Pub Date : 2026-02-04DOI: 10.1001/jamapsychiatry.2025.4431
Min Gao, Megan Kirk, Heather Knight, Eva Lash, Moscho Michalopoulou, Nicola Guess, Richard Stevens, Michael Browning, Scott Weich, Philip W. J. Burnet, Susan A. Jebb, Paul Aveyard
Importance Preclinical evidence and case reports suggest potential therapeutic benefits of ketogenic diets (KDs) in the treatment of depression, but evidence from well-controlled randomized clinical trials (RCTs) is lacking. Objective To assess the efficacy of a KD compared with a control diet in adults with treatment-resistant depression (TRD). Design, Setting, and Participants This RCT was conducted between February 22 and June 15, 2024. Participants aged 18 to 65 years with TRD and a score of 15 or greater on the 9-item Patient Health Questionnaire (PHQ-9) from across the UK were included. Intervention Participants were randomized 1:1 to one of two 6-week dietary interventions: (1) KD of prepared foods providing less than 30 g of carbohydrates per day with weekly individual dietetic support or (2) a control (phytochemical [phyto]) diet with vouchers to purchase 1 extra serving of vegetables or fruit and replace saturated fats with unsaturated fats, with equal dietetic support. The last follow-up was at 12 weeks. Main Outcomes and Measures The primary outcome was the between-group difference in change in PHQ-9 score from baseline to week 6. Secondary outcomes included PHQ-9 score at 12 weeks, depression remission, anxiety, anhedonia, cognitive impairment, quality of life, and functional outcomes. Results The study included 88 participants (mean [SD] age, 42.1 [13.1] years; 61 women [69%]): 44 in the KD group and 44 in the phyto diet group. Depression severity decreased markedly in both groups; the mean (SD) change in PHQ-9 score from baseline to week 6 was −10.5 (7.0) in the KD group and −8.3 (5.1) in the phyto group. The mean between-group differences in PHQ-9 score at 6 and 12 weeks were −2.18 (95% CI, −4.33 to −0.03; P = .05; Cohen d , −0.68; 95% CI −1.35 to −0.01) and −1.85 (95% CI, −4.04 to 0.33; P = .10; Cohen d , −0.58; 95% CI, −1.26 to 0.10), respectively. There were no differences in secondary outcomes between the KD and phyto groups. No serious adverse events occurred. Conclusions and Relevance In this RCT, a KD had antidepressant benefits compared with a well-matched control diet at 6 weeks. However, the clinical relevance is uncertain, as the mean effect size compared with the control was modest and not evident in secondary analyses. Trial Registration ClinicalTrials.gov Identifier: NCT06091163
{"title":"A Ketogenic Diet for Treatment-Resistant Depression","authors":"Min Gao, Megan Kirk, Heather Knight, Eva Lash, Moscho Michalopoulou, Nicola Guess, Richard Stevens, Michael Browning, Scott Weich, Philip W. J. Burnet, Susan A. Jebb, Paul Aveyard","doi":"10.1001/jamapsychiatry.2025.4431","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.4431","url":null,"abstract":"Importance Preclinical evidence and case reports suggest potential therapeutic benefits of ketogenic diets (KDs) in the treatment of depression, but evidence from well-controlled randomized clinical trials (RCTs) is lacking. Objective To assess the efficacy of a KD compared with a control diet in adults with treatment-resistant depression (TRD). Design, Setting, and Participants This RCT was conducted between February 22 and June 15, 2024. Participants aged 18 to 65 years with TRD and a score of 15 or greater on the 9-item Patient Health Questionnaire (PHQ-9) from across the UK were included. Intervention Participants were randomized 1:1 to one of two 6-week dietary interventions: (1) KD of prepared foods providing less than 30 g of carbohydrates per day with weekly individual dietetic support or (2) a control (phytochemical [phyto]) diet with vouchers to purchase 1 extra serving of vegetables or fruit and replace saturated fats with unsaturated fats, with equal dietetic support. The last follow-up was at 12 weeks. Main Outcomes and Measures The primary outcome was the between-group difference in change in PHQ-9 score from baseline to week 6. Secondary outcomes included PHQ-9 score at 12 weeks, depression remission, anxiety, anhedonia, cognitive impairment, quality of life, and functional outcomes. Results The study included 88 participants (mean [SD] age, 42.1 [13.1] years; 61 women [69%]): 44 in the KD group and 44 in the phyto diet group. Depression severity decreased markedly in both groups; the mean (SD) change in PHQ-9 score from baseline to week 6 was −10.5 (7.0) in the KD group and −8.3 (5.1) in the phyto group. The mean between-group differences in PHQ-9 score at 6 and 12 weeks were −2.18 (95% CI, −4.33 to −0.03; <jats:italic>P</jats:italic> = .05; Cohen <jats:italic>d</jats:italic> , −0.68; 95% CI −1.35 to −0.01) and −1.85 (95% CI, −4.04 to 0.33; <jats:italic>P</jats:italic> = .10; Cohen <jats:italic>d</jats:italic> , −0.58; 95% CI, −1.26 to 0.10), respectively. There were no differences in secondary outcomes between the KD and phyto groups. No serious adverse events occurred. Conclusions and Relevance In this RCT, a KD had antidepressant benefits compared with a well-matched control diet at 6 weeks. However, the clinical relevance is uncertain, as the mean effect size compared with the control was modest and not evident in secondary analyses. 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/NCT06091163\">NCT06091163</jats:ext-link>","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"20 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115564","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 : 2026-02-04DOI: 10.1001/jamapsychiatry.2025.4390
Nurul Husna Salahuddin, Emilia Herlitzius, Alexandra Schütz, Spyridon Siafis, Josef Priller, Stefan Leucht, Irene Bighelli
Importance Substance use disorder (SUD) is commonly found in individuals with schizophrenia, with a high co-occurrence rate of approximately 41.7%. Despite this high prevalence, people with both schizophrenia and SUD are frequently excluded from clinical trials and systematic reviews; this special group is particularly challenging to treat and imposes a significant economic burden on health care systems. Objective To evaluate the efficacy, acceptability, and tolerability of psychological and psychosocial interventions in patients with schizophrenia and co-occurring SUD. Data Sources The Cochrane Schizophrenia Group registry was searched up to January 13, 2025. Data analysis was performed from March to April 2025. Study Selection Randomized clinical trials (RCTs) examining psychological and psychosocial interventions compared with control groups in adults with schizophrenia and concomitant SUD were identified. No restrictions were applied regarding the type of substance used, including alcohol, cannabis, nicotine, and stimulants, such as amphetamines. Data Extraction and Synthesis A systematic review and random-effect pairwise meta-analyses were conducted to estimate standardized mean differences (SMD) with 95% confidence intervals and were reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses ( <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.equator-network.org/reporting-guidelines/prisma/">PRISMA</jats:ext-link> ) reporting guidelines. Confidence in the estimate was assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main Outcomes and Measures The primary outcomes were overall symptoms and substance use reduction measured by validated scales at posttreatment. Results A total of 35 RCTs were included (4136 participants), with 29 trials involving 3831 participants contributing to pairwise meta-analyses comparing psychological and psychosocial interventions with control conditions. Among the 3748 participants with reported sex, 951 (25.4%) were female, and mean (range) age was 37.2 (20.6-57.5) years. A very small effect favoring the intervention group was observed in reducing overall symptoms (SMD, –0.11; 95% CI, –0.27 to 0.05; 13 trials; low confidence in the estimate), mainly driven by nicotine studies. No difference was found between intervention and control groups in reducing all types of substance use (SMD, –0.01; 95% CI, –0.21 to 0.18; 8 trials; moderate confidence). When considered separately, alcohol, cannabis, amphetamines, and other stimulants showed similar no-effect results, while nicotine use indicated a small effect. Conclusion and Relevance The findings of this systematic review and meta-analysis suggest that current psychological and psychosocial interventions provide limited benefit in reducing symptoms and no effect in reducing substance use in individuals with schizophrenia and SUD compared to con
{"title":"Psychological and Psychosocial Interventions for People With Schizophrenia and Co-Occurring Substance Use Disorders","authors":"Nurul Husna Salahuddin, Emilia Herlitzius, Alexandra Schütz, Spyridon Siafis, Josef Priller, Stefan Leucht, Irene Bighelli","doi":"10.1001/jamapsychiatry.2025.4390","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.4390","url":null,"abstract":"Importance Substance use disorder (SUD) is commonly found in individuals with schizophrenia, with a high co-occurrence rate of approximately 41.7%. Despite this high prevalence, people with both schizophrenia and SUD are frequently excluded from clinical trials and systematic reviews; this special group is particularly challenging to treat and imposes a significant economic burden on health care systems. Objective To evaluate the efficacy, acceptability, and tolerability of psychological and psychosocial interventions in patients with schizophrenia and co-occurring SUD. Data Sources The Cochrane Schizophrenia Group registry was searched up to January 13, 2025. Data analysis was performed from March to April 2025. Study Selection Randomized clinical trials (RCTs) examining psychological and psychosocial interventions compared with control groups in adults with schizophrenia and concomitant SUD were identified. No restrictions were applied regarding the type of substance used, including alcohol, cannabis, nicotine, and stimulants, such as amphetamines. Data Extraction and Synthesis A systematic review and random-effect pairwise meta-analyses were conducted to estimate standardized mean differences (SMD) with 95% confidence intervals and were reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses ( <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"http://www.equator-network.org/reporting-guidelines/prisma/\">PRISMA</jats:ext-link> ) reporting guidelines. Confidence in the estimate was assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Main Outcomes and Measures The primary outcomes were overall symptoms and substance use reduction measured by validated scales at posttreatment. Results A total of 35 RCTs were included (4136 participants), with 29 trials involving 3831 participants contributing to pairwise meta-analyses comparing psychological and psychosocial interventions with control conditions. Among the 3748 participants with reported sex, 951 (25.4%) were female, and mean (range) age was 37.2 (20.6-57.5) years. A very small effect favoring the intervention group was observed in reducing overall symptoms (SMD, –0.11; 95% CI, –0.27 to 0.05; 13 trials; low confidence in the estimate), mainly driven by nicotine studies. No difference was found between intervention and control groups in reducing all types of substance use (SMD, –0.01; 95% CI, –0.21 to 0.18; 8 trials; moderate confidence). When considered separately, alcohol, cannabis, amphetamines, and other stimulants showed similar no-effect results, while nicotine use indicated a small effect. Conclusion and Relevance The findings of this systematic review and meta-analysis suggest that current psychological and psychosocial interventions provide limited benefit in reducing symptoms and no effect in reducing substance use in individuals with schizophrenia and SUD compared to con","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"8 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115562","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 : 2026-02-01DOI: 10.1001/jamapsychiatry.2025.3562
Federico Cevoli, Husseini K Manji, Andrew H Miller, Brenda W J H Penninx, Martien Kas, Carmine Pariante, Livia De Picker, Pawel Swieboda, Marion Leboyer
Importance: Neuropsychiatric disorders impose a substantial burden on individuals and societies worldwide. Despite significant advances in the understanding of the brain, only a handful of mechanism-based treatments for psychiatric disorders have been discovered and validated in the past 50 years.
Observations: After discussing the reasons for poor progress in drug discovery in mental disorders, this article outlines recommendations for a paradigm shift toward precision psychiatry, emphasizing the need for biomarker discovery and suggesting a reform of clinical trial methodology. To drive this transformation, increased public and private investment must be aligned with the societal impact of mental disorders, while regulatory agencies should adopt more flexible and biomarker-informed trials, as seen in oncology and other medical fields.
Conclusion and relevance: Promoting cross-sector collaboration between academia, biotech, industry, and health care systems will be critical to support high-risk, high-reward innovations. This article reflects the broad consensus of experts from academia, industry, regulatory agencies, and patient representatives to advance the agenda for precision psychiatry.
{"title":"Implementing Precision Medicine in Psychiatry.","authors":"Federico Cevoli, Husseini K Manji, Andrew H Miller, Brenda W J H Penninx, Martien Kas, Carmine Pariante, Livia De Picker, Pawel Swieboda, Marion Leboyer","doi":"10.1001/jamapsychiatry.2025.3562","DOIUrl":"10.1001/jamapsychiatry.2025.3562","url":null,"abstract":"<p><strong>Importance: </strong>Neuropsychiatric disorders impose a substantial burden on individuals and societies worldwide. Despite significant advances in the understanding of the brain, only a handful of mechanism-based treatments for psychiatric disorders have been discovered and validated in the past 50 years.</p><p><strong>Observations: </strong>After discussing the reasons for poor progress in drug discovery in mental disorders, this article outlines recommendations for a paradigm shift toward precision psychiatry, emphasizing the need for biomarker discovery and suggesting a reform of clinical trial methodology. To drive this transformation, increased public and private investment must be aligned with the societal impact of mental disorders, while regulatory agencies should adopt more flexible and biomarker-informed trials, as seen in oncology and other medical fields.</p><p><strong>Conclusion and relevance: </strong>Promoting cross-sector collaboration between academia, biotech, industry, and health care systems will be critical to support high-risk, high-reward innovations. This article reflects the broad consensus of experts from academia, industry, regulatory agencies, and patient representatives to advance the agenda for precision psychiatry.</p>","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":" ","pages":"207-211"},"PeriodicalIF":17.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145714295","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 : 2026-02-01DOI: 10.1001/jamapsychiatry.2025.4225
Kerim M Munir
{"title":"Recognizing Grief in Neurodivergent Minds.","authors":"Kerim M Munir","doi":"10.1001/jamapsychiatry.2025.4225","DOIUrl":"10.1001/jamapsychiatry.2025.4225","url":null,"abstract":"","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":" ","pages":"116-117"},"PeriodicalIF":17.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810161","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 : 2026-01-28DOI: 10.1001/jamapsychiatry.2025.4383
Holly B Krasa,James R Baumgardner,Iris P Brewer,Jacquelyn W Chou,Thomas Flottemesch,Jessica T Markowitz,Cory Williams,Arundati Nagendra
ImportanceSchizophrenia imposes a substantial burden on individuals and society. Population-specific cost estimates are essential to inform evidence-based policy, allocate resources, and support recovery-focused care that improves outcomes.ObjectiveTo estimate national and state-level burden of schizophrenia to inform population-specific care and services in the US in 2024.Design, Setting, and ParticipantsThis was an observational prevalence-based cost-of-illness model estimating total excess direct medical, direct nonmedical, and indirect costs of schizophrenia by combining inputs from a targeted literature review and an analysis of Medical Expenditure Panel Survey data, adjusted to 2024 US dollars. The setting included independent households, supportive housing, long-term care and skilled nursing facilities, unhoused settings, and prisons and jails. Disease-related costs were estimated for adults living with schizophrenia spectrum disorders.ExposuresHealth care, supportive housing, homelessness, social security disability benefits, justice system, employment, productivity, quality of life, mortality, and caregiver impact across settings of care.Main Outcomes and MeasuresPrevalence-based national and state cost of schizophrenia by category or sector.ResultsThe societal cost of schizophrenia in 2024 was estimated at $366.8 billion in the US for 3 070 739 adults (1.17%) across all settings (68.4% independent households, 18.6% supportive housing, 5.0% long-term care or skilled nursing facility, 4.7% incarcerated, 3.3% unhoused). Direct costs ($75.0 billion) were attributable to health care ($36.7 billion), supportive housing and homelessness ($35.2 billion), justice system interactions ($11.9 billion), and social security disability benefits ($5.1 billion). Indirect costs ($291.8 billion) resulted from lost wages ($55.4 billion) and reduced quality of life ($41.4 billion) and life expectancy ($47.5 billion). Indirect costs for caregivers of individuals with schizophrenia included unpaid wages for time providing care ($104.6 billion) and impact on caregiver health, productivity, and out-of-pocket costs ($60.5 billion). Per-person costs of schizophrenia were estimated at $119 436 nationally in 2024. State-level per-person costs ranged from $110 975 in Utah to $126 225 in Alaska.Conclusions and RelevanceIn 2024, the national and state-level costs of schizophrenia in the US estimated from a societal perspective suggest a substantial burden of disease on individuals, families, and society. These findings provide an important framework to guide prevention, care, and management strategies to reduce costs and improve public health outcomes.
{"title":"National and State Societal Costs of Schizophrenia in the US in 2024.","authors":"Holly B Krasa,James R Baumgardner,Iris P Brewer,Jacquelyn W Chou,Thomas Flottemesch,Jessica T Markowitz,Cory Williams,Arundati Nagendra","doi":"10.1001/jamapsychiatry.2025.4383","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.4383","url":null,"abstract":"ImportanceSchizophrenia imposes a substantial burden on individuals and society. Population-specific cost estimates are essential to inform evidence-based policy, allocate resources, and support recovery-focused care that improves outcomes.ObjectiveTo estimate national and state-level burden of schizophrenia to inform population-specific care and services in the US in 2024.Design, Setting, and ParticipantsThis was an observational prevalence-based cost-of-illness model estimating total excess direct medical, direct nonmedical, and indirect costs of schizophrenia by combining inputs from a targeted literature review and an analysis of Medical Expenditure Panel Survey data, adjusted to 2024 US dollars. The setting included independent households, supportive housing, long-term care and skilled nursing facilities, unhoused settings, and prisons and jails. Disease-related costs were estimated for adults living with schizophrenia spectrum disorders.ExposuresHealth care, supportive housing, homelessness, social security disability benefits, justice system, employment, productivity, quality of life, mortality, and caregiver impact across settings of care.Main Outcomes and MeasuresPrevalence-based national and state cost of schizophrenia by category or sector.ResultsThe societal cost of schizophrenia in 2024 was estimated at $366.8 billion in the US for 3 070 739 adults (1.17%) across all settings (68.4% independent households, 18.6% supportive housing, 5.0% long-term care or skilled nursing facility, 4.7% incarcerated, 3.3% unhoused). Direct costs ($75.0 billion) were attributable to health care ($36.7 billion), supportive housing and homelessness ($35.2 billion), justice system interactions ($11.9 billion), and social security disability benefits ($5.1 billion). Indirect costs ($291.8 billion) resulted from lost wages ($55.4 billion) and reduced quality of life ($41.4 billion) and life expectancy ($47.5 billion). Indirect costs for caregivers of individuals with schizophrenia included unpaid wages for time providing care ($104.6 billion) and impact on caregiver health, productivity, and out-of-pocket costs ($60.5 billion). Per-person costs of schizophrenia were estimated at $119 436 nationally in 2024. State-level per-person costs ranged from $110 975 in Utah to $126 225 in Alaska.Conclusions and RelevanceIn 2024, the national and state-level costs of schizophrenia in the US estimated from a societal perspective suggest a substantial burden of disease on individuals, families, and society. These findings provide an important framework to guide prevention, care, and management strategies to reduce costs and improve public health outcomes.","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"60 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056899","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 : 2026-01-28DOI: 10.1001/jamapsychiatry.2025.4372
Alicia Walker,Brittany L Mitchell,Tian Lin,Jacob J Crouse,Clara Albiñana,Chloe X Yap,Mary Ellen Lynall,Penelope A Lind,Andrea Cipriani,Enda M Byrne,Sarah E Medland,Nicholas G Martin,Maxime Taquet,Ian B Hickie,Naomi R Wray
ImportanceAntidepressant treatment remains a trial-and-error process: one-third of people with major depressive disorder (MDD) report inefficacy of first-line medications. Predictors of prescription patterns are needed to improve prescribing precision.ObjectiveTo investigate phenotypic and genetic heterogeneity of MDD subgroups defined by antidepressant prescription patterns.Design, Setting, and ParticipantsThis was a retrospective cohort study of Australian Genetics of Depression Study (2017-2018) adult participants (aged ≥18 years) with lifetime MDD who filled 1 or more prescriptions of the 10 most commonly used antidepressants across 4.5 years (2013-2017). Data were analyzed from August 2024 to October 2025.ExposuresTreatment complexity was assessed as number of different antidepressant classes in prescriptions filled in 4.5 years. Sustained-use 360 groups were defined as 360 or more cumulative days (in 4.5 years) of a single antidepressant. Participants with genome-wide genotypes were contrasted across mutually exclusive sustained-use 360 groups.Main Outcomes and MeasuresAssociations of 44 self-reported phenotypes and polygenic scores (PGSs) for 15 traits with sustained-use 360 subgroups. Genome-wide association studies (GWASs) were conducted for selective serotonin reuptake inhibitor (SSRI) or SSRI/serotonin-norepinephrine reuptake inhibitor sustained use contrasted to other participants.ResultsOf 12 074 participants (9041 [75%] female with a mean [SD] age of 41.8 [14.6] years; 3022 [25%] male with a mean [SD] age of 47.7 [14.6] years) with 1 or more prescriptions and lifetime MDD, 8898 had genotyping data. High treatment complexity was significantly associated with 37 of 44 self-reported phenotypes (eg, higher rates of smoking, recurrent MDD, suicidal ideation, chronic pain, and circadian and atypical depression subtypes) and higher PGSs for psychiatric traits (MDD PGS: β, 0.04; 95% CI, 0.03-0.06; P = 1.2 × 10-8; ADHD PGS: β, 0.03; 95% CI, 0.02-0.05; P = 2.1 × 10-5 ; bipolar disorder PGS: β, 0.03; 95% CI, 0.01-0.04. P = 1.2 × 10-4 ; neuroticism PGS: β, 0.02; 95% CI, 0.01-0.04; P = 1.3 × 10-3). A total of 5453 (61%) met criteria for an exclusive antidepressant sustained-use 360 group. These groups had distinct phenotypic profiles, including associations with body mass index, suicidal ideation, and co-occurring conditions. GWASs identified novel loci, including an immune-related gene SLAMF3/LY9, for which single-nucleotide variant rs4656934 was associated with reduced odds of sustained SSRI use (G allele; odds ratio, 0.81; 95% CI, 0.75-0.87; P = 3.5 × 10-8).Conclusions and RelevanceThis study found that phenotypic factors were associated with sustained antidepressant use and treatment complexity. PGSs for traits studied were associated with treatment complexity but showed little association with sustained-use 360 groups. These findings support further research to guide treatment selection and to identify patients at risk of difficult-to-treat
{"title":"Genetic and Phenotypic Associations With Sustained Antidepressant Use in Major Depressive Disorder.","authors":"Alicia Walker,Brittany L Mitchell,Tian Lin,Jacob J Crouse,Clara Albiñana,Chloe X Yap,Mary Ellen Lynall,Penelope A Lind,Andrea Cipriani,Enda M Byrne,Sarah E Medland,Nicholas G Martin,Maxime Taquet,Ian B Hickie,Naomi R Wray","doi":"10.1001/jamapsychiatry.2025.4372","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.4372","url":null,"abstract":"ImportanceAntidepressant treatment remains a trial-and-error process: one-third of people with major depressive disorder (MDD) report inefficacy of first-line medications. Predictors of prescription patterns are needed to improve prescribing precision.ObjectiveTo investigate phenotypic and genetic heterogeneity of MDD subgroups defined by antidepressant prescription patterns.Design, Setting, and ParticipantsThis was a retrospective cohort study of Australian Genetics of Depression Study (2017-2018) adult participants (aged ≥18 years) with lifetime MDD who filled 1 or more prescriptions of the 10 most commonly used antidepressants across 4.5 years (2013-2017). Data were analyzed from August 2024 to October 2025.ExposuresTreatment complexity was assessed as number of different antidepressant classes in prescriptions filled in 4.5 years. Sustained-use 360 groups were defined as 360 or more cumulative days (in 4.5 years) of a single antidepressant. Participants with genome-wide genotypes were contrasted across mutually exclusive sustained-use 360 groups.Main Outcomes and MeasuresAssociations of 44 self-reported phenotypes and polygenic scores (PGSs) for 15 traits with sustained-use 360 subgroups. Genome-wide association studies (GWASs) were conducted for selective serotonin reuptake inhibitor (SSRI) or SSRI/serotonin-norepinephrine reuptake inhibitor sustained use contrasted to other participants.ResultsOf 12 074 participants (9041 [75%] female with a mean [SD] age of 41.8 [14.6] years; 3022 [25%] male with a mean [SD] age of 47.7 [14.6] years) with 1 or more prescriptions and lifetime MDD, 8898 had genotyping data. High treatment complexity was significantly associated with 37 of 44 self-reported phenotypes (eg, higher rates of smoking, recurrent MDD, suicidal ideation, chronic pain, and circadian and atypical depression subtypes) and higher PGSs for psychiatric traits (MDD PGS: β, 0.04; 95% CI, 0.03-0.06; P = 1.2 × 10-8; ADHD PGS: β, 0.03; 95% CI, 0.02-0.05; P = 2.1 × 10-5 ; bipolar disorder PGS: β, 0.03; 95% CI, 0.01-0.04. P = 1.2 × 10-4 ; neuroticism PGS: β, 0.02; 95% CI, 0.01-0.04; P = 1.3 × 10-3). A total of 5453 (61%) met criteria for an exclusive antidepressant sustained-use 360 group. These groups had distinct phenotypic profiles, including associations with body mass index, suicidal ideation, and co-occurring conditions. GWASs identified novel loci, including an immune-related gene SLAMF3/LY9, for which single-nucleotide variant rs4656934 was associated with reduced odds of sustained SSRI use (G allele; odds ratio, 0.81; 95% CI, 0.75-0.87; P = 3.5 × 10-8).Conclusions and RelevanceThis study found that phenotypic factors were associated with sustained antidepressant use and treatment complexity. PGSs for traits studied were associated with treatment complexity but showed little association with sustained-use 360 groups. These findings support further research to guide treatment selection and to identify patients at risk of difficult-to-treat","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":"87 1","pages":""},"PeriodicalIF":25.8,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056897","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 : 2026-01-28DOI: 10.1001/jamapsychiatry.2025.4447
Mark Abie Horowitz, James O'Neill, David Taylor
{"title":"Interpretation of the HAMLETT Study.","authors":"Mark Abie Horowitz, James O'Neill, David Taylor","doi":"10.1001/jamapsychiatry.2025.4447","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.4447","url":null,"abstract":"","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":" ","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146063583","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 : 2026-01-28DOI: 10.1001/jamapsychiatry.2025.4444
Lex Wunderink
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Pub Date : 2026-01-28DOI: 10.1001/jamapsychiatry.2025.4450
Iris E Sommer, Shiral S Gangadin, Franciska de Beer
{"title":"Interpretation of the HAMLETT Study-Reply.","authors":"Iris E Sommer, Shiral S Gangadin, Franciska de Beer","doi":"10.1001/jamapsychiatry.2025.4450","DOIUrl":"https://doi.org/10.1001/jamapsychiatry.2025.4450","url":null,"abstract":"","PeriodicalId":14800,"journal":{"name":"JAMA Psychiatry","volume":" ","pages":""},"PeriodicalIF":17.1,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146063598","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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