Coombes, Brandon

Abstract Introduction Observational studies have reported associations between hypnotic use and increased risk of cognitive decline. These findings may reflect confounding from insomnia severity, healthcare utilization, and comorbidity burden. We evaluated whether hypnotic exposure is independently associated with incident mild cognitive impairment (MCI) or dementia after rigorous adjustment, including a comprehensive propensity score (PS) and Apolipoprotein E (APOE) ε4 status. Methods We conducted a retrospective cohort study using a biobank sample with linked electronic health records and genetic data. Hypnotic exposure was derived from orders data and categorized as unexposed (n=27,055), single prescription (n=4243), shorter-term use (n=3999), long-term use (≥6 orders for ≥1 year; n=3214), and by drug class: benzodiazepines (n=376), Z-drugs (n=6222), trazodone (n=2395), and mixed exposure (≥2 classes; n=2435). Incident MCI/dementia diagnoses (ICD-9/10) occurring ≥12 months after initial prescription constituted outcomes. The PS modeled likelihood of receiving hypnotics based on demographics; sleep-related conditions; healthcare utilization (record length, visit frequency, diagnostic burden); psychiatric comorbidities; alcohol use and chronic pain. Hypnotic users were 1:2 matched to unexposed individuals on age, sex, healthcare utilization, and PS. Cox proportional hazards models with a 60-month lag tested associations of exposure category, duration, and class with outcomes. Models adjusted for all PS covariates, cardiovascular risk score, and APOE ε4 status. Results Matched but unadjusted analyses suggested slightly higher hazards of MCI/dementia among hypnotic users versus unexposed (HR=1.08; CI=0.99–1.18). However, after PS adjustment and APOE ε4 inclusion, hypnotic users showed significantly lower hazards (HR=0.81; CI=0.74–0.89). Class-specific analyses indicated reduced hazards for Z-drugs (HR=0.83; CI=0.74–0.93), trazodone (HR=0.71; CI=0.60–0.86), and mixed users (HR=0.79; CI=0.68–0.91), with all classes showing lower hazards than benzodiazepine-only users. Long-term hypnotic use was associated with lower hazards than no prescription (HR=0.69; CI=0.61–0.80), single prescription (HR=0.81; CI=0.68–0.97), or short-term use (HR=0.76; CI=0.65–0.90). Conclusion The elevated cognitive risk among hypnotic users appears largely attributable to underlying clinical/utilization factors rather than hypnotic exposure itself. After comprehensive confounding control, all hypnotic classes except benzodiazepines demonstrated lower risk of MCI/dementia. These findings underscore the need for rigorous adjustment in studies of insomnia pharmacotherapy and suggest potential protective effects of certain hypnotics that warrant further investigation. Support (if any) None

Abstract Background Anxiety disorders (ANX) affect 30–60% of individuals with bipolar disorder (BD), yet limited research has systematically examined clinical characteristics and treatment patterns in this comorbid population. This study investigated demographic, clinical, and pharmacotherapeutic differences between individuals with BD with and without comorbid ANX. Methods Cross-sectional data from 2,225 adults with BD enrolled in the Mayo Clinic Bipolar Disorder Biobank were analyzed. Participants were assessed for comorbid ANX, demographics, clinical characteristics, medication use, and treatment response using the Alda-A scale. Results Overall, 61% (n = 1,366) had comorbid ANX. Individuals with BD + ANX were younger (40.4 vs. 43.6 years, p < 0.001), more likely female (66.6% vs. 54.8%, p < 0.001), and exhibited higher rates of rapid cycling (64.2% vs. 45.2%, p < 0.001), suicide attempts (40.4% vs. 24.8%, p < 0.001), substance use disorders (63.5% vs. 54.8%, p < 0.001), and somatic comorbidities (MCIRS: 6.68 vs. 5.42, p < 0.001). Pharmacotherapeutically, BD + ANX individuals were less likely to receive lithium (37.1% vs. 47.8%, p = 0.005) and valproic acid (21.7% vs. 29.6%, p = 0.047), but more likely to receive antidepressants (53.8% vs. 39.5%, p < 0.001), benzodiazepines (39.9% vs. 26.6%, p < 0.001), and gabapentinoids (8.5% vs. 4.5%, p < 0.001). Notably, 17.3% of BD + ANX individuals received antidepressants without mood stabilizer coverage. Treatment response (Alda-A) scores were significantly lower in BD + ANX for lithium (4.91 vs. 6.05, p < 0.001), mood-stabilizing anticonvulsants (5.09 vs. 6.22, p < 0.001), and second-generation antipsychotics (4.67 vs. 5.73, p < 0.001). Similar patterns were observed in both BD-I and BD-II subtypes. Conclusions Individuals with BD + ANX represent a more severely affected subgroup with distinct prescribing patterns favoring antidepressants over mood stabilizers and attenuated mood stabilizers response. These findings highlight the need for anxiety-informed treatment algorithms recognizing anxiety comorbidity as a negative prognostic factor.

Alcohol use disorder (AUD) is the most prevalent substance use disorder. Excessive alcohol consumption leads to a range of health issues. We set out to identify inflammatory markers linked to alcohol consumption, which might ultimately offer novel insight into genetic underpinnings and have implications for alcohol-associated disease. Alcohol consumption and blood-based multi-omics data were collected by The Mayo Clinic Center for Individualized Treatment of Alcohol Dependence study. Plasma samples from patients with AUD were used for proteomics analysis using the OLINK “Explore Inflammation” panel (n=410). Liver enzymes were also measured. A genome-wide association study (GWAS) was performed to explore the relationship between genetic variants and plasma TREM2 levels. Our findings show thatplasma triggering receptor expressed on myeloid cells 2 (TREM2), a key gene associated with neurodegenerative disease, was the most significant signal correlated with alcohol consumption, and has also been associated with liver enzyme levels in patients with AUD. We identified the rs7232 single nucleotide polymorphism (SNP) in MS4A6A as a key genetic variant associated with plasma TREM2 levels, with the minor allele (A) linked to higher TREM2 levels and increased alcohol consumption, particularly in men. Furthermore, MA4A6A is an ethanol-responsive gene in a SNP-dependent manner, and the variant genotype of the rs7232 SNP was associated with lower expression for MA4A6A due to proteasome-mediated protein degradation. In summary, this study provides insight into the relationship between plasma TREM2 levels, alcohol consumption, and liver function in AUD patients, shedding light on genetic factors underlying alcohol-related diseases.