JAMA Psychiatry最新文献

{"title":"Links Between Toxic Exposures and Mental Health Conditions Among US Military.","authors":"Jack Tsai, Carl A Castro, Bhramar Mukherjee, Deborah A Cory-Slechta","doi":"10.1001/jamapsychiatry.2026.0879","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2026.0879","url":null,"abstract":"","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":" ","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147838083","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":"Intermittent Theta Burst Stimulation of the Dorsomedial PFC and Expectancy-Driven Placebo Mood Effects: A Randomized Clinical Trial.","authors":"Ian Snyder, Kevin Handoko, Alyssa Neppach, Gaurav Badhan, Helmet T Karim, Rebecca B Price, Fabio Ferrarelli, Alexandre Y Dombrovski, Marta Peciña","doi":"10.1001/jamapsychiatry.2026.0647","DOIUrl":"10.1001/jamapsychiatry.2026.0647","url":null,"abstract":"<p><strong>Importance: </strong>Default mode network (DMN) activity has been implicated in mechanisms of antidepressant treatment response, particularly expectancy processes that contribute to placebo effects. However, causal evidence is limited.</p><p><strong>Objective: </strong>To test whether modulating DMN function via theta burst stimulation (TBS) over the dorsomedial prefrontal cortex (PFC) alters placebo-related neural activity and expectancy-driven mood responses.</p><p><strong>Design, setting, and participants: </strong>This randomized clinical trial was conducted from October 2020 to March 2025 and represented a within-person, counterbalanced design. Adults with depressive symptoms aged 18 to 53 years not taking psychotropic medication were included in the analysis. Participants were recruited from the University of Pittsburgh Medical Center. Trial × trial expectancy and mood ratings were recorded. Data analysis was performed on a rolling basis from October 2021 to March 2025.</p><p><strong>Interventions: </strong>Three TBS sessions over the dorsomedial PFC (electroencephalogram coordinate F2; 80% resting motor threshold, 1 week apart): intermittent (iTBS), continuous (cTBS), and sham (sTBS). One hour later, they completed the antidepressant placebo functional magnetic resonance imaging (MRI) task, which manipulated anticipatory beliefs using expectancy cues and sham neurofeedback.</p><p><strong>Main outcomes and measures: </strong>Outcomes included expectancy and mood ratings during the antidepressant placebo functional MRI task and placebo-related neural activation in the DMN.</p><p><strong>Results: </strong>A total of 103 individuals were enrolled in the study. Of those enrolled, 67 completed at least 1 session, and 50 (mean [SD] age, 28.3 [9.5] years; 26 male [52.0%]) composed the final analytic sample. Voxelwise analyses showed that iTBS increased dorsomedial PFC activity relative to cTBS in the DMN (threshold-free cluster enhancement corrected P = .98). Cluster-based analyses confirmed a main effect of stimulation, with a significant monotonic pattern (iTBS > sTBS > cTBS, F2,144 = 4.55; P = .01; η2 = 0.06). In models predicting mood, greater DMN activation predicted stronger expectancy-related mood responses under iTBS compared with sTBS (β = 0.30; 95% credible interval [CrI], 0.07-0.52). In contrast, in models predicting expectancies, greater DMN activation predicted higher expectancy ratings in response to the treatment cue (β = 0.38; 95% CrI, 0.22-0.55), but this coupling was strongest under cTBS (β = -0.22; 95% CrI, -0.44 to 0), likely reflecting engagement of upstream regions. Behaviorally, cTBS increased expectancy ratings relative to the other conditions.</p><p><strong>Conclusions and relevance: </strong>Results of this randomized clinical trial show that a single session of iTBS targeting the dorsomedial PFC enhanced expectancy-related modulation of the DMN and amplified placebo-induced mood improvement. These findings imp","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":" ","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13150734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837945","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":"Adjunctive Antipsychotics in Major Depressive Disorder: A Systematic Review and Network Meta-Analysis.","authors":"Roger S McIntyre, Stephen M Stahl, Sung Ryul Shim, Maurizio Pompili, Joseph F Goldberg, Christoph U Correll, Angela T H Kwan, Christine E Dri, Heidi Xu, Maj Vinberg, Taeho Greg Rhee","doi":"10.1001/jamapsychiatry.2026.0658","DOIUrl":"10.1001/jamapsychiatry.2026.0658","url":null,"abstract":"<p><strong>Importance: </strong>Most adults living with major depressive disorder (MDD) fail to achieve remission with conventional antidepressants. The US Food and Drug Administration (FDA) has approved 5 atypical antipsychotics in MDD on the basis of their substantial evidence of efficacy and safety.</p><p><strong>Objective: </strong>To compare the efficacy and acceptability of FDA-approved atypical antipsychotics for the adjunctive treatment of MDD in order to provide decision support to practitioners and persons with lived experience.</p><p><strong>Data sources: </strong>A systematic search was conducted using PubMed/MEDLINE, PsycINFO, the Cochrane Library, and Embase from database inception through July 15, 2025.</p><p><strong>Study selection: </strong>Six independent raters screened publications for eligibility. Inclusion criteria were atypical antipsychotics that are FDA approved in the adjunctive treatment of MDD.</p><p><strong>Data extraction and synthesis: </strong>Two independent raters obtained data and examined risk of bias in accordance with the Cochrane criteria. Effect sizes were synthesized using random-effects models. Data were analyzed from August to September 2025.</p><p><strong>Main outcomes and measures: </strong>The primary outcomes were efficacy (ie, ≥50% reduction from baseline in the total Montgomery-Åsberg Depression Rating Scale [MADRS] score) and acceptability (ie, all-cause discontinuation).</p><p><strong>Results: </strong>A total of 22 short-term studies comprising 10 962 participants (aripiprazole: n = 1297; brexpiprazole: n = 1973; cariprazine: n = 1894; lumateperone: n = 483; quetiapine extended release [XR]: n = 719; and placebo: n = 4596) were included for analysis. Lumateperone had the highest effect size for efficacy (risk ratio [RR], 1.72; 95% credible interval [CrI], 1.40-2.15), followed by aripiprazole (RR, 1.53; 95% CrI, 1.32-1.77), brexpiprazole (RR, 1.38; 95% CrI, 1.18-1.65), cariprazine (RR, 1.20; 95% CrI, 1.07-1.36), and quetiapine XR (RR, 1.15; 95% CrI, 0.96-1.35). A hierarchy of acceptability was observed, with aripiprazole exhibiting the highest acceptability (RR, 1.16; 95% CrI, 0.89-1.50), followed by cariprazine (RR, 1.44; 95% CrI, 1.15-1.82), brexpiprazole (RR, 1.47; 95% CrI, 1.18-1.85), quetiapine XR (RR, 1.56; 95% CrI, 1.14-2.12), and lumateperone (RR, 2.30; 95% CrI, 1.45-3.84). Secondary outcomes (eg, symptomatic remission) and exploratory outcomes (eg, clinically significant weight gain) accorded with the coprimary outcomes.</p><p><strong>Conclusions and relevance: </strong>This systematic review and meta-analysis indicates that differences exist between adjunctive atypical antipsychotics in the treatment of MDD with respect to overall efficacy and acceptability, which should be simultaneously considered. The absence of adequate and well-controlled studies documenting maintenance efficacy of adjunctive atypical antipsychotics in MDD remains a knowledge gap.</p>","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":" ","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13150735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837862","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":"Ketamine Infusions and Rapid Reduction of Suicidal and Depressive Symptoms in Major Depressive Episode: A Systematic Review and Meta-Analysis.","authors":"Sung Ryul Shim, Hye Su Jeong, Tanner J Bommersbach, Andrew A Nierenberg, Carlos A Zarate, Tyler S Kaster, Christoph U Correll, Roger S McIntyre, John H Krystal, Taeho Greg Rhee","doi":"10.1001/jamapsychiatry.2026.0612","DOIUrl":"10.1001/jamapsychiatry.2026.0612","url":null,"abstract":"<p><strong>Importance: </strong>While intravenous ketamine is not approved by the US Food and Drug Administration, it is increasingly used with off-label indications as a novel treatment for suicidal and depressive symptoms.</p><p><strong>Objective: </strong>To systematically review and metasynthesize the efficacy and safety data for intravenous ketamine in treating major depressive episodes (MDEs).</p><p><strong>Data sources: </strong>PubMed, PsycInfo, Cochrane Library, and Embase were systematically searched from database inception through November 7, 2025, with no language limits.</p><p><strong>Study selection: </strong>Randomized clinical trials (RCTs) with (1) diagnosis of an MDE; (2) intervention and comparator groups consisting of intravenous ketamine and controls (eg, saline or midazolam); and (3) suicidal and depressive symptoms as efficacy outcomes were included.</p><p><strong>Data extraction and synthesis: </strong>Hedges g standardized mean differences (SMDs) were used to analyze improvement in suicidal and depressive symptoms using random-effects models. Multiple subgroup analyses were also conducted.</p><p><strong>Main outcomes and measures: </strong>The main outcomes included the following: (1) changes in suicidal and depressive symptoms; (2) response and remission rates of depressive symptoms; and (3) safety measures (eg, adverse events and serious adverse events).</p><p><strong>Results: </strong>A total of 26 RCTs comprising 1166 patients with an MDE (n = 626 receiving ketamine and n = 540 as control patients) were included. For suicidal symptoms, patients receiving a single ketamine infusion, compared with control patients, had significantly lower symptoms at 24 hours (SMD, -0.69 [95% CI, -0.98 to -0.40]) and at 1 month (SMD, -0.70 [95% CI, -1.17 to -0.24]). Those with repeated ketamine infusions showed a similar reduction of suicidal symptoms at the end of the treatment (SMD, -0.72 [95% CI, -1.00 to -0.43]). For depressive symptoms, significant reductions were shown at 4 hours (SMD, -1.74 [95% CI, -2.43 to -1.06]), 24 hours (SMD, -1.15 [95% CI, -1.58 to -0.72]), 3 days (SMD, -0.97 [95% CI, -1.73 to -0.20]), and 1 week (SMD, -0.89 [95% CI, -1.65 to -0.13]) after a single ketamine infusion and at the end of the treatment after repeated infusions (SMD, -0.81 [95% CI, -1.16 to -0.46]). Reported serious adverse events (eg, hospitalizations and deaths) were unrelated to the interventions, and other adverse events (eg, headache) were transient and resolved during the trials.</p><p><strong>Conclusions and relevance: </strong>The findings of this systematic review and meta-analysis suggest that single and repeated intravenous ketamine infusions are efficacious in reducing suicidal and depressive symptoms in patients with an MDE in the acute phase, while longer-term outcomes are not well established.</p>","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":" ","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13150733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147838125","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 Closer Look at Ketogenic Diet Effects in Depression.","authors":"Karyn Richardson, Tetyana Rocks, Adrienne O'Neil","doi":"10.1001/jamapsychiatry.2026.0947","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2026.0947","url":null,"abstract":"","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":" ","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837896","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 Closer Look at Ketogenic Diet Effects in Depression.","authors":"Jan Stubberud","doi":"10.1001/jamapsychiatry.2026.0944","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2026.0944","url":null,"abstract":"","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":" ","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837928","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 Developmentally Informed Study of Sleep and Circadian Polygenic Scores in Adolescence.","authors":"Katie J S Lewis, Joanna Martin, Jon Heron, Lucy Riglin, Frances Rice, Michael C O'Donovan, Alice M Gregory","doi":"10.1001/jamapsychiatry.2025.4647","DOIUrl":"10.1001/jamapsychiatry.2025.4647","url":null,"abstract":"<p><strong>Importance: </strong>Genome-wide association studies (GWAS) of sleep and circadian phenotypes have identified common genetic variants associated with these phenotypes in adults, but the relevance of these findings for younger age groups is unclear. It is important to determine whether genetic variants identified in these studies also index sleep phenotypes in adolescence, a time where sleep problems often emerge and have high heritability.</p><p><strong>Objective: </strong>To examine whether polygenic scores, calculated using results from adult sleep/circadian GWAS, index corresponding sleep phenotypes in adolescents.</p><p><strong>Design, setting, and participants: </strong>Data were from 3903 adolescents (1820 males, 2083 females) with genetic and sleep questionnaire data available at 15 years of age who were participants in the Avon Longitudinal Study of Parents and Children (ALSPAC), an ongoing, longitudinal, population-based birth cohort study. Data were analyzed for the current study from August 19, 2024, to March 28, 2025.</p><p><strong>Exposures: </strong>Polygenic scores were derived using summary statistics from large adult GWAS of sleep duration, insomnia, daytime sleepiness, napping, and chronotype.</p><p><strong>Main outcomes and measures: </strong>The following self-reported sleep phenotypes were assessed via questionnaire: sleep duration, sleep onset latency, chronotype, insomnia symptoms, and napping. Associations between polygenic scores with corresponding phenotypes in adolescence were analyzed using logistic or linear regression. Secondary analyses examined whether associations differed by sex or school nights vs weekends.</p><p><strong>Results: </strong>Polygenic scores were associated with corresponding sleep phenotypes in adolescence for sleep duration (B = 0.04 [95% CI, 0.02-0.07] hours; P = .002), insomnia symptoms (odds ratio [OR], 1.16 [95% CI, 1.09-1.25]; P = 1.18 × 10-5), napping (OR, 1.37 [95% CI, 1.26-1.49]; P = 8.11 × 10-13), chronotype (B = -0.13 [95% CI, -0.16 to -0.10] hours; P = 6.91 × 10-16), and daytime sleepiness (OR, 1.08 [95% CI, 1.01-1.15]; P = .02). Associations did not substantially differ by sex or by school nights/weekends, except for napping, the effect estimate for weekends was smaller than on school days.</p><p><strong>Conclusions and relevance: </strong>Results of this study suggest overlap in the genetic etiology of sleep and circadian phenotypes in adolescence and adulthood. This has importance for studies using genomic designs for causal inference about sleep and understanding of the extent to which genetic influences vary across the lifespan. Future research, including larger GWAS across developmental periods, is required to further understand genetic influences on sleep across the lifespan, as well as environmental influences on adolescent sleep disturbances.</p>","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":" ","pages":"523-528"},"PeriodicalIF":17.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12936963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283856","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":"Mapping ADHD Heterogeneity and Biotypes by Topological Deviations in Morphometric Similarity Networks.","authors":"Nanfang Pan, Yajing Long, Kun Qin, Isaac Z Pope, Qiuxing Chen, Ziyu Zhu, Ying Cao, Lei Li, Manpreet K Singh, Robert K McNamara, Melissa P DelBello, Ying Chen, Alex Fornito, Qiyong Gong","doi":"10.1001/jamapsychiatry.2026.0001","DOIUrl":"10.1001/jamapsychiatry.2026.0001","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;Attention-deficit/hyperactivity disorder (ADHD) is characterized by considerable clinical heterogeneity, and existing classification frameworks constrain the development of neurobiologically informed subtyping approaches.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To investigate whether normative modeling of topological properties derived from brain morphometry similarity networks can provide robust stratification markers for children with ADHD.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Design, settings, and participants: &lt;/strong&gt;This case-control study leveraged multisite cross-sectional neurodevelopmental datasets with a longitudinal follow-up cognitive assessment for a subset. Morphometric similarity networks were constructed and normative models were developed for 3 topological metrics: degree centrality, nodal efficiency, and participation coefficient. Through semisupervised clustering, putative biotypes were delineated and their clinical profiles were examined. Brain profiles of these biotypes were further contextualized in terms of their neurochemical and functional correlates using large-scale databases, and model generalizability was assessed with external validation performed in an independent transdiagnostic cohort. Study data were analyzed from November 2023 to January 2025.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Exposures: &lt;/strong&gt;Normative modeling of topological properties derived from brain morphometry.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main outcomes and measures: &lt;/strong&gt;Topological deviations in morphometric similarity networks derived from brain structural image.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The discovery cohort comprised 446 children with ADHD (mean [SD] age, 11.5 [2.6] years; 339 male [76.0%]) and 708 controls (mean [SD] age, 11.0 [2.3] years; 429 male [60.6%]), whereas the validation cohort included 554 children with ADHD (mean [SD] age, 10.1 [2.8]; 372 male [67.1%]) and 123 controls (mean [SD] age, 10.1 [3.0]; 70 male [56.9%]). ADHD exhibited atypical hub organization across all 3 topological metrics, with significant case-control differences primarily localized to a covarying multimetric component in the orbitofrontal cortex. Three biotypes emerged: severe-combined with emotional dysregulation (widespread medial prefrontal cortex-pallidum alterations, n = 142), predominantly hyperactive/impulsive (anterior cingulate cortex-pallidum circuit alterations, n = 177), and predominantly inattentive (superior frontal gyrus alterations, n = 127), each characterized by distinct clinical profiles and longitudinal trajectories. These neural profiles of each biotype showed distinct neurochemical and functional correlates. Critically, the core findings were replicated in the validation cohort, demonstrating robust generalizability.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions and relevance: &lt;/strong&gt;Results of this case-control study reveal that the integration of normative modeling with semisupervised clustering provided both dimensional and categorical insights into ADHD heterogeneity, identifyin","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":" ","pages":"478-490"},"PeriodicalIF":17.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12936971/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283854","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 Year in Review, 2025.","authors":"Dost Öngür","doi":"10.1001/jamapsychiatry.2026.0279","DOIUrl":"10.1001/jamapsychiatry.2026.0279","url":null,"abstract":"","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":" ","pages":"443-444"},"PeriodicalIF":17.1,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147473796","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":"Semaglutide and Effort-Based Decision-Making in Major Depressive Disorder: A Randomized Clinical Trial.","authors":"Hartej Gill,Sebastian Badulescu,Hiya Shah,Ryan M Brudner,Lee Phan,Joshua D Di Vincenzo,Aniqa Tabassum,Sharmili Edwin Thanarajah,Cristian-Daniel Llach,Joshua D Rosenblat,Roger S McIntyre,Rodrigo B Mansur","doi":"10.1001/jamapsychiatry.2026.0594","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2026.0594","url":null,"abstract":"ImportanceConsistent results from preclinical and clinical studies indicate that activation of glucagon-like peptide-1 receptors (GLP-1 Rs) affects reward processes; however, to our knowledge, no study has previously evaluated whether a GLP-1 R agonist (GLP-1 RA) affects motivated behavior in individuals with major depressive disorder (MDD) in a randomized clinical trial.ObjectiveTo assess the effects of a GLP-1 RA, semaglutide, on reward-related dysfunction in a population with MDD.Design, Setting, and ParticipantsThis study was a 16-week, double-blind, placebo-controlled, parallel-group randomized clinical trial. A total of 72 participants with a diagnosis of MDD and a body mass index (calculated as weight in kilograms divided by height in meters squared) of 25 or higher were randomized to oral semaglutide (n = 35) or placebo (n = 37). Participants were recruited from the Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, a university-based mood disorders program. Participants were enrolled between March 14, 2022, and July 26, 2024. Data analysis was performed from January 7, 2025, through February 3, 2025.InterventionPatients were randomized 1:1 to receive placebo or oral semaglutide, 14 mg (initiated at 4 mg and titrated using a 4-week dose-escalation regimen), adjunctive to their treatment as usual.Main Outcome and MeasureThe preregistered outcome of this secondary analysis was performance on the Effort-Expenditure for Rewards Task (EEfRT).ResultsA total of 72 participants were randomized to oral semaglutide (n = 35 [49.7%]; mean [SD] age, 38.17 [11.79] years; 18 female participants [51.4%]) or placebo (n = 37 [51.3%]; mean [SD] age, 40.27 [9.32] years; 19 female participants [51.3%]). Semaglutide-treated participants exhibited a pattern of increased willingness to exert physical efforts with higher expected values of reward (treatment × visit × expected value interaction: χ2 = 12.024; P = .02). Computational modeling indicated that semaglutide's effects on choice behavior were a result of reduced effort discounting. Sensitivity to effort was significantly reduced by treatment with semaglutide (β = -1.737; P = .03), whereas there was no treatment effect on sensitivity to probability (β = -0.776; P = .51).Conclusions and RelevanceIn this secondary analysis of a double-blind randomized clinical trial, treatment with semaglutide significantly improved measures of motivation in patients with MDD. Semaglutide reduced the perceived cost of effort, relative to the monetary reward; the results of this trial have implications for the treatment of multiple neuropsychiatric disorders, which are characterized by varied reward dysfunctions.Trial RegistrationClinicalTrials.gov Identifier: NCT04466345.","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"2 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754952","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}