Importance:Antidepressant efficacy of intravenous (IV) ketamine has been demonstrated in major depressive disorder; however, the efficacy and safety of ketamine for bipolar depression remain largely unknown, with limited data available in this specific population. Objective:To evaluate the efficacy, safety, and tolerability of adjunctive IV ketamine compared with midazolam for treatment-resistant bipolar I or II depression (TRBD). Design, Setting, and Participants:The Ket-BD study (Ketamine for Treatment-Resistant Bipolar Disorder) was an investigator-led, double-blind, midazolam-controlled randomized clinical trial conducted at 3 sites in Ontario, Canada, from July 2022 to November 2025. Participants included adult outpatients (aged 21-65 years) with a primary bipolar I or II disorder DSM-5 diagnosis with a current moderate to severe major depressive episode (Montgomery-Åsberg Depression Rating Scale [MADRS] score ≥21), having had at least 2 failed trials of evidence-based pharmacotherapies. Data were analyzed from November 2025 through February 2026. Interventions:Participants were randomized 1:1 to receive 4 flexibly dosed 40-minute infusions over 2 weeks of either ketamine (0.5-0.75 mg/kg) or midazolam (0.02-0.03 mg/kg) adjunctive to a stable dose of at least 1 mood stabilizer or antipsychotic. Main Outcomes and Measures:The primary outcome was change in depression symptom severity measured by the observer-rated MADRS score from baseline to end of treatment (day 14). Safety and tolerability were assessed with close evaluation for potential treatment-emergent mania, hypomania, mixed features, or psychosis. Results:Of 68 randomized participants (mean [SD] age, 44.4 [11.8] years; 38 female [55.8%]), 63 were included in the final efficacy analysis as 5 participants withdrew (1 ketamine, 4 midazolam) before the primary end point. In the primary efficacy analysis, controlling for sex, bipolar type, and baseline MADRS, the mean MADRS score at day 14 was significantly lower in the ketamine group compared to the midazolam group (between-group difference = -7.3 points; 95% CI, -12.0 to -2.5; P = .003; Cohen d = 0.7). No cases of mania, hypomania, psychosis, or suicide attempts were observed in either group. One case of mixed features (subthreshold hypomanic symptoms) was observed in each group. After the first infusion, 31 of 66 participants (47%) correctly guessed treatment allocation. Conclusions and Relevance:In TRBD, adjunctive IV ketamine was well tolerated and associated with significant antidepressant effects compared to midazolam. Trial Registration:ClinicalTrials.gov Identifier: NCT05004896.
This cross-sectional study examines glucagon-like peptide-1 (GLP-1) prescriptions among adults with vs without severe mental illness from 2018 to 2024 using national insurance claims.
Importance Antidepressant efficacy of intravenous (IV) ketamine has been demonstrated in major depressive disorder; however, the efficacy and safety of ketamine for bipolar depression remain largely unknown, with limited data available in this specific population. Objective To evaluate the efficacy, safety, and tolerability of adjunctive IV ketamine compared with midazolam for treatment-resistant bipolar I or II depression (TRBD). Design, Setting, and Participants The Ket-BD study (Ketamine for Treatment-Resistant Bipolar Disorder) was an investigator-led, double-blind, midazolam-controlled randomized clinical trial conducted at 3 sites in Ontario, Canada, from July 2022 to November 2025. Participants included adult outpatients (aged 21-65 years) with a primary bipolar I or II disorder DSM-5 diagnosis with a current moderate to severe major depressive episode (Montgomery-Åsberg Depression Rating Scale [MADRS] score ≥21), having had at least 2 failed trials of evidence-based pharmacotherapies. Data were analyzed from November 2025 through February 2026. Interventions Participants were randomized 1:1 to receive 4 flexibly dosed 40-minute infusions over 2 weeks of either ketamine (0.5-0.75 mg/kg) or midazolam (0.02-0.03 mg/kg) adjunctive to a stable dose of at least 1 mood stabilizer or antipsychotic. Main Outcomes and Measures The primary outcome was change in depression symptom severity measured by the observer-rated MADRS score from baseline to end of treatment (day 14). Safety and tolerability were assessed with close evaluation for potential treatment-emergent mania, hypomania, mixed features, or psychosis. Results Of 68 randomized participants (mean [SD] age, 44.4 [11.8] years; 38 female [55.8%]), 63 were included in the final efficacy analysis as 5 participants withdrew (1 ketamine, 4 midazolam) before the primary end point. In the primary efficacy analysis, controlling for sex, bipolar type, and baseline MADRS, the mean MADRS score at day 14 was significantly lower in the ketamine group compared to the midazolam group (between-group difference = −7.3 points; 95% CI, −12.0 to −2.5; P = .003; Cohen d = 0.7). No cases of mania, hypomania, psychosis, or suicide attempts were observed in either group. One case of mixed features (subthreshold hypomanic symptoms) was observed in each group. After the first infusion, 31 of 66 participants (47%) correctly guessed treatment allocation. Conclusions and Relevance In TRBD, adjunctive IV ketamine was well tolerated and associated with significant antidepressant effects compared to midazolam. Trial Registration ClinicalTrials.gov Identifier: NCT05004896
This cohort study examines racial and ethnic disparities in retention in buprenorphine and methadone treatment among pregnant females with opioid use disorder (OUD) in the US.
This article implores clinicians to consider whether artificial intelligence models may induce delusionlike beliefs—and how to help overcome this phenomenon.
This Viewpoint argues that suicide risk prediction models are advancing faster than the shared infrastructure health systems need to evaluate, select, and sustain them and proposes a federated framework for closing that gap.
Importance:The number of US adults with alcohol use disorder (AUD) has declined, whereas the number with cannabis use disorder (CUD) has increased. Little is known about how changes in the prevalence and severity of AUD and CUD vary by age and sex. Objective:To investigate trends in AUD and CUD prevalence and severity by age and sex. Design, Setting, and Participants:This cross-sectional study examined data from adult participants in the 2021 to 2024 National Surveys on Drug Use and Health. This study was started and completed in March 2026. Exposure:Alcohol and cannabis use. Main Outcomes and Measures:Past-year prevalence and severity of AUD and CUD using DSM-5 criteria. Results:From 2021 through 2024 among 186 823 participants (51.3% female; 4.9% aged 18-20 years; 24.1% aged 21-34 years; 24.7% aged 35-49 years), past-year CUD prevalence increased among males (from 7.3% [95% CI, 6.6%-8.1%] to 9.3% [95% CI, 8.6%-10.1%]; P < .001) and females (from 4.5% [95% CI, 4.1%-5.0%] to 5.6% [95% CI, 5.2%-6.1%]; P = .01). Moderate-to-severe CUD prevalence among males increased from 3.1% (95% CI, 2.8%-3.6%) to 4.1% (95% CI, 3.7%-4.5%) (P < .001), especially among males aged 35 to 49 years (from 2.7% [95% CI, 2.0%-3.6%] to 3.9% [95% CI, 3.2%-4.8%]; P = .01) and males aged 50 years or older (from 0.6% [95% CI, 0.3%-1.0%] to 1.2% [95% CI, 0.8%-1.7%]; P = .02). Among females, moderate-to-severe CUD prevalence increased from 1.7% (95% CI, 1.5%-2.0%) to 2.5% (95% CI, 2.3%-2.8%) (P < .001), specifically for females aged 21 to 34 years (from 4.2% [95% CI, 3.5%-5.1%] to 5.6% [95% CI, 4.8%-6.5%]; P = .04), 35 to 49 years (from 1.2% [95% CI, 0.8%-1.8%] to 2.0% [95% CI, 1.6%-2.5%]; P = .01), and 50 years or older (from 0.1% [95% CI, 0.04%-0.3%] to 0.7% [95% CI, 0.5%-1.0%]; P < .001). Among females with CUD, moderate-to-severe CUD prevalence increased from 37.0% (95% CI, 32.5%-41.8%) to 45.0% (95% CI, 41.1%-49.0%) (P = .03). However, moderate-to-severe AUD prevalence remained stable among males overall (except for declines among males aged 21-34 years) and was stable among females overall and within all subgroups. Most males and females aged 18 to 20 years and males aged 21 to 34 years with CUD had moderate-to-severe CUD (eg, 51.0%-61.0% in 2024), with consistent patterns from 2022 through 2024. Conclusions and Relevance:This cross-sectional study found divergent age- and sex-specific patterns from 2021 through 2024, with moderate-to-severe CUD prevalence increasing and moderate-to-severe AUD prevalence remaining stable across males, females, and most subgroups. The increased prevalence underscores the importance of early detection, routine screening, timely access to evidence-based CUD treatment, and targeted strategies to counter increasing acceptance, availability, and potency of cannabis products. High prevalence of moderate-to-severe CUD among adults who use cannabis challenges the notion that cannabis has low addictive potential.
Importance:In the US, 5% to 6% of pregnant patients are treated with selective serotonin reuptake inhibitors (SSRI), primarily for major depressive disorder (MDD), which has a prevalence of about 12%. Psychiatric conditions are a leading cause of maternal morbidity and mortality. MDD is a common disorder that must be treated during pregnancy to improve outcomes for the mother, infant, family, and community. Observations:MDD is a complex, multifactorial brain disease arising from genetic, environmental, and epigenetic factors. Factors unique to the perinatal period are associated with additional pathophysiologic changes specific to MDD. Maternal stress and psychiatric illnesses adversely affect fetal and infant outcomes. SSRI are an essential component of perinatal mental health care. Studies that define the benefits of SSRI treatment in pregnancy are fewer than those defining risks; however, several describe adverse effects with drug discontinuation in women with moderate to severe MDD. Evaluating the safety of SSRI treatment during pregnancy has been challenging due to the potential for confounding in observational studies by the underlying indication and associated factors. Once the impact of the drug is disentangled from that of MDD and its sequelae, accumulated evidence suggests that SSRI carry little or no risk for serious adverse outcomes. The thrust of the field has shifted to prioritize treatment of MDD to optimize maternal health. Conclusions and Relevance:Meaningful advances in the treatment of perinatal MDD require coordinated attention to multiple aspects of clinical care delivery and research, informed by a perspective accounting for the health needs of 2 generations. Expanding access to care-particularly in maternity, child health, and psychiatric care deserts-is a public health imperative. A structured decision-making process facilitates the provision of balanced information on the potential maternal and fetal risks of untreated or undertreated illness, the benefits of treatment, and the risks associated with SSRI exposure.
This article explores the therapeutic potential of low-intensity focused ultrasound to modulate focal brain regions for noninvasive and reversible deep brain stimulation.
Importance:Suicide is the leading cause of death among active-duty US Army soldiers. Evidence-based preventive interventions exist but need to be targeted to be cost-effective. Objectives:To develop machine learning models using administrative data available during periodic health assessments (PHAs) to determine eligibility for a remote group dialectical behavior therapy-based skills training intervention for soldiers with elevated risk of suicide or nonfatal suicide attempt. Design, Setting, and Participants:From regular US Army soldier PHAs completed from 2015 to 2019, separate 70% training samples were created for suicides and SAs. Each training sample contained all cases and a stratified equal-probability sample of 10 times as many controls, with inverse-probability of selection weights applied to controls. Model performance was evaluated in the remaining 30% test sample. Data analysis was conducted September 2025 through January 2026. Main Outcomes and Measures:Suicides were recorded in the National Death Index for soldiers either still in or out of active service. SAs were recorded in US Army records only for soldiers still in active service. A 24-month risk horizon was used because successive PHAs, though designed to occur annually, are sometimes separated by this much time. A loss to follow-up weight was used in the SA model to adjust for leaving service within 24 months. Results:PHA data were available from 668 684 regular US Army soldiers. A total of 1 932 243 PHAs (including 85.5% by male soldiers, 46.7% by soldiers aged 28 years or older, and 58.1% by married soldiers) completed during the 2015 to 2019 period were included in analyses. Over 24 months, suicide prevalence was 66.7 per 100 000 (SE = 3.6) and SA prevalence was 704.1 per 100 000 (SE = 14.7) adjusted for loss to follow-up. Test sample area under the receiver operating characteristic curve (AUROC) for suicide was 0.72 (SE = 0.17), with Integrated Calibration Index (ICI) of 0.0003 and Brier score of 0.0007. Test sample AUROC for SA was 0.81 (SE = 0.02), with ICI of 0.0014 and Brier score of 0.0070. Suicide prevalence was meaningfully elevated (at least twice that expected by chance) only in the 5% of PHAs with highest predicted risk (sensitivity = 18.6%; SE = 2.0%). SA risk was elevated only in the 10% of PHAs with highest predicted risk (sensitivity = 46.5%; SE = 1.0%). Predicted probabilities of suicide and SA were correlated (Pearson r = 0.29; t = 233.8; P < .001). Overall, 11.9% of PHAs revealed US Army soldiers at elevated risk of either suicide or SA, and 3.1% were at elevated risk of both outcomes. Conclusions and Relevance:Results of this prognostic study suggest that as suicides and SAs have distinct predictors, an attempt to optimize resource allocation will require thoughtful postintervention considerations of costs and benefits of interventions to optimize net benefit.
Importance:Killing in war is associated with multiple adverse outcomes, including posttraumatic stress disorder (PTSD), moral injury (MI), and suicide. Impact of killing (IOK) is an individual psychotherapy developed to treat the mental health impact of killing in war. Objective:To determine whether IOK improves veterans' mental health symptoms and functioning at posttreatment and 6-month follow-up. Design, Setting, and Participants:This multisite, superiority, randomized clinical trial was conducted from August 2018 to November 2023. Participants were veterans randomized to IOK or present-centered therapy (PCT). Diagnostic assessments were administered at screening and posttreatment by blinded evaluators. Self-report measures were collected at baseline, midtreatment, posttreatment, and 6-month follow-up at 3 Veterans Affairs health care systems in California, New York, and North Carolina via in-person and remote appointments. Participants were a sample of veterans with PTSD who reported distress related to killing in war or feeling responsible for the death of others. Primary exclusion criteria were a psychotic disorder diagnosis, moderate or severe alcohol or substance use disorder, untreated mania, or recent suicidal or homicidal behavior. Interventions:IOK, an individual psychotherapy that focuses on killing cognitions, acceptance, self-forgiveness, and moral repair, and PCT, which addresses current functional issues due to moral distress with related problem-solving. Main Outcomes and Measures:The primary outcomes were psychosocial functioning assessed by the World Health Organization Quality of Life Scale-Brief (WHOQOL-BREF) and the Sheehan Disability Scale (SDS). Secondary outcomes included PTSD and MI measures. Results:A total of 100 individuals (98 male; mean [SD] age, 48.4 [13.7] years) were randomized. Linear mixed models revealed that psychosocial functioning improved for both groups at posttreatment (WHOQOL-BREF and SDS) and the IOK group had a significantly greater improvement than those in PCT on the SDS (-3.50; z score, -2.42; Cohen d, -0.51; P = .02; 95% CI, -5.65 to -0.59). There was no significant difference between treatments on the WHOQOL-BREF at posttreatment. Compared to PCT participants, IOK participants also reported significantly greater improvement in PTSD and MI symptoms. Conclusions and Relevance:Individuals in both treatments improved on measures of psychosocial functioning (WHOQOL-BREF and SDS). Those who received IOK evidenced greater improvements in work or school, social life, and home or family life (as measured by the SDS) compared to those in PCT at posttreatment. IOK participants also reported improved PTSD and MI symptoms. The findings suggest that IOK may improve several outcomes for those who experience distress due to killing in war. Trial Registration:ClinicalTrials.gov Identifier: NCT03764033.
Importance Killing in war is associated with multiple adverse outcomes, including posttraumatic stress disorder (PTSD), moral injury (MI), and suicide. Impact of killing (IOK) is an individual psychotherapy developed to treat the mental health impact of killing in war. Objective To determine whether IOK improves veterans’ mental health symptoms and functioning at posttreatment and 6-month follow-up. Design, Setting, and Participants This multisite, superiority, randomized clinical trial was conducted from August 2018 to November 2023. Participants were veterans randomized to IOK or present-centered therapy (PCT). Diagnostic assessments were administered at screening and posttreatment by blinded evaluators. Self-report measures were collected at baseline, midtreatment, posttreatment, and 6-month follow-up at 3 Veterans Affairs health care systems in California, New York, and North Carolina via in-person and remote appointments. Participants were a sample of veterans with PTSD who reported distress related to killing in war or feeling responsible for the death of others. Primary exclusion criteria were a psychotic disorder diagnosis, moderate or severe alcohol or substance use disorder, untreated mania, or recent suicidal or homicidal behavior. Interventions IOK, an individual psychotherapy that focuses on killing cognitions, acceptance, self-forgiveness, and moral repair, and PCT, which addresses current functional issues due to moral distress with related problem-solving. Main Outcomes and Measures The primary outcomes were psychosocial functioning assessed by the World Health Organization Quality of Life Scale–Brief (WHOQOL-BREF) and the Sheehan Disability Scale (SDS). Secondary outcomes included PTSD and MI measures. Results A total of 100 individuals (98 male; mean [SD] age, 48.4 [13.7] years) were randomized. Linear mixed models revealed that psychosocial functioning improved for both groups at posttreatment (WHOQOL-BREF and SDS) and the IOK group had a significantly greater improvement than those in PCT on the SDS (−3.50; z score, −2.42; Cohen d , −0.51; P = .02; 95% CI, −5.65 to −0.59). There was no significant difference between treatments on the WHOQOL-BREF at posttreatment. Compared to PCT participants, IOK participants also reported significantly greater improvement in PTSD and MI symptoms. Conclusions and Relevance Individuals in both treatments improved on measures of psychosocial functioning (WHOQOL-BREF and SDS). Those who received IOK evidenced greater improvements in work or school, social life, and home or family life (as measured by the SDS) compared to those in PCT at posttreatment. IOK participants also reported improved PTSD and MI symptoms. The findings suggest that IOK may improve several outcomes for those who experience distress due to killing in war. Trial Registration ClinicalTrials.gov Identifier: NCT03764033
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
Importance Auditory hallucinations (AHs) are a hallmark characteristic of schizophrenia spectrum disorders (SSDs) and are often associated with severe distress. Previous research lacks comprehensive evidence on the overall efficacy of approaches targeting AHs in SSDs. Objective To evaluate the efficacy and acceptability of all available psychological and psychosocial interventions targeting AHs in SSDs. Data Sources Embase, MEDLINE, PsycArticles, PsycInfo, PSYNDEX, and the Cochrane library were searched for eligible studies published until August 18, 2025. Study Selection Randomized clinical trials that analyzed psychological interventions targeting AHs compared to controls in adults with SSDs. Data Extraction and Synthesis This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two independent reviewers screened publications, extracted data, and assessed risk of bias. A random-effects meta-analysis was performed (Hedges g) . Main Outcomes and Measures The main outcomes were between-group differences in AHs and clinical characteristics at posttreatment and follow-up, measured with validated rating scales. Additional number-needed-to-treat (NNT) analyses and rating of evidence certainty (GRADE approach) were conducted. Results A total of 23 studies with 2016 participants were included, with 1081 in the intervention groups across 5 different therapeutic approaches and 935 in the control groups. At posttreatment, targeted interventions reduced the severity of AHs compared with control groups (standardized mean difference [SMD], −0.18; 95% CI, −0.31 to −0.05; P = .007; NNT, 16; GRADE, low evidence). This effect was also observed for numerous secondary outcomes, comprising frequency and distress of AHs, total symptoms, positive symptoms, delusions, depression, and anxiety. Subgroup analysis showed that avatar therapy reduced the severity of AHs with the largest effect size (SMD, −0.37; 95% CI, −0.51 to −0.22; P < .001). Sensitivity analyses indicated robustness of results. Dropout rates and reports on adverse events indicated high tolerability and acceptability of treatments. Conclusion and Relevance Although targeted psychological and psychosocial interventions for AHs in SSDs were found to be effective in reducing the severity and other characteristics of AHs, with effect sizes ranging from small to medium, substantial differences were observed between approaches. In particular, avatar therapy seems to be effective at addressing AH symptoms. These findings could influence future studies and clinical care by advancing the development of targeted, novel approaches for AHs that address relevant treatment characteristics.
Importance:Psychiatric diagnosis, prognosis, and management currently rely on subjective assessments. There is hope that peripheral (eg, blood) biomarkers or combinations thereof could transform clinical care by bringing objectivity and patient stratification while being accessible and scalable. The time is ripe to find molecular biomarkers: omics technologies can now profile hundreds to millions of molecules across thousands of individuals, while funders recognize the clinical need and have responded with ambition. However, this enthusiasm will likely be finite, and there is no guarantee that a biomarker will be found. Observations:It is essential to design and perform studies that are most likely to deliver robust peripheral biomarkers with a clear path to translation. This narrative review provides recommendations to optimize peripheral psychiatric biomarker study design. The review first introduces conceptual grounding illustrating how biomarker study design must triangulate clinical utility, technological fit, and biological plausibility. Biomarker studies should optimize for signal-to-noise ratio via careful phenotype selection and minimization of biological and technical noise. However, feasibility issues-in collecting sufficient data on enough representative participants for an adequately powered and clinically translatable analysis-constrain study design. Conclusions and Relevance:Study design is the single most influential and controllable factor for future psychiatric biomarker discovery. This is because many years elapse between study design and data analysis (particularly for biobanked samples held for future use) and because no technological or analytical advances can answer questions that the dataset was not designed for, or overcome unmeasured confounding. Moreover, the direction of biomarker research is constrained by what is possible to design. Many clinical questions and contexts need biomarkers, but realistically, some are better primed for biomarker discovery than others. In this generation of peripheral psychiatric biomarker studies, designs most likely to demonstrate proof-of-principle should be prioritized to ensure the long-term sustainability of the field.
