis. Readmission may represent a marker of psychopathological vulnerability. Our primary aim was to evaluate the impact of clinical and socio-demographic variables on readmission at 12-month follow-up. Secondly, our goal was to determine whether the use of Long-Acting Injection (LAI) antipsychotics provides notable benefits compared to oral medications in preventing subsequent readmissions., Subjects and Methods: 80 patients hospitalised for the first time with a diagnosis of psychotic disorder (ICD-10 criteria) were retrospectively assessed through clinical records. The mean age was 21.7 years. Patients were predominantly male (n = 62, 77.5%), and 55 subjects had at least 8 years of education. 50% of the sample was "NEET" (not in education, employment, or training)., Results: 35 patients (43.8%) were discharged with a LAI antipsychotic, while 45 (56.2%) recieved oral antipsychotic therapy. Substance use ( p = 0.04) and oral antipsychotics at discharge ( p = 0.003) were significantly associated with readmission at 1 year. We did not find any significant predictors of being discharged with LAI therapy., Conclusion: Our findings underlined the importance of identifying patients at risk of readmission in order to prevent future rehospitalization and promote appropriate prevention strategies. LAIs should be considered as a first-choice treatment for patients hospitalised for FEP since they proved to be effective in preventing relapse.

Introduction and Aims: Treatment-resistant depression (TRD) occurs when at least two different antidepressants, taken at the right dosage, for adequate period of time and with continuity, fail to give positive clinical effects. Esketamine, the S-enantiomer of ketamine, was recently approved for TRD treatment from U.S. Food and Drug Administration and European Medicine Agency. Despite proved clinical efficacy, many misconceptions by clinicians and patients accompany this medication. We aimed to review the most common "false myths" regarding TRD and esketemine, counterarguing with evidence-based facts., Methods: The keywords "esketamine", "treatment resistance depression", "depression", "myth", "mythology", "pharmacological treatment", and "misunderstanding" were entered in the main databases and combined through Boolean operators., Results: Misconceptions regarding the TRD prevalence, clinical features and predictors have been found. With respect of esketamine, criteria to start treatment, dissociative symptoms, potential addiction and aspects of administration and monitoring, were found to be affected by false beliefs by clinicians and patients., Discussion and Conclusion: TRD represents a challenging condition, requiring precise diagnosis in order to achieve patient's full recovery. Esketamine has been proved as an effective medication to treat TRD, although it requires precautions. Evidence can inform clinical practice, in order to offer this innovative treatment to all patients with TRD., 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 Di Vincenzo, Martiadis, Della Rocca, Arsenio, D’Arpa, Volpicelli, Luciano, Sampogna and Fiorillo.)

Introduction: 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 states. As a result, ketamine improves short-term plasticity in depression by enhancing sensitivity to interoceptive signals., Methods: We selected 2 case studies for their paradigmatic description of "depersonalized depression" (Entfremdungsdepression) symptoms. Patients were included in a 6-month-long esketamine program for treatment resistant depression, during which we collected their spontaneous experience with esketamine. According to a neurophenomenological approach, we combined subjective reports from unstructured clinical interviews and the review of previous objective neuroimaging results and neurocomputational models to unveil the relation between esketamine antidepressant effects and interoceptive sensitivity., Results: According to our clinical observations, esketamine-induced dissociation might be particularly effective in the depersonalized depression subtype, in which interoceptive awareness and interaffectivity are particularly compromised. Ketamine and esketamine's dissociative effects and particularly disembodiment might suspend previously acquired patterns of feeling, sensing, and behaving., Conclusions: Coherently with previous research, we suggest that esketamine-induced disembodiment allows for a transient window of psychological plasticity and enhanced sensitivity, where the body recovers its permeability to affective affordances., (© 2024 S. Karger AG, Basel.)

Background: Treatment-resistant bipolar depression is one of the leading problems in psychiatry with serious consequences on patients functioning, quality of life and resource utilization. Despite this, there is a lack of consensus on diagnostic criteria and treatment algorithms., Objective: The objective of the present study is to assess the acute effectiveness and tolerability of cariprazine in the management of treatment resistant bipolar depression., Methods: This is a four weeks retrospective multicentric observational study on patients with treatment resistant bipolar depression receiving cariprazine in augmentation to the current treatment. Cariprazine dosage changed during the follow-up period according to clinical judgment. Since data followed a non-normal distribution, non-parametric tests were used to pursue the analysis. The effectiveness of cariprazine was assessed through the mean change in Hamilton Depression rating scale (HAM-D) scores from baseline to endpoint. For missing values, a "Last Observation Carried Forward" approach was applied., Results: Fifty-one patients were enrolled. Four patients (7.8%) discontinued cariprazine mainly due to adverse events. Mean cariprazine dose was 1.7 mg/day. The mean HAM-D score decreased significantly from baseline (T0) to week 4 (T4) at each evaluation point. Fourty-five one percent of the patients benefited of cariprazine add-on strategy: 23.5% achieved a clinical response and 21.6% were remitters. Among the completers, 70.6% experienced at least one adverse event. All side effects were mild to moderate., Conclusion: Cariprazine seems to be an effective and well tolerated option in the management of patients with treatment resistant bipolar depression., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Treatment-resistant depression (TRD) is a serious and debilitating psychiatric disorder that frequently affects older patients. Esketamine nasal spray (ESK-NS) has recently been approved as a treatment for TRD, with multiple studies establishing its efficacy and tolerability. However, the real-world effectiveness, tolerability, and safety of this treatment in older adults is still unclear., Objectives: To evaluate the efficacy and tolerability of ESK-NS in older subjects with TRD., Methods: This is a post-hoc analysis of the REAL-ESK study, a multicenter, retrospective, observational study. Participants here selected were 65 years or older at baseline. The Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A) were used to assess depressive and anxiety symptoms, respectively. Data were collected at three-time points: baseline, 1 month after the start of treatment (T1), and 3 months after treatment (T2)., Results: The sample included older adults with TRD (n = 30). MADRS and HAM-A values decreased significantly at T1 (T0 versus T1: p holm <0.001, Cohen's d = 0.840) and T2 follow-ups (T0 versus T2: p holm <0.001, Cohen's d = 1.419). At T2, 53.3% of subjects were responders (MADRS score reduced ≥50%), while 33.33% were in remission (MADRS<10). ESK-NS-related adverse effects were in order of frequency dizziness (50%), followed by dissociation (33.3%), sedation (30%), and hypertension (13.33%). Six out of 30 participants (20%) discontinued treatment., Conclusions: Our findings provide preliminary evidence of ESK-NS effectiveness in older adults with TRD, a highly debilitating depressive presentation. Furthermore, we observe high levels of treatment-emergent adverse events, which, in the majority of instances, did not require treatment suspension., Competing Interests: DISCLOSURES 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, Neuraxpharm, Rovi, and Recordati. Giorgio Di Lorenzo has been a speaker and / or a consultant for Angelini, Janssen-Cilag, Livanova, Lundbeck, Neuraxpharm, Otsuka, 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Among individuals receiving an adequate pharmacological treatment for Major Depressive Disorder (MDD), only 30% reach a full symptom recovery; the remaining 70% will experience either a pharmacological response without remission or no response at all thus configuring treatment resistant depression (TRD). After an inadequate response to an antidepressant, possible next step options include optimizing the dose of the current antidepressant, switching to a different antidepressant, combining antidepressants, or augmenting with a non-antidepressant medication. Augmentation strategies with the most evidence-based support include atypical antipsychotics (AAs). Few data are available in literature about switching to another antipsychotic when a first augmentation trial has failed. We present a case-series of patients with unipolar treatment resistant depression who were treated with a combination of antidepressant and low dose of cariprazine after failing to respond to a first augmentation with another AA. We report data about ten patients affected by unipolar depression, visited at the outpatients unit of Mental Health Department of ASL CN2 of Bra and NA1 of Napoli (Italy). All patients failed to respond to conventional antidepressant therapy. A low dose of AA (aripiprazole, risperidone or brexpiprazole) was added for one month to the ongoing antidepressant treatment without clinical improvement. A second augmentation trial was then made with cariprazine. Seven out of ten patients were responders at the end of period, of them 1 patient reached responder status by week 2. HAM-D mean scores decreased from 23.9 ± 3.9 (baseline) to 14.8 ± 5.3 (4 weeks). Cariprazine was well tolerated, no severe side effect was observed during the trial. Our sample of treatment resistant unipolar patients showed good response to augmentation with cariprazine. Failure to a first AA-augmentation trial does not preclude response to a second one. This preliminary result requires confirmation through more rigorous studies conducted over greater samples., 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., (Copyright © 2023 Pessina, Martini, Raffone and Martiadis.)

Pharmacological antipsychotic drug interventions represent the cornerstone of the management of patients with schizophrenia and other psychotic spectrum disorders. The choice of the "best" treatment should be made on the basis of several clinical domains. However, despite available treatments, the quality of life reported by patients with schizophrenia taking antipsychotics is still very poor, and this outcome is rarely taken into account in trials assessing the efficacy and effectiveness of antipsychotic treatments. Therefore, we performed a systematic review in order to assess the impact of antipsychotic treatment on patients' quality of life. In particular, we aimed to identify any differences in the improvement in quality of life according to the (a) type of formulation of antipsychotic drugs (i.e., oral vs. depot vs. long-acting injectable); (b) type of the drug (first vs. second vs. third generation); and (c) patients' clinical characteristics. One hundred and eleven papers were included in the review. The main findings were as follows: (1) quality of life is usually considered a secondary outcome in trials on the efficacy and effectiveness of drugs; (2) second-generation antipsychotics have a more positive effect on quality of life; and (3) long-acting injectable antipsychotics are associated with a more stable improvement in quality of life and with a good safety and tolerability profile. Our systematic review confirms that quality of life represents a central element for selecting the appropriate treatment for people with schizophrenia. In particular, the availability of new treatments with a better tolerability profile, a proven effectiveness on patients' cognitive and social functioning, and with a more stable blood concentration might represent the appropriate strategy for improving the quality of life of people with schizophrenia.

Treatment-resistant depression (TRD) represents a severe clinical condition with high social and economic costs. Esketamine Nasal Spray (ESK-NS) has recently been approved for TRD by EMA and FDA, but data about predictors of response are still lacking. Thus, a tool that can predict the individual patients' probability of response to ESK-NS is needed. This study investigates sociodemographic and clinical features predicting responses to ESK-NS in TRD patients using machine learning techniques. In a retrospective, multicentric, real-world study involving 149 TRD subjects, psychometric data (Montgomery-Asberg-Depression-Rating-Scale/MADRS, Brief-Psychiatric-Rating-Scale/BPRS, Hamilton-Anxiety-Rating-Scale/HAM-A, Hamilton-Depression-Rating-Scale/HAMD-17) were collected at baseline and at one month/T1 and three months/T2 post-treatment initiation. We trained three different random forest classifiers, able to predict responses to ESK-NS with accuracies of 68.53% at T1 and 66.26% at T2 and remission at T2 with 68.60% of accuracy. Features like severe anhedonia, anxious distress, mixed symptoms as well as bipolarity were found to positively predict response and remission. At the same time, benzodiazepine usage and depression severity were linked to delayed responses. Despite some limitations (i.e., retrospective study, lack of biomarkers, lack of a correct interrater-reliability across the different centers), these findings suggest the potential of machine learning in personalized intervention for TRD., Competing Interests: Declaration of Competing Interest 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Metacognition refers to the cognitive ability to control, monitor and modulate cognitive processes thus guiding and orienting behavior: a continuum of mental activities that ranges from more discrete ones, such as the awareness of the accuracy of others' judgment, to more integrated activities, such as the knowledge of cognitive processes. Metacognition impairment in schizophrenia, which is considered a core feature of the illness, has become a growing research field focusing on a wide range of processes including reasoning, autobiographical memory, memory biases, cognitive beliefs and clinical insight. There is a well-established relationship between metacognition and schizophrenia symptoms severity, as well as between impaired metacognitive functioning and specific symptomatic sub-domains, such as positive symptoms, negative symptoms, or disorganization. The development of specific cognitive-derived psychotherapies for metacognitive deficits in schizophrenia has been ongoing in the last years. Although sharing a metacognitive feature, these treatments focus on different aspects: false or unhelpful beliefs for metacognitive therapy; cognitive biases for metacognitive training; schematic dysfunctional beliefs for cognitive behavioral therapy (CBT) for psychoses; metacognitive knowledge and sense of identity for MERIT; interpersonal ideas or events triggering delusional thinking for MIT-P. This article reviews the instruments designed to assess metacognitive domains and functions in individuals with schizophrenia, providing mental health professionals with an overview of the heterogeneous current scenario ranging from self-administered scales to semi-structured interviews, which are supported by a variety of theoretical frameworks. Future directions may address the need for more specific and refined tools, also able to follow-up psychotherapeutic-induced improvements., 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., (Copyright © 2023 Martiadis, Pessina, Raffone, Iniziato, Martini and Scognamiglio.)

Background: Treatment-resistant Depression (TRD) represents a widespread disorder with significant direct and indirect healthcare costs. esketamine, the S-enantiomer of ketamine, has been recently approved for TRD, but real-world studies are needed to prove its efficacy in naturalistic settings., Objectives: Evaluate the effectiveness and safety of esketamine nasal spray in a clinical sample of patients with TRD from several Italian mental health services., Methods: REAL-ESK study is an observational, retrospective and multicentric study comprising a total of 116 TRD patients treated with esketamine nasal spray. Anamnestic data and psychometric assessment (MADRS, HAMD-21, HAM-A) were collected from medical records at baseline (T0), one month (T1) and three month (T2) follow-ups., Results: A significant reduction of depressive symptoms was found at T1 and T2 compared to T0. A dramatic increase in clinical response (64.2 %) and remission rates (40.6 %) was detected at T2 compared to T1. No unexpected safety concerns were observed, side effects rates were comparable to those reported in RCTs. No differences in efficacy have been found among patients with and without psychiatric comorbidities., Limitations: The open design of the study and the absence of a placebo or active comparator group are limitations. The study lacks an inter-rater reliability evaluation of the assessments among the different centres. Side effects evaluation did not involve any specific scale., Conclusions: Our findings support the safety and tolerability of esketamine in a real-world TRD sample. The later response and the non-inferiority in effectiveness in patients with comorbidities represent novel and interesting findings., Competing Interests: Conflict of interest 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. Alessandro Bertolino and Ileana Andriola were both speakers at Jannssen-sponsored conference. Andrea Fagiolini has been a consultant and/or a speaker and/or has received research grants from Allergan, Angelini, Apsen, Boehringer Ingelheim, Doc Generici, FB-Health, Italfarmaco, Janssen, Lundbeck, Mylan, Otsuka, Pfizer, Recordati, Sanofi Aventis, Sunovion, Vifor. Bernardo Dell'Osso has received lecture honoraria from Angelini, Lundbeck, Janssen, Pfizer, Neuraxpharm, Arcapharma, and Livanova. Massimo di Giannantonio has been a consultant and/or a speaker and/or has received research grants from Angelini, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Servier, Recordati. 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. Giuseppe Maina has been a consultant/speaker for Angelini, Boheringer, Fb Health, Innovapharma, Italfarmaco, Janssen, Otsuka, Lundbeck, Sanofi. Gabriele Sani has been a consultant/speaker for Angelini, Fb Health, Italfarmaco, Janssen, Otsuka, Lundbeck, Sanofi. Roger McIntyre has received grant/research support from CIHR/GACD/Chinese National Natural Research Foundation and speaking or consultation fees from AbbVie, Bausch Health, Eisai, Intra-Cellular, Janssen, Kris, Lundbeck, Minerva, Neurocrine, Novo Nordisk, Eli Lilly, Otsuka, Pfizer, Purdue, Sunovion, and Takeda; he is also the CEO of Champignon Brands, Inc. 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.