Articles publicats en revistes (Institut de Neurociències (UBNeuro))

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Cannabinoid CB1Receptor Activation Mitigates N-Methyl-d-aspartate Receptor-Mediated Neurotoxicity
(American Chemical Society, 2025-12-09) Reyes Resina, Irene; Franco Fernández, Rafael; Navarro Brugal, Gemma; Raïch, Iu; Rebassa, Joan-Biel; Lillo, Jaume; Pérez-Olives, C.; Capó, Toni; Cubeles, Erik; Saura, Carlos A.; Cordomí, Arnau; Sotelo, Eddy
Alzheimer’s disease (AD) is characterized by synaptic dysfunction and excitotoxicity, yet effective therapeutic strategies remain limited. This study explores the functional and physical interplay between cannabinoid CB1 receptors (CB1Rs) and N-methyl-d-aspartate receptors (NMDARs), which are implicated in AD pathology. Using bioluminescence resonance energy transfer and imaging assays in HEK-293T cells, we demonstrate a direct interaction between CB1R and the N1 subunit of NMDAR, supporting the formation of receptor complexes. Functional assays further reveal a bidirectional negative crosstalk: NMDA attenuates CB1R-mediated cAMP inhibition, while CB1R activation reduces NMDA-induced calcium influx and mitogen-activated protein kinase signaling pathway activation. This negative crosstalk suggests the existence of receptor–receptor interactions with functional consequences. Complexes of CB1Rs and N1 subunits of NMDARs are present in both neurons and microglia, and their expression is upregulated in response to Aβ1–42 and in cells derived from the APPSw/Ind AD model mice. However, upregulation did not always correlate with stronger CB1R–NMDAR cross-modulation, suggesting that cell-specific signalosome composition shapes the signaling outcome. Functionally, CB1R activation confers neuroprotection: It rescues neurite loss induced by NMDA and Aβ1–42, highlighting the therapeutic potential of modulating CB1R–NMDAR interactions. These findings support a model in which CB1R–NMDAR interactions, through dynamic functional cross-modulation, finely tune excitotoxic and inflammatory signaling pathways. This mechanism offers therapeutic prospects for addressing cannabinoid-glutamatergic interactions.
The Potential Effect of Forbrain as an Altered Auditory Feedback Device
(American Speech-Language-Hearing Association, 2018-04) Escera i Micó, Carles; López Caballero, Francisco José; Gorina-Careta, Natàlia
Purpose: The purpose of this study was to run a proof of concept on a new commercially available device, Forbrain® (Sound For Life Ltd/Soundev, Luxemburg, model UN38.3), to test whether it can modulate the speech of its users. Method: Participants were instructed to read aloud a text of their choice during 3 experimental phases: baseline, test, and posttest, while wearing a Forbrain® headset. Critically, for half of the participants (Forbrain group), the device was turned on during the test phase, whereas for the other half (control group), the device was kept off. Voice recordings were analyzed to derive 6 quantitative measures of voice quality over each of the phases of the experiment. Results: A significant Group × Phase interaction was obtained for the smoothed cepstral peak prominence, a measure of voice harmony, and for the trendline of the long-term average spectrum, a measure of voice robustness, this latter surviving Bonferroni correction for multiple comparisons. Conclusions: The results of this study indicate the effectiveness of Forbrain® in modifying the speech of its users. It is suggested that Forbrain® works as an altered auditory feedback device. It may hence be used as a clinical device in speech therapy clinics, yet further studies are warranted to test its usefulness in clinical groups.
Body ownership and vicarious Agency: Behavioural consequences in a virtual reality rock concert
(Elsevier, 2025-08-01) Itatani, Reiya; Senel, Gizem; Topcu, A. Sencer; Slater, Mel
Illusory body ownership, the sense that a life-sized virtual body seen from first person perspective (1PP) in virtual reality (VR), is your body, is a well-established result. Previous work has demonstrated that illusory body ownership also results in vicarious agency over actions of the virtual body (VB). Moreover, how those actions are carried out influences later real life behaviour. In our study participants entered a VR depicting a dressing room before a concert performance, embodied from 1PP as the lead singer of a famous historical rock group. Their VB either moved synchronously with their own movements (n = 20), or asynchronously (n = 20). Those in the Synchronous condition had greater body ownership over the VB. Moreover, in a later appearance on stage in front of a virtual audience, those in the Synchronous condition had greater vicarious agency with respect to their VB, were more likely to adopt the guitar playing posture of the VB and carry out greater movements than those in the Asynchronous group. Hence body ownership in the context of 1PP over the VB with synchrony was associated with vicarious agency and also behaviour concomitant with the concert situation. These findings highlight the powerful impact of embodied experiences on agency and action.
In their own words: A qualitative focus group study of resilience in bipolar disorder
(Elsevier B.V., 2026-12-15) Clougher, Derek; Hidalgo Mazzei, Diego; Miskowiak, Kamilla W.; Garcia Diaz, Cesar; Martínez-Arán, Anabel, 1971-; Vieta i Pascual, Eduard, 1963-; Amoretti Guadall, Silvia; Torrent Font, Carla
Background Bipolar disorder (BD) is a debilitating mood disorder. Empowering people to live well in the context of their illness represents an ongoing clinical challenge. Resilience research offers potential opportunities to address these complexities, yet debates regarding its definition and operationalisation limit interpretations of findings and future study designs. Including the voices of patients in this debate is crucial to understand resilience from a nuanced, multidimensional perspective. Method We aimed to understand how patients with BD experienced resilience. Four focus groups including a total of 39 people with BD were held. Data was analysed using reflective thematic analysis. Results Four central themes and twelve subthemes related to resilience in BD emerged: (1) illness course – subthemes: chronic illness stages, tools and knowledge via lived experience, and pressure of successful stability; (2) self-awareness – subthemes: accepting diagnosis, embracing inevitable downfalls, self-exploration; (3) coping and growth strategies – subthemes: emotional first-aid kit, routine and available resources, and cultivating optimism; (4) support networks – subthemes: positive support outlets, communication and disclosure of needs, and stigma and rejection. Conclusions The themes and subthemes highlight the need to assess and address resilience in BD given the unique challenges faced by people with this chronic condition. The insights from this qualitative study provide opportunities to redefine currently limited definitions and measurement of resilience in this population.
Cognitive Performance in Older-Age Bipolar Disorder: A Cross-Sectional Study of Anticholinergic Load and Clinical Characteristics
(Cambridge University Press (CUP), 2026-07-31) Pardossi, Simone; Solé Cabezuelo, Brisa; Ruiz Muñoz, Andrea; Bort, Marta; Rodríguez-Rey, Arturo; Espluga Gálvez, Ainara; González Campos, Meritxell; Valentí Ribas, Marc; Fico, Giovanna; Murru, Andrea; Sánchez Moreno, José; Martínez-Arán, Anabel, 1971-; Fagiolini, Andrea; Vieta i Pascual, Eduard, 1963-; De Prisco, Michele; Montejo Egido, Laura
Background Cognitive deficits are one of the core features of older-age bipolar disorder (OABD). Psychotropic medications may influence cognition, especially in older populations, where anticholinergic effects are relevant. This cross-sectional study aimed to investigate the potential impact of anticholinergic load on cognitive performance in individuals with OABD. Methods One hundred and twenty-one euthymic or partially remitted OABD patients were included. Cognitive performance was assessed using a neuropsychological battery and summarized into attention, processing speed, working memory, visual and verbal memory, and executive functions. Anticholinergic load was assessed using the CRIDECO Anticholinergic Load Scale (CALS), and pharmacological burden was quantified using the defined daily dose (DDD). Associations were examined using hierarchical multivariable linear regression models, considering also relevant clinical covariates. Results The interaction between CALS and DDD was associated with lower visual and verbal memory scores (p = 0.04). Age was inversely associated with cognitive performance across all domains (all p < 0.01). A higher number of manic episodes was associated with poorer attention, visual and verbal memory, and processing speed (all p < 0.01). Lifetime psychotic symptoms were associated with worse working memory (p = 0.02), and higher diazepam-equivalent doses were associated with worse visual and verbal memory performance (p = 0.02). Conclusions Although anticholinergic medications may contribute to cognitive burden, their impact appears dose-related and limited compared with the broader influence of illness-related factors. In OABD patients, prioritizing the management of illness-related characteristics alongside careful pharmacological management may therefore be crucial for preserving cognitive functioning.
Non-suicidal self-injury as a behavioural addiction: A Systematic review
(Springer Nature Switzerland, 2025-07-01) Carenys, Aina Zhe; Adan Puig, Ana
Purpose of the Review Despite the growing interest in non-suicidal self-injury (NSSI) research over the past decades, there is no comprehensive synthesis of findings on whether this behaviour should be considered an addiction. This study carries out a systematic review of theoretical and experimental studies to evaluate the empirical evidence supporting the addictive nature of NSSI. Recent Findings In accordance with PRISMA guidelines, 36 studies were selected from a search across PubMed, Scopus, and Web of Science, covering publications from 2000 to November 2024. This review suggests that the subjective experiences of individuals who self-injure, the DSM-5 diagnostic criteria, and some relevant assessment instruments, all point to there being addictive characteristics in NSSI. These characteristics include compelling urges, altered control, and behaviour intensification. Neurobiological findings, particularly those involving the endocannabinoid and opioid systems, support the addictive-like nature, with tolerance being a key mediating factor that leads to the NSSI cyclical structure. Additionally, findings related to brain activity, connectivity, and gene expression also hint at similarities between NSSI and addictive disorders, suggesting some shared mechanisms. Summary Existing research on NSSI emphasises its potentially addictive nature. The subjective experiences of those who self-injure together with diagnostic criteria and neurobiological findings, collectively support the conceptualization of NSSI from an addictive model. While further studies are needed to fully understand the underlying mechanisms and factors contributing to addictive patterns in NSSI, this perspective has significant implications for the prevention and treatment of NSSI.
Emerging Insights into Brain Inflammation: Stem-Cell-Based Approaches for Regenerative Medicine
(MDPI, 2025-04-01) Karam, Marie; Ortega Gasco, Alba; Tornero, Daniel
Neuroinflammation is a complex immune response triggered by brain injury or pathological stimuli, and is highly exacerbated in neurodegenerative diseases. It plays a dual role in the central nervous system, promoting repair in acute stages while aggravating disease progression by contributing to neuronal loss, synaptic dysfunction, and glial dysregulation in chronic phases. Inflammatory responses are mainly orchestrated by microglia and infiltrated monocytes, which, when dysregulated, not only harm existing neurons, but also impair the survival and differentiation of neural stem and progenitor cells in the affected brain regions. Modulating neuroinflammation is crucial for harnessing its protective functions while minimizing its detrimental effects. Current therapeutic strategies focus on fine-tuning inflammatory responses through pharmacological agents, bioactive molecules, and stem cell-based therapies. These approaches aim to restore immune homeostasis, support neuroprotection, and promote regeneration in various neurological disorders. However, animal models sometimes fail to reproduce human-specific inflammatory responses in the brain. In this context, stem-cell-derived models provide a powerful tool to study neuroinflammatory mechanisms in a patient-specific and physiologically relevant context. These models facilitate high-throughput screening, personalized medicine, and the development of targeted therapies while addressing the limitations of traditional animal models, paving the way for more targeted and effective treatments.
Efficacy, acceptability, and related outcomes of pharmacological interventions for acute bipolar depression: A systematic review and dose-related network meta-analysis across different age groups
(Elsevier B.V., 2026-06-23) Fornaro, Michele; Di Lorenzo, Chiara; Oliva, Vincenzo; De Prisco, Michele; Vieta i Pascual, Eduard, 1963-
Background: Acute bipolar depression poses a significant burden and socioeconomic costs. We investigated the comparative efficacy/response/acceptability of pharmacological interventions for acute bipolar depression, considering dose effects across different age groups. Methods: We conducted a network meta-analysis (NMA), searching for randomized controlled trials (RCTs) comparing pharmacological interventions against each other/or placebo in patients with acute bipolar depression (Type-I/Type-II/other), indexed in PubMed/MEDLINE, Embase, Web-of-Science/and Scopus (database inception up to 2025.11.25). Co-primary outcomes were change in depressive symptoms/response/and acceptability. Tolerability/remission/change in anxious symptoms/and risk-of-manic/hypomanic switches were secondary outcomes. Confidence-In-Network-Meta-Analysis was likewise appraised. Results: 103 RCTs, encompassing 71 distinct treatment combinations, included 20,941 participants. Sensitivity analysis including low-risk-of-bias studies only and excluding outliers for possible effect modifiers indicated that lamotrigine 50 mg/day or 200 mg/day, quetiapine extended-release 150 mg/day and 300 mg/day, and lumateperone 42 mg/day outperformed placebo for depressive symptoms, with estimates ranging from -1.53(95%C.I. = -2.13;-0.93) for lamotrigine 50 mg/day, to -0.36(95%C.I. = -0.68;-0.04) for lumateperone 42 mg/day. Several additional drugs might be efficacious, although they emerged as outliers for either mean age of participants/proportion of females/BD-II participants/psychotic features/rapid cycling/baseline severity of depression/and trial duration. No treatment outperformed placebo for response/remission/acceptability/tolerability/and manic/hypomanic switches. Conclusions: Our findings are consistent with previous NMAs and current guidelines, thereby expanding knowledge by concurrently appraising different drugs, doses, and age groups.
Neuroprogression happens
(Cambridge University Press (CUP), 2024-10-01) Vieta i Pascual, Eduard, 1963-
I read with interest the contribution by Samamé on neuroprogression in bipolar disorder (Samamé, in press) in response to a commentary on the same topic (Vieta, 2024), and appreciate the opportunity to further discuss the nuances around the origin and course of cognitive impairment in patients with bipolar disorder from a scientific perspective. The neuroprogression model fits well in some patients, but not all. When addressing cognition and functioning in conditions such as bipolar disorder, heterogeneity is the rule.
Cognition Assessment in Virtual Reality (CAVIR)-Spanish Version: Validation of a Novel Virtual Reality Test for Daily-Life Cognitive Skills in Bipolar Disorder
(John Wiley & Sons, 2026-06-01) Fares Otero, Natalia Elena; Solé Cabezuelo, Brisa; Elleby Jespersen, Andreas; Roberto, Natalia; Martín Parra, Sara; López Escribano, Ricardo; Pérez Ramos, Anaid; Piazza, Flavia; Ruiz Muñoz, Andrea; Varo, Cristina; Lumbye, Anders; Vieta i Pascual, Eduard, 1963-; Martínez-Arán, Anabel, 1971-; Woznica Miskowiak, Kamilla
Objectives: There is a need for ecologically valid measures of real-life cognitive functioning. We investigated: (I) the sensitivity of the Cognition Assessment in Virtual Reality (CAVIR) test, which assesses daily-life cognitive skills in an immersive virtual reality kitchen scenario, to capture cognitive impairments in a Spanish sample of patients with bipolar disorder (BD) compared to healthy controls (HCs); (II) the convergent validity of CAVIR against standard neuropsychological tests and functional measures. Methods: Patients with BD in full/partial remission (n = 40) and HCs (n = 40) completed the CAVIR–Spanish version and standard neuropsychological tests; the Hamilton Depression Rating Scale (HRDS-17), the Young Mania Rating Scale (YMRS), the Functioning Assessment Short-Test (FAST) and the Brief University of California Performance-based Skills Assessment (UPSA-B). Between-group comparisons of CAVIR global and subtask scores were conducted, together with correlation and linear regression analyses adjusting for age and mood symptoms. Results: CAVIR was sensitive to cognitive impairments in BD, with patients showing poorer performance than HCs on CAVIR global composite (BD = −1.09, 95% CI [−1.44, 0.74] vs. HCs = −0.19, 95% CI [−0.53, 0.15]) (F(1,72) = 9.52, p = 0.003, 2 = 0.12) and subtasks of sustained attention (BD = −1.25, 95% CI [−1.83, −0.70] vs. HCs = −0.14, 95% CI [−0.66, 0.37]) (F(1,69) = 6.12, p = 0.016, 2 = 0.08), processing speed (BD = −1.64, 95% CI [−2.11, −1.18] vs. HCs = −0.20, 95% CI [−0.66, 0.25]) (F(1,68) = 13.67, p < 0.001, 2 = 0.17) and working memory (BD = −0.91, 95% CI [−1.42, −0.41] vs. HCs = 0.05, 95% CI [−0.42, 0.52]) (F(1,71) = 5.50, p = 0.022, 2 = 0.07). The global CAVIR composite and subtasks scores were associated with standard global neurocognitive composite and domains, respectively (σ = 0.50–0.74, p < 0.001). The global CAVIR and all subtasks scores were associated with both observed/interview-based (FAST; σ = −0.29 to −0.55, p < 0.001) and performance-based (UPSA-B; σ = 0.29–0.49, p < 0.05) functional outcomes. Conclusions: The CAVIR-Spanish version is a sensitive and valid instrument for measuring real-life cognitive skills in BD and may be implemented in clinical settings and treatment trials targeting cognition following further studies.
Resilience in Bipolar Disorder Compared to Clinical and Non-Clinical Populations: A Systematic Review and Meta-Analysis
(John Wiley & Sons, 2026-01-01) Clougher, Derek; De Prisco, Michele; Solé Cabezuelo, Brisa; Montejo Egido, Laura; Serra Navarro, Maria; Forte, Maria Florencia; Camprodon Boadas, Patricia; Serna, Elena de la, 1978-; Oliva, Vincenzo; Martín Parra, Sara; Sánchez-Moreno, José; Amann, Benedikt L.; Garriga, Marina; Verdolini, Norma; Ribasés Haro, Marta; Miskowiak, Kamilla W.; Martínez-Arán, Anabel, 1971-; Vieta i Pascual, Eduard, 1963-; Amoretti Guadall, Silvia; Torrent Font, Carla
Introduction: Resilience is present in both clinical and non-clinical populations; yet, there is a paucity of literature examining its role in bipolar disorder (BD). The goal of the present systematic review and meta-analysis was to substantiate the extant literature investigating resilience in BD in comparison to clinical and non-clinical populations. Method: PubMed/MEDLINE, PsycINFO, and Scopus were systematically searched from inception to August 8th, 2024. Results: Twenty-eight studies using a validated resilience scale with a total of 3094 people with BD, 4100 healthy controls, and 1768 with other mental diagnoses were included in the systematic review, and 21 were analyzed in a random effects meta-analysis. A statistically significant result with a medium effect (SMD = −0.787, p < 0.001) indicated that people with BD reported lower levels of resilience than healthy controls. Similarly, patients with BD showed higher levels of resilience than patients with schizophrenia (SCZ) (SMD = 0.336, p = 0.013). No significant differences were found between BD and major depressive disorder (MDD). Conclusion: Findings should be interpreted with caution due to the high heterogeneity observed and methodological challenges in the definition and measurement of resilience. Future research should aim to better characterize resilience in BD by improving its assessment as a standardized element of clinical evaluation. This will provide a basis for strategies to reduce the burden of this chronic condition.
Time-course evolution of counterfactual thinking after early pregnancy loss
(Nature Publishing Group, 2026-03-19) Mallorquí, Aida; Pauta, Montse; Cardona, Gemma; Álvarez Martín, Claudia; Paz y Miño, Fernanda; Nogué, Laura; Segú, Xavier; Ardiles-Ruesjas, Victoria; Rodríguez Fornells, Antoni; Borrell i Vilaseca, Antoni
Counterfactual thinking (CT), the tendency to consider how events might have been different, is a common cognitive process following negative life events. This longitudinal study examines the prevalence and time-course evolution of CT immediately after early pregnancy loss. A sample of 119 women who experienced early pregnancy loss completed an online psychological assessment measuring traumatic impact, trait rumination, and CT presence, frequency, and content. The survey was administered at one week, one month, and four months post-loss. CT was highly prevalent (72%) and decreased over time. 99% of CT had an upward focus, imagining a better outcome than reality. Moreover, 91.6% were also self-referential, perceived as dependent on one’s own behaviors and emotions, frequently involving a heightened sense of personal responsibility for the loss. Rumination and traumatic impact predicted counterfactual thinking frequency over time, identifying psychological risk patterns. Findings support the idea that CT may serve an adaptive function by helping to process the loss and support future goal setting, including subsequent pregnancy. However, in individuals with high traumatic impact and rumination, CT may contribute to prolonged distress. Integrating psychological care alongside physical healthcare is essential to promoting long-term well-being after early pregnancy loss.
The American Society of Clinical Psychopharmacology task force consensus statement on the deprescribing of stimulant medications in adults with ADHD✰
(Elsevier B.V., 2026-10-01) Goodman, David W.; Mago, Rajnish; Citrome, Leslie; Swartz, Holly A.; McIntyre, Roger S.; Freeman, Marlene P.; Clayton, Anita H.; Kasper, Siegfried; Vieta i Pascual, Eduard, 1963-; Williams, Arthur Robin; Frye, Mark A.; Gitlin, Michael J.; Cohen, Lawrence J.; Correll, Christoph U.; Gorwood, Philip; Iosifescu, Dan V.; Jha, Manish K.; Kupka, Ralph; Macaluso, Matthew; Malhi, Gin S.; Mitchell, Philip B.; Bhatt, Snehal; Tohen, Mauricio; Nierenberg, Andrew A.; Sajatovic, Martha; Thase, Michael E.; Zohar, Joseph; Aaronson, Scott T.; Young, Joel L.; Goldberg, Joseph F.
There is a lack of consensus in the field about the indefinite use of psychostimulants for adult ADHD and the circumstances under which their deprescribing warrants consideration. To address this gap in knowledge, the American Society of Clinical Psychopharmacology (ASCP) convened a Task Force on the deprescribing of psychotropic medications, including stimulant medications for adult ADHD, which entailed a focused literature review and 2-round Delphi survey querying 45 international psychopharmacology experts on factors related to deprescribing. Consensus (≥75% agreement, defined by endorsements of “strongly agree” or “moderately agree”) was reached on 10 of 11 (91%) Delphi statements. Survey responses plus literature review suggest that stimulant deprescribing may be appropriate when 1) the diagnosis of ADHD is deemed incorrect upon reevaluation unless another stimulant-responsive condition is evident; 2) cognitive complaints have other more likely etiologies for which stimulant medications are inappropriate; 3) cognitive benefits are absent; 4) stimulant medications exacerbate medical or other psychiatric comorbidities; 5) adverse effects, if present, are non-remediable; 6) stimulant medications are misused; and 7) untreated comorbid non-cannabis substance use disorders are present. Panelists just fell short of consensus in perceiving regular use of cannabis as an insufficient reason to deprescribe stimulant medications in adult ADHD patients. In sum, clinical circumstances and rationales can be identified that support decisions to deprescribe stimulant medications for adult ADHD. Deliberate stimulant misuse or abuse, comorbid medical or psychiatric contraindications, and diagnostic inaccuracy pose strong reasons to consider deprescribing stimulants, potentially in favor of alternative pharmacotherapies and psychotherapies for adult ADHD.
Mapping behavioural mechanisms linking childhood maltreatment, cognition, impulsivity, and suicidality in bipolar disorder: A network approach
(Nature Publishing Group, 2026-06-20) Fares Otero, Natalia Elena; Iversen, Astrid E.; Gutiérrez Zotes, José Alfonso; Zarp, Jeff; Jiménez Martínez, Esther; Sánchez-Moreno, José; Pomarol-Clotet, Edith; Vieta i Pascual, Eduard, 1963-; Kjærstad, Hanne Lie; Vilella, Elisabet; Miskowiak, Kamilla W.
Childhood maltreatment (CM) has been consistently associated with increased risk and poorer outcomes in bipolar disorder (BD). However, the behavioural and cognitive mechanisms linking CM and suicidality remain poorly understood, limiting the development of targeted preventive interventions. We estimated a regularised partial correlation network to explore the interplay between CM subtypes (emotional, physical, or sexual abuse; emotional and physical neglect), cognitive domains (attention/processing speed, executive function/working memory, socio-emotional cognition, decision-making), impulsivity traits (attentional, motor, non-planning), and suicidal behaviours (ideation, planning, attempts) in 249 euthymic individuals with BD (mean age = 46.14, SD = 8.60; 59.84% female; 71.89% BD type I). CM was assessed using the Childhood Trauma Questionnaire (CTQ), cognition with a comprehensive neuropsychological battery, impulsivity with the Barratt Impulsiveness Scale (BIS-11), and suicidality with the Columbia Suicide Severity Rating Scale (C-SSRS) and structured interview. Age, sex, and social desirability (CTQ minimisation/denial subscale) were included as covariates. CM was associated with both cognitive functioning (poorer executive function and working memory, attention/processing speed, and socio-emotional cognition) and suicidality (suicidal ideation and, to a lesser extent, suicide attempts). Emotional abuse was linked to suicidal ideation (strongest association among CM subtypes; r = 0.27, p <0.001) and showed the highest centrality within the network (strength z = 1.76; expected influence z = 1.95). All CM subtypes were associated with impulsivity traits. Motor impulsivity emerged as a behavioural bridge between CM and suicidality (bridge expected influence z = 0.21), whereas higher socio-emotional cognition, particularly the ability to manage emotions, was associated with fewer suicide attempts. These findings highlight specific cognitive and behavioural mechanisms linking CM and suicidality in BD. Emotional abuse and socio-emotional cognition represent promising targets for trauma-informed and personalised interventions.
Prediction models for suicide reattempts by lasso regression through machine learning models: Single versus multiple suicide attempters
(Elsevier B.V., 2026-06-15) Roberto, Natalia; De Prisco, Michele; Andreo-Jover, Jorge; Arqueros, María; Ayad Ahmed, Wala; Bobes-Bascarán, Teresa ; Canal Rivero, Manuel; Cebrià Meca, Ana Isabel; Crespo-Facorro, Benedicto; Torre Luque, Alejandro de la; Diaz Marsá, Marina; Elices, Matilde; García Martínez, Daniel; Grande, Iria; Jiménez Treviño, Luis; Mann, J. John; McIntyre, Roger S.; Oliva, Vincenzo; Palao-Tarrero, Angela; Palao Vidal, Diego J.; Pérez Diez, Iván; Ruiz Veguilla, Miguel; Sáiz Martínez, Pilar Alejandra; Zorrilla, Iñaki; SURVIVE CONSORTIUM; Pérez Solà, Víctor
The best predictor of a suicide attempt is a previous attempt, apart from psychiatric diagnoses also associated. Some studies found other indicators of great risk for suicide reattempts. Machine Learning algorithms offer the potential for systematic detection of features that carry greater risk for an event. This study sought to develop a classification algorithm distinguishing between Single Suicide Attempters (SSA) and Multiple Suicide Attempters (MSA) in a Spanish multicentre national cohort to explore prediction of subsequent attempts in suicidal patients. Two models including the same sociodemographic and clinical variables grouped in more specific (Model I) or broad (Model II) categories were developed to explore risk factors for suicide reattempts. A Least Absolute Shrinkage and Regression Operator logistic regression with a 10-fold cross-validation was adopted. 1443 adult patients from the SURVIVE cohort were included (582 SSA and 861 MSA). Both Model I (AUC = 0.696; BAC = 0.644) and Model II (AUC = 0.678; BAC = 0.621) outperformed naïve majority-class classification for SSA and MSA. Bipolar disorder type II, binge-eating disorder, and schizophrenia variables weighted heavier on Model I for suicide reattempt-related; while eating disorder diagnosis, Africa as birthplace, affective disorder diagnosis, being employed, schizophrenia-spectrum disorder and substance use disorder diagnoses were the most important suicide reattempt-related of Model II. Affective disorders, eating disorders and schizophrenia-spectrum disorders emerged as the most important variables in predicting reattempts. Both models showed similar sensitivity and specificity when discriminating between SSA and MSA. Identifying specific risk factors for reattempts could have a significant impact on tailoring prevention strategies and interventions.
Treatment of bipolar depression: results from a comprehensive network meta-analysis and updated systematic review
(Elsevier B.V., 2026-07-01) Yalin, Nefize; Yildiz, Aysegul; Siafis, Spyridon; Vieta i Pascual, Eduard, 1963-; Leucht, Stefan
Depressive episodes present a treatment challenge in bipolar disorder (BD), and an urgent need exists for novel treatment options. This review sought to revisit the results from a recent network meta-analysis (NMA) that examined treatment options for bipolar depression and to update those findings with a complementary systematic review (PROSPERO-ID: CRD42020171726). The NMA was based on the qualitative synthesis of 145 studies and the quantitative analysis of 101 studies investigating acute depression in adults with bipolar depression from inception to April 2023. A complementary systematic review was conducted using MEDLINE, OVID, EMBASE, PsychINFO, CINAHL, LILACS, Cochrane, Web of Science Core Collaboration, and Google Scholar databases from April 2023 to November 2024 to identify the most recent randomized controlled trials on the treatment of bipolar depression. Studies identified via systematic review were subjected to narrative synthesis and quality assessment was completed using revised Cochrane risk of bias tool. The original NMA showed that olanzapine plus fluoxetine, quetiapine, olanzapine, lurasidone, lumateperone, cariprazine, and lamotrigine were more efficacious than placebo in reducing depressive symptoms in BD with good confidence. Several other drugs might also be efficacious, but confidence in the evidence was very low to low. The complementary systematic review identified 24 clinical trials, seven of which had published results suitable for meta-analysis; the remaining 17 studies were either ongoing or completed with no available results. Collectively, the NMA and systematic review findings can inform evidence-based care and the development of international treatment guidelines for bipolar depression.
Seasonal longitudinal effects of winter birth on psychopathology, cognition, and functioning in schizophrenia-spectrum and affective disorders: Findings from the PsyCourse Study
(Elsevier B.V., 2026-09-01) Pérez Ramos, Anaid; Budde, Monika; Adorjan, Kristina; Amoretti Guadall, Silvia; Anghelescu, Ion-George; Arolt, Volker; Baune, Bernhard T.; Dannlowski, Udo; Dietrich, Detlef E.; Fallgatter, Andreas J.; Figge, Christian; Garriga, Marina; García Rizo, Clemente; Guasch Capella, Nora; Heilbronner, Maria; Lang, Fabian U.; Juckel, Georg; Kohshour, Mojtaba Oraki; Konrad, Carsten; Martínez-Arán, Anabel, 1971-; Mezquida Mateos, Gisela; Navarro Flores, Alba; Reich-Erkelenz, Daniela; Reimer, Jens; Reininghaus, Eva Z.; Senner, Fanny; Schmauß, Max; Schmitt, Andrea; Schulte, Eva C.; Spitzer, Carsten; Vieta i Pascual, Eduard, 1963-; Wiltfang, Jens; Falkai, Peter; Schulze, Thomas G.; Papiol, Sergi; Torrent Font, Carla; Heilbronner, Urs
Aims Winter birth (WB) is a replicated risk factor for mental health conditions, potentially due to third-trimester Vitamin D deficiency and maternal viral infections. Beyond diagnosis, WB is associated with psychopathology, cognition, and functionality as epiphenomena. We analysed these outcomes in psychosis and affective disorders, considering illness duration and sex-specific effects. Methods We included 535 individuals with schizophrenia-spectrum and 667 with affective disorders from the PsyCourse Study, evaluated at four time points over 18 months. Participants were stratified by the birth season: winter vs. other seasons and by duration of illness (</≥5 years). Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) for psychosis, Inventory of Depressive Symptomatology (IDS-C30) and Young Mania Rating Scale (YMRS) for affective disorders, functionality with the Global Assessment of Functioning Scale (GAF), and cognitive performance with Trail Making Tests A (TMT-A) and B (TMT-B), Verbal Digit Span, and Digit Symbol Test (DST). Linear mixed models adjusted for covariates were applied. Results No interaction effects between WB and diagnostic group or time remained significant after correction for multiple comparisons. In sex-stratified models, a significant WB × time interaction emerged for DST in females, with WB participants showing improvements over time in schizophrenia-spectrum disorders, and a crossover pattern in affective disorders. Conclusions WB has no robust effect on long-term outcomes on schizophrenia-spectrum or affective disorders. Subtle, sex-dependent effects on cognition were observed in females, with divergent longitudinal patterns between diagnostic groups, suggesting a possible early-life influence that attenuates over the course of illness.
Age-stratified associations between severe mental illness, dementia, and ischemic stroke: findings from the PADRIS-PRESTO cohort
(Elsevier B.V., 2026-04-20) De Prisco, Michele; Oliva, Vincenzo; Sánchez del Valle Díaz, Raquel; Parellada Rodón, Eduard; Junqué i Plaja, Carme, 1955-; Martí Domènech, Ma. Josep; Bortolozzi Biasoni, Analía; Alberch i Vié, Jordi, 1959-; Garrabou Tornos, Glòria; Sánchez-Vives, María Victoria; Giralt Torroella, Albert; Segura i Fàbregas, Bàrbara; Lladó Plarrumaní, Albert; Compta, Yaroslau; Radua, Joaquim; Vieta i Pascual, Eduard, 1963-; Hidalgo Mazzei, Diego; Anmella, Gerard
People with severe mental illnesses (SMIs), including schizophrenia spectrum disorders (SSD), major depressive disorder (MDD), and bipolar disorder (BD), experience elevated rates of physical comorbidity and premature mortality. Dementia and ischemic stroke contribute substantially to this burden, yet age-specific patterns of these associations remain poorly characterized. To bridge this gap, we conducted a population-based cross-sectional study using the PADRIS-PRESTO cohort, integrating primary and specialized care records from the Catalan public health system (Spain). Adults with a lifetime SMI diagnosis were compared with controls without any psychiatric condition. Weighted age-stratified prevalence was calculated and logistic regression models estimated age-specific odds ratios (ORs) with 95% confidence intervals (CIs), adjusting for socioeconomic status and medical comorbidity burden. Among 694,086 participants, 176,870 had an SMI diagnosis. Dementia prevalence was 3.49% (range, 0.33% at ages 20-29 to 39.51% at 90-99 years) in SMIs and 0.36% (0.02%-17.7%) in controls. Ischemic stroke prevalence was 5.3% (0.22%-16.4%) in SMIs and 2.75% (0.08%-14.67%) in controls. The ORs between SMI and dementia were significant across all age groups, with the strongest association observed at younger ages (OR = 23.21, 95% CIs = 13.74-39.19 at 30-39 years). Elevated ORs for stroke persisted up to 70-79 years, peaking at 40-49 years (OR = 2.99, 95% CIs = 2.63-3.41). Patterns were consistent across SMI subtypes. These findings highlight the need for earlier and more systematic neurological and cardiometabolic screening and management within psychiatric care and support policies that recognize SMIs as risk factors for vascular diseases and dementia.
Efficacy and safety of adjunctive treatment with the fatty acid amide hydrolase inhibitor JNJ-42165279 in participants with major depressive disorder with anxious distress: A double-blind, placebo-controlled, randomised study
(Elsevier B.V., 2026-05-01) Schmidt, Mark E.; Gargano, Cynthia; Zhou, Xianhuang; Palmer, James A.; Saad, Ziad S.; Vieta i Pascual, Eduard, 1963-; Drevets, Wayne C.; Stuyckens, Kim; Pandina, Gahan
JNJ-42165279 is a potent, selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of the endocannabinoid N-arachidonoylethanolamide (anandamide), which plays a role in regulation of fear and anxiety responses. This double-blind, randomised, placebo-controlled, phase 2a study assessed the efficacy, safety and pharmacodynamics of adjunctive treatment with JNJ-42165279 in participants with major depressive disorder (MDD) with anxious distress and inadequate response to selective serotonin reuptake inhibitors (SSRI) or serotonergic/noradrenergic reuptake inhibitors (SNRI). Eligible participants (18-64 years; N = 153) were randomised (1:1) to receive JNJ-42165279 (25 mg) or placebo orally once daily and were maintained on their current SSRI/SNRI treatment. The primary endpoint was the change from baseline at week 6 in the 17-item Hamilton Depression Rating Scale (HDRS17). The study results did not show a significant treatment effect of adjunctive JNJ-42165279 on the primary endpoint versus placebo (least square mean difference [standard error]: -0.2 [1.04]; one-sided p=0.416) in the enriched intent-to-treat population. Findings for the key secondary efficacy endpoints also did not demonstrate an additional benefit of adjunctive JNJ-42165279 treatment over placebo. Treatment with JNJ-42165279 produced substantial increases in the mean concentrations of fatty acid amides in plasma, and the plasma JNJ-42165279 and anandamide levels were strongly correlated. The safety results were consistent with the known safety profile of JNJ-42165279. Overall, adjunctive treatment with JNJ-42165279 at the dose tested did not provide significant benefit in reducing depression/anxiety symptoms versus placebo but showed no new safety signals in participants with MDD and anxious distress.
Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for posttraumatic stress disorder: A systematic review and meta-analysis of clinical and functional outcomes
(Elsevier B.V., 2026-06-01) Fares Otero, Natalia Elena; Furukawa, Yuki; Sijbrandij, Marit; Leucht, Stefan; Vieta i Pascual, Eduard, 1963-; Cuijpers, Pim; Harrer, Mathias; Seedat, Soraya
Posttraumatic stress disorder (PTSD) is a chronic and disabling condition and identifying beneficial therapies is timely and important. We aimed to estimate the efficacy of 3,4-methylenedioxymethamphetamine-assisted therapy (MDMA-AT) compared with control on clinical and functional outcomes in PTSD. A PRISMA-compliant search (PROSPEROCRD42022353261) up to August 14, 2025, covered nine databases and manual searches to identify randomised controlled trials (RCTs). Methodological quality was assessed using the Cochrane Risk of Bias tool (RoB2), and the certainty of the evidence for each outcome was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Of 1035 records identified, 14 studies met inclusion criteria for qualitative synthesis; eight trials provided sufficient data for quantitative synthesis (k = 24). Random-effects meta-analyses indicated that MDMA-AT was associated with reductions in PTSD symptom severity (n = 298, k = 9, SMD = -1.19, 95 % CI [-1.95, -0.42]; I² = 68.8 %, τ2 = 1.02), dissociative symptoms (n = 148, k = 5, SMD = -0.37, 95 % CI [-0.70, -0.04]; I² = 0.0 %, τ2 = 0), and may improve functioning (n = 227, k = 4, SMD = -0.83, 95 % CI [-1.47, -0.19]; I² = 61.2 %, τ2 = 0.27). No clear evidence of benefit was observed for depressive symptoms. Most studies showed a high risk of bias in the measurement of the outcome, and some concerns due to deviations from the intended intervention; the overall certainty of the evidence was very low. The number of trials remains limited, with considerable heterogeneity in certain outcomes, small sample sizes, and the absence of active controls in most studies, which likely compromised blinding integrity. Current findings suggest that MDMA-AT may warrant further investigation as a potential treatment for PTSD; however, larger, higher-quality RCTs with active controls and long-term follow-up are needed to determine its efficacy.

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