Am J Psychiatry
· 2026 Mar · PMID 41764060
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Transcranial magnetic stimulation (TMS) is an established treatment for depression, yet response rates remain at 50% 1 month after treatment. Despite two decades of clinical use, substantial room for improvement remains....Transcranial magnetic stimulation (TMS) is an established treatment for depression, yet response rates remain at 50% 1 month after treatment. Despite two decades of clinical use, substantial room for improvement remains. This overview examines biomarker-guided personalization of brain stimulation. The authors trace the translational path from invasive circuit-level insights through noninvasive biomarkers to clinical deployment. With validated biomarkers, systematic optimization becomes possible: stimulation parameter tuning, state-dependent approaches, augmentation strategies, and closed-loop systems. The path forward requires randomized trials demonstrating that biomarker-guided personalization improves outcomes beyond standard care, justifying increased complexity and costs. Success would mark an important pathway in interventional psychiatry's evolution to precision medicine.
Am J Psychiatry
· 2026 Jul · PMID 41703691
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OBJECTIVE: The authors sought to examine substance use patterns across the sexual identity spectrum, particularly among individuals who describe their sexual identity using different terms or express uncertainty about th...OBJECTIVE: The authors sought to examine substance use patterns across the sexual identity spectrum, particularly among individuals who describe their sexual identity using different terms or express uncertainty about their orientation-groups that remain poorly understood beyond lesbian, gay, or bisexual (LGB) categories. METHODS: Using data from the 2023 National Survey on Drug Use and Health among individuals ≥12 years of age (N=52,525), the authors examined past-year substance use across five sexual identity groups: heterosexual, gay/lesbian, bisexual, those using a different term to describe their sexual identity, and those unsure of their identity. Associations were examined between sexual identity (overall and disaggregated by sex using sex-specific heterosexual reference groups) and past-year use of cannabis, hallucinogens, cocaine, inhalants, methamphetamine, and misuse of prescription opioids, tranquilizers/sedatives, and stimulants. RESULTS: Substance use was higher across all other sexual identity groups compared with heterosexual individuals. Bisexual and gay/lesbian individuals showed elevated odds across most substances examined, particularly inhalants, hallucinogens, and cannabis. Both individuals using different terms and those unsure of their sexual identity showed elevated odds for inhalants, hallucinogens, cannabis, and prescription tranquilizer/sedative misuse, with those using different terms additionally showing elevated odds for prescription stimulant misuse. In sex-disaggregated analyses, both males and females showed elevated odds across multiple substances, with females generally showing elevations across a greater number of substances, although some estimates for males were suppressed due to small sample sizes. CONCLUSIONS: These findings extend our understanding of substance use beyond LGB categories, revealing nuanced patterns among emerging identity groups, underscoring the importance of targeted screening and prevention strategies.
van der Meer D, Shadrin AA, Stinson SE
… +16 more, Koch E, Rokicki J, Rahman Z, Bergstedt J, Ottas A, Sønderby IE, Rødevand L, Fuhrer J, Quintana DS, Dale AM, O'Connell KS, Djurovic S, Lehto K, Milani L, Alver M, Andreassen OA
Am J Psychiatry
· 2026 Jul · PMID 41703690
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OBJECTIVE: Bipolar disorder, major depressive disorder (MDD), and schizophrenia are severe mental disorders and are each associated with poor cardiometabolic health. Mapping genetic relationships of these heritable disor...OBJECTIVE: Bipolar disorder, major depressive disorder (MDD), and schizophrenia are severe mental disorders and are each associated with poor cardiometabolic health. Mapping genetic relationships of these heritable disorders with blood markers of metabolic activity may uncover biological pathways underlying this important shared clinical feature. METHODS: The authors charted genetic overlap of the three disorders, type 2 diabetes, coronary artery disease, and body mass index (BMI) with 249 circulating metabolites through linkage disequilibrium score regression and bivariate Gaussian mixture modeling. Causal relationships and functionally annotated shared genetic variants were estimated, and enrichment across brain and body tissues was investigated. RESULTS: All three disorders had extensive overlap with the metabolites. The pattern of genetic correlations was similar between MDD, type 2 diabetes, coronary artery disease, and BMI (Spearman's correlation r>0.93), opposite in direction to the pattern found for schizophrenia and bipolar disorder (MDD-bipolar disorder r=-0.74; MDD-schizophrenia r=-0.83). Notably, this genetic divergence contrasted with phenotypic associations, which were similar across all three disorders. The metabolites had widespread, robust causal effects on the disorders and cardiometabolic traits. The authors mapped 1,056 genes shared between the individual disorders and metabolites to disorder-specific processes related to metabolic activity, mitochondrial function, and synaptic processes. These genes were expressed throughout the brain, heart, and liver. CONCLUSIONS: Severe mental disorders have strong associations with metabolites, and MDD has a distinctly different genetic relationship than bipolar disorder and schizophrenia do. The study findings suggest that metabolic pathways are involved in the development of severe mental disorders and can play a central role in disentangling disorder-specific etiologies. The "metabolic psychiatry" approach applied here has high potential to guide development of targeted interventions.
OBJECTIVE: Self-harm in childhood and adolescence is associated with a range of adverse outcomes. Limited evidence suggests that these individuals are at elevated risk of experiencing sexual violence in adolescence and y...OBJECTIVE: Self-harm in childhood and adolescence is associated with a range of adverse outcomes. Limited evidence suggests that these individuals are at elevated risk of experiencing sexual violence in adolescence and young adulthood. This population-based cohort study identified children and adolescents with a first presentation to health services for self-harm and examined their risk of subsequent presentation for sexual abuse or assault. METHODS: Health administrative data were used to identify all children and adolescents with a first presentation for self-harm over a 10-year period (2013-2022) in the province of Ontario, Canada (population 16 million). Time to first presentation for sexual abuse or assault was compared to that of individuals in a control group matched on age, sex, and area-level socioeconomic status using Cox proportional hazards modeling. RESULTS: The cohort included 139,233 individuals. After a first presentation for self-harm, the 10-year cumulative incidence of presentation for sexual abuse was 9.06% (95% CI=8.55, 9.57), compared to 1.26% (95% CI=1.17, 1.36) for the control group (hazard ratio=8.32, 95% CI=7.68, 9.02). Risk remained elevated after adjustment for factors influencing vulnerability to sexual abuse (hazard ratio=5.06, 95% CI=4.53, 5.65). Results were similar for the outcome of sexual assault (cumulative incidence, 4.14% [95% CI=3.76, 4.51] versus 0.48% [95% CI=0.41, 0.54]; fully adjusted hazard ratio=6.44, 95% CI=5.38, 7.71). Sex-stratified analyses revealed a greater absolute risk for females. CONCLUSIONS: Presentation for self-harm during childhood and adolescence, in addition to being concerning for potential sexual abuse history, may be a marker of vulnerability for future sexual abuse or assault. These findings suggest a need for further research and implications for clinical practice.
Am J Psychiatry
· 2026 Apr · PMID 41634908
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OBJECTIVE: Although mobile health-tracking technologies have burgeoned, offering objective health information to consumers on an unprecedented scale, opportunities to directly test effects of such monitoring have been li...OBJECTIVE: Although mobile health-tracking technologies have burgeoned, offering objective health information to consumers on an unprecedented scale, opportunities to directly test effects of such monitoring have been limited. Low-cost mobile breathalyzers are one tool commonly employed for blood alcohol concentration (BAC) assessment. The authors explored outcomes linked with BAC-tracking technologies, examining effects on alcohol use and self-estimation of BAC levels in a large U.S. sample. METHODS: Participants (N=32,179) were individuals who voluntarily purchased a mobile breathalyzer and provided at least three ad-lib readings between 2016 and 2022. A paired smartphone application prompted users to enter a BAC self-estimate (a guess) before the measured BAC level was displayed. Analyses included observations collected during active consumption (BAC >0.00%) from breathalyzer users who opted to share anonymized data. Breathalyzer users who displayed inattentive patterns of guessing were excluded from self-estimation analyses. The final dataset comprised 787,393 BAC readings and 387,643 self-estimates. RESULTS: The accuracy of BAC guesses increased by 2.38% over the course of breathalyzer use. Associations between breathalyzer use and BAC levels varied significantly according to participants' initial drinking levels (b=-0.0062, 95% CI=-0.0065, -0.0059). Among heavy-drinking participants, BAC levels decreased on average from 0.106% to 0.096%, whereas the reverse trend was observed for lighter-drinking participants, whose levels increased from 0.058% to 0.067%. A similar interaction emerged for BAC underestimation (b=-0.0058, 95% CI=-0.0066, -0.0049), with odds of underestimation decreasing among heavy-drinking and increasing among light-drinking participants. CONCLUSIONS: The results indicate promise for mobile BAC-tracking technologies as a low-impact intervention with the potential to decrease drinking among individuals who drink heavily-a population particularly susceptible to alcohol-related problems. In contrast, inverted trends emerged for light-drinking individuals, highlighting the need for empirical research in the fast-moving landscape of digital health.
OBJECTIVE: Smoking is associated with an approach bias toward smoking-related stimuli. Approach bias modification (ApBM), a computerized training specifically designed to modify this approach bias, has shown positive eff...OBJECTIVE: Smoking is associated with an approach bias toward smoking-related stimuli. Approach bias modification (ApBM), a computerized training specifically designed to modify this approach bias, has shown positive effects in patients with alcohol use disorder; however, its efficacy as an add-on in smoking cessation treatment is inconclusive. The aim of this clinical trial was to investigate whether ApBM as an add-on to smoking cessation treatment results in higher 6-month prolonged abstinence rates compared to two control conditions. METHODS: In this randomized, controlled, double-blind, single-center superiority trial, 351 participants received a 1-day cognitive-behavioral smoking cessation treatment (treatment as usual [TAU]) and were subsequently randomized to either TAU+ApBM (N=119), TAU+sham training (N=115), or TAU only (N=117). Training sessions were conducted over 7 days. The primary outcome was prolonged abstinence at 6-month follow-up. Participants were classified as either nonsmoking (continuous abstinence for 6 months, ≤5 cigarettes since quit attempt, and breath CO level ≤9 ppm) or relapsed (no objective verification of smoking status, breath CO level ≥10 ppm, >5 cigarettes since quit attempt). RESULTS: In the intention-to-treat analyses, abstinence rates at 6 months were 19.3% (95% CI=12.13, 26.53) for TAU+ApBM, 17.4% (95% CI=10.36, 24.42) for TAU+sham training, and 16.2% (95% CI=9.46, 23.02) for TAU only, with no significant differences between groups. CONCLUSIONS: This large-scale clinical trial demonstrates that TAU+ApBM is not significantly superior to TAU+sham training or TAU only. ApBM has been included in Australian and German alcohol use disorder treatment guidelines, but this randomized controlled trial shows that positive effects do not apply to tobacco use disorder.
Kaul I, Claxton A, Sauder C
… +7 more, Patel T, Chaturvedi S, Brown D, Zhu H, Marcus R, Sawchak S, Brannan SK
Am J Psychiatry
· 2026 Mar · PMID 41634905
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OBJECTIVE: Xanomeline and trospium chloride (X/T) reduced symptoms and was generally well tolerated in two phase 3, 5-week, randomized, double-blind, placebo-controlled trials in adults with schizophrenia. The authors ev...OBJECTIVE: Xanomeline and trospium chloride (X/T) reduced symptoms and was generally well tolerated in two phase 3, 5-week, randomized, double-blind, placebo-controlled trials in adults with schizophrenia. The authors evaluated the long-term safety, tolerability, and efficacy of X/T in an open-label extension of the two phase 3 trials. METHODS: EMERGENT-4 was a 52-week open-label extension trial of participants who completed the EMERGENT-2 and EMERGENT-3 acute trials. Between February 2021 and October 2023, 152 participants initiated twice-daily oral doses of xanomeline 50 mg/trospium 20 mg and titrated to a maximum dosage of twice-daily oral xanomeline 125 mg/trospium 30 mg. The primary endpoint was the proportion of participants reporting a treatment-emergent adverse event (TEAE). Efficacy measures included Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions severity scale (CGI-S). RESULTS: A total of 156 (42.6%) of the 366 participants who completed EMERGENT-2 or EMERGENT-3 enrolled in EMERGENT-4; of these 34 (21.8%) enrolled participants completed the 52-week treatment period. Overall, 81 (53.3%) of 152 treated participants experienced at least one TEAE. Consistent with the acute trials, the most common treatment-related adverse events were gastrointestinal disorders (e.g., nausea, vomiting, dyspepsia, dry mouth) that were mild or moderate in intensity and resolved with continued treatment. No new safety or tolerability issues were observed. X/T was not associated with clinically meaningful motor symptoms, hyperprolactinemia, weight gain, or adverse effects on metabolic parameters. X/T was associated with continued symptom improvement over the trial duration. Mean changes in PANSS total score from acute trial baseline to week 52 were -33.8 and -31.3 in the treatment groups receiving X/T and placebo, respectively, in the acute trials. Similar patterns of continued improvement were observed for scores on the CGI-S, PANSS positive subscale, and PANSS negative subscale. CONCLUSIONS: Long-term treatment with X/T over 52 weeks was safe, generally well tolerated, and associated with durable symptom improvement in people with schizophrenia.