Biological Psychiatry最新文献

{"title":"Impaired Activity-Regulated Proteostasis: A Shared Mechanism in Neurodevelopmental Disorders.","authors":"Kiran Pandey","doi":"10.1016/j.biopsych.2026.06.032","DOIUrl":"10.1016/j.biopsych.2026.06.032","url":null,"abstract":"<p><p>Proteostasis is the process by which cells control how much of each protein is made, how long it persists, and when it is removed. In neurons, proteostasis is not merely a housekeeping function; it is actively regulated by neuronal activity. When neurons fire, protein synthesis and degradation are simultaneously and transiently regulated to support synaptic plasticity. In neurodevelopmental disorders (NDDs), neurons lose this capacity to dynamically regulate their proteome in response to stimulation, disrupting synaptic plasticity and leading to cognitive impairments. This review establishes that despite diverse genetic origins, failure of activity-regulated proteostasis is a shared vulnerability across NDDs. This framework also explains why increasing or blocking protein synthesis or degradation alone under basal conditions is insufficient to restore normal function. Restoring the coupling between neuronal activity and proteostatic response rescues both molecular and cognitive impairments in NDDs, which offers a new perspective for investigating disease biology and developing novel therapeutic strategies.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148468781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polygenic Risk for Major Depression: Diagnostic Specificity and Developmental Trajectories in an Admixed Youth Cohort","authors":"Marcelo José Abduch Adas Brañas, Lucas Toshio Ito, Marcos Signoretti Croci, Ana Beatriz Ravagnani Salto, Victoria Fogaça Doretto, Marcos Leite Santoro, Vanessa Kiyomi Ota, Luis Augusto Rohde, Giovanni Abrahão Salum, Lois W. Choi-Kain, Síntia Belangero, Euripedes Constantino Miguel, Maurício Scopel Hoffmann, Pedro Mario Pan","doi":"10.1016/j.biopsych.2026.07.006","DOIUrl":"https://doi.org/10.1016/j.biopsych.2026.07.006","url":null,"abstract":"","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"262 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148461870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reductive Stress and Dysregulated Energy Metabolism in Schizophrenia: Mechanisms and Therapeutic Targets","authors":"Onur Memetoglu,&nbsp;Fei Du,&nbsp;Virginie-Anne Chouinard,&nbsp;Dost Öngür","doi":"10.1016/j.biopsych.2025.10.008","DOIUrl":"10.1016/j.biopsych.2025.10.008","url":null,"abstract":"<div><div>Reductive stress, defined by excessive accumulation of reducing equivalents such as NADH, disrupts cellular redox balance and is emerging as a detrimental factor in schizophrenia (SZ). It is closely related to the mitochondrial defects commonly seen in SZ, which implies its importance in impaired energy metabolism. Reductive stress intersects with oxidative stress pathways and causes an underappreciated additional burden on cellular systems. The integrated stress response (ISR) is an adaptive pathway typically activated by mitochondrial oxidative phosphorylation defects and other stressors. Emerging evidence indicates that reductive stress can independently activate the ISR. These findings highlight the crucial role of reductive stress in disease pathophysiology, although the process is not fully understood. Therefore, there is a need for innovative therapeutic approaches that can address reductive stress and mitochondrial dysfunction.</div></div>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"100 2","pages":"Pages 132-139"},"PeriodicalIF":10.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A 20-Year Population-Based Follow-Up Study on the Association Between Clozapine and Hospitalization in People With Treatment-Resistant Schizophrenia","authors":"Huiquan Zhou,&nbsp;Hao Luo,&nbsp;Le Gao,&nbsp;Jennifer Yee-Man Tang,&nbsp;Simon Sai Yu Lui,&nbsp;Edwin Ho Ming Lee,&nbsp;Sherry Kit Wa Chan","doi":"10.1016/j.biopsych.2026.02.015","DOIUrl":"10.1016/j.biopsych.2026.02.015","url":null,"abstract":"<div><h3>Background</h3><div>Clozapine is the gold-standard treatment for treatment-resistant schizophrenia (TRS), but its real-world effectiveness compared with other antipsychotics, including long-acting injectable antipsychotics (LAIAs), remains underevaluated. We aimed to compare hospitalization risk of patients during periods receiving clozapine versus other antipsychotics.</div></div><div><h3>Methods</h3><div>In this population-based, self-controlled case series study, we analyzed data from the Hong Kong Clinical Data Analysis and Reporting System. We included all patients with schizophrenia who initiated clozapine treatment between 2003 and 2020. Periods of clozapine exposure (initial and subsequent) were compared with periods of use of other oral antipsychotics and LAIAs (first-generation and second-generation). The primary outcome was incidence rate ratio (IRR) for psychiatric hospitalization.</div></div><div><h3>Results</h3><div>The study included 4794 patients (52.5% female; mean [SD] age 39.3 [13.3] years). Compared with other antipsychotics, clozapine use was associated with a significantly reduced risk of psychiatric hospitalization (during initial exposure: IRR, 0.21; 95% CI, 0.19–0.22; during subsequent exposure: IRR, 0.27; 95% CI, 0.26–0.29). Use of LAIAs alone was associated with a nearly 4 times higher risk of psychiatric hospitalization compared with clozapine monotherapy (IRR, 3.90; 95% CI, 3.66–4.15). Clozapine combined with second-generation LAIAs was associated with a lower risk of any hospitalization compared with clozapine alone in female patients.</div></div><div><h3>Conclusions</h3><div>Clozapine is associated with a substantially lower risk of hospitalization than other antipsychotics, including LAIAs, in patients with TRS, confirming its superior effectiveness in a real-world setting. The potential benefit of combining clozapine with second-generation LAIAs, particularly in female patients, suggests a role for stratified treatment strategies and warrants further prospective investigation.</div></div>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"100 2","pages":"Pages 170-177"},"PeriodicalIF":10.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147360546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Single, Interpretable Vocal Biomarker for Enriching Antipsychotic Clinical Trials","authors":"Alex S. Cohen,&nbsp;Brian Kirkpatrick,&nbsp;Mark Opler,&nbsp;Kazunori Tatsumi,&nbsp;Seema Bhat,&nbsp;Laxminarayan Bhat","doi":"10.1016/j.biopsych.2025.11.025","DOIUrl":"10.1016/j.biopsych.2025.11.025","url":null,"abstract":"<div><h3>Background</h3><div>Speech latency, an objective measure of verbal response time, is sensitive to cognitive, social, and motivational factors and can be measured using recordings of psychiatric interviews. Emerging evidence suggests that it can be used to enrich participants in antidepressant clinical trials, resulting in nearly double the drug-placebo effect at half the sample size. Here, we evaluated whether enrichment of participants using speech latency ratios, a variant of speech latency accounting for duration of response, improved outcomes in a clinical trial of schizophrenia.</div></div><div><h3>Methods</h3><div>Audio recordings from psychiatric interviews in a phase 3, 28-day, randomized, double-blind, placebo-controlled, fixed-dose, multicenter, parallel-group monotherapy study of brilaroxazine (RP5063) were examined. There were 2320 recordings for 406 participants with acute psychosis from 3 countries representing 8 languages.</div></div><div><h3>Results</h3><div>Speech latency ratios showed excellent internal consistency, good temporal stability, and minimal convergence with potential confounders. Patients with (vs. without) moderate-to-severe negative symptoms showed longer speech latencies, with large effect sizes observed in nearly every country and language. A single speech latency ratio value (area under the curve = 0.71) identified 180 and 228 participants as being vocal biomarker negative (VBM neg; unremarkable speech) and VBM positive (VBM pos; relatively high ratios), respectively. Brilaroxazine showed statistically significant outcomes versus placebo from baseline to end of treatment in the VBM-pos group for nearly every outcome measure despite having fewer participants. Treatment effects for VBM-pos patients were large for nearly every outcome measure.</div></div><div><h3>Conclusions</h3><div>Speech latency ratios are a face-valid, objective biomarker derived from standard clinical assessments. As an enrichment tool, it reduced sample size needs and enhanced outcomes. This has important implications for reducing clinical trial costs and burden.</div></div>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"100 2","pages":"Pages 160-169"},"PeriodicalIF":10.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Board Page","authors":"","doi":"10.1016/S0006-3223(26)01299-0","DOIUrl":"10.1016/S0006-3223(26)01299-0","url":null,"abstract":"","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"100 2","pages":"Page A1"},"PeriodicalIF":10.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148529152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabis Perturbs Dynamic Brain States","authors":"Katharina S. Lege,&nbsp;Pablo Mallaroni,&nbsp;Sepehr Mortaheb,&nbsp;Natasha L. Mason,&nbsp;Eef L. Theunissen,&nbsp;Desmond H.Y. Tse,&nbsp;Stefan W. Toennes,&nbsp;Athena Demertzi,&nbsp;Johannes G. Ramaekers","doi":"10.1016/j.biopsych.2025.10.015","DOIUrl":"10.1016/j.biopsych.2025.10.015","url":null,"abstract":"<div><h3>Background</h3><div>The impact of acute cannabis exposure on brain function and cognitive performance varies among individuals. Acute effects of cannabis on behavior may be absent or benign in chronic users, while occasional users experience significant impairment in day-to-day operations. It is hypothesized that repeated cannabis use induces neuroadaptations leading to tolerance and desensitization, although the precise mechanisms underlying these adaptations remain unclear.</div></div><div><h3>Methods</h3><div>In this study, we investigated acute and persistent effects of vaporized cannabis on brain dynamics in a placebo-controlled neuroimaging trial involving occasional (<em>n</em> = 23) and chronic (<em>n</em> = 20) cannabis users. Functional resting-state data were collected to assess dynamic functional connectivity changes during intoxication and their association with attentional performance and normative cannabinoid CB₁ receptor density.</div></div><div><h3>Results</h3><div>Cannabis intoxication induced significant acute alterations in the dynamics of brain network organization, as shown by a reduced occurrence of a hyperconnected brain state in both user groups. Chronic users also displayed decreased segregation of brain networks independent of treatment condition, suggesting persisting neuroadaptations. Dynamic reconfiguration of hyperconnected brain motifs correlated with attentional performance, which was most impaired in occasional users, indicating tolerance in chronic users. Both the acute and persistent effects of cannabis on dynamic brain state organization were significantly associated with spatial CB₁ receptor density.</div></div><div><h3>Conclusions</h3><div>Acute cannabis-induced cognitive impairment is influenced by (persistent) network reconfigurations and CB₁ receptor density. These findings emphasize the relevance of neural dynamics and individual neuroadaptations to (prolonged) cannabis use when assessing the behavioral effects of cannabis in therapeutic, legal, and societal settings.</div></div>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"100 2","pages":"Pages 219-229"},"PeriodicalIF":10.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Mechanisms by Which RhoA Activity and Associated Synaptic Effects Are Controlled by the DISC1 Scaffolding-Like Protein","authors":"Kathryn J. Bjornson,&nbsp;Michael E. Cahill","doi":"10.1016/j.biopsych.2025.11.022","DOIUrl":"10.1016/j.biopsych.2025.11.022","url":null,"abstract":"<div><h3>Background</h3><div><em>ARHGEF11</em> encodes PDZ-RhoGEF, a RhoA-specific activator enriched in dendritic spines. Profiling studies have implicated increased PDZ-RhoGEF activity in causing dysfunction of the dorsolateral prefrontal cortex in individuals with bipolar disorder, including dendritic spine loss. This suggests that biochemical mechanisms that attenuate excessive PDZ-RhoGEF activity could be critical for maintaining baseline RhoA activity and proper neural phenotypes. The DISC1 scaffolding protein is able to directly bind PDZ-RhoGEF. However, the mechanisms by which DISC1’s interaction with PDZ-RhoGEF restricts downstream RhoA activation with potential effects on dendritic spine stability remain fully unknown.</div></div><div><h3>Methods</h3><div>Enzyme activity assays, protein domain mapping, subcellular fraction, and viral-mediated gene transfer were used to delineate the biochemical mechanisms by which DISC1 controls PDZ-RhoGEF’s ability to bind to, and activate, RhoA. Imaging and analysis investigated the mechanisms by which DISC1 controls the effects of PDZ-RhoGEF on spine phenotypes.</div></div><div><h3>Results</h3><div>Here, we identified 2 biochemical processes by which PDZ-RhoGEF–mediated RhoA activation is inhibited by DISC1: 1) DISC1 sequesters RhoA from PDZ-RhoGEF, and 2) DISC1 directly reduces PDZ-RhoGEF’s catalytic activity. Furthermore, we demonstrate that interfering with DISC1’s ability to bind to PDZ-RhoGEF causes a multifold increase in RhoA activation and dendritic spine destabilization. Finally, we show that in vivo DISC1 knockdown increases the biochemical signatures of RhoA activation.</div></div><div><h3>Conclusions</h3><div>Excessive PDZ-RhoGEF–mediated RhoA activation in the prefrontal cortex has been implicated in contributing to dendritic spine loss in bipolar disorder. Thus, our mechanistic findings have potential translational significance in understanding the pathophysiology of disease-mediated dendritic spine destabilization.</div></div>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"100 2","pages":"Pages 208-218"},"PeriodicalIF":10.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Visual P300 and Risk for Psychosis Onset in Youth at Clinical High Risk","authors":"Holly K. Hamilton,&nbsp;Brian J. Roach,&nbsp;Spero Nicholas,&nbsp;Renée Dembo,&nbsp;Peter M. Bachman,&nbsp;Aysenil Belger,&nbsp;Ricardo E. Carrión,&nbsp;Erica Duncan,&nbsp;Jason K. Johannesen,&nbsp;Gregory A. Light,&nbsp;Margaret A. Niznikiewicz,&nbsp;Jean Addington,&nbsp;Carrie E. Bearden,&nbsp;Kristin S. Cadenhead,&nbsp;Diana O. Perkins,&nbsp;Elaine F. Walker,&nbsp;Scott W. Woods,&nbsp;Tyrone D. Cannon,&nbsp;Daniel H. Mathalon","doi":"10.1016/j.biopsych.2026.02.013","DOIUrl":"10.1016/j.biopsych.2026.02.013","url":null,"abstract":"<div><h3>Background</h3><div>Current clinical criteria are not sufficiently predictive of psychosis onset to inform treatment decision-making among individuals who are at clinical high risk for psychosis (CHR). Identifying biomarkers may improve outcome prediction among CHR individuals and clarify the pathogenesis of psychosis. Using data from the 8-site North American Prodrome Longitudinal Study (NAPLS-2), we examined whether visual P300 event-related potential amplitude, which is reduced in schizophrenia, is affected in CHR individuals and associated with future outcomes.</div></div><div><h3>Methods</h3><div>Five hundred thirty-eight CHR individuals and 230 healthy comparison (HC) participants completed baseline electroencephalography recording during a 3-stimulus visual oddball task. The P3b elicited by infrequent target stimuli and P3a elicited by infrequent nontarget novel stimuli were measured. CHR participants who converted to psychosis (<em>n</em> = 71) were compared with nonconverters who were followed for 24 months (<em>n</em> = 218), whose risk symptoms either persisted (<em>n</em> = 132) or remitted (<em>n</em> = 86) during follow-up.</div></div><div><h3>Results</h3><div>P300 amplitudes were modestly reduced across target (P3b) and novel (P3a) stimuli in CHR individuals compared with HCs (Cohen’s <em>d</em> = 0.14), with greater deficits observed in future CHR-converters than in CHR-nonconverters (<em>d</em> = 0.28) and HCs (<em>d</em> = 0.39). CHR-converters had reduced target P3b compared with CHR-nonconverters (<em>d</em> = 0.32) and HCs (<em>d</em> = 0.41), whereas CHR-nonconverters and HCs did not differ (<em>d</em> = 0.07). Novelty P3a was reduced in CHR-converters compared with HCs (<em>d</em> = 0.37) but not CHR-nonconverters (<em>d</em> = 0.24). Adjusting for symptom severity, greater target P3b deficits predicted earlier psychosis conversion (odds ratio, 0.76 [95% CI, 0.59–0.97], <em>p</em> = .029).</div></div><div><h3>Conclusions</h3><div>Visual target P3b deficits are associated with future psychosis conversion and the imminence of conversion, showing promise as a biomarker of psychosis onset among at-risk individuals.</div></div>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"100 2","pages":"Pages 150-159"},"PeriodicalIF":10.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147330142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ulotaront (SEP363856) Reduces Dopamine Release and Synthesis Capacity in Mice and Patients With Schizophrenia","authors":"Per Svenningsson","doi":"10.1016/j.biopsych.2026.05.007","DOIUrl":"10.1016/j.biopsych.2026.05.007","url":null,"abstract":"","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":"100 2","pages":"Pages 127-128"},"PeriodicalIF":10.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}