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Introduction: Suicide attempts (SA) leading to highly lethal consequences have been associated with heightened suicide planning (Barker et al., 2022), along with deficits in social cognition (Levi-Belz et al., 2022). Hypomentalizing, characterized by excessive uncertainty regarding mental states, may contribute to heightened social withdrawal and an increased risk of SA (Nestor & Sutherland, 2022). Although certain studies have identified a connection between hypomentalizing profiles and self-harm (Badoud et al., 2015), research into the lethality of SA remains limited. Objectives: This study aimed to explore the association between hypomentalizing and SA lethality. Methods: Our study encompassed a cohort of 1,371 patients who committed a SA. We conducted assessments of mentalizing using the RFQ-8 instrument, and evaluations of suicidal ideation and behavior employing the CSRSS questionnaire. Demographic and clinical characteristics were compared using the T-student and Chi-square tests. To investigate the relationship between hypomentalizing and the SA lethality, we employed logistic regression models. Results: Descriptive date are presented in Table 1. Our results show that hypomentalizing do not predict a higher SA lethality. Additionally, hypomentalizing increased the risk of SA planning (p≤0.001, B=-0.182), and SA planning predicted a higher SA lethality (see Table 2). Table 1. Means Comparison for low and high lethality (N=1371) Low lethality N=539 High lethality N=832 p value Effect size Age, mean (SD) 38.65 (15.65) 41.91 (15.37) ≤0.001 -0.209a Female sex, N (%) 392 (72.7) 571 (68.6) 0.116 0.044b Educational years, mean (SD) 12.45 (2.99) 12.43 (3.41) 0.890 0.0076a Employed, N (%) 220 (41.2) 332 (40) 0.692 0.012b Suicide Ideation, N (%) 475 (88.1) 742 (89.2) 0.541 0.016b Suicide Planning, N (%) 159 (39.2) 400 (58.1) ≤0.001 0.183b Number of attempts, mean (SD) 3.28 (5.48) 3.63 (5.74) 0.269 -0.169a RFQ, mean (SD) 4.68 (1.27) 4.56 (1.32) 0.087 0.095a Table 2. Logistic regression analyses for high SA lethality (N=1371). Univariate analysis Multivariate analysis OR p value OR p value Age 1.014 (1.007-1.021) ≤0.001 1.014 (1.005-1.022) 0.001 Female sex 0.820 (0.646-1.042) 0.105 Educational years 0.998 (0.965-1.031) 0.890 Employed 0.952 (0.763-1.187) 0.660 Suicide ideation 1.111 (0.790-1.562) 0.545 Suicide planning 2.150 (1.674-2.761) ≤0.001 2.183 (1.697-2.808) ≤0.001 Number SA 1.012 (0.990-1.034) 0.277 RFQ 0.929 (0.854-1.011) 0.088 Conclusions: While the association between hypomentalizing and high SA lethality was not significant, a discernible trend toward such relationship can be noted. Further studies examining the moderating effects of planning in the association between hypomentalizing and SA lethality are required. Disclosure of Interest: None Declared [ABSTRACT FROM AUTHOR]

Background: Child maltreatment is associated with a higher probability of mental disorders and suicidal behavior in adolescence. Therefore, accurate psychometric instruments are essential to assess this., Objective: To validate the Spanish version of the Childhood Trauma Questionnaire-Short Form (CTQ-SF) in adolescents with suicide attempts., Methods: Multisite cohort study of 208 adolescents with suicide attempts using data from the following scales: Mini International Neuropsychiatric Interview (MINI), Columbia Suicide Severity Rating Scale (C-SSRS), Patient Health Questionnaire (PHQ-9), and CTQ-SF. Statistical analysis: CTQ-SF scores analyzed by descriptive statistics. Internal consistency: McDonald's omega and Cronbach's alpha. Concurrent validity with PHQ-9 and C-SSRS scores: Spearman correlation coefficient. Structural validity: Confirmatory factor analysis., Results: Floor and ceiling effects: Physical abuse and neglect as well as sexual abuse demonstrated high floor effects (50.0, 35.1, and 61.1% of adolescents, respectively). No ceiling effects were found. The CTQ-SF had excellent internal consistency (McDonald's omega = 0.94), as did the majority of its subscales (Cronbach's alpha 0.925-0.831) except for physical neglect (0.624). Its concurrent validity was modest, and the emotional neglect subscale had the lowest Spearman correlation coefficients (0.067-0.244). Confirmatory factor analysis: Compared with alternative factor structures, the original CTQ-SF model (correlated 5-factor) exhibited a better fit [S-B χ 2 = 676.653, p < 0; RMSEA (90% CI = 0.076-0.097) = 0.087; SRMR = 0.078; CFI = 0.980; TLI = 0.978]., Conclusion: The Spanish CTQ-SF is a reliable, valid instrument for assessing traumatic experiences in adolescents at high risk of suicide. It appears appropriate for use in routine clinical practice to monitor maltreatment in this group., Competing Interests: IG has received grants and served as consultant, advisor or CME speaker for the following entities: ADAMED, Angelini, Casen Recordati, Esteve, Ferrer, Gedeon Richter, Janssen Cilag, Lundbeck, Lundbeck-Otsuka, Luye, SEI Healthcare, and Viatris outside the submitted work. She also receives royalties from Oxford University Press, Elsevier, and Editorial Médica Panamericana. EV has received grants and served as consultant, advisor, or CME speaker for the following entities: AB-Biotics, AbbVie, Angelini, Biogen, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypha Gedeon Richter, GH Research, Glaxo- Smith Kline, Idorsia, Janssen, Lundbeck, Medincell, Novartis, Orion Corporation, Organon, Otsuka, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris outside the submitted work. AG-P has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen-Cilag, Lundbeck, Otsuka, Alter, Angelini, Novartis, Rovi, Takeda, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute), the Basque Government, and the European Framework Program of Research. IZ has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen-Cilag, Lundbeck, Otsuka, Angelini, Rovi and Takeda. MPG-P has been a consultant to and/or has received honoraria/grants from Alter, Angelini, Cassen-Recordati, Janssen- Cilag, Idorsia, Lundbeck, Otsuka, Rovi, and SAGE Therapeutics. PS has been a consultant to and/or has received honoraria or grants from Adamed, Alter Medica, Angelini Pharma, CIBERSAM, Ethypharm Digital Therapy, European Commission, Government of the Principality of Asturias, Instituto de Salud Carlos III, Johnson & Johnson, Lundbeck, Otsuka, Pfizer, Plan Nacional Sobre Drogas, and Servier. 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 © 2024 García-Fernández, Martínez-Cao, Sánchez-Fernández-Quejo, Bobes-Bascarán, Andreo-Jover, Ayad-Ahmed, Cebriá, Díaz-Marsá, Garrido-Torres, Gómez, González-Pinto, Grande, Iglesias, March, Palao, Pérez-Díez, Roberto, Ruiz-Veguilla, de la Torre-Luque, Zorrilla, Pérez, SURVIVE Group, Sáiz and García-Portilla.)

Background: Intellectual disability (ID) affects approximately 1% of the worldwide population and individuals with ID have a higher comorbidity with mental illness, and specifically psychotic disorders. Unfortunately, among individuals with ID, limited research has been conducted since ID individuals are usually excluded from mental illness epidemiological studies and clinical trials. Here we perform a clinical trial to investigate the effectiveness of clozapine in the treatment of resistant psychosis in individuals with ID. The article highlights the complexity of diagnosing and treating psychopathological alterations associated with ID and advocates for more rigorous research in this field., Methods: A Phase IIB, open-label, randomized, multicenter clinical trial (NCT04529226) is currently ongoing to assess the efficacy of oral clozapine in individuals diagnosed with ID and suffering from treatment-resistant psychosis. We aim to recruit one-hundred and fourteen individuals (N=114) with ID and resistant psychosis, who will be randomized to TAU ( treatment as usual ) and treatment-with-clozapine conditions. As secondary outcomes, changes in other clinical scales (PANSS and SANS) and the improvement in functionality, assessed through changes in the Euro-QoL-5D-5L were assessed. The main outcome variables will be analyzed using generalized linear mixed models (GLMM), assessing the effects of status variable (TAU vs. Clozapine), time, and the interaction between them., Discussion: The treatment of resistant psychosis among ID individuals must be directed by empirically supported research. CLOZAID clinical trial may provide relevant information about clinical guidelines to optimally treat adults with ID and treatment-resistant psychosis and the benefits and risks of an early use of clozapine in this underrepresented population in clinical trials., Trial Registration: Clinicaltrials.gov: NCT04529226. EudraCT: 2020-000091-37., 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 © 2024 Alemany-Navarro, Sánchez-Barbero, Reguera-Pozuelo, Altea-Manzano, Gómez-Garrido, Rocha-González, Garrido-Torres, Ruiz-Veguilla, García-Cerro, Rosso-Fernández, Villagrán-Moreno, Sarramea, Cervilla-Ballesteros, Martínez-Leal, Mayoral-Cleries and Crespo-Facorro.)

Background: More than half of women with psychosis take care of their children despite the difficulties caused by the disease. Additionally, these kids have a higher risk of developing a mental health disorder. However, no interventions have been developed to meet these needs. Metacognitive Training (MCT) is a psychological intervention that has demonstrated its efficacy in improving cognitive insight, symptom management and social cognition in people with first-episode psychosis (FEP). Additionally, MCT has shown better results in women than men with FEP. This study aims to adapt and evaluate the efficacy of MCT-F in mothers and adolescent children in an online group context with the main purpose of improving family relationships, cognitive awareness and symptoms in women with psychosis and increase their children's knowledge of the disease and their functioning. As secondary objectives, it also aims to evaluate improvements in metacognition, social cognition, symptoms, protective factors and self-perception of stigma., Materials and Methods: A quasi-experimental design with participants acting as their own control will be carried out. Forty-eight mothers with psychosis and their adolescent children (between 12 and 20 years old) recruited from a total of 11 adult mental health care centers will receive MCT-F. Participants will be evaluated 11 weeks before the intervention (T1), at baseline (T2), and post-intervention (T3) with a cognitive insight scale, as a primary outcome. Measures of metacognitive and social cognition, symptoms, cognitive functioning, family and social functioning, protective factors (self-esteem, resilience, and coping strategies) and self-perceived stigma will be addressed as secondary outcomes. Assessment will also address trauma and attachment in mothers and, lastly, the feasibility and acceptability of MCT-F in both participant groups., Discussion: This will be the first investigation of the efficacy, acceptability, and viability of the implementation of MCT-F. The results of this study may have clinical implications, contributing to improving mothers' with psychosis and adolescents' functioning and better understanding of the disease, in addition to the possible protective and preventive effect in adolescents, who are known to be at higher risk of developing severe mental disorders. Clinical trial registration: https://clinicaltrials.gov/, identifier [NCT05358457]., 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 © 2024 Ochoa, Espinosa, López-Carrilero, Martinez, Barrera, Birulés, Barajas, Pélaez, Díaz-Cutraro, Coromina, González-Rodríguez, Verdaguer-Rodríguez, Gutiérrez-Zotes, Palma-Sevillano, Montes, Gallego, Paya, Casanovas, Roldán, Noval, Varela Casals, Salas-Sender, Aznar, Ayesa-Arriola, Pousa, Canal-Rivero, Garrido-Torres, Montserrat, Muñoz-Lorenzo and Crosas.)

Over half of women with psychosis are mothers. Research suggests that mothers with psychosis face unique challenges affecting both their mental health prognosis and their relationship with their children. Moreover, those children have a higher risk of developing a mental disorder. Notwithstanding, interventions specifically tailored to these families remain largely uncovered. Metacognitive Training (MCT) has demonstrated its efficacy in improving cognitive insight, symptom management, and social cognition in people with psychosis. However, there is no evidence of the efficacy of MCT in a family setting (MCT-F). This study describes the first adaptation of MCT for mothers with psychosis and their adolescent children in an online group setting. The phases (assessment, decision, adaptation, production, topical experts' integration) of the ADAPT-ITT model were systematically applied through a participatory approach ( n = 22), including a first-person perspective and involving qualitative (e.g., topical expert literature review and consensus groups, interviews, thematic analyses) and quantitative methods. While MCT's core components were retained, participants guided adaptations both in content and delivery. The findings suggest the importance of community engagement and sharing decision-making processes to demonstrate the acceptability and feasibility of the adapted intervention. Employing a structured approach such as the ADAPT-ITT model ensures readiness of the new training for efficacy trials.

Background: There is a lack of standardised psychometric data in electronic health record (EHR)-based research. Proxy measures of symptom severity based on patients' clinical records may be useful surrogates in mental health EHR research., Aims: This study aimed to validate proxy tools for the short versions of the Positive and Negative Syndrome Scale (PANSS-6), Young Mania Rating Scale (YMRS-6) and Montgomery-Åsberg Depression Rating Scale (MADRS-6)., Method: A cross-sectional, multicentre study was conducted in a sample of 116 patients with first-episode psychosis from 12 public hospitals in Spain. Concordance between PANSS-6, YMRS-6 and MADRS-6 scores and their respective proxies was evaluated based on information from EHR clinical notes, using a variety of statistical procedures, including multivariate tests to adjust for potential confounders. Bootstrapping techniques were used for internal validation, and an independent cohort from the Treatment and Early Intervention in Psychosis Program (TIPP-Lausanne, Switzerland) for external validation., Results: The proxy versions correlated strongly with their respective standardised scales (partial correlations ranged from 0.75 to 0.84) and had good accuracy and discriminatory power in distinguishing between patients in and not in remission (percentage of patients correctly classified ranged from 83.9 to 91.4% and bootstrapped optimism-corrected area under the receiver operating characteristic curve ranged from 0.76 to 0.89), with high interrater reliability (intraclass correlation coefficient of 0.81). The findings remained robust in the external validation data-set., Conclusions: The proxy instruments proposed for assessing psychotic and affective symptoms by reviewing EHR provide a feasible and reliable alternative to traditional structured psychometric procedures, and a promising methodology for real-world practice settings.

Background: Understanding the evolution of negative symptoms in first-episode psychosis (FEP) requires long-term longitudinal study designs that capture the progression of this condition and the associated brain changes., Aims: To explore the factors underlying negative symptoms and their association with long-term abnormal brain trajectories., Method: We followed up 357 people with FEP over a 10-year period. Factor analyses were conducted to explore negative symptom dimensionality. Latent growth mixture modelling (LGMM) was used to identify the latent classes. Analysis of variance (ANOVA) was conducted to investigate developmental trajectories of cortical thickness. Finally, the resulting ANOVA maps were correlated with a wide set of regional molecular profiles derived from public databases., Results: Three trajectories (stable, decreasing and increasing) were found in each of the three factors (expressivity, experiential and attention) identified by the factor analyses. Patients with an increasing trajectory in the expressivity factor showed cortical thinning in caudal middle frontal, pars triangularis, rostral middle frontal and superior frontal regions from the third to the tenth year after the onset of the psychotic disorder. The F -statistic map of cortical thickness expressivity differences was associated with a receptor density map derived from positron emission tomography data., Conclusions: Stable and decreasing were the most common trajectories. Additionally, cortical thickness abnormalities found at relatively late stages of FEP onset could be exploited as a biomarker of poor symptom outcome in the expressivity dimension. Finally, the brain areas with less density of receptors spatially overlap areas that discriminate the trajectories of the expressivity dimension.

The coronavirus SARS-CoV-2 generated an alert that became a state of emergency in health issues worldwide, a situation that affected the entire population, including pregnant women. The present study aims to understand the effect of the psychopathological profile of a sample of pregnant women at the time of the COVID-19 pandemic on themselves during childbirth (Phase 1) and after childbirth and the anthropometric measures of the neonate at birth (Phase 2). The total sample comprises 81 pregnant women aged 32.07 years (SD = 5.45) and their neonates. Sociodemographic and obstetric data of the sample were collected. During pregnancy, psychopathology was measured by means of the SCL-90, as well as other psychological measures on stress and social support. Cluster k-means techniques were used to uncover the heterogeneous profiles of psychopathology in Phase 1. Two main psychopathological profiles were found (Cluster 1: High psychopathological symptoms; Cluster 2: Low psychopathological symptoms). The clusters generated show significant differences in all the SCL-90-R subscales used and in the general index at Phase 1. After childbirth, high psychopathology profile membership was associated with a greater probability of having a non-eutocic delivery. On the other hand, the low psychopathological symptoms cluster shows higher levels of depressive symptoms, hostility, paranoid ideation, and psychotic symptoms in Phase 2. In conclusion, there seemed to exist two heterogeneous profiles of psychopathology in pregnant women during the pandemic; the stress related to the pandemic seemed uninfluential on the development of a profile of high psychopathological symptoms and the psychopathology profile may influence delivery and postpartum outcomes.

The COVID-19 pandemic represents a valuable opportunity to carry out cohort studies that allow us to advance our knowledge on pathophysiological mechanisms of neuropsychiatric diseases. One of these opportunities is the study of the relationships between inflammation, brain development and an increased risk of suffering neuropsychiatric disorders. Based on the hypothesis that neuroinflammation during early stages of life is associated with neurodevelopmental disorders and confers a greater risk of developing neuropsychiatric disorders, we propose a cohort study of SARS-CoV-2-infected pregnant women and their newborns. The main objective of SIGNATURE project is to explore how the presence of prenatal SARS-CoV-2 infection and other non-infectious stressors generates an abnormal inflammatory activity in the newborn. The cohort of women during the COVID-19 pandemic will be psychological and biological monitored during their pregnancy, delivery, childbirth and postpartum. The biological information of the umbilical cord (foetus blood) and peripheral blood from the mother will be obtained after childbirth. These samples and the clinical characterisation of the cohort of mothers and newborns, are tremendously valuable at this time. This is a protocol report and no analyses have been conducted yet, being currently at, our study is in the recruitment process step. At the time of this publication, we have identified 1,060 SARS-CoV-2 infected mothers and all have already given birth. From the total of identified mothers, we have recruited 537 SARS-COV-2 infected women and all of them have completed the mental health assessment during pregnancy. We have collected biological samples from 119 mothers and babies. Additionally, we have recruited 390 non-infected pregnant women., 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., (© 2022 Garrido-Torres, Cerrillos, García Cerro, Pérez Gómez, Canal-Rivero, de Felipe, Alameda, Marqués Rodríguez, Anillo, Praena, Duque Sánchez, Roca, Paniagua, López Díaz, Romero-García, Olbrich, Puertas Albarracín, Reguera Pozuelo, Sosa, Moreno Dueñas, Pineda Cachero, Zamudio Juan, García Rumi, Guerrero Benitez, Figueroa, Martín Rendón, Partida, Rodríguez Cocho, Gallardo Trujillo, Gallego Jiménez, García Spencer, Gómez Verdugo, Bermejo Fernández, Pérez Benito, Castillo Reina, Cejudo López, Sánchez Tomás, Chacón Gamero María Ángeles, Rubio, Moreno Mellado, Ramos Herrero, Starr, González Fernández de Palacios, García Victori, Pavón Delgado, Fernández Cuervo, Arias Ruiz, Menéndez Gil, Domínguez Gómez, Coca Mendoza, Ayesa-Arriola, Fañanas, Leza, Cisneros, Sánchez Céspedes, Ruiz-Mateos, Crespo-Facorro and Ruiz-Veguilla.)

Objective: Aripiprazole and risperidone are 2 of the most used second-generation antipsychotics (SGAs) worldwide. Previous evidence shows a similar effect of these SGAs on weight and metabolic changes in the short term. However, a longer period is necessary for a better assessment of the SGA´s metabolic profile. We aimed to compare the long-term (1-year) metabolic profile of these 2 antipsychotics on a sample of drug-naïve first episode-psychosis (FEP) patients., Methods: A total 188 drug-naïve patients, suffering from a first episode of non-affective psychosis (FEP), were randomly assigned to treatment with either aripiprazole or risperidone. Weight and glycemic/lipid parameters were recorded at baseline and after 1-year follow-up., Results: We observed significant weight increments in both groups (9.2 kg for aripiprazole and 10.5 kg for risperidone) after 1 year of treatment. Despite this, weight and body mass index changes did not significantly differ between treatment groups (P &gt; .05). Similarly, both treatment groups presented similar metabolic clinical impact with a comparable increase in the proportion of participants meeting criteria for metabolic disorders such as obesity or hypercholesterolemia, but not for metabolic syndrome (Δ9.2% vs Δ4.3%) or hypertriglyceridemia (Δ21.9% vs Δ8.0%), where aripiprazole showed worse outcomes than risperidone., Conclusion: This study shows that aripiprazole and risperidone share a similar long-term metabolic profile. After 1 year of antipsychotic treatment, drug-naïve FEP patients in both treatment groups presented a significant increase in weight and metabolic changes, leading to a greater prevalence of metabolic disorders., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

Background: Cardiometabolic dysfunction is common in young people with psychosis. Recently, the Psychosis Metabolic Risk Calculator (PsyMetRiC) was developed and externally validated in the UK, predicting up-to six-year risk of metabolic syndrome (MetS) from routinely collected data. The full-model includes age, sex, ethnicity, body-mass index, smoking status, prescription of metabolically-active antipsychotic medication, high-density lipoprotein, and triglyceride concentrations; the partial-model excludes biochemical predictors., Methods: To move toward a future internationally-useful tool, we externally validated PsyMetRiC in two independent European samples. We used data from the PsyMetab (Lausanne, Switzerland) and PAFIP (Cantabria, Spain) cohorts, including participants aged 16-35y without MetS at baseline who had 1-6y follow-up. Predictive performance was assessed primarily via discrimination (C-statistic), calibration (calibration plots), and decision curve analysis. Site-specific recalibration was considered., Findings: We included 1024 participants (PsyMetab n= 558, male=62%, outcome prevalence=19%, mean follow-up=2.48y; PAFIP n =466, male=65%, outcome prevalence=14%, mean follow-up=2.59y). Discrimination was better in the full- compared with partial-model (PsyMetab=full-model C=0.73, 95% C.I., 0.68-0.79, partial-model C=0.68, 95% C.I., 0.62-0.74; PAFIP=full-model C=0.72, 95% C.I., 0.66-0.78; partial-model C=0.66, 95% C.I., 0.60-0.71). As expected, calibration plots revealed varying degrees of miscalibration, which recovered following site-specific recalibration. PsyMetRiC showed net benefit in both new cohorts, more so after recalibration., Interpretation: The study provides evidence of PsyMetRiC's generalizability in Western Europe, although further local and international validation studies are required. In future, PsyMetRiC could help clinicians internationally to identify young people with psychosis who are at higher cardiometabolic risk, so interventions can be directed effectively to reduce long-term morbidity and mortality., Funding: NIHR Cambridge Biomedical Research Centre (BRC-1215-20014); The Wellcome Trust (201486/Z/16/Z); Swiss National Research Foundation (320030-120686, 324730- 144064, and 320030-173211); The Carlos III Health Institute (CM20/00015, FIS00/3095, PI020499, PI050427, and PI060507); IDIVAL (INT/A21/10 and INT/A20/04); The Andalusian Regional Government (A1-0055-2020 and A1-0005-2021); SENY Fundacion Research (2005-0308007); Fundacion Marques de Valdecilla (A/02/07, API07/011); Ministry of Economy and Competitiveness and the European Fund for Regional Development (SAF2016-76046-R and SAF2013-46292-R).For the Spanish and French translation of the abstract see Supplementary Materials section., Competing Interests: RU has in the past 3 years received honoraria for speaking events from Oktuska, Synovion and Vyalife; has participated as a Chair TSC for an NIHR-funded clinical trial on antipsychotic medication for treatment resistant depression, and as an Expert Member for an NIHR-funded clinical trial on psychological therapies for common mental disorders; is honorary general secretary for the British Association of Psychopharmacology and a Deputy Editor for British Journal of Psychiatry. PBJ is Chair of the MQ Mental Health Sciences Council and has participated in an advisory board for MSD on an unrelated mental health topic. FV received in the past 3 years honoraria for conferences or teaching CME courses from Forum für MedizinischeFortbildung and Sysmex Suisse AG. NA received in the past 3 years honoraria for a conference from Sysmex Suisse AG. SC received in the past 3 years honoraria for teaching CME courses from Forum pour la formation médicale, Barr Switzerland and for consultancy from the Swiss Health Observatory (Obsan) of the Swiss Federal Office of Public Health. CBE received in the past 3 years honoraria for conferences or teaching CME courses from Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Sysmex Suisse AG, Takeda, Vifor-Pharma and Zeller. All other authors declare no potential conflicts of interest., (© 2022 The Author(s).)

Background: Antipsychotics modulate expression of inflammatory cytokines and inducible inflammatory enzymes. Elopiprazole (a phenylpiperazine antipsychotic drug in phase 1) has been characterized as a therapeutic drug to treat SARS-CoV-2 infection in a repurposing study. We aim to investigate the potential effects of aripiprazole (an FDA approved phenylpiperazine) on COVID-19-related immunological parameters. Methods: Differential gene expression profiles of non-COVID-19 vs. COVID-19 RNA-Seq samples (CRA002390 project in GSA database) and drug-naïve patients with non-affective psychosis at baseline and after three months of aripiprazole treatment were identified. An integrative transcriptomic analyses of aripiprazole effects on differentially expressed genes in COVID-19 patients was performed. Findings: 82 out the 377 genes (21.7%) with expression significantly altered by aripiprazole have also their expression altered in COVID-19 patients and in 93.9% of these genes their expression is reverted by aripiprazole. The number of common genes with expression altered in both analyses is significantly higher than expected (Fisher's Exact Test, two tail; p value = 3.2e-11). 11 KEGG pathways were significantly enriched with genes with altered expression both in COVID-19 patients and aripiprazole medicated non-affective psychosis patients ( p adj<0.05). The most significant pathways were associated to immune responses and mechanisms of hyperinflammation-driven pathology (i.e.,"inflammatory bowel disease (IBD)" (the most significant pathway with a p adj of 0.00021), "Th1 and Th2 cell differentiation" and "B cell receptor signaling pathway") that have been also associated with COVID19 clinical outcome. Interpretation: This exploratory investigation may provide further support to the notion that a protective effect is exerted by aripiprazole (phenylpiperazine) by modulating the expression of genes that have shown to be altered in COVID-19 patients. Along with many ongoing studies and clinical trials, repurposing available medications could be of use in countering SARS-CoV-2 infection, but require further studies and trials., Competing Interests: BC-F has received unrestricted research funding from Instituto de Salud Carlos III, MINECO, Gobierno de Cantabria, Spanish Network for Research in Mental Health (CIBERSAM), from the seventh European Union Framework Program and Lundbeck. He has also received honoraria for his participation as a consultant and/or as a speaker at educational events from Janssen Johnson & Johnson, Mylan, Lundbeck, and Otsuka Pharmaceuticals. MR-V has received unrestricted research funding from Instituto de Salud Carlos III. He has also received honoraria for his participation as a consultant and/or as a speaker at educational events from Janssen, Lundbeck, and Otsuka Pharmaceuticals. JV-B has received unrestricted research funding from Instituto de Investigación Marqués de Valdecilla (IDIVAL). He has also received honoraria for his participation as a consultant and/or as a speaker at educational events from Janssen-Cilag and Lundbeck. JC has received honoraria as a speaker from Novartis, Astellas Pharma, Pfizer, MSD, Janssen Pharmaceuticals, and AstraZeneca, outside the submitted work. He has also received report grants from Instituto de Salud Carlos III, Spanish Government, co-financed by the European Development Regional Fund “A way to achieve Europe,” during the conduct of the study. 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 © 2021 Crespo-Facorro, Ruiz-Veguilla, Vázquez-Bourgon, Sánchez-Hidalgo, Garrido-Torres, Cisneros, Prieto and Sainz.)