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

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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.
Diminished anticipatory pleasure predicts anhedonia in women with endometrisois: a case-control study
(BioMed Central, 2026-03-19) Mallorquí, Aida; Segura, Emma; Magí, Cristina; Quintas Marquès, Lara; Gracia, Meritxell; Courbiere, Blandine; Carmona Herrera, Francisco; Martínez Zamora, María Ángeles
Anhedonia, a diminished response to pleasurable stimuli extensively studied in mental disorders and chronic pain, has been reported as prevalent among patients with deep endometriosis. Anhedonia is considered a multifaceted transdiagnostic construct involving cognitive, affective, and behavioral processes related to the anticipation and experience of pleasure. In this study, we aim to expand on previous findings by exploring the presence of anhedonia in patients with ultrasound diagnosed (UD) endometriosis compared to a control group, and by examining how its anticipatory and consummatory components contribute to the loss of pleasure in this condition.
ℛSCZ: A Riemannian schizophrenia diagnosis framework based on the multiplexity of EEG-based dynamic functional connectivity patterns
(Elsevier Ltd., 2024-09-01) Stavros, Dimiatriadis
Abnormal electrophysiological (EEG) activity has been largely reported in schizophrenia (SCZ). In the last decade, research has focused to the automatic diagnosis of SCZ via the investigation of an EEG aberrant activity and connectivity linked to this mental disorder. These studies followed various preprocessing steps of EEG activity focusing on frequency-dependent functional connectivity brain network (FCBN) construction disregarding the topological dependency among edges. FCBN belongs to a family of symmetric positive definite (SPD) matrices forming the Riemannian manifold. Due to its unique geometric properties, the whole analysis of FCBN can be performed on the Riemannian geometry of the SPD space. The advantage of the analysis of FCBN on the SPD space is that it takes into account all the pairwise interdependencies as a whole. However, only a few studies have adopted a FCBN analysis on the SPD manifold, while no study exists on the analysis of dynamic FCBN (dFCBN) tailored to SCZ. In the present study, I analyzed two open EEG-SCZ datasets under a Riemannian geometry of SPD matrices for the dFCBN analysis proposing also a multiplexity index that quantifies the associations of multi-frequency brainwave patterns. I adopted a machine learning procedure employing a leave-one-subject-out cross-validation (LOSO-CV) using snapshots of dFCBN from (N-1) subjects to train a battery of classifiers. Each classifier operated in the inter-subject dFCBN distances of sample covariance matrices (SCMs) following a rhythm-dependent decision and a multiplex-dependent one. The proposed ℛSCZ decoder supported both the Riemannian geometry of SPD and the multiplexity index DC reaching an absolute accuracy (100 %) in both datasets in the virtual default mode network (DMN) source space.
Allosterism in the adenosine A2A and cannabinoid CB2 heteromer
(Blackwell, 2024-07-23) Llinàs del Torrent, Clàudia; Raïch, Iu; González, Andrea; Lillo, Jaume; Casajuana-Martin, Nil; Franco Fernández, Rafael; Pardo, Leonardo; Navarro Brugal, Gemma
Background and Purpose Allosterism is a regulatory mechanism for GPCRs that can be attained by ligand-binding or protein–protein interactions with another GPCR. We have studied the influence of the dimer interface on the allosteric properties of the A2A receptor and CB2 receptor heteromer. Experimental Approach We have evaluated cAMP production, phosphorylation of signal-regulated kinases (pERK1/2), label-free dynamic mass redistribution, β-arrestin 2 recruitment and bimolecular fluorescence complementation assays in the absence and presence of synthetic peptides that disrupt the formation of the heteromer. Molecular dynamic simulations provided converging evidence that the heteromeric interface influences the allosteric properties of the A2AR–CB2R heteromer. Key Results Apo A2AR blocks agonist-induced signalling of CB2R. The disruptive peptides, with the amino acid sequence of transmembrane (TM) 6 of A2AR or CB2R, facilitate CB2R activation, suggesting that A2AR allosterically prevents the outward movement of TM 6 of CB2R for G protein binding. Significantly, binding of the selective antagonist SCH 58261 to A2AR also facilitated agonist-induced activation of CB2R.
GADD45A: With or without you
(Wiley, 2024-07-01) Palomer Tarridas, Francesc Xavier; Salvador, Jesús M.; Griñán Ferré, Christian; Barroso Fernández, Emma; Pallàs i Llibería, Mercè, 1964-; Vázquez Carrera, Manuel
The growth arrest and DNA damage inducible (GADD)45 family includes three small and ubiquitously distributed proteins (GADD45A, GADD45B, and GADD45G) that regulate numerous cellular processes associated with stress signaling and injury response. Here, we provide a comprehensive review of the current literature investigating GADD45A, the first discovered member of the family. We first depict how its levels are regulated by a myriad of genotoxic and non-genotoxic stressors, and through the combined action of intricate transcriptional, posttranscriptional, and even, posttranslational mechanisms. GADD45A is a recognized tumor suppressor and, for this reason, we next summarize its role in cancer, as well as the different mechanisms by which it regulates cell cycle, DNA repair, and apoptosis. Beyond these most well-known actions, GADD45A may also influence catabolic and anabolic pathways in the liver, adipose tissue and skeletal muscle, among others. Not surprisingly, GADD45A may trigger AMP-activated protein kinase activity, a master regulator of metabolism, and is known to act as a transcriptional coregulator of numerous nuclear receptors. GADD45A has also been reported to display a cytoprotective role by regulating inflammation, fibrosis and oxidative stress in several organs and tissues, and is regarded an important contributor for the development of heart failure. Overall data point to that GADD45A may play an important role in metabolic, neurodegenerative and cardiovascular diseases, and also autoimmune-related disorders. Thus, the potential mechanisms by which dysregulation of GADD45A activity may contribute to the progression of these diseases are also reviewed below.
G9a an Epigenetic Therapeutic Strategy for Neurodegenerative Conditions: From Target Discovery to Clinical Trials
(Wiley, 2025-01-06) Bellver Sanchis, Aina; Ribalta Vilella, Marta; Irisarri, Alba; Gehlot, Pinky; Choudhary, Bhanwar Singh; Jana, Abhisek; Vyas, Vivek Kumar; Banerjee, Deb Ranjan; Pallàs i Llibería, Mercè, 1964-; Guerrero López, Ana; Griñán Ferré, Christian
This review provides a comprehensive overview of the role of G9a/EHMT2, focusing on its structure and exploring the impact of its pharmacological and/or gene inhibition in various neurological diseases. In addition, we delve into the advancements in the design and synthesis of G9a/EHMT2 inhibitors, which hold promise not only as a treatment for neurodegeneration diseases but also for other conditions, such as cancer and malaria. Besides, we presented the discovery of dual therapeutic approaches based on G9a inhibition and different epigenetic enzymes like histone deacetylases, DNA methyltransferases, and other lysine methyltransferases. Hence, findings offer valuable insights into developing novel and promising therapeutic strategies targeting G9a/EHMT2 for managing these neurological conditions.
The role of childhood maltreatment and mental health disorders on suicidal behaviour in adolescents
(Elsevier Ltd., 2025-01-01) Gómez Vallejo, Sandra; Díaz-Marsá, Marina; Fernández Rodrigues, Verónica; Andreo-Jover, Jorge; Bobes-Bascarán, Teresa ; Cebrià Meca, Ana Isabel ; Crespo-Facorro, Benedicto; Garrido Torres, Nathalia; González-Pinto, Ana; Jiménez Treviño, Luis; Lara, Elvira; López Pena, Purificación; Palao-Tarrero, Angela; Palao Vidal, Diego J.; Pérez, Solà Víctor; Ruiz Veguilla, Miguel; Sáiz Martínez, Pilar Alejandra; Sánchez Carro, Yolanda; Torre Luque, Alejandro de la; Vidal Bermejo, Emma; Vieta i Pascual, Eduard, 1963-; Zorrilla, Iñaki; Roberto, Natalia; Grande, Iria; Bobes García, Julio; Lázaro García, Luisa; Bracco, Lorenzo; Corbalán, Fernando; Fares Otero, Natalia Elena; Ayad Ahmed, Wala; Ayuso Mateos, José Luis; Fernández Fernández, Jennifer; García Fernández, Ainoa; Garcia Ramos, Adriana; Imaz, Carlos; Leal Leturia, Itziar; Olivares, Luís; Payá, Beatriz; Pemau, Andres; Pérez Guerra, Carla; Seijo Zazo, Elisa; Tur, Nuria
Abstract Background Suicide stands as a grave and pressing public health concern, ranking among the foremost causes of death in the youth demographics. While childhood maltreatment (CM) and mental disorders have garnered substantial attention as risk factors for suicide, there remains an enigmatic aspect concerning how these two elements interact, influencing the nature of suicidal ideation and suicidal behaviour, and the transition between them. Objective This study endeavours to shed light on the intricate interplay between CM, mental disorders, and suicide. Participants and setting We gathered data from 289 adolescents aged 12–17 (87.2 % female) drawn from eight different hospitals across Spain, all of whom had attempted suicide within the past 10 days. Methods We assessed suicidal ideation severity and intensity, suicidal behaviour by attempts using the C-SSRS, and the presence of CM using CTQ and identified concurrent mental disorders according to the MINI. Regression analysis and moderation analysis were conducted by PROCESS macro. Results Moderation analysis revealed that higher scores of CM were associated with a higher number of suicide attempts with the presence of a mental disorder. Additionally, we found that those with higher scores of CM reported less severe characteristics of suicidal ideation, when presenting along with an anxiety disorder. Conclusions These findings revealed CM increased risk of suicidal behaviour among young individuals. Additionally, the results suggest that adolescents with CM and anxiety disorder might under-report suicidal ideation. Hence, these findings offer a potential key to identifying and preventing suicide risk among young individuals.
NRF2 deficit prevents pathologic Tau seeding and spreading in an induced tauopathy mouse model
(Elsevier B.V., 2026-02-05) López-Sampere, Yaiza; Mengod, Pol; Roca-Pereira, Sergio; Vinyals, Antònia; Mato-Blanco, Xoel; Vela-Martínez, Marta; Dakterzada, Farida; Romero, Leila; Santamaría Martínez, Enrique; Fernández Irigoyen, Joaquín; Ferrer, Isidro (Ferrer Abizanda); Povedano Panades, Mónica; Río Fernández, José Antonio del; Santpere Baró, Gabriel; Portero Otin, Manuel; Piñol Ripoll, Gerard; Andrés-Benito, Pol
Background Nuclear factor erythroid 2–related factor 2 (NRF2) regulates antioxidant defenses and protects against neurodegeneration, including Alzheimer's disease (AD). Its age-related decline disrupts redox balance and increases neuronal vulnerability, but the early hippocampal effects remain unclear. Here, we tested whether NRF2 loss affects tau seeding and spreading in a PHF-tau–inoculated mouse model, contributing to accelerated aging. Methodology Three-month-old NRF2-knockout (Nfe2l2−/−) and wild-type (WT) mice received hippocampal inoculations of human AD-derived PHF-tau, and tau propagation was analyzed after three months. To elucidate the molecular underpinnings of the observed changes, we performed integrative phosphoproteotranscriptomic analyses of hippocampal tissue, supported by RT-qPCR and Western blot validation. Results PHF-tau inoculation at 3 months of age in Nfe2l2−/− mice, surprisingly, exhibited markedly reduced tau seeding and spreading compared to WT after 3 months of incubation. Molecular characterization of the Nfe2l2−/− hippocampus was carried out to unravel the molecular changes associated with impaired tau propagation. Transcriptomic profiling revealed 745 deregulated genes in Nfe2l2−/− mice, characterized by upregulation of immune and metabolic pathways but downregulation of oxidative stress and redox-related genes. RT-qPCR confirmed diminished expression of antioxidant enzymes and anti-inflammatory receptors, alongside altered astrocytic markers. Proteomic analysis identified 157 dysregulated proteins associated with mitochondrial, synaptic, and inflammatory processes, while phosphoproteomics detected 824 altered phosphosites enriched in cytoskeletal and synaptic networks. Western blot showed increased GFAP-C-term, AQP4, 8-OHdG, and MDAL, with reduced GSTM2 expression. Notably, total and 4R-tau levels were decreased, while 3R-tau was elevated in Nfe2l2−/− mice. Conclusion Our findings suggest that NRF2 loss induces a hippocampal state marked by impaired antioxidant defenses, astrocytic remodeling, and disrupted tau isoform balance. This environment, while metabolically altered, paradoxically hinders tau propagation, highlighting NRF2 as a key regulator of both redox and cellular maturity programs essential for tau spread and as a potential therapeutic target in tauopathies.
An emerging role for synaptic Zn2+ in substance use disorders
(Elsevier, 2026-04) Solis, Oscar; Curry, Fallon P.; Frangos, Zachary J.; Dunne, William; Schoenborn, Ingrid; Lauer, Alyssa; Gomez, Juan L.; Ventriglia, Emilya; Bonaventura, Jordi; Michaelides, Michael
Synaptic zinc (Zn2+) modulates dopamine and glutamate neurotransmission by binding to the dopamine transporter and glutamate receptors. Among other neurotransmitters, dopamine and glutamate critically regulate physiological processes and behaviors relevant to substance use disorders (SUDs) and addiction. In addition, Zn2+ interacts with inhibitory neurotransmitter systems, including GABA and glycine receptors, further influencing the excitatory-inhibitory balance within circuits relevant to addiction. Nevertheless, the specific involvement of synaptic Zn2+ in such processes is unknown. We propose that synaptic Zn2+ serves as an environmentally derived factor that can influence the vulnerability to and development of SUDs and addiction via its interaction with proteins that regulate dopamine and glutamate neurotransmission in addiction-relevant brain circuits.
Astrocytes, via RTP801, contribute to cognitive decline by disrupting GABAergic-regulated connectivity and driving neuroinflammation in an Alzheimer's disease mouse model
(Elsevier Masson, 2025-04-01) Chicote González, Almudena; Solana Balaguer, Júlia; García Segura, Pol; Campoy Campos, Genís; Pérez Pérez, Inés; Pérez Navarro, Esther; Rodríguez Allué, Manuel José; Alberch i Vié, Jordi, 1959-; Giralt Torroella, Albert; Soria, Guadalupe; Malagelada Grau, Cristina
Introduction: Alzheimer's disease (AD) pathogenesis involves astrocytic responses to extracellular amyloid beta deposits and phospho-tau neurofibrillary tangles, which drive inflammatory activation. RTP801, a stress-responsive protein, has been implicated in mediating neuroinflammation. Its levels are increased in AD hippocampal samples, correlating with disease severity and cognitive decline. Methods: Using astrocyte-specific RTP801 silencing in the hippocampus of 5xFAD mice, we evaluated cognition, neuroinflammation, and hippocampal connectivity by magnetic resonance spectroscopy (MRS) and resting-state functional connectivity analyses. Histological and biochemical analyses assessed microgliosis, astrogliosis, and inflammasome-related protein levels. Results: Astrocytic RTP801 silencing in 5xFAD mice preserved spatial memory, maintained hippocampal γ-aminobutyric acid (GABA) levels, and preserved resting-state brain networks. In addition, RTP801 silencing significantly reduced markers of microgliosis, astrogliosis, and inflammasome effectors. Discussion: Astrocytic RTP801 contributes to AD-associated cognitive decline by disrupting GABAergic-regulated connectivity and amplifying inflammatory responses. Targeting astrocytic RTP801 may therefore offer therapeutic potential to mitigate AD progression by preserving neural connectivity and reducing neuroinflammation. Highlights: The 5xFAD mouse model of Alzheimer's disease presents higher levels of RTP801 in hippocampal astrocytes. Normalizing the levels of astrocytic RTP801 prevents cognitive decline and restores anxiety-like behavior in the 5xFAD mouse model. Knocking down astrocytic RTP801 preserves the resting-state functional connectivity in the 5xFAD mouse model. Astrocytic RTP801 mediates the loss of Parvalbumin+ interneurons, negatively affecting the levels of γ-aminobutyric acid (GABA) in the 5xFAD mouse model. Astrocytic RTP801 contributes to astro- and microgliosis and inflammasome expression in the 5xFAD mouse model.
Sensory-cell population integrity required to preserve minimal and normal vestibulo-ocular reflexes reveals the critical role of type I hair cells in canal- and otolith-specific functions
(The Society for Neuroscience, 2026-02-09) Schenberg, Louise; Simon, François; Palou Miranda, Aida; Dijan, Cassandre; Tagliabue, Michele; Llorens i Baucells, Jordi; Beraneck, Mathieu
Vestibular dysfunction constitutes a major medical concern, and regeneration of hair cells (HC) is a primary target of gene therapy aimed at restoring vestibular functions. Thus far, therapeutic trials in animal models targeting vestibular loss associated with genetic diseases have yielded variable and partial results, and the functional identity and quantity of HCs required to restore minimal or normal vestibular function remain undefined. Indeed, direct comparisons between structural pathology and quantitative assessments of vestibular dysfunctions are lacking in humans and are rather limited in animal models, representing a significant gap in current knowledge. Here, we present an innovative methodology to bridge the gap between HC integrity and functional vestibular loss in individual mice of either sex. Gradual vestibular deficits were induced through a dose-dependent ototoxic lesion, quantified with canal or utricular-specific vestibulo-ocular reflex tests, and were then correlated in all individuals with the loss of type I and type II HCs in different regions of ampulla and macula. Our findings reveal that the structure-function relationship is nonlinear, with lower bound of approximately 50% of HCs necessary to retain minimal vestibular function, and threshold exceeding 80% to preserve normal function, thus shedding light on population coding mechanisms for vestibular response. Our data further support the decisive role of type I, rather than type II, HC in the tested VOR functions.
Impact of cognitive reserve in clinical, neurocognitive and lifestyle factors in chronic schizophrenia and early stages of schizophrenia
(Elsevier España, 2024-07-01) Amoretti Guadall, Silvia; Arranz, Belén; Anmella, Gerard; Bernardo Arroyo, Miquel; Alfonso, Miqueu; Hernández, Carla; García-Portilla González, María Paz, 1962-; González-Blanco, Leticia; Safont, Gemma; Garrido, Ignacio; Sanchez Autet, Mónica
Introduction Although there is evidence that higher cognitive reserve (CR) is a protective factor and it has been related to better prognosis, there have been no studies to date that have explored the CR level and its impact in clinical, neurocognitive and lifestyle outcomes according to the stage of the disease: early stage of psychosis (ESP) or chronic schizophrenia (SCZ). Material and methods A total of 60 patients in the ESP and 225 patients with SCZ were enrolled in the study. To test the predictive capacity of CR for each diagnostic group, a logistic regression analysis was conducted. Hierarchical linear regression analyses were performed to explore the associations between CR and different outcomes. The mediation analyses were performed according to the principles of Baron and Kenny. Results Patients with SCZ showed lower CR than those in the ESP (p < 0.001). CR correctly classified 79.6% of the cases (p < 0.001; Exp(B) = 1.062). In ESP group, CR was related to working memory (p = 0.030) and negative symptoms (p = 0.027). CR (t = 3.925, p < 0.001) and cannabis use (t = 2.023, p = 0.048) explained 26.7% of the variance on functioning (p = 0.003). In patients with SCZ, CR predicted all cognitive domains, negative symptoms (R2 = 0.091, p = 0.001) and functioning (R2 = 0.074, p = 0.005). In both ESP and SCZ groups, higher CR was associated with lower body mass index and circumference. In ESP group, the effect of adherence to Mediterranean diet on functioning (p = 0.037) was mediated by CR level (p = 0.003).

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