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Psychomotor agitation (PMA) is a prominent clinical issue frequently observed in various psychiatric and neurological conditions, including schizophrenia, bipolar disorder, Parkinson disease, dementia and substance use disorder. Characterized by motor restlessness, anxiety and irritability, PMA can rapidly escalate into aggression and violence, necessitating prompt intervention to ensure patient and caregiver safety. The prevalence of PMA in psychiatric emergency settings ranges from 4.3% to 10%, imposing a substantial burden on healthcare systems. Despite the critical nature of PMA, there is a lack of standardized treatment protocols, particularly concerning the use of liquid formulations of antipsychotics such as liquid promazine, which may offer unique advantages in emergency care. This review aims to provide a comprehensive analysis of the existing literature on the efficacy, safety and tolerability of liquid antipsychotics, with a particular focus on promazine, in the management of PMA. An extensive literature search was conducted across publicly available databases with no time limitations to ensure the inclusion of all relevant articles. The findings suggest that liquid promazine offers several benefits, including ease of administration, rapid onset of action and improved patient compliance, making it a valuable option in acute PMA management. However, the review also highlights the need for future research, particularly long-term studies and head-to-head comparisons with other antipsychotics, to better establish the clinical utility of liquid promazine. Future research should focus on expanding the evidence base for liquid antipsychotic formulations, which will contribute to improved clinical outcomes in the management of PMA.

Abstract Background Although second-generation antipsychotics (SGAs) have proven to be effective therapeutic options for patients with schizophrenia, there is a notable lack of evidence on patients’ subjective perspectives regarding their well-being, quality of life, and satisfaction with these medications. This study aimed to evaluate the treatment satisfaction and effectiveness of lurasidone on quality of life and functioning in adult patients with schizophrenia in real-world Italian clinical practice. Methods This was a multicentre, national, non-interventional, single-arm, 3-month prospective study. Patients who were naive to lurasidone treatment and whose treating physician had decided to start them on this medication were enrolled and evaluated over a 3-month period. Eligible patients were adults (≥ 18 years of age) with a primary diagnosis of schizophrenia who were being treated with lurasidone (for the first time [i.e., they were lurasidone naive]) as part of routine clinical practice. Efficacy endpoints were changes in patient/caregiver treatment satisfaction (seven-point Likert scale from the Treatment Satisfaction Questionnaire for Medication), patient quality of life and functioning (QLS), investigator-rated global assessment of functioning (CGI-S, IAQ) after 6 weeks and 3 months of lurasidone, and number of relapses and hospitalizations. Results Sixty-one patients were enrolled and 59 completed the study. The median dosage of lurasidone at baseline was 37.00 mg/day. The median duration of titration was 86.0 days (Min 28; Max 115 days); the median number of dosage changes was 1.0. At the end of 3-month observation period, the median dose of lurasidone was 74.00 mg/day. QoL and Functioning Score showed a trend of improvement over time, reaching a mean change from baseline of 9.8 at the end of the study. According to the CGI-S, the percentage of patients who were “markedly or severely ill” showed a continuous decrease from baseline to 3 months, from 62.29% to 8.20%. Patient satisfaction increased over time, with 80.32% of patients reporting that they were somewhat, fairly, or very satisfied (including 63.93% who were completely or very satisfied) at the end of the study. No relapses/hospitalizations for psychiatric reasons were reported. Lurasidone was well tolerated with no safety concerns or discontinuations due to AEs. Conclusions Lurasidone represents a valid option for the treatment of schizophrenia and positively affects subjective well-being, quality of life and satisfaction. Trial registration NCT06527885 retrospectively registered (01/08/2024).

Abstract Introduction Gender- and age-specific research on medications is essential for personalizing treatment plans, optimizing dosing, minimizing adverse effects and improving outcomes. Women are twice as likely to be diagnosed with major depressive disorder (MDD), and it is commonly reported during their reproductive years. This post-hoc pooled analysis evaluated the efficacy of sertraline (one of the most studied medications in women) in women of reproductive age (18–44 years). Methods Data was pooled from nine clinical trials of sertraline that included 1832 subjects with MDD. The analysis set included 1097 women, 651 of those were of reproductive age. Sertraline was compared with placebo for changes in total HAM-D17 and CGI scores measured over time through MMRM analysis. The change from baseline to the end of study (-week 8) was assessed using ANCOVA. Results The changes from baseline in total HAM-D17 and CGI scores were significantly higher for sertraline than for placebo at the end of 8 weeks for all women (LS Mean difference, 95% CI: -1.81(-3.01,-0.62), P = 0.0029; -0.38(-0.55,-0.20), P

Christoph U Correll,1– 4 Celso Arango,5 Andrea Fagiolini,6 Giulia Maria Giordano,7 Stefan Leucht,4,8 Gonzalo Salazar de Pablo5,9,10 1Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA; 2Department of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/ Northwell, Hempstead, NY, USA; 3Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany; 4German Center for Mental Health (DZPG), Partner Site Berlin, Berlin, Germany; 5Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, Madrid, Spain; 6Department of Molecular Medicine, School of Medicine, University of Siena, Siena, Italy; 7Department of Psychiatry, University of Campania “Luigi Vanvitelli”, Naples, Italy; 8Technical University of Munich, TUM School of Medicine and Health, Department of Psychiatry and Psychotherapy, Munich, Germany; 9Child and Adolescent Mental Health Services (CAMHS) South London and Maudsley NHS Foundation Trust London, London, UK; 10Department of Child and Adolescent Psychiatry Institute of Psychiatry, Psychology & Neuroscience King’s College London, London, UKCorrespondence: Christoph U Correll, The Zucker Hillside Hospital, Department of Psychiatry, 75-59 263rd Street Glen Oaks, New York, NY, 11004, USA, Email ccorrell@northwell.eduBackground: Schizophrenia is most times a chronic and often debilitating illness associated with poor mental health outcomes. Early and effective treatment of schizophrenia in the most appropriate setting can make a significant difference in the long-term recovery. The aim of this narrative review was to provide suggestions and recommendations for effectively managing patients with schizophrenia during acute exacerbations and to enhance awareness and skills related to personalized medicine.Methods: A panel of academics and clinicians with experience in the field of psychosis met virtually on July 13th 2023 to narratively review and discuss the research evidence and their clinical experience about the most appropriate acute treatments for patients with schizophrenia. This manuscript represents a synthesis of the panel analysis and discussion.Results: First contact is very important for service users, as is finding the most adequate treatment setting. If patients present to the emergency department, which may be a traumatic setting for service users, a dedicated environment with adequate space and specialized mental health support, including personnel trained in de-escalation techniques, is recommended. A well-connected continuum of care is strongly recommended, possibly with seamless links between inpatient units, day hospital services, outpatient facilities and rehabilitation services. Ideally, this should be structured as part of a coordinated step-down service line. Treatment challenges include suboptimal response, side effects, and nonadherence, which is reduced by the use of long-acting injectable antipsychotics.Conclusion: Individual circumstances, including age, gender, and presence of hostility/aggression or self-harm, cognitive impairment and negative symptoms, comorbidities (depression, substance use disorders) or associated symptoms (anxiety, insomnia), should be considered when selecting the most appropriate treatment for the acute phase of schizophrenia. Efficacy and feasibility, as well as acceptability and tolerability of treatments, require joint consideration from the early stages of schizophrenia, thereby enhancing the possibility of improved short- and long-term outcomes.Keywords: schizophrenia, first-episode psychosis, acute setting, clinical care

Daniel Guinart,1– 3 Andrea Fagiolini,4 Paolo Fusar-Poli,5– 8 Giulia Maria Giordano,9 Stefan Leucht,10 Carmen Moreno,11– 13 Christoph U Correll3,14– 16 1Institut de Salut Mental, Parc de Salut Mar, Barcelona, Spain; 2Hospital Del Mar Research Institute, CIBERSAM, Barcelona, Spain; 3Department of Psychiatry, The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA; 4Department of Molecular Medicine, University of Siena School of Medicine, Siena, Italy; 5Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy; 6Department of Psychosis Studies, King’s College London, London, UK; 7Outreach and Support in South-London (OASIS) Service, South London and Maudsley (Slam) NHS Foundation Trust, London, UK; 8Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University Munich, Munich, Germany; 9Department of Psychiatry, University of Campania “Luigi Vanvitelli”, Naples, Italy; 10Technical University of Munich, TUM School of Medicine and Health, Department of Psychiatry and Psychotherapy, Munich, Germany; 11Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (LISGM), Madrid, Spain; 12Centro de Investigación Biomedica en Red (CIBERSAM), ISCIII, Madrid, Spain; 13School of Medicine, Universidad Complutense, Madrid, Spain; 14Department of Psychiatry, The Zucker Hillside Hospital, New York, NY, USA; 15Department of Child and Adolescent Psychiatry, Charité Universitatsmedizin, Berlin, Germany; 16German Center for Mental Health (DZPG), Partner Site, Berlin, GermanyCorrespondence: Christoph U Correll, Department of Psychiatry, The Zucker Hillside Hospital, 75-59 263rd Street Glen Oaks, New York, NY, 11004, USA, Email ccorrell@northwell.eduIntroduction: Schizophrenia is a severe mental illness that usually begins in late adolescence or early adulthood. Current pharmacological treatments, while acceptably effective for many patients, are rarely clinically tailored or individualized. The lack of sufficient etiopathological knowledge of the disease, together with overall comparable effect sizes for efficacy between available antipsychotics and the absence of clinically actionable biomarkers, has hindered the advance of individualized medicine in the treatment of schizophrenia. Nevertheless, some degree of stratification based on clinical markers could guide treatment choices and help clinicians move toward individualized psychiatry. To this end, a panel of experts met to formally discuss the current approach to individualized treatment in schizophrenia and to define how treatment individualization could help improve clinical outcomes.Methods: A task force of seven experts iteratively developed, evaluated, and refined questionnaire items, which were then evaluated using the Delphi method. Descriptive statistics were used to summarize and rank expert responses. Expert discussion, informed by the results of a scoping review on personalizing the pharmacologic treatment of adults and adolescents with schizophrenia, ultimately generated recommendations to guide individualized pharmacologic treatment in this population.Results: There was substantial agreement among the expert group members, resulting in the following recommendations: 1) individualization of treatment requires consideration of the patient’s diagnosis, clinical presentation, comorbidities, previous treatment response, drug tolerability, adherence patterns, and social factors; 2) patient preferences should be considered in a shared decision-making approach; 3) identified barriers to personalized care that need to be overcome include the lack of actionable biomarkers and mechanistic similarities between available treatments, but digital tools should be increasingly used to enhance individualized treatment.Conclusion: Individualized care can help provide effective, tailored treatments based on an individual’s clinical characteristics, disease trajectory, family and social environment, and goals and preferences.Keywords: psychosis, psychopharmacology, treatment, personalized, psychiatry

Abstract Background Depression is a highly heterogeneous disorder, often resulting in suboptimal response and remission rates. This underscores the need for more nuanced clinical characterization of patients to tailor individualized treatment plans. Emerging evidence highlights the critical role of cognitive and emotional dysfunction in major depression, prompting the exploration of novel therapeutic interventions that target these specific symptom domains. Main text Vortioxetine, a multimodal antidepressant, enhances serotonergic activity while also modulating several other neurotransmitter systems involved in depressive symptoms such as emotional blunting, anhedonia, and cognitive dysfunction. Numerous randomized, placebo-controlled trials have demonstrated vortioxetine’s efficacy and safety in treating depression, particularly in specific subgroups of depressed patients, including those with cognitive deficits and comorbid anxiety symptoms or disorders. Although not randomized or placebo-controlled, studies have also shown vortioxetine’s efficacy in depressed patients with emotional blunting or anhedonia. Vortioxetine’s ability to effectively treat a range of depressive symptoms, including anhedonia, emotional blunting, anxiety, and cognitive dysfunction, provides an individualized treatment solution for depressed individuals suffering from these symptoms. The purpose of this paper is to identify clinical profiles of patients who may benefit from vortioxetine, with the goal of optimizing therapeutic outcomes. Conclusion Vortioxetine has been shown to be effective for patients with depression and symptoms such as anhedonia, emotional blunting, anxiety, and cognitive dysfunction. Tailoring treatment plans to individual needs and personalizing treatment choices based on the specific symptoms presented by depressed patients improve treatment outcomes.

Abstract Background BIPCOM aims to (1) identify medical comorbidities in people with bipolar disorder (BD); (2) examine risk factors and clinical profiles of Medical Comorbidities (MC) in this clinical group, with a special focus on Metabolic Syndrome (MetS); (3) develop a Clinical Support Tool (CST) for the personalized management of BD and medical comorbidities. Methods The BIPCOM project aims to investigate MC, specifically MetS, in individuals with BD using various approaches. Initially, prevalence rates, characteristics, genetic and non-genetic risk factors, and the natural progression of MetS among individuals with BD will be assessed by analysing Nordic registers, biobanks, and existing patient datasets from 11 European recruiting centres across 5 countries. Subsequently, a clinical study involving 400 participants from these sites will be conducted to examine the clinical profiles and incidence of specific MetS risk factors over 1 year. Baseline assessments, 1-year follow-ups, biomarker analyses, and physical activity measurements with wearable biosensors, and focus groups will be performed. Using this comprehensive data, a CST will be developed to enhance the prevention, early detection, and personalized treatment of MC in BD, by incorporating clinical, biological, sex and genetic information. This protocol will highlight the study's methodology. Discussion BIPCOM's data collection will pave the way for tailored treatment and prevention approaches for individuals with BD. This approach has the potential to generate significant healthcare savings by preventing complications, hospitalizations, and emergency visits related to comorbidities and cardiovascular risks in BD. BIPCOM's data collection will enhance BD patient care through personalized strategies, resulting in improved quality of life and reduced costly interventions. The findings of the study will contribute to a better understanding of the relationship between medical comorbidities and BD, enabling accurate prediction and effective management of MetS and cardiovascular diseases. Trial registration: ISRCTN68010602 at https://www.isrctn.com/ISRCTN68010602 . Registration date: 18/04/2023.

Background: Out-of-hospital cardiac arrest (OHCA) is a major health concern in Europe, leading to significant morbidity and mortality. Survivors often suffer from cognitive deficits, anxiety, and depression, that affect significantly their quality of life. Current post-discharge care is inconsistent and frequently overlooks subtle but disabling symptoms. The ENFORCER trial aims to significantly enhance the health and quality of life of OHCA survivors by providing a comprehensive, accessible, and user-friendly internet-based lifestyle intervention. Methods: ENFORCER is a multicentre, parallel group randomized controlled trial involving OHCA survivors aged 18–80 years with cognitive impairment or anxiety/depression measured through validated instruments.Participants will be randomized 1:1 to the intervention or the control group. The intervention group will receive a one-year program via a secure web application, offering cognitive, emotional, and physical rehabilitation support. The control group will receive standard care.The primary outcome is the difference in the proportion of patients without cognitive or emotional symptoms between the two groups after one year.Secondary outcomes include changes in the level of patients’ cognitive and emotional symptoms, quality of life, sleep quality, sexual interest and satisfaction, and caregivers’ burden, quality of life, sleep quality and emotional symptoms in the two groups. Discussion: The trial addresses the need for consistent post-discharge care, and the timely detection and treatment of cognitive and emotional problems. The internet-based approach allows to potentially reach many patients, ensuring cost-effectiveness and high adherence rates.The study results could establish a standard for post-OHCA care, improving long-term recovery and quality of life for survivors.Trial registration.The trial is registered at clinicaltrials.gov (NCT06395558).

Intimate partner violence (IPV) is one of the most common forms of violence against women. Gender-based violence is a major issue for women throughout their lifespan and comorbid mental health complaints are documented. The estimated worldwide prevalence is nearly 1 in 3, with female survivors reporting physical and/or sexual assault by an intimate partner at some time in their life. Scientific panels are currently addressing interest in both understanding risk factors and improving support services for this population. Up to now, previous research made poor efforts to explore the effectiveness of psychological interventions, in particular psychotherapy, in addressing mental health problems among women survivors of intimate partner violence. Our search aimed to summarize the available literature about psychological treatments for post-traumatic stress disorder (PTSD) in female survivors with a focus on the effectiveness of cognitive-behavioral therapy in addressing those symptoms. Twenty-six studies providing cognitive-behavioral therapies, psychodrama, interpersonal therapy, and active psychological intervention were included in a systematic review. Meta-analysis was restricted to thirteen studies that implemented cognitive behavioral therapies with similar treatment components. A strong reduction of PTSD severity was found (g = 1.52; 95 %-CI = 1.33, 1.71; p < 0.01) with moderate to large heterogeneity between studies (I2= 64 %; Q = 80.81). Evidence for publication bias was observed (Egger's test; t = 2.396; p = 0.02). Results suggest cognitive behavioral therapy is effective for PTSD symptoms improvement in women survivors of intimate partner violence. The core interventions’ components included psychoeducation, relaxation with diaphragmatic breathing, trauma exposure, imagery, and problem-solving.

Background: This systematic review and meta-analysis aimed to synthesize the evidence of efficacy and tolerability of adjunctive topiramate treatment for patients with obsessive-compulsive disorder. Methods: A systematic search was conducted on MEDLINE, Cochrane Central Register of Controlled Trials, and OpenGrey to identify randomized controlled trials assigning participants with OCD to pharmacological intervention with topiramate. Study inclusion and data extraction were undertaken by two reviewers independently. The primary outcome was the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scale score, as a continuous variable within-subject OCD illness severity before and after treatment. The weighted mean difference (WMD) with 95 % confidence interval was calculated between the topiramate group and the control group. Results: Five studies were selected for inclusion in the systematic review, 4 of which were also included in the quantitative synthesis of data. The WMD in the Y-BOCS score between topiramate and placebo subjects was -0.49 (-2.28, 1.30) (p = 0.00); The results show a trend towards an effect of topiramate, but the estimate was not significant. Subgroup analysis revealed a significant effect at 12 weeks but not at 16 weeks (p = 0.00). Limitations: Low quality of the studies included and small sample size. Conclusion: There is a small positive signal for an anti-obsessive/compulsive effect in OCD patients which should encourage further research with larger, randomized, and placebo-controlled trials to assess topiramate's potential role in OCD treatment comprehensively.

Bipolar disorder is heterogeneous in phenomenology, illness trajectory, and response to treatment. Despite evidence for the efficacy of multimodal-ity interventions, the majority of persons affected by this disorder do not achieve and sustain full syndromal recovery. It is eagerly anticipated that combining datasets across various information sources (e.g., hierarchical "multi-omic" measures, electronic health records), analyzed using advanced computational methods (e.g., machine learning), will inform future diagnosis and treatment selection. In the interim, identifying clinically meaningful subgroups of persons with the disorder having differential response to specific treatments at point-of-care is an empirical priority. This paper endeavours to synthesize salient domains in the clinical characterization of the adult patient with bipolar disorder, with the overarching aim to improve health outcomes by informing patient management and treatment considerations. Extant data indicate that characterizing select domains in bipolar disorder provides actionable information and guides shared decision making. For example, it is robustly established that the presence of mixed features - especially during depressive episodes - and of physical and psychiatric comorbidities informs illness trajectory, response to treatment, and suicide risk. In addition, early environmental exposures (e.g., sexual and physical abuse, emotional neglect) are highly associated with more complicated illness presentations, inviting the need for developmentally-oriented and integrated treatment approaches. There have been significant advances in validating subtypes of bipolar disorder (e.g., bipolar I vs. II disorder), particularly in regard to pharmacological interventions. As with other severe mental disorders, social functioning, interpersonal/family relationships and internalized stigma are domains highly relevant to relapse risk, health outcomes, and quality of life. The elevated standardized mortality ratio for completed suicide and suicidal behaviour in bipolar disorder invites the need for characterization of this domain in all patients. The framework of this paper is to describe all the above salient domains, providing a synthesis of extant literature and recommendations for decision support tools and clinical metrics that can be implemented at point-of-care.

This paper reports on the use of co-simulation techniques to build prototypes of co-operative autonomous robotic cyber-physical systems. Designing such systems involves a mission-specific planner algorithm, a control algorithm to drive an agent performing its task; and the plant model to simulate the agent dynamics. An application aimed at positioning a swarm of unmanned aerial vehicles (drones) in a bounded area, exploiting a Voronoi tessellation algorithm developed in this work, is taken as a case study. The paper shows how co-simulation allows testing the complex system at the design phase using models created with different languages and tools. The paper then reports on how the adopted co-simulation platform enables control parameters calibration, by exploiting design space exploration technology. The INTO-CPS co-simulation platform, compliant with the Functional Mock-up Interface standard to exchange dynamic simulation models using various languages, was used in this work. The different software modules were written in Modelica, C, and Python. In particular, the latter was used to implement an original variant of the Voronoi algorithm to tesselate a convex polygonal region, by means of dummy points added at appropriate positions outside the bounding polygon. A key contribution of this case study is that it demonstrates how an accurate simulation of a cooperative drone swarm requires modeling the physical plant together with the high-level coordination algorithm. The coupling of co-simulation and design space exploration has been demonstrated to support control parameter calibration to optimize energy consumption and convergence time to the target positions of the drone swarm. From a practical point of view, this makes it possible to test the ability of the swarm to self-deploy in space in order to achieve optimal detection coverage and allow unmanned aerial vehicles in a swarm to coordinate with each other.

Andrea Fagiolini,1 Ana González Pinto,2,3 Kamilla Woznica Miskowiak,4– 6 Pedro Morgado,7– 9 Allan H Young,10,11 Eduard Vieta12 1Department of Molecular and Developmental Medicine, Division of Psychiatry, University of Siena School of Medicine, Siena, 53100, Italy; 2Bioaraba Research Institute, Department of Psychiatry, Araba University Hospital, Vitoria, 01004, Spain; 3CIBERSAM, University of the Basque Country, Vitoria, Spain; 4Copenhagen Affective Disorder research Centre (CADIC), Psychiatric Centre, Copenhagen, Denmark; 5Copenhagen, Copenhagen University Hospital, Rigshospitalet, Denmark; 6Department of Psychology, University of Copenhagen, Copenhagen, Denmark; 7Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, 4710-057, Portugal; 8ICVS/3B’s, PT Government Associate Laboratory, Braga/Guimarães, 4710-057, Portugal; 9Clinical Academic Center-Braga (2CA), Braga, 4710-243, Portugal; 10Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, UK; 11South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Kent, UK; 12Bipolar and Depressive Disorders Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, SpainCorrespondence: Andrea Fagiolini, Department of Molecular and Developmental Medicine, Division of Psychiatry, University of Siena School of Medicine, Viale Bracci 12, Siena, 53100, Italy, Tel +39- 0577-586275, Email andreafagiolini@gmail.com; andrea.fagiolini@unisi.itObjective: Major depressive disorder (MDD) often co-occurs with dementia and other neurological disorders, and treatment with antidepressants can improve symptoms, quality of life, and survival in these patients. This narrative review provides an expert opinion about the role and effectiveness of trazodone in the treatment of older adults with MDD and cognitive impairment due to physical illnesses, such as dementia.Results: Because of its mechanism of action, trazodone can treat several depression symptoms often seen in people with dementia, including insomnia, agitation, anxiety, cognitive impairment, and irritability.Conclusion: Trazodone may be beneficial for patients with dementia or other neurological disorders comorbid with MDD, especially when the clinical picture of depression includes or is comorbid to symptoms of insomnia, irritability, inner tension, anxiety, or psychomotor agitation.Keywords: major depressive disorder, depression, dementia, cognitive impairment, trazodone

Developmental dyscalculia (DD) has long been thought to be determined by multiple components. Dyscalculia has high comorbidity with other learning and developmental disabilities, including reading and writing disorders, attention deficits, and problems in visual/spatial skills, short memory, and working memory. This study aims to assess prevalence rates for isolated as well as comorbid DD in a sample of Italian-speaking children. In addition, we studied the neuropsychological profile of children with isolated or combined dyscalculia. We tested 380 children (176 males and 204 females) between the ages of 8.17 and 9.33 years using an extensive battery to determine the neuropsychological profile. The assessment included an arithmetic battery and nonverbal intelligence, short-term memory, reading, and writing tests. The results indicated that children with DD more frequently have a reading disorder and writing disorder. They also have a lower nonverbal intelligence quotient (IQ) and obtain significantly lower scores in short-term memory tests and on a visuospatial skills questionnaire. They also had significantly higher scores (indicative of greater attentional difficulties) on the Conners subscale for attentional problems. Children with DD present different cognitive and neuropsychological profiles.

Introduction In ESCAPE-TRD, esketamine nasal spray (ESK-NS) significantly increased the probability of remission at Week (Wk)8 and being relapse‑free through Wk32 after remission at Wk8 versus (vs) quetiapine extended-release (QTP-XR), in patients (pts) with treatment resistant depression (TRD). Safety data were consistent with established profiles of each treatment, with no new safety signals identified (Reif et al. DGPPN 2022; P-01-04). Objectives To explore weight changes and their impact on treatment discontinuation in ESCAPE-TRD. Methods ESCAPE‑TRD (NCT04338321) was a randomised, open-label, rater-blinded, phase IIIb trial comparing efficacy and safety of ESK-NS vs QTP-XR in pts with TRD. Safety analyses were conducted on pts who received ≥1 dose of study treatment. Treatment-emergent adverse events (TEAEs) were defined as occurring at or after the first dose of study treatment and within 14 days/30 days (non-serious/serious) of the last dose. A ≥7% increase/decrease in weight from screening was considered for evaluation as a TEAE. Weights were measured and are reported as observed, with no missing data imputation. Results 336 and 340 pts were randomised to ESK-NS and QTP-XR; 334 and 336 were included in the safety population. Over the 32-week study, a TEAE of weight increase was reported in fewer pts treated with ESK-NS than QTP-XR (9 [2.7%] vs 42 [12.5%]), leading to treatment discontinuation in 0 vs 6 (1.8%) pts, respectively. Incidences of weight increase TEAEs were balanced across pts categorised as normal, overweight or obsese by baseline body mass index (BMI; Figure). A weight decrease TEAE was reported in 7 pts (2.1%) in the ESK-NS arm vs 0 pts in the QTP-XR arm. Mean (standard deviation [SD]) weight at baseline was 76.4 (16.2) kg (ESK-NS; n=334) vs 79.1 (16.9) kg (QTP-XR; n=336). At Wk32, mean weight was maintained (76.5 [16.3] kg) in ESK-NS treated pts (n=249; mean [SD] change from baseline: 0.1 [4.0] kg) and increased (80.7 [15.6] kg) in QTP-XR treated pts (n=203; mean [SD] change from baseline: 2.5 [5.1] kg). Image: Conclusions Increase in weight was uncommon with ESK-NS; weight increases were more common with QTP-XR and resulted in more treatment discontinuations. Weight increase was independent from baseline BMI. Acknowledgements We thank the patients who participated. Funding: Janssen, medical writing: Costello Medical, UK Disclosure of Interest None Declared

Introduction Vortioxetine is mainly prescribed as oral tablets, usually starting at 5-10 mg per day, and is well tolerated by most patients. However, some patients may experience side effects, the most common of which is nausea, which occurs in 20.9-31.2% of people treated with doses of 5-20 mg/day (Baldwin et al, J Psychopharmacol. 2016;30:242-52). In some countries, vortioxetine is also available as an oral solution (1 drop = 1 mg), which allows a very slow titration schedule that may improve tolerability. Objectives To evaluate whether vortioxetine oral drop solution, started with 1-2 drops (1-2 mg per day) and increased by 1-2 drops per day to 10-20 drops (10-20 mg), is associated with better tolerability and a lower risk of nausea than that observed with oral tablets started with 5-10 mg per day, while maintaining efficacy. To provide pilot data for the design of a multicentre, prospective study. Methods Retrospective, single-centre, observational study. Participants were 58 consecutive patients (mean age 45 + 17 years, 55.2% female) treated with vortioxetine for a depressive episode. Vortioxetine was initiated and titrated up to 1 drop (1 mg) per day in 58.6% of subjects, and initiated and titrated up to 2 drops in 41.4% of subjects. Tolerability was assessed at all visits. CGI and MADRAS scores were recorded at the following time points: T0-baseline, T1=week 1, T2=week 2, T3=week 4, T4=week 8). Comparisons were made using repeated measures ANOVA with Bonferroni correction. Results Nausea was reported by 8 subjects (13.8%) at T1, 4 subjects (6.9%) at T2, 1 subject at T3 (1.7%) and none at T4. Other adverse reactions (mainly dizziness, pruritus/itching, vomiting, diarrhoea, and xerostomia) were reported by a total of 6 subjects (10.3%) at T1, none at T2 and T3, and 1 subject (1.7%) at T4. The maximum dose administered was 20 mg in 75.9% of patients. No patients discontinued vortioxetine due to adverse events, but vortioxetine was discontinued prior to T4 (8 weeks of treatment) in 2 subjects due to lack of efficacy. The mean CGI at baseline was 4.3 ±0.8. The mean value decreased to 3.9±0.7 at week 1 and to 3.4±0.6, 2.7±0.6, 1.9±0.5 at weeks 2, 4 and 8, respectively. All differences were statistically significant (p

Introduction Major depressive disorder (MDD) is twice as common in women than men and is more frequently reported during their reproductive years (Shi et al. Front. Psychiatr 2021; 12 589687). MDD affects up to 12.7% of pregnant women and can significantly impact foetal and maternal health. Hence, clinical practice guidelines recommend focused screening and expedited management of MDD in women (Guo et al. Obstet. Gynecol 2018; 131(4) 671-679). Despite this, drug labelling or dosing recommendations rarely account for gender or physiological differences between sexes, even though sex steroid level variations can impact drug absorption, distribution, metabolism, and activity both pharmacokinetically and pharmacodynamically (Soldin et al. Clin Pharmacokinet. 2009; 48(3): 143–157). Sertraline, an SSRI approved for the treatment of MDD, is one of the safer agents which can be given to childbearing or breastfeeding women (Cuomo et al. Expert Opin Drug Saf 2018; 17(7) 719-725). However, studies on the efficacy of sertraline for the treatment of MDD among women of childbearing age are limited. Objectives This post-hoc pooled analysis evaluated the efficacy of sertraline in women with MDD, with a particular focus on women of reproductive age. Methods A pooled data analysis of 8 short-term clinical studies of sertraline in persons with MDD (comprising 1600 participants from North America and Europe, of whom 947 were females; with moderate to severe MDD [mean±SD baseline HAM-D17 score was 23.73±3.58 for sertraline and 23.37± 3.47 for placebo]; sertraline dose, 50-200 mg) was performed. HAM-D17 total score was used to assess the efficacy of sertraline compared with placebo. The study period was 8 weeks. An MMRM method was used to analyse changes over time and ANCOVA to evaluate the change from baseline at week 8 with LOCF employed to manage missing data. Results The analysis set consisted of 947 women (sertraline, 612; placebo, 335). The change from baseline in HAM-D17 total score was significantly higher for sertraline than for placebo at the end of 8 weeks (LS mean difference, 95% CI: -1.81 [-3.01, -0.62], p=0.0029, Figure 1A). This change from baseline was statistically significant starting from week 2 and increased over time (Week 2-8; Figure 2A). The analysis set for women of child-bearing age consisted of 572 participants aged 18-44 (sertraline, 359; placebo, 213) from 7 clinical studies. The change from baseline in HAM-D17 total score was significantly higher for sertraline than for placebo at the end of 8 weeks (LS mean difference, 95% CI: -2.08 [-3.52, -0.64], p=0.0047, Figure 1B). This change from baseline was statistically significant starting from week 2 (Figure 2B). Image: Image 2: Conclusions Significant improvement in HAM-D17 scores was observed in the analysis, suggesting that sertraline is efficacious in treating women with MDD, including those in the childbearing age. Disclosure of Interest A. Fagiolini Grant / Research support from: Angelini, Boheringer Ingelheim, Janssen, Consultant of: Angelini, Biogen, Boheringer Ingelheim, Lundbeck, Janssen, Mylan, Neuraxpharm, Otsuka, Pfizer, Recordati, Rovi, Sanofi Aventis, Viatris, Speakers bureau of: Angelini, Apsen, Biogen, Boheringer Ingelheim, Glaxo Smith Kline, Lundbeck, Janssen, Mylan, Neuraxpharm, Otsuka, Pfizer, Recordati, Rovi, Sanofi Aventis, Viatris, Vifor, M. Mariano Consultant of: Johnson & Johnson, Otsuka Pharmaceutical Inc., Speakers bureau of: Viatris Pharmaceuticals, Inc. Otsuka (Philippines) Pharmaceutical, Inc. H. Lundbeck A/S, Johnson & Johnson Philippines, Inc., E. Biesheuvel Employee of: Viatris Inc. Netherlands, P. Purushottamahanti Employee of: Viatris Inc. India

Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.

Abstract Background Treatment-resistant depression (TRD) is defined by the European Medicines Agency as a lack of clinically meaningful improvement after treatment, with at least two different antidepressants. Individual, familiar, and socio-economic burden of TRD is huge. Given the lack of clear guidelines, the large variability of TRD approaches across different countries and the availability of new medications to meet the need of effective and rapid acting therapeutic strategies, it is important to understand the consensus regarding the clinical characteristics and treatment pathways of patients with TRD in Italian routine clinical practice, particularly in view of the recent availability of esketamine nasal spray. Methods A Delphi questionnaire with 17 statements (with a 7 points Likert scale for agreement) was administered via a customized web-based platform to Italian psychiatrists with at least 5 years of experience and specific expertise in the field of depression. In the second-round physicians were asked to answer the same statements considering the interquartile range of each question as an index of their colleagues’ responses. Stata 16.1 software was used for the analyses. Results Sixty panellists, representative of the Italian territory, answered the questionnaire at the first round. For 8/17 statements more than 75% of panellists reached agreement and a high consensus as they assigned similar scores; for 4 statements the panellists assigned similar scores but in the middle of the Likert scale showing a moderate agreement with the statement, while for 5 statements there was indecision in the agreement and low consensus with the statement. Conclusions This Delphi Panel showed that there is a wide heterogeneity in Italy in the management of TRD patients, and a compelling need of standardised strategies and treatments specifically approved for TRD. A high level of consensus and agreement was obtained about the importance of adding lithium and/or antipsychotics as augmentation therapies and in the meantime about the need for long-term maintenance therapy. A high level of consensus and agreement was equally reached for the identification of esketamine nasal spray as the best option for TRD patients and for the possibility to administrate without difficulties esketamine in a community outpatient setting, highlighting the benefit of an appropriate educational support for patients.

Abstract Major depressive disorder (MDD) is the most common mood disorder and a leading cause of disability worldwide. Trazodone, a triazolopyridine serotonin receptor antagonist and reuptake inhibitor (SARI) antidepressant approved for major depressive disorder (MDD) in adults, has established efficacy that is comparable to other available antidepressants, and is effective for a range of depression symptoms, including insomnia, which is one of the most common and bothersome symptoms of depression. Also, trazodone’s pharmacodynamic properties allow it to avoid the side effects of insomnia, anxiety and sexual dysfunction often associated with selective serotonin reuptake inhibitor antidepressants. In this narrative review, we have summarized recent clinical trials and real-world data on trazodone, including the recently introduced once-daily formulation, which has single dose pharmacokinetic properties that maintain effective blood trazodone levels for 24 h, while avoiding concentration peaks associated with side effects. This, combined with a low incidence of weight gain, and sexual dysfunction, may improve adherence to treatment. The most common adverse effects of trazodone are somnolence, headache, dizziness and xerostomia. It has minimal anticholinergic activity but may be associated infrequently with orthostatic hypotension (especially in patients with cardiovascular disease or older adults), QT interval prolongation, cardiac arrhythmias, and rare episodes of priapism. The low liability for activating side effects, the efficacy on symptoms such as insomnia and psychomotor agitation and the rapid onset of action make it useful for many depressed patients, both in monotherapy at nominal dosages of 150–300 mg/day, and in combination with other antidepressants at lower dosages.

According to the World Health Organization (WHO), major depressive disorder (MDD) is the fourth leading cause of disability worldwide and the second most common disease after cardiovascular events. Approximately 280 million people live with MDD, with incidence varying by age and gender (female to male ratio of approximately 2:1). Although a variety of antidepressants are available for the different forms of MDD, there is still a high degree of individual variability in response and tolerability. Given the complexity and clinical heterogeneity of these disorders, a shift from “canonical treatment” to personalized medicine with improved patient stratification is needed. OPADE is a non-profit study that researches biomarkers in MDD to tailor personalized drug treatments, integrating genetics, epigenetics, microbiome, immune response, and clinical data for analysis. A total of 350 patients between 14 and 50 years will be recruited in 6 Countries (Italy, Colombia, Spain, The Netherlands, Turkey) for 24 months. Real-time electroencephalogram (EEG) and patient cognitive assessment will be correlated with biological sample analysis. A patient empowerment tool will be deployed to ensure patient commitment and to translate patient stories into data. The resulting data will be used to train the artificial intelligence/machine learning (AI/ML) predictive tool.

Treating depression in adolescents is a significant challenge, and major depressive disorder (MDD) with suicidal ideation and treatment-resistant depression (TRD) are common and potentially devastating to optimal psychological and physical development in this age group. Suicide is among the leading causes of youth mortality, and TRD occurs in up to 40% of adolescents with MDD. TRD involves severe, persistent symptoms that are hard to treat, significantly reducing functioning and quality of life. We conducted a literature search focusing on key terms related to ketamine and esketamine for MDD with suicidal ideation and TRD in adolescents, aiming to review the potential utility of these molecules in adolescents for these conditions. Ketamine has shown efficacy in reducing depressive symptoms in adolescents with TRD. Esketamine has shown efficacy in reducing depressive symptoms and treating suicidal ideation in adolescents. Both ketamine and esketamine have demonstrated favorable safety and tolerability profiles. Using these drugs for serious conditions like adolescent MDD with suicidal thoughts and TRD can effectively treat symptoms, reduce self-harm and suicide risks, and provide a window for longer-term therapeutic interventions. The prompt and effective treatment of TRD could improve adolescents’ quality of life. However, more research is needed to optimize treatment protocols and evaluate long-term effects.

Abstract Background Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample. Methods Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001. Results The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger. Conclusion UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.

Abstract Background Schizophrenia is mostly a chronic disorder whose symptoms include psychosis, negative symptoms and cognitive dysfunction. Poor adherence is common and related relapse can impair outcomes. Long-acting injectable antipsychotics (LAIs) may promote treatment adherence and decrease the likelihood of relapse and rehospitalization. Using LAIs in first-episode psychosis (FEP) and early-phase (EP) schizophrenia patients could benefit them, yet LAIs have traditionally been reserved for chronic patients. Methods A three-step modified Delphi panel process was used to obtain expert consensus on using LAIs with FEP and EP schizophrenia patients. A literature review and input from a steering committee of five experts in psychiatry were used to develop statements about patient population, adverse event management, and functional recovery. Recruited Delphi process psychiatrists rated the extent of their agreement with the statements over three rounds (Round 1: paper survey, 1:1 interview; Rounds 2–3: email survey). Analysis rules determined whether a statement progressed to the next round and the level of agreement deemed consensus. Measures of central tendency (mode, mean) and variability (interquartile range) were reported back to help panelists assess their previous responses in the context of those of the overall group. Results The Delphi panelists were 17 psychiatrists experienced in treating schizophrenia with LAIs, practicing in seven countries (France, Italy, US, Germany, Spain, Denmark, UK). Panelists were presented with 73 statements spanning three categories: patient population; medication dosage, management, and adverse events; and functional recovery domains and assessment. Fifty-five statements achieved ≥ 80% agreement (considered consensus). Statements with low agreement (40-79%) or very low agreement (

BackgroundUnipolar and bipolar depression present treatment challenges, with patients sometimes showing limited or no response to standard medications. Ketamine and its enantiomer, esketamine, offer promising alternative treatments that can quickly relieve suicidal thoughts. This Overview of Reviews (OoR) analyzed and synthesized systematic reviews (SRs) with meta-analysis on randomized clinical trials (RCTs) involving ketamine in various formulations (intravenous, intramuscular, intranasal, subcutaneous) for patients with unipolar or bipolar depression. We evaluated the efficacy and safety of ketamine and esketamine in treating major depressive episodes across various forms, including unipolar, bipolar, treatment-resistant, and non-resistant depression, in patient populations with and without suicidal ideation, aiming to comprehensively assess their therapeutic potential and safety profile.MethodsFollowing PRIOR guidelines, this OoR’s protocol was registered on Implasy (ID:202150049). Searches in PubMed, Scopus, Cochrane Library, and Epistemonikos focused on English-language meta-analyses of RCTs of ketamine or esketamine, as monotherapy or add-on, evaluating outcomes like suicide risk, depressive symptoms, relapse, response rates, and side effects. We included studies involving both suicidal and non-suicidal patients; all routes and formulations of administration (intravenous, intramuscular, intranasal) were considered, as well as all available comparisons with control interventions. We excluded meta-analysis in which the intervention was used as anesthesia for electroconvulsive therapy or with a randomized ascending dose design. The selection, data extraction, and quality assessment of studies were carried out by pairs of reviewers in a blinded manner. Data on efficacy, acceptability, and tolerability were extracted.ResultsOur analysis included 26 SRs and 44 RCTs, with 3,316 subjects. The intervention is effective and well-tolerated, although the quality of the included SRs and original studies is poor, resulting in low certainty of evidence.LimitationsThis study is limited by poor-quality SRs and original studies, resulting in low certainty of the evidence. Additionally, insufficient available data prevents differentiation between the effects of ketamine and esketamine in unipolar and bipolar depression.ConclusionWhile ketamine and esketamine show promising therapeutic potential, the current evidence suffers from low study quality. Enhanced methodological rigor in future research will allow for a more informed application of these interventions within the treatment guidelines for unipolar and bipolar depression.Systematic review registration[https://inplasy.com/inplasy-2021-5-0049/], identifier (INPLASY202150049).

Abstract Background Although obsessive–compulsive disorder (OCD) is highly prevalent in schizophrenia, its relationship with patients’ real-life functioning is still controversial. Methods The present study aims at investigating the prevalence of OCD in a large cohort of non-preselected schizophrenia patients living in the community and verifying the relationship of OCD, as well as of other psychopathological symptoms, with real-life functioning along a continuum of OCD severity and after controlling for demographic variables. Results A sample of 327 outpatients with schizophrenia was enrolled in the study and collapsed into three subgroups according to OCD severity (subclinical, mild–moderate, severe). A series of structural equation modeling (SEM) was performed to analyze in each subgroup the association of obsessive–compulsive symptoms with real-life functioning, assessed through the Specific Levels of Functioning Scale and the UCSD Performance-Based Skills Assessment. Moreover, latent profile analysis (LPA) was performed to infer latent subpopulations. In the subclinical OCD group, obsessive–compulsive symptoms (OCS) were not associated with functioning, whereas in the mild–moderate OCD group, they showed a positive relationship, particularly in the domains of work and everyday life skills. The paucity of patients with severe OCD did not allow performing SEM analysis in this group. Finally, LPA confirmed a subgroup with mild–moderate OCS and more preserved levels of functioning. Conclusions These findings hint at a positive association between mild–moderate OCD and real-life functioning in individuals with schizophrenia and encourage a careful assessment of OCD in personalized programs to sustain daily life activities.