Pub Date : 2026-03-25DOI: 10.1001/jamapsychiatry.2026.0096
Wiesław J. Cubała, Malek Bajbouj, Michael Bauer, Bernhard T. Baune, Narcís Cardoner, Fabian Devlin, Kelly Doolin, Rosa Maria Dueñas Herrero, Matilde Elices, Avril Feeney, Maria Gałuszko-Węgielnik, Katarzyna Jakuszkowiak-Wojten, Luboš Janů, John R. Kelly, Kathryn Ledden, Rachael Maclsaac, Santiago Madero, Shane J. McInerney, Angel L. Montejo, Alexander Nawka, Tomáš Páleníček, Víctor Pérez Solà, Johannes G. Ramaekers, Andreas Reif, Philipp Ritter, Fiona Ryan, Claus Bo Svendsen, Claire Sweeney, Theis H. Terwey, Madhukar H. Trivedi, Velichka Valcheva, Eduard Vieta, Michael E. Thase
Importance Few pharmacotherapies are approved for treatment-resistant depression, and many patients do not achieve remission following treatment with those therapies. Objective To examine the efficacy and safety of single-day treatment with a synthetic formulation of inhaled mebufotenin (GH001) vs placebo in patients with treatment-resistant depression. Design, Setting, and Participants This was a 7-day, randomized, double-blind, placebo-controlled phase 2b trial with a 6-month open-label extension phase conducted at 16 sites in Europe from May 2023 to March 2025. Adult patients aged 18 to 64 years with treatment-resistant depression, defined as nonresponse to 2 to 5 oral antidepressant treatments, with current episode duration of up to 2 years were included. Of 128 assessed for eligibility, 81 were randomized and completed the placebo-controlled period of the trial. Interventions Patients were randomly assigned 1:1 to receive an individualized dosing regimen of up to 3 escalating doses of GH001 (6, 12, and 18 mg) or a placebo individualized dosing regimen on a single day (day 1). Main Outcomes and Measures The primary efficacy end point was the change from baseline to day 8 in Montgomery-Åsberg Depression Rating Scale total score (range, 0-60; higher scores indicate greater severity of depression), comparing GH001 with placebo. Secondary end points included remission (Montgomery-Åsberg Depression Rating Scale score ≤10) at day 8. Results Among the 81 patients randomized to GH001 (n = 40) or placebo (n = 41), the mean (SD) age was 41.6 (11.4) years and 43.9 (10.9) years and 24 (60.0%) and 22 (53.7%) were female, respectively. Change in Montgomery-Åsberg Depression Rating Scale score from baseline to day 8 was significantly greater for GH001 vs placebo (least squares mean difference [SE], −15.5 [1.7]; P < .001; effect size, −2.0). Day 8 remission rates were 23/40 (57.5%) with GH001 and 0/41 (0%) with placebo. No severe or serious adverse events were reported in the placebo-controlled period. Conclusions and Relevance In this study, an individualized dosing regimen of inhaled GH001 resulted in significant improvements in depression symptoms relative to placebo and was well tolerated, supporting its potential as a novel, rapid-acting treatment for treatment-resistant depression. Trial Registration ClinicalTrials.gov Identifier: NCT05800860
{"title":"GH001 vs Placebo in Patients With Treatment-Resistant Depression","authors":"Wiesław J. Cubała, Malek Bajbouj, Michael Bauer, Bernhard T. Baune, Narcís Cardoner, Fabian Devlin, Kelly Doolin, Rosa Maria Dueñas Herrero, Matilde Elices, Avril Feeney, Maria Gałuszko-Węgielnik, Katarzyna Jakuszkowiak-Wojten, Luboš Janů, John R. Kelly, Kathryn Ledden, Rachael Maclsaac, Santiago Madero, Shane J. McInerney, Angel L. Montejo, Alexander Nawka, Tomáš Páleníček, Víctor Pérez Solà, Johannes G. Ramaekers, Andreas Reif, Philipp Ritter, Fiona Ryan, Claus Bo Svendsen, Claire Sweeney, Theis H. Terwey, Madhukar H. Trivedi, Velichka Valcheva, Eduard Vieta, Michael E. Thase","doi":"10.1001/jamapsychiatry.2026.0096","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2026.0096","url":null,"abstract":"Importance Few pharmacotherapies are approved for treatment-resistant depression, and many patients do not achieve remission following treatment with those therapies. Objective To examine the efficacy and safety of single-day treatment with a synthetic formulation of inhaled mebufotenin (GH001) vs placebo in patients with treatment-resistant depression. Design, Setting, and Participants This was a 7-day, randomized, double-blind, placebo-controlled phase 2b trial with a 6-month open-label extension phase conducted at 16 sites in Europe from May 2023 to March 2025. Adult patients aged 18 to 64 years with treatment-resistant depression, defined as nonresponse to 2 to 5 oral antidepressant treatments, with current episode duration of up to 2 years were included. Of 128 assessed for eligibility, 81 were randomized and completed the placebo-controlled period of the trial. Interventions Patients were randomly assigned 1:1 to receive an individualized dosing regimen of up to 3 escalating doses of GH001 (6, 12, and 18 mg) or a placebo individualized dosing regimen on a single day (day 1). Main Outcomes and Measures The primary efficacy end point was the change from baseline to day 8 in Montgomery-Åsberg Depression Rating Scale total score (range, 0-60; higher scores indicate greater severity of depression), comparing GH001 with placebo. Secondary end points included remission (Montgomery-Åsberg Depression Rating Scale score ≤10) at day 8. Results Among the 81 patients randomized to GH001 (n = 40) or placebo (n = 41), the mean (SD) age was 41.6 (11.4) years and 43.9 (10.9) years and 24 (60.0%) and 22 (53.7%) were female, respectively. Change in Montgomery-Åsberg Depression Rating Scale score from baseline to day 8 was significantly greater for GH001 vs placebo (least squares mean difference [SE], −15.5 [1.7]; <jats:italic>P</jats:italic> &amp;lt; .001; effect size, −2.0). Day 8 remission rates were 23/40 (57.5%) with GH001 and 0/41 (0%) with placebo. No severe or serious adverse events were reported in the placebo-controlled period. Conclusions and Relevance In this study, an individualized dosing regimen of inhaled GH001 resulted in significant improvements in depression symptoms relative to placebo and was well tolerated, supporting its potential as a novel, rapid-acting treatment for treatment-resistant depression. Trial Registration ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"https://clinicaltrials.gov/study/NCT05800860\">NCT05800860</jats:ext-link>","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"23 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506869","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}
Pub Date : 2026-03-25DOI: 10.1001/jamapsychiatry.2026.0152
Colm Healy, Kirstie O’Hare, Ulla Lång, Johanna Metsälä, Anna Pulakka, Jane McGrath, Maria Migone, Dolores Keating, Liana Romaniuk, David Gyllenberg, Eero Kajantie, George Perrett, Jennifer Hill, Felix Elwert, Ian Kelleher
Importance Methylphenidate is the leading pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD) in childhood and adolescence. Individuals with ADHD have a higher risk of psychosis, but the long-term relationship between methylphenidate and risk of developing psychotic disorders is unknown. Objective To estimate the relationship between methylphenidate treatment and the risk of nonaffective psychosis in children and adolescents diagnosed with ADHD. Design, Setting, and Participants This cohort study included instrumental variable analysis of data linkage from multiple national Finnish registries for all individuals born from 1987 to 1997 (n = 697 289). These registries were used to identify childhood and adolescent ADHD diagnoses (age &lt;18 years) from 2003 onwards. Data were analyzed from June 2023 to December 2025. Exposure Cumulative amount of treatment with methylphenidate used in 4 intervention windows: within 1, 2, 3, and 4 years after ADHD diagnosis. Hospital district prescribing propensities (average prescribing within each hospital district, within each intervention window) were used as instruments. Main Outcome and Measures Diagnosis of nonaffective psychotic disorder (by code from <jats:italic toggle="yes">International Statistical Classification of Diseases and Related Health Problems, Tenth Revision</jats:italic> ) by the end of follow-up (December 31, 2016). Instrumental variable analyses were conducted using 2-stage least squares modeling and the Anderson-Rubin test. Risk differences (RDs) were estimated for each intervention window. Results Among 3956 individuals diagnosed with ADHD (3181 male [80.4%], 775 female [19.6%]; median [IQR] age, 14.16 [11.78-15.93] years), 2728 (69.0%) received methylphenidate at least once. A total of 222 individuals (5.7%) were diagnosed with nonaffective psychosis by mean (SD) age 22.16 (2.39) years (range, 19.00-29.81 years). There was substantial variation in hospital district prescribing propensity (for example, first-year range, 0.07 to 0.30). Instrumental variable analysis indicated that sustained treatment with methylphenidate (30 mg/d) was not associated with the risk of nonaffective psychosis in the overall ADHD sample (1-year RD, −0.14; 95% CI, −0.85 to 0.42; and 4-year RD, −0.15; 95% CI, −0.49 to 0.11). Secondary analyses indicated a reduced risk of nonaffective psychosis among individuals diagnosed in childhood (age &lt;13 years: 3-year RD, –0.24; 95% CI, –0.45 to –0.03; <jats:italic toggle="yes">P</jats:italic> = .03; 4-year RD, –0.21; 95% CI, –0.48 to –0.07; <jats:italic toggle="yes">P</jats:italic> = .02). An insufficiently strong instrument precluded the same secondary analyses in those diagnosed in adolescence. Conclusion and Relevance This study of national Finnish registry data for individuals with ADHD found no overall relationship between sustained treatment with methylphenidate risk of nonaffective psychosis; in secondary analyses, a potent
{"title":"Methylphenidate Treatment and Risk of Psychotic Disorder","authors":"Colm Healy, Kirstie O’Hare, Ulla Lång, Johanna Metsälä, Anna Pulakka, Jane McGrath, Maria Migone, Dolores Keating, Liana Romaniuk, David Gyllenberg, Eero Kajantie, George Perrett, Jennifer Hill, Felix Elwert, Ian Kelleher","doi":"10.1001/jamapsychiatry.2026.0152","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2026.0152","url":null,"abstract":"Importance Methylphenidate is the leading pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD) in childhood and adolescence. Individuals with ADHD have a higher risk of psychosis, but the long-term relationship between methylphenidate and risk of developing psychotic disorders is unknown. Objective To estimate the relationship between methylphenidate treatment and the risk of nonaffective psychosis in children and adolescents diagnosed with ADHD. Design, Setting, and Participants This cohort study included instrumental variable analysis of data linkage from multiple national Finnish registries for all individuals born from 1987 to 1997 (n = 697 289). These registries were used to identify childhood and adolescent ADHD diagnoses (age &amp;lt;18 years) from 2003 onwards. Data were analyzed from June 2023 to December 2025. Exposure Cumulative amount of treatment with methylphenidate used in 4 intervention windows: within 1, 2, 3, and 4 years after ADHD diagnosis. Hospital district prescribing propensities (average prescribing within each hospital district, within each intervention window) were used as instruments. Main Outcome and Measures Diagnosis of nonaffective psychotic disorder (by code from <jats:italic toggle=\"yes\">International Statistical Classification of Diseases and Related Health Problems, Tenth Revision</jats:italic> ) by the end of follow-up (December 31, 2016). Instrumental variable analyses were conducted using 2-stage least squares modeling and the Anderson-Rubin test. Risk differences (RDs) were estimated for each intervention window. Results Among 3956 individuals diagnosed with ADHD (3181 male [80.4%], 775 female [19.6%]; median [IQR] age, 14.16 [11.78-15.93] years), 2728 (69.0%) received methylphenidate at least once. A total of 222 individuals (5.7%) were diagnosed with nonaffective psychosis by mean (SD) age 22.16 (2.39) years (range, 19.00-29.81 years). There was substantial variation in hospital district prescribing propensity (for example, first-year range, 0.07 to 0.30). Instrumental variable analysis indicated that sustained treatment with methylphenidate (30 mg/d) was not associated with the risk of nonaffective psychosis in the overall ADHD sample (1-year RD, −0.14; 95% CI, −0.85 to 0.42; and 4-year RD, −0.15; 95% CI, −0.49 to 0.11). Secondary analyses indicated a reduced risk of nonaffective psychosis among individuals diagnosed in childhood (age &amp;lt;13 years: 3-year RD, –0.24; 95% CI, –0.45 to –0.03; <jats:italic toggle=\"yes\">P</jats:italic> = .03; 4-year RD, –0.21; 95% CI, –0.48 to –0.07; <jats:italic toggle=\"yes\">P</jats:italic> = .02). An insufficiently strong instrument precluded the same secondary analyses in those diagnosed in adolescence. Conclusion and Relevance This study of national Finnish registry data for individuals with ADHD found no overall relationship between sustained treatment with methylphenidate risk of nonaffective psychosis; in secondary analyses, a potent","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"10 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506836","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}
Pub Date : 2026-03-18DOI: 10.1001/jamapsychiatry.2026.0070
James I Hudson,Harrison G Pope
{"title":"Enlightenment in a Pill-Testing the Efficacy of Psilocybin.","authors":"James I Hudson,Harrison G Pope","doi":"10.1001/jamapsychiatry.2026.0070","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2026.0070","url":null,"abstract":"","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"4 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471634","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}
Pub Date : 2026-03-18DOI: 10.1001/jamapsychiatry.2026.0279
Dost Öngür
{"title":"The Year in Review, 2025.","authors":"Dost Öngür","doi":"10.1001/jamapsychiatry.2026.0279","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2026.0279","url":null,"abstract":"","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":" ","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-03-18","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}
Pub Date : 2026-03-18DOI: 10.1001/jamapsychiatry.2025.4809
Zachary J Williams,Hannah Barnett,Balázs Szigeti
ImportancePsychedelic-assisted therapy (PAT) trials have high levels of functional unblinding, which biases results when comparing PAT with blinded interventions. Because PAT is effectively always open label, treatment results should be compared with those of open-label traditional antidepressants (TADs), so potential benefits associated with patients knowing their treatment is equal between the interventions.ObjectiveTo investigate the comparative effectiveness of PAT vs open-label traditional antidepressants (TADs; such as selective serotonin and norepinephrine reuptake inhibitors) for the treatment of major depression.Data SourcesPubMed was systematically searched in March 2024 for trials of PAT and open-label TADs for the treatment of major depression without comorbidity in adults without psychosis in the outpatient setting. Extraction was supplemented with data from a review and meta-analysis of antidepressant drugs to assess the open-label vs blinded TAD difference.Data Extraction and SynthesisDepression scores were extracted by 2 independent reviewers; estimates were pooled with both bayesian and frequentist mixed-effects models. Reporting follows the PRISMA guideline.Main Outcomes and MeasureFollowing predefined hypotheses, the mean within-arm effect from baseline to primary end point (ie, patient improvement between PAT and open-label TAD trials on the 17-item Hamilton Depression Rating Scale) was compared. To assess the potential role of blinding, the within-arm effect of blinded vs open-label trials in both PAT and TADs was also compared.ResultsOf the initially retrieved PubMed 619 records, 24 met inclusion criteria. Contrary to the first of 3 hypotheses, PAT (8 trials; 249 patients) was no more effective than open-label TAD treatment (16 open-label TAD trials; 7921 patients), with an estimated difference of 0.3 favoring open-label TADs (95% CI, -1.39 to 1.98; P = .73). Open-label TADs were associated with better outcomes than blinded treatment (144 blinded TAD trials; 31 792 patients), with an estimated difference of 1.3 (95% CI, 0.07-2.51; P = .04;), but the same difference was not observed for PAT (0.67; 95% CI, -3.08 to 1.73; P = .58).Conclusions and RelevanceIn trials of depression, PAT was not more effective than open-label TADs. Blinding made a difference for TADs, but not for PAT, confirming that PAT trials are effectively always open label. These results argue against highly optimistic narratives surrounding PAT and highlight the importance of blinding integrity.
{"title":"Psychedelic Therapy vs Antidepressants for the Treatment of Depression Under Equal Unblinding Conditions: A Systematic Review and Meta-Analysis.","authors":"Zachary J Williams,Hannah Barnett,Balázs Szigeti","doi":"10.1001/jamapsychiatry.2025.4809","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.4809","url":null,"abstract":"ImportancePsychedelic-assisted therapy (PAT) trials have high levels of functional unblinding, which biases results when comparing PAT with blinded interventions. Because PAT is effectively always open label, treatment results should be compared with those of open-label traditional antidepressants (TADs), so potential benefits associated with patients knowing their treatment is equal between the interventions.ObjectiveTo investigate the comparative effectiveness of PAT vs open-label traditional antidepressants (TADs; such as selective serotonin and norepinephrine reuptake inhibitors) for the treatment of major depression.Data SourcesPubMed was systematically searched in March 2024 for trials of PAT and open-label TADs for the treatment of major depression without comorbidity in adults without psychosis in the outpatient setting. Extraction was supplemented with data from a review and meta-analysis of antidepressant drugs to assess the open-label vs blinded TAD difference.Data Extraction and SynthesisDepression scores were extracted by 2 independent reviewers; estimates were pooled with both bayesian and frequentist mixed-effects models. Reporting follows the PRISMA guideline.Main Outcomes and MeasureFollowing predefined hypotheses, the mean within-arm effect from baseline to primary end point (ie, patient improvement between PAT and open-label TAD trials on the 17-item Hamilton Depression Rating Scale) was compared. To assess the potential role of blinding, the within-arm effect of blinded vs open-label trials in both PAT and TADs was also compared.ResultsOf the initially retrieved PubMed 619 records, 24 met inclusion criteria. Contrary to the first of 3 hypotheses, PAT (8 trials; 249 patients) was no more effective than open-label TAD treatment (16 open-label TAD trials; 7921 patients), with an estimated difference of 0.3 favoring open-label TADs (95% CI, -1.39 to 1.98; P = .73). Open-label TADs were associated with better outcomes than blinded treatment (144 blinded TAD trials; 31 792 patients), with an estimated difference of 1.3 (95% CI, 0.07-2.51; P = .04;), but the same difference was not observed for PAT (0.67; 95% CI, -3.08 to 1.73; P = .58).Conclusions and RelevanceIn trials of depression, PAT was not more effective than open-label TADs. Blinding made a difference for TADs, but not for PAT, confirming that PAT trials are effectively always open label. These results argue against highly optimistic narratives surrounding PAT and highlight the importance of blinding integrity.","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"190 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471637","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}
Pub Date : 2026-03-18DOI: 10.1001/jamapsychiatry.2026.0246
Roger D Weiss,Edward V Nunes,Scott E Provost
{"title":"Research Ethics in Stopping Opioid Use Disorder Medication.","authors":"Roger D Weiss,Edward V Nunes,Scott E Provost","doi":"10.1001/jamapsychiatry.2026.0246","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2026.0246","url":null,"abstract":"","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"14 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471635","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}
Pub Date : 2026-03-18DOI: 10.1001/jamapsychiatry.2026.0144
Sofie von Känel,Anastasia Pavlidou,Niluja Nadesalingam,Victoria Chapellier,Melanie G Nuoffer,Lydia Maderthaner,Alexandra Kyrou,Alexios Malifatouratzis,Florian Wüthrich,Stephanie Lefebvre,Victor Pokorny,Zachary Anderson,Stewart A Shankman,Vijay A Mittal,Sebastian Walther
{"title":"Transdiagnostic Patterns of Grip Strength in Schizophrenia, Current Depression, and Remitted Depression.","authors":"Sofie von Känel,Anastasia Pavlidou,Niluja Nadesalingam,Victoria Chapellier,Melanie G Nuoffer,Lydia Maderthaner,Alexandra Kyrou,Alexios Malifatouratzis,Florian Wüthrich,Stephanie Lefebvre,Victor Pokorny,Zachary Anderson,Stewart A Shankman,Vijay A Mittal,Sebastian Walther","doi":"10.1001/jamapsychiatry.2026.0144","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2026.0144","url":null,"abstract":"","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"17 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471636","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}
ImportancePsilocybin shows promise in treating depression, although limitations of previous research warrant further research.ObjectiveTo investigate the efficacy and safety of oral psilocybin, 25 mg, with adjunct psychotherapy in treatment-resistant depression (TRD).Design, Setting, and ParticipantsThis was a 2-center, triple-blinded (investigator, participant, rater), phase 2b, active placebo-controlled randomized clinical trial. Participants were randomized to 4 groups in ratios 2:2:1:1, receiving 2 doses 6 weeks apart (week 0, week 6) as follows: (1) placebo (nicotinamide, 100 mg) then psilocybin, 25 mg; (2) psilocybin, 5 mg, then 25 mg; and (3) psilocybin, 25 mg, then 5 mg or psilocybin, 25 mg, twice embedded in psychotherapeutic sessions. Participants aged 25 to 65 years with TRD and withdrawn from antidepressant medication were recruited predominantly from 2 outpatient settings in Germany. Study data were analyzed from April 2024 to November 2025.InterventionsOral synthetic psilocybin, 25 mg; psilocybin, 5 mg; or nicotinamide, 100 mg administered with psychotherapeutic sessions.Main Outcomes and MeasuresThe primary end point was treatment response (≥50% reduction on the Hamilton Rating Scale for Depression [HAMD17]) at week 6 before the second dose. Key secondary end points were response on the Beck Depression Inventory II (BDI-II) and mean change from baseline on the HAMD17 and BDI-II at week 6.ResultsA total of 144 participants (mean [SD] age, 42.6 [10.8] years; 85 male [59.0%]) were randomized, and 142 were included in the primary efficacy analysis: psilocybin, 25 mg (n = 47), psilocybin, 5 mg (n = 48), and nicotinamide (n = 47). Response rates on the primary end point were 17.0% in the group receiving psilocybin, 25 mg; 12.5% in the group receiving psilocybin, 5 mg; and 10.6% in the group receiving nicotinamide. The first hierarchical comparison was nonsignificant (psilocybin, 25 mg vs nicotinamide, adjusted odds ratio [OR], 1.73; 95% CI, 0.53-6.23; P = .19; 1-sided α P = .03); consequently, further formal testing was not performed. Analyses of key secondary end points (mean changes from baseline on HAMD17 and BDI-II) provided exploratory evidence of a clinically meaningful effect of psilocybin, 25 mg. Psilocybin, 25 mg, was linked to adverse events, predominantly acutely, and was associated with higher reports of suicidal ideation on dosing days (4% vs 1%-2% in comparator conditions). Two serious adverse reactions were reported after psilocybin, 25 mg, including 1 case of hallucinogen persisting perception disorder.Conclusion and RelevanceIn this randomized clinical trial, psilocybin, 25 mg, with adjunct psychotherapy, was associated with a clinically meaningful reduction in depressive symptoms in individuals with TRD, although findings did not show a significant effect on the primary outcome. The treatment was well tolerated by most participants, although safety signals were observed. While overall this constituted an inconclusive tr
{"title":"Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial.","authors":"Lea J Mertens,Michael Koslowski,Felix Betzler,Manuela Brand,Ricarda Evens,Laura Kärtner,Andrea Jungaberle,Henrik Jungaberle,Tomislav Majic,Christian N Schmitz,Andreas Ströhle,Dennis Scharf,Moritz Spangemacher,Max Wolff,Zahra Assadi,Scharif Bahri,Lilith Becher,Luca V Färber,Niklas Kirchen,Eugenia Kulakova,Linda Kunz,Andy Meijer,Barbara Rohrmoser,Stefan Wellek,Moritz M Berger,Gerhard Gründer","doi":"10.1001/jamapsychiatry.2026.0132","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2026.0132","url":null,"abstract":"ImportancePsilocybin shows promise in treating depression, although limitations of previous research warrant further research.ObjectiveTo investigate the efficacy and safety of oral psilocybin, 25 mg, with adjunct psychotherapy in treatment-resistant depression (TRD).Design, Setting, and ParticipantsThis was a 2-center, triple-blinded (investigator, participant, rater), phase 2b, active placebo-controlled randomized clinical trial. Participants were randomized to 4 groups in ratios 2:2:1:1, receiving 2 doses 6 weeks apart (week 0, week 6) as follows: (1) placebo (nicotinamide, 100 mg) then psilocybin, 25 mg; (2) psilocybin, 5 mg, then 25 mg; and (3) psilocybin, 25 mg, then 5 mg or psilocybin, 25 mg, twice embedded in psychotherapeutic sessions. Participants aged 25 to 65 years with TRD and withdrawn from antidepressant medication were recruited predominantly from 2 outpatient settings in Germany. Study data were analyzed from April 2024 to November 2025.InterventionsOral synthetic psilocybin, 25 mg; psilocybin, 5 mg; or nicotinamide, 100 mg administered with psychotherapeutic sessions.Main Outcomes and MeasuresThe primary end point was treatment response (≥50% reduction on the Hamilton Rating Scale for Depression [HAMD17]) at week 6 before the second dose. Key secondary end points were response on the Beck Depression Inventory II (BDI-II) and mean change from baseline on the HAMD17 and BDI-II at week 6.ResultsA total of 144 participants (mean [SD] age, 42.6 [10.8] years; 85 male [59.0%]) were randomized, and 142 were included in the primary efficacy analysis: psilocybin, 25 mg (n = 47), psilocybin, 5 mg (n = 48), and nicotinamide (n = 47). Response rates on the primary end point were 17.0% in the group receiving psilocybin, 25 mg; 12.5% in the group receiving psilocybin, 5 mg; and 10.6% in the group receiving nicotinamide. The first hierarchical comparison was nonsignificant (psilocybin, 25 mg vs nicotinamide, adjusted odds ratio [OR], 1.73; 95% CI, 0.53-6.23; P = .19; 1-sided α P = .03); consequently, further formal testing was not performed. Analyses of key secondary end points (mean changes from baseline on HAMD17 and BDI-II) provided exploratory evidence of a clinically meaningful effect of psilocybin, 25 mg. Psilocybin, 25 mg, was linked to adverse events, predominantly acutely, and was associated with higher reports of suicidal ideation on dosing days (4% vs 1%-2% in comparator conditions). Two serious adverse reactions were reported after psilocybin, 25 mg, including 1 case of hallucinogen persisting perception disorder.Conclusion and RelevanceIn this randomized clinical trial, psilocybin, 25 mg, with adjunct psychotherapy, was associated with a clinically meaningful reduction in depressive symptoms in individuals with TRD, although findings did not show a significant effect on the primary outcome. The treatment was well tolerated by most participants, although safety signals were observed. While overall this constituted an inconclusive tr","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"25 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471685","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}
Pub Date : 2026-03-11DOI: 10.1001/jamapsychiatry.2026.0073
Eiko I Fried
ImportancePsychiatric classification faces longstanding challenges, including heterogeneous diagnostic categories, high comorbidity rates, limited interrater reliability, and modest clinical utility. Successive revisions of systems such as the DSM since 1980 have done little to resolve these issues. How to move forward?ObservationsThis narrative review draws an analogy to biology, which has grappled for centuries with the hard problem of species classification. Following Darwin's insights that species are not fixed categories, contemporary theorists of classification have moved away from the natural kind view toward understanding species as homeostatic property clusters (HPCs): sets of properties contingently clustered in nature because the presence of some properties favors the presence of others. Probabilistic associations among these properties lead to imperfect aggregations and gray areas between species. This work adapts the HPC view for mental disorders, where probabilistic associations among biopsychosocial mental health properties form statistical aggregations: property clusters. These clusters are just as messy as in biology and usually lack sharp boundaries. Similar to species, diagnostic structures cannot be straightforwardly discovered in this space-they must be superimposed. To advance this view, a research agenda is outlined for mapping out a mental health atlas by identifying properties, their associations, and their dynamics and illustrating this idea using example data.Conclusions and RelevanceThe HPC view accounts for many robust phenomena in mental health science, turning classification challenges from isolated anomalies into natural consequences of superimposing structure on the landscape of mental health problems. It aligns with major clinical and research frameworks-including Engel's biopsychosocial model, network and systems approaches, the Hierarchical Taxonomy of Psychopathology, and the Research Domain Criteria project-highlighting its role as a mental health science meta-framework. Doing so, it helps sidestep unproductive debates over the best universal classification system. Clinicians, researchers, and policymakers have different priorities and constraints, and no single classification system will optimally serve all stakeholders.
{"title":"Mental Disorders as Homeostatic Property Clusters: A Narrative Review.","authors":"Eiko I Fried","doi":"10.1001/jamapsychiatry.2026.0073","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2026.0073","url":null,"abstract":"ImportancePsychiatric classification faces longstanding challenges, including heterogeneous diagnostic categories, high comorbidity rates, limited interrater reliability, and modest clinical utility. Successive revisions of systems such as the DSM since 1980 have done little to resolve these issues. How to move forward?ObservationsThis narrative review draws an analogy to biology, which has grappled for centuries with the hard problem of species classification. Following Darwin's insights that species are not fixed categories, contemporary theorists of classification have moved away from the natural kind view toward understanding species as homeostatic property clusters (HPCs): sets of properties contingently clustered in nature because the presence of some properties favors the presence of others. Probabilistic associations among these properties lead to imperfect aggregations and gray areas between species. This work adapts the HPC view for mental disorders, where probabilistic associations among biopsychosocial mental health properties form statistical aggregations: property clusters. These clusters are just as messy as in biology and usually lack sharp boundaries. Similar to species, diagnostic structures cannot be straightforwardly discovered in this space-they must be superimposed. To advance this view, a research agenda is outlined for mapping out a mental health atlas by identifying properties, their associations, and their dynamics and illustrating this idea using example data.Conclusions and RelevanceThe HPC view accounts for many robust phenomena in mental health science, turning classification challenges from isolated anomalies into natural consequences of superimposing structure on the landscape of mental health problems. It aligns with major clinical and research frameworks-including Engel's biopsychosocial model, network and systems approaches, the Hierarchical Taxonomy of Psychopathology, and the Research Domain Criteria project-highlighting its role as a mental health science meta-framework. Doing so, it helps sidestep unproductive debates over the best universal classification system. Clinicians, researchers, and policymakers have different priorities and constraints, and no single classification system will optimally serve all stakeholders.","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"14 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383232","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}
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