Canuso CM, Bossie C, Fu DJ
… +12 more, Lane R, Doherty T, Lignugaris A, Fagiolini A, Llorca PM, McIntyre RS, Reif A, Sanacora G, Shelton RC, Vieta E, Young AH, Drevets WC
Am J Psychiatry
· 2025 Oct · PMID 41030001
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Am J Psychiatry
· 2025 Nov · PMID 40988466
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OBJECTIVE: Quantifying the contribution of environmental and genetic factors to alcohol use disorder (AUD) criterion count across different ancestries may provide insight into the biopsychosocial etiology of AUD. Althoug...OBJECTIVE: Quantifying the contribution of environmental and genetic factors to alcohol use disorder (AUD) criterion count across different ancestries may provide insight into the biopsychosocial etiology of AUD. Although polygenic risk prediction represents an important future application, its utility may be enhanced when considered in the context of environmental predictors. The authors used large African- and European-ancestry samples to examine how genetic, psychiatric, and environmental factors predict AUD criterion count. METHODS: The authors analyzed data from 11,021 individuals in the Yale-Penn Study sample: 5,843 of African ancestry (AFR) and 5,178 of European ancestry (EUR). Polygenic risk scores (PRSs) were generated from genome-wide association studies of problematic alcohol use (PAU). Generalized linear regression and relative importance analyses determined the independent and interactive effects of environmental and genetic factors on AUD criterion count. RESULTS: PRSs for PAU were positively associated with AUD criterion count in both ancestries and predicted 1.9% of AUD criterion count in the EUR sample and 1.3% in the AFR sample. A combination of education, substance use in the household before age 13, annual household income, and male sex explained 73.1% of the variance in AUD criterion count in the AFR sample and 58.9% in the EUR sample. Among examined psychiatric disorders, posttraumatic stress disorder explained the most variance (10.0% in AFR, 9.4% in EUR), followed by anxiety disorders (3.4% in AFR, 6.2% in EUR) and major depressive disorder (1.3% in AFR, 2.1% in EUR). In the EUR sample, education level moderated the relationship between PRS for PAU and AUD criterion count. CONCLUSIONS: In both African and European ancestry groups, environmental factors explained the majority of the variance in AUD criterion count, but polygenic risk was also a statistically significant predictor. These findings may help inform clinical, research, and policy efforts to mitigate AUD risk.
Sanacora G, Ahmed M, Brown B
… +11 more, Cabrera P, Doherty T, Himedan M, Kern DM, Lim L, Lopena O, Naranjo RR, Nuamah I, Sarayani A, Turkoz I, Bowrey HE
Am J Psychiatry
· 2025 Oct · PMID 40926574
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OBJECTIVE: The objective of this study was to comprehensively examine the real-world safety of esketamine using 58 months of postapproval data in the United States. METHODS: U.S. safety data from patient monitoring forms...OBJECTIVE: The objective of this study was to comprehensively examine the real-world safety of esketamine using 58 months of postapproval data in the United States. METHODS: U.S. safety data from patient monitoring forms submitted to the esketamine Risk Evaluation and Mitigation Strategy (REMS) program and reports submitted to the Janssen U.S. Global Medical Safety (US-GMS) database were evaluated (March 5, 2019, to January 5, 2024). Patient characteristics, use and dosage patterns, adverse events of interest (actively solicited reports of sedation, dissociation, and increased blood pressure), and serious adverse events following esketamine administration were described. The incidence of suicidality and drug abuse/misuse was also evaluated. RESULTS: Most patients were 26-55 years of age (64.3%) and female (61.1%). A total of 1,486,213 outpatient treatment sessions were completed by 58,483 patients who had at least one esketamine treatment session. Sedation, dissociation, and increased blood pressure were reported in 34.7%, 41.0%, and 0.9% of sessions, respectively. Serious adverse events were reported in <0.1% and 0.18% of treatment sessions in REMS and US-GMS, respectively; suicide rates were lower than background rates; and 210 incidences of all-cause abuse/misuse were reported. CONCLUSIONS: Analysis of almost 5 years of real-world use of esketamine in the United States remains consistent with the established safety profile from clinical studies and current product labeling. No new safety signals were identified.
Li SW, Kumpf KT, Urrutia J
… +3 more, Krystal JH, Sanacora G, Wilkinson ST
Am J Psychiatry
· 2025 Oct · PMID 40926573
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This review examines ketamine's neurotoxic potential across preclinical and clinical studies. The authors synthesized data from preclinical models, then integrated findings from human clinical trials of esketamine and ob...This review examines ketamine's neurotoxic potential across preclinical and clinical studies. The authors synthesized data from preclinical models, then integrated findings from human clinical trials of esketamine and observational studies in recreational users. Animal studies have found that repeated or high-dose subanesthetic ketamine administration results in consistent excitotoxic neuronal damage and lasting cognitive deficits, especially in perinatal animals. Infrequently administered relatively low and moderate subanesthetic doses (<1 mg/kg approximate human intravenous equivalent) do not yield overt histopathology in rat and nonhuman primate models. In humans, observational studies in frequent high-dose (>1 g/day) ketamine users show memory and executive function impairments. In contrast, a large clinical trial found that intranasal esketamine at doses up to 84 mg, administered weekly or every other week for several years, is associated with maintained or slightly improved cognitive function in adults with major depression. Lower cognitive function (attention, processing speed) showed some potential worsening among elderly patients; the clinical significance of this is unknown. Direct comparisons of esketamine and off-label racemic ketamine at higher doses have not been done. These studies underscore the potential for neurotoxic effects when ketamine is used at doses or frequencies beyond those utilized in clinical trials, highlighting a critical need for robust longitudinal research. Clinicians are advised to exercise caution, particularly when prescribing ketamine off-label at doses significantly higher than those used in clinical trials. When deviating from this in clinical practice, strong consideration should be given to conducting repeated cognitive assessments. Funding agencies should incentivize preclinical researchers to conduct studies that further elucidate the threshold of ketamine's neurotoxicity.
Coughlin LN, Tomlinson DC, Zhang L
… +6 more, Kim HM, Frost MC, Khazanov G, McKay JR, DePhilippis D, Lin LA
Am J Psychiatry
· 2025 Nov · PMID 40926572
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OBJECTIVE: While opioid overdose has begun to decrease in recent years, stimulant overdose has continued to increase and has not been adequately addressed. Unlike opioid use disorder, there are no medications approved by...OBJECTIVE: While opioid overdose has begun to decrease in recent years, stimulant overdose has continued to increase and has not been adequately addressed. Unlike opioid use disorder, there are no medications approved by the U.S. Food and Drug Administration to treat stimulant use disorder (StUD). The most effective treatment is contingency management (CM), a behavioral intervention that provides tangible rewards to reinforce target behaviors, such as biochemically verified abstinence. Despite the effectiveness of CM on near-term substance use behaviors, the long-term impact on key outcomes such as mortality are unclear. The objective of this work was to examine whether patients with StUD who receive CM have a decreased risk of mortality. METHODS: This was a retrospective cohort study of patients with StUD who received or did not receive CM, using linked electronic health records and death records in the largest integrated health system in the United States, the Veterans Health Administration (VHA), from July 2018 through December 2020. The primary outcome was mortality in the year following the index CM visit. All-cause mortality data were obtained from the National Death Index and linked to electronic health record data. Adjusted hazard ratios were estimated using stratified Cox proportional hazards models. RESULTS: A total of 1,481 patients with StUD who received CM were included alongside 1,481 matched control subjects. Over the 1-year follow-up period, those who received CM were 41% less likely to die (adjusted hazard ratio=0.59, 95% CI=0.36, 0.95) than those who did not receive CM. CONCLUSIONS: This study provides the first evidence that CM use in real-world health care settings is associated with reduced risk of mortality among patients with StUD.
Vano LJ, McCutcheon RA, Sedlacik J
… +13 more, Kaar SJ, Rutigliano G, Nordio G, Finelli V, Townsend L, Berry A, Statton B, Fazlollahi A, Veronese M, Hopkins SC, Koblan KS, Everall IP, Howes OD
Am J Psychiatry
· 2025 Sep · PMID 40887951
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OBJECTIVE: Neuroimaging studies have independently associated schizophrenia with low iron and elevated dopamine synthesis. While preclinical research demonstrates that midbrain iron deficiency leads to striatal hyperdopa...OBJECTIVE: Neuroimaging studies have independently associated schizophrenia with low iron and elevated dopamine synthesis. While preclinical research demonstrates that midbrain iron deficiency leads to striatal hyperdopaminergia, this relationship has not been studied in schizophrenia. The authors conducted a case-control study to examine differences in tissue magnetic susceptibility, a marker of brain iron, and correlated these with striatal dopamine synthesis capacity. METHODS: Magnetic susceptibility in the substantia nigra and ventral tegmental area (SN-VTA) was measured using quantitative susceptibility mapping (QSM) MRI in 159 participants (control subjects, N=80; early-course schizophrenia, N=79, including patients who were antipsychotic-naïve or antipsychotic-free). Because magnetic susceptibility is increased by neuromelanin and reduced by myelin, neuromelanin-sensitive MRI (NM-MRI) and diffusion tensor imaging (DTI) were employed to investigate the influence of neuromelanin and myelin on the QSM findings in 99 participants (control subjects, N=38; schizophrenia patients, N=61). Dopamine synthesis capacity (K ) was then assessed with [F]-DOPA positron emission tomography in 40 people from the schizophrenia group to test whether low SN-VTA magnetic susceptibility was related to high striatal K . RESULTS: SN-VTA magnetic susceptibility was lower in patients with schizophrenia than in control subjects (d=-0.66, 95% CI=-0.98, -0.34). This difference remained significant in analyses controlling for mean diffusivity (a DTI measure inversely correlating with myelin concentration) and NM-MRI contrast-to-noise ratios. SN-VTA magnetic susceptibility was significantly inversely correlated with striatal K , independent of mean diffusivity and NM-MRI contrast-to-noise ratios (r=-0.44). In both analyses, the strongest effects were observed in the ventral SN-VTA. CONCLUSIONS: These findings suggest that lower levels of non-neuromelanin-bound iron in the SN-VTA contribute to striatal hyperdopaminergia in schizophrenia. Further investigation is warranted to understand the role of low iron in schizophrenia and its potential as a treatment target.
Crone C, Fochtmann LJ, Ahmed I
… +12 more, Balas MC, Boland R, Escobar JI, Heinrich T, Jackson-Triche M, Levenson JL, Mattison M, McCullen Truett J, Oldham MA, Seritan A, Fochtmann LJ, Hong SH
Anglin DM, Olfson M, van der Ven E
… +8 more, Oh H, Lewis-Fernández R, DeVylder J, Oluwoye O, Dixon L, Stroup TS, Guyer H, Bareis N
Am J Psychiatry
· 2025 Sep · PMID 40887946
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OBJECTIVE: The study aim was to identify ethnoracial disparities in the prevalence of schizophrenia spectrum disorders (SSDs) and positive psychotic symptoms in the United States and examine the role of social neighborho...OBJECTIVE: The study aim was to identify ethnoracial disparities in the prevalence of schizophrenia spectrum disorders (SSDs) and positive psychotic symptoms in the United States and examine the role of social neighborhood inequities. METHODS: Participants in the Mental and Substance Use Disorders Prevalence Study, a national household sample of nonelderly adults (N=4,764), were assessed by clinicians with the Structured Clinical Interview for DSM-5 (SCID-5) for SSDs (past year and lifetime), including schizophrenia, schizoaffective disorder, and schizophreniform disorder, and for psychotic symptoms. Weighted logistic regression models estimated ethnoracial differences in the prevalence of SSDs and psychotic symptoms in unadjusted models, age- and sex-adjusted models, and models further adjusted for a neighborhood Social Vulnerability Metric (SVM) score, a composite index of five social determinants of health domains. RESULTS: Compared to non-Hispanic White individuals, non-Hispanic Black individuals had a significantly higher prevalence of SSDs (4.1% vs. 1.2%; adjusted odds ratio=3.49, 95% CI=1.37, 8.91) and psychotic symptoms (9.3% vs. 4.9%; adjusted odds ratio=2.04, 95% CI=1.15, 3.63), and non-Hispanic multiracial individuals had a significantly higher prevalence of SSDs (5.6%; adjusted odds ratio=4.59, 95% CI=1.53, 13.76). Further adjustment for SVM score lowered the Black-White group difference for SSDs (adjusted odds ratio=2.49, 95% CI=0.63, 9.90) and psychotic symptoms (adjusted odds ratio=1.69, 95% CI=0.83, 3.44), and the associations were no longer statistically significant. The difference in SSDs between the non-Hispanic multiracial and White groups was attenuated after SVM score adjustment (adjusted odds ratio=3.95, 95% CI=1.30, 12.00) but remained significant. CONCLUSIONS: This national U.S. household study found ethnoracial differences in the prevalence of clinician-assessed SCID-based schizophrenia spectrum disorders and positive psychotic symptoms. The higher prevalence among minoritized groups, particularly Black individuals, was connected to social inequities and community-level vulnerabilities embedded in neighborhoods and associated with structural racism.