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Background: Ketamine and esketamine are increasingly used for treatment-resistant depression (TRD), yet their hepatic safety profile with repeated or long-term use remains poorly characterized. Chronic recreational ketamine abuse has been linked to cholestasis and cholangiopathy, raising concern that therapeutic use may carry similar risks. No systematic data exist on liver enzyme trajectories or biliary injury at subanesthetic doses used for depression. Methods: This historical cohort study included adults with TRD receiving IV ketamine or intranasal (IN) esketamine at the Mayo Clinic Ketamine Clinic (2017 to 2024). Patients were eligible if they had at least one liver enzyme value (AST, ALT, ALP, or bilirubin) within 12 months before through 3 months after treatment. Longitudinal enzyme trajectories were modeled using generalized linear-mixed models with a Gamma distribution. Clinically significant elevation was defined as ≥2× the upper limit of normal (ULN). Wilcoxon signed-rank tests compared pretreatment and post-treatment paired values. Results: Of 104 enrolled patients, 74 had liver enzyme data available; 51 had post-initiation data. Median age was 51.5 years; 72% were female. Most (78.4%) received IV ketamine. No clinically meaningful changes in enzyme trajectories were observed. Three patients (5.9%) had elevations ≥2× ULN, all attributable to alcohol use, myalgias, or pre-existing hepatic steatosis rather than (es)ketamine. Conclusions: Subanesthetic IV ketamine (0.5 mg/kg) and FDA-approved IN esketamine doses were not associated with clinically significant liver enzyme elevations in this real-world TRD cohort. Current evidence does not support routine hepatic monitoring for asymptomatic patients, although prospective, larger-scale studies are needed to confirm these findings.

Background: Ketamine and esketamine ((es)ketamine) rapidly reduce depressive symptoms and suicidal ideation (SI) in treatment-resistant depression (TRD), but whether early SI improvement during the acute phase of the treatment predicts reduced suicide-associated emergency department (SAED) visits over the longer term remains unclear. Objectives: To examine whether early improvements in SI, measured using item 12 of the Quick Inventory of Depressive Symptomatology – Self Reported (QIDS-SR), following (es)ketamine treatment are associated with SAED visits over 6 months Design: Retrospective cohort study. Methods: Individuals with TRD who had available data on SI measured using the QIDS-SR during the acute phase, as well as data on SAED visits over 6 months, were included. Participants were classified based on changes in SI as resolved, partially improved, or unchanged/worsened using the QIDS-SR item 12 during acute treatment (up to six intravenous (IV) or eight intranasal (IN) treatments) and were followed for SAED visits. Results: Among 96 patients with SI data, 73 (76%) had baseline SI. Following acute-phase treatment, 36 (49%) achieved SI resolution, 14 (19%) partially improved, and 23 (32%) were unchanged/worsened. During the 6-month follow-up, 8 (11%) had post-acute SAED visits. While not statistically significant, patients with resolved SI had lower odds of post-acute ED visits (OR = 0.16, p = 0.12). Kaplan–Meier estimates of SAED visit-free survival across three SI change groups trended toward significance ( p = 0.066), suggesting lower cumulative healthcare (ED) utilization in more favorable change groups. Secondary analysis among 57 patients who received IV ketamine and had baseline SI showed that, after two infusions, 33 (47.2%) demonstrated a reduction in SI. Early SI improvement (⩾50% reduction in SI) was associated with a lower likelihood of any post-treatment SAED visit at 6 months after adjusting for pre-treatment SAED (OR = 0.17, 95% CI: 0.02–0.98, p = 0.047), corresponding to numbers needed to treat of 4.3. Conclusion: Early SI changes may have prognostic implications, though larger studies are needed to confirm clinical significance.

ABSTRACT Introduction Sodium‐glucose cotransporter‐2 inhibitors (SGLT2i), initially developed for type 2 diabetes, have shown promise in improving renal outcomes in patients with and without diabetes. However, their effect on lithium‐associated kidney dysfunction remains unknown. Methods This historical cohort study included patients from Mayo Clinic (2001–2023) with mood disorders who received lithium for ≥ 6 months and later used SGLT2i for ≥ 1 month. Data on SGLT2i use and lithium treatment were extracted from electronic health records. Serum creatinine values were used to calculate estimated glomerular filtration rate (eGFR) trajectories. Linear mixed‐effects models with piecewise linear splines were used to estimate eGFR slopes before and after SGLT2i initiation, adjusted for age and sex. Results Fifty‐six patients (mean age 57.4 years, 46.4% female), predominantly with bipolar disorder (87.5%), were included. The mean eGFR, measured nearest to SGLT2i initiation, was 77.9 ± 26.0 mL/min/1.73 m 2 , and the mean duration of SGLT2i use was 19.5 ± 17.8 months. Before SGLT2i initiation, eGFR declined at a rate of −1.43 mL/min/1.73 m 2 per year ( p < 0.001). After initiation, eGFR increased by 0.69 mL/min/1.73 m 2 per year, reflecting a + 2.13 change ( p = 0.025). Sensitivity analyses, including only patients on lithium at SGLT2i initiation ( n = 22) or who had > 1 year of SGLT2i use ( n = 29) showed similar, though non‐significant, changes in slopes. Conclusion SGLT2i treatment was associated with a significant improvement in eGFR trajectory in patients with mood disorders who received long‐term lithium therapy. These findings suggest a potential role for SGLT2is in mitigating lithium‐associated kidney dysfunction and highlight the need for randomized controlled trials in this population.

Abstract Diffuse hemispheric glioma, H3 G34‐mutant (DHG‐H3 G34) has been primarily molecularly characterized by methylation profiling and sequencing studies. We describe an integrated histomolecular evaluation including high‐resolution copy number profiling of a series of 60 DHG‐H3 G34 to further our understanding of the spectrum of genetic changes associated with this tumor type. Cases were clinically tested using an 187‐gene mutation and fusion targeted neuro‐oncology next‐generation sequencing panel ( n = 60) and Oncoscan chromosomal microarray ( n = 26) by a single laboratory (2018–2022). A subset of cases had immunohistochemical results for OLIG2 ( n = 42), p53 ( n = 48), and ATRX ( n = 46), and methylation array data ( n = 8). Median age at testing was 21 years (range, 12–50). No significant difference was noted in clinical, histopathological, and mutational profile between pediatric and adult patients. H3‐3A G34 mutations included G34R ( n = 56; 94%), G34V ( n = 3), and a non‐canonical G34E ( n = 1). Concurrent mutations most often involved TP53 ( n = 55; 92%), ATRX ( n = 50; 83%), and PDGFRA ( n = 34; 57%). A reportedly primary tumor was confirmed to be hypermutant and had a PMS2 mutation. A single case also showed an FGFR3::FAM184B fusion. All cases with available chromosomal microarray data had unbalanced genomes, which were often complex (14/26; 54%). The most frequent recurrent copy number abnormalities were losses involving 3q, 4q, 10q, 13q, and 18q, and 17p copy‐neutral loss of heterozygosity (cnLOH) encompassing TP53 . This copy number profile was reminiscent of that seen in Grade 4 IDH‐mutant astrocytomas. Collectively, a TP53 abnormality at copy number (12/26, all cnLOH), sequence (55/60) and protein expression (46/48) level was detected in all 60 cases. In conclusion, integrated high‐resolution copy number and histomolecular analysis expanded the spectrum of genetic changes associated with DHG‐H3 G34, including the presence of universal TP53 abnormalities with frequent cnLOH—a copy number abnormality that has been largely unrecognized—for this new 2021 World Health Organization central nervous system tumor type.

IntroductionAlcohol withdrawal syndrome (AWS) is among the most severe components of alcohol dependence (AD). Severe AWS, especially complicated with seizures and delirium, was a common reason for medical complications and death. The introduction of benzodiazepines decreased but did not eliminate those risks. The definition of AWS evolved in different versions of Diagnostic and Statistical Manual for Mental Disorders (DSM) from having hand tremor plus one or more other symptoms in DSM-III-R to any two or more symptoms in DSM-IV, which was retained in the current version of DSM-5.ObjectivesComparing subgroups of individuals with AUD based on AWS symptoms profile to define phenotypes for investigation of biological underpinnings of AWS phenomenology and treatment response.MethodsTreatment-seeking individuals diagnosed with DSM-IV alcohol dependence (AD; n=473; 35.5% females) were assessed with Psychiatric Research Interview for Substance and Mental Disorders (PRISM), Timeline Follow back (past 90 days) alcohol consumption, Penn Alcohol Craving Scale (PACS), Pittsburgh Sleep Quality Index (PSQI), Patient Health Questionnaire-9 (PHQ9), and General Anxiety Disorder-7 (GAD-7). Latent class analysis was used to classify subjects according to lifetime prevalence of AWS symptoms according to DSM-III-R or DSM-IV/5. Demographic and other clinical variables were compared among clusters by linear model ANOVA and chi-squared test.ResultsFour clusters were identified: subjects with (1) no history of meeting any AWS criteria (n=50); (4) with complete number of AWS symptoms, meeting both DSM definitions (n=259); and two clusters of subjects with smaller number of AWS symptoms: (3) those meeting only DSM-IV/5 criteria (n=94) and (2) those also meeting DSM-III-R criteria (n=70). Compared to cluster 2, the Cluster 3 members had higher frequency of anxiety, insomnia, and restlessness during withdrawal. The clusters also differed in the total number of drinks (p=0.021), average drinks per drinking days (p=0.013), history of anxiety disorder (p=0.006), substance-induced depression (p=0.019), and higher scores of PSQI (p<0.001), PHQ9 (p<0.001), and GAD-7 (p<0.001) with a relative increase in frequency between clusters as follows 1<2<3<4. Group 4 also had the highest percentages of subjects with history of seizure, delirium or hallucinations.ConclusionsDifferent definitions of AWS capture clusters of AD patients with different symptomatology, comorbidity and consumption patterns. Understanding of biological underpinnings behind those differences may guide improvement in personalized treatment selection.Disclosure of InterestNone Declared

ABSTRACT Objectives To investigate the value of cytokine, chemokine, and neurofilament light chain (NfL) concentrations in predicting relapse risk, chronic epilepsy, and functional impairment in LGI1 autoimmune encephalitis (AE). Methods Cytokines/chemokines (IL‐1‐beta, IL‐2, IL‐4, IL‐5, IL‐6, IL‐8/CXCL8, IL‐10, IL‐12p70, IL‐13, IL‐17A, GM‐CSF, TNF‐alpha, IFN‐gamma, CXCL9, CXCL10, CXCL13, BAFF) and NfL concentrations were measured in CSF and paired serum from LGI1‐AE patients evaluated at Mayo Clinic (01/2015–02/2024), using a multiplex immunoassay system (ELLA, Bio‐Techne) and correlated with clinical outcomes. A laboratory‐based cohort of LGI1‐IgG‐positive patients and control cohorts, including patients with mixed non‐inflammatory disorders (MNID), Alzheimer's disease (AD), and temporal lobe epilepsy (TLE) were analyzed. Results Forty‐four patients with LGI1‐AE were included; 29 (66%) were male, with a median age of 68.5 years (range, 8–85). Median time from symptom onset to CSF sampling was eight months (IQR, 3–17); 19/42 (45%) experienced a clinical relapse and 27% developed chronic epilepsy. Serum IL‐6, serum and CSF IL‐8/CXCL8, and IL‐17A were higher in LGI1‐IgG positive patients than MNID ( p < 0.05). TLE cytokine/chemokine profiles were similar to LGI1 AE; AD patients had lower serum IL‐6 and CSF IL‐8/CXCL8 ( p = 0.04; p = 0.01), and higher serum IL‐17A and GM‐CSF ( p = 0.004; p = 0.01) than LGI1‐AE. Higher CSF IL‐6 and IL‐8/CXCL8 in LGI1‐AE associated with clinical relapse ( p < 0.05) and higher CSF NfL associated with chronic epilepsy ( p = 0.01). Conclusion Elevations in IL‐6, IL‐8/CXCL8, and IL‐17A were identified in this LGI1‐AE cohort. CSF IL‐6, IL‐8/CXCL8, and NfL levels are potential prognostic biomarkers for risk of relapse and chronic epilepsy in LGI1‐AE.

AbstractBackground and AimsSex‐related hormones and proteins may underlie sex differences in alcohol use disorder characteristics and consequences. Previous reports suggest steroid sex hormones may influence alcohol consumption behaviors while proteins that regulate their circulation levels are rarely investigated. Following up on our earlier study of individual sex‐related hormones' associations with alcohol dependence (AD), this study measured the associations between the combinations of sex‐related hormones and proteins and AD in a larger sample.DesignSex‐stratified case‐control comparison and clustering of plasma sex‐related hormone and protein levels, plus a genome‐wide association study on the AD‐associated hormone and protein combinations.SettingAddiction treatment programs in the United States.ParticipantsFour hundred treatment‐seeking recently abstained AD patients (median = 24.5 days) and 388 age‐and‐sex‐matched controls from a community biobank (male:female ≈ 2:1).MeasurementsPlasma levels of total testosterone, estrone (E1), estradiol (E2), follicle‐stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin (SHBG) and albumin.FindingsIn males, we found higher E2 [β = 0.13, Punadjusted < 0.001, false discovery rate (FDR) = 0.005], progesterone (β = 0.01, Punadjusted = 0.025, FDR = 0.054), LH (β = 0.12, Punadjusted = 0.017, FDR = 0.044) and albumin (β = 0.09, Punadjusted < 0.001, FDR = 0.005) in AD patients than controls; in females, we observed lower E1 (β = −0.24, Punadjusted = 0.024, FDR = 0.113) and progesterone (β = −1.86, Punadjusted = 0.026, FDR = 0.113) and higher albumin (β = 0.18, Punadjusted < 0.001, FDR = 0.001) in AD patients than controls. Three principal components (PCs), reflecting hormone signatures, were statistically significantly associated with AD in each sex: PC1 (TT, E2 and SHBG; β = −0.15, P = 0.016), PC3 (E1, progesterone and albumin; β = 0.28, P = 0.007) and PC4 (SHBG and albumin; β = 0.34, P = 0.001) in males; PC3 (progesterone and albumin; β = −0.38, P = 0.009), PC4 (TT and albumin; β = −0.49, P = 0.001) and PC5 (TT and progesterone; β = 0.54, P = 0.004) in females. Statistically significant SNP × group associations were found in females between PC4 and polymorphisms in RP51004I9.1 (top SNP: rs6082693; P = 5.41E‐12) and in males between PC3 and a genomic locus that contained SLC35E4, DUSP18 and OSBP2 (top SNP: rs13053277; P = 1.77E‐07).ConclusionsThree sex‐related hormone and protein signatures appear to be associated with alcohol dependence in each sex. Peripheral levels of sex‐related hormones and proteins, as well as their combinations, could be altered in people with alcohol dependence who have abstained for a few weeks compared with controls, and such differences may be sex‐specific.

ABSTRACT Background Despite the classic Kraepelinian dichotomy between bipolar disorder (BD) and schizophrenia (SZ), contemporary evidence suggests shared antecedent risk factors and similarities in the early course. This study aimed to identify distinct trajectories leading to first‐episode mania (FEM) and first‐episode psychosis (FEP) by examining antecedent psychopathology, including psychiatric diagnoses, symptoms, substance use, and psychotropic medication exposure. Methods Individuals born after 1985 who resided in Olmsted County, Minnesota, USA, and had FEM/FEP were identified through the Rochester Epidemiology Project. Latent class analysis (LCA) was used to identify subgroups based on antecedent psychopathology incorporating 57 dichotomous antecedent measures before FEM/FEP. Results A total of 202 individuals ( BD n = 73, SZ n = 129; 26.7% female, mean age 20.8 ± 3.7 years) were included. A 3‐class LCA model optimally fits the data. Class 1 (Neurodevelopmental, 29.7%) had a high prevalence of neurodevelopmental disorders, behavioral symptoms, and ADHD medication use. Class 2 (Depressive‐Anxious, 31.2%) included depressive and anxiety disorders, mood‐related symptoms, and SSRI / SNRI use. Class 3 (Minimal Psychiatric Morbidity, 39.1%) had a low prevalence of antecedent diagnoses and symptoms, with comparable substance use to other classes. There were significant diagnostic differences, with SZ being more common in the Neurodevelopmental (71.7%) and Minimal Psychiatric Morbidity (70.9%) classes, while BD was more common in the Depressive‐Anxious class ( p = 0.007). Neurodevelopmental and Minimal Psychiatric Morbidity classes had higher proportions of males (85.0% and 82.3%, respectively) compared to the Depressive‐Anxious class (50.8%, p < 0.001). The Neurodevelopmental class showed an earlier age at first mental health visit (9.5 ± 5.5 years) and a longer antecedent illness duration (10.8 ± 6.1 years) than the other classes ( p < 0.001). Conclusion This study identified three distinct pathways to FEM and FEP, offering a transdiagnostic perspective on the antecedent illness trajectories of BD and SZ. Future research should validate these categories that are more inclusive than the classic BD versus SZ dichotomy and explore their potential for predicting illness course and guiding personalized early interventions.

ImportanceThe rates of suicide and suicide attempts are rising precipitously among early adolescents aged 10 to 14 years in the US. While suicide attempts in this age group are more common and associated with lower lethality than in older age groups, very little is known about these individuals’ long-term social and psychiatric outcomes.ObjectivesTo examine the adult outcomes of individuals making index suicide attempts that came to medical attention between the ages of 10 and 14 years.Design, Setting, and ParticipantsThis population-based cohort constitutes a subsample (n = 164) of a previously reported retrospective-prospective study examining individuals who made index suicide attempts during a 22-year period (1986-2007) in Olmsted County, Minnesota.Main Outcomes and MeasuresTo collect outcome measures, the medical records of all individuals were queried until March 31, 2023, comprising up to 36 years of follow-up data after the index attempt. Measures included current social, psychiatric, and mortality outcomes as well as lifetime measures of psychiatric hospitalizations and repeat suicide attempts. K-means clustering generated adult groupings based on aggregates of psychiatric hospitalizations and repeat attempts. Multivariable logistic regression identified index attempt factors associated with poor adult outcomes.ResultsOf 164 individuals aged 10 to 14 years who made index attempts (128 [78.0%] female; mean [SD] age at index attempt, 13.7 [1.1] years), 3 (1.8%) died on the index attempt. In the follow-up period, no individuals died by suicide. K-means clustering generated a 2-group solution reflecting low (120 [80%]) and high (30 [20%]) rates of adult psychopathology. While a minority of the sample belonged to the high-rate group, characterized by multiple repeat attempts and hospitalizations, the majority had favorable social indicators and fewer reattempts and hospitalizations. Poor adult outcomes were associated with being male (odds ratio, 2.44; 95% CI, 1.00-5.80; P = .04) and having a psychiatric diagnosis prior to the index attempt (odds ratio, 3.27; 95% CI, 1.42-8.07; P = .007).Conclusions and RelevanceIn this sample of early adolescents with index suicide attempts followed into adulthood, all who died by suicide did so on the index attempt. While a small number of individuals went on to develop chronic severe psychopathology, the majority demonstrated little evidence of long-term impairment. Given this discrepancy, future studies should focus on using risk stratification after index attempts to direct postvention resources toward adolescents more susceptible to poor outcomes.

ABSTRACTBackgroundInsomnia and substance use disorders (SUD) are common comorbidities of bipolar disorder (BD). Genome‐wide association studies (GWAS) have uncovered shared genetic contributions to insomnia and BD as well as SUDs and BD. Electronic health record (EHR) derived phenotypes (phecodes) and questionnaire data were used to examine the relationship between insomnia genetic liability and SUDs in BD.Methods40,839 participants from the Mayo Clinic Bipolar Disorder Biobank (BD Biobank; n = 774) and Mayo Clinic Biobank (n = 485 BD cases, n = 39,580 controls) were included in the analyses of diagnosis (phecode) outcomes (insomnia, SUD, alcohol use disorder [AUD] and tobacco use disorder [TUD]). Analyses of specific SUD outcomes obtained through the BD Biobank questionnaire included 1789 cases and considered BD subtype. Logistic regression was used to test for associations between insomnia polygenic risk scores (PRS) and insomnia and SUD outcomes in BD cases and controls.ResultsInsomnia PRS was associated with having an insomnia diagnosis (phecode) in the EHR in controls (OR = 1.19, p = 9.64e‐33) but not in BD cases (OR = 1, p = 0.95). Associations between insomnia PRS and SUD diagnoses were significant in BD cases and controls, with the association being stronger in BD cases (interaction p = 0.024). In the BD Biobank data, the insomnia PRS was associated with increased odds of AUD (OR = 1.19, p = 4.26e‐04), TUD (OR = 1.21, p = 1.25e‐05) and cannabis use disorder (OR = 1.16, p = 4.19e‐03).ConclusionThe effect of genetic predisposition to insomnia on SUD risk may be stronger in BD cases than in controls, which could have clinical care implications for individuals with BD and comorbid SUD.