Cerebellar abnormalities have been associated with attention-deficit/hyperactivity disorder (ADHD) in human studies. Animal models also implicate cerebellar microcircuit dysfunction, particularly reduced inhibitory control of granule cells (GCs) in mice lacking Git1, an ADHD risk gene. Excitatory GCs are the most abundant neuronal population in the cerebellum and are enriched in α6 subunit-containing GABAA (α6GABAA) receptors. Thus, α6GABAA receptor-selective positive allosteric modulators (PAMs), such as pyrazoloquinolinones (PQs), may represent a novel therapeutic approach for ADHD. Here, we tested this hypothesis using PQ Compound 6 in juvenile (P28) ICR mice treated with dizocilpine (MK-801, 0.2 mg/kg, intraperitoneally, i.p.), an NMDA receptor antagonist. In both sexes, MK-801 induced behavioral abnormalities resembling the three core symptoms of ADHD- hyperlocomotion, impulsivity, and inattention-as assessed by locomotor activity, cliff avoidance reaction, and novel object recognition tests, respectively. Compound 6 (3 mg/kg, i.p.) normalized these ADHD-like behavioral impairments. Atomoxetine, an approved ADHD medication, also attenuated ADHD-like phenotypes, although with sedative effects. The therapeutic-like effects of Compound 6 were abolished by intracerebellar microinjection of furosemide, an α6GABAA receptor antagonist, and were absent in Gabra6 (α6-encoding gene)-knockout mice, indicating that positive modulation of cerebellar α6GABAA receptors underlies the observed behavioral improvements. Together, these findings provide proof-of-concept that enhancing cerebellar α6GABAA receptor-mediated inhibition can ameliorate ADHD-relevant behavioral impairments and highlight α6GABAA receptor-selective PAMs as a potential pharmacotherapeutic strategy for ADHD.

Attention deficit hyperactivity disorder (ADHD) lacks validated biomarkers for tracking symptom trajectories or guiding treatment selection in youth. Here we quantify individual deviations from normative age-related trajectories of white-matter structural connectivity across two independent datasets: 6,687 typically developing and 1,114 ADHD scans from a longitudinal developmental cohort, and 355 typically developing and 477 ADHD participants from an independent cohort. Youths with ADHD showed pronounced structural connectivity deviations enriched towards the association end of the sensorimotor-association connectional axis. A subset of higher-order association connections showed ADHD-specific developmental reductions in deviations beyond typical developmental patterns, and these changes mediated age-related declines in ADHD symptoms. Within-individual decreases in deviation over 2 years tracked symptom improvement. Baseline deviations predicted 12-week treatment response to atomoxetine but not methylphenidate, and follow-up imaging revealed treatment-related reductions in deviation. Together, these findings identify structural connectivity deviation as a developmental biomarker with prognostic relevance for ADHD, supporting precision care through symptom monitoring and treatment stratification.

Diabetic kidney disease (DKD) differs transcriptionally across renal compartments. We assessed whether Lycii Fructus-annotated targets showed reproducible DKD-associated changes and enrichment beyond matched expectations. Linked glomerular (GSE30528) and tubulointerstitial (GSE30529) cohorts were used for discovery; GSE96804 and platform-specific GSE104954 subsets provided external assessment. Phenotype-independent probe aggregation preceded limma analysis. Of 106 standardized HERB targets, 91 were measurable. Specificity was tested by hypergeometric analysis and 10,000 expression- and publication-matched permutations; external evidence was graded symmetrically. Thirty-six targets met the primary criterion in at least one compartment, but the target set was not enriched. CASP8 and VEGFA met Tier A external criteria, whereas ADRB2 and SLC6A2 met Tier B criteria. At the stricter |log2FC| ≥ 0.585 threshold, ADRB2 passed in both discovery compartments, VEGFA only in glomeruli, and CASP8/SLC6A2 in neither. STRING analysis used the measured-gene background. Reference redocking reproduced carazolol in ADRB2 and atomoxetine in SLC6A2 (RMSD, 1.08 and 1.09 Å). Thus, the four genes are reproducible DKD-perturbed candidates carrying Lycii Fructus annotations, not evidence of a Lycii Fructus-specific mechanism; they warrant targeted pharmacological testing.

Obstructive sleep apnea (OSA) is a highly prevalent sleep-related breathing disorder affecting an estimated 1.36 billion people worldwide. It is associated with excessive daytime sleepiness, impaired quality of life, cardiovascular and cerebrovascular disease, and increased all-cause mortality, and is a substantial economic burden. Although positive airway pressure (PAP) remains the gold-standard therapy, its effectiveness is limited by suboptimal tolerance and adherence, leading to interest in pharmacological alternatives. Among emerging options, AD109, a combination of the selective noradrenergic reuptake inhibitor atomoxetine (75 mg) and the antimuscarinic aroxybutynin (2.5 mg), taken once daily, represents a mechanistically targeted approach that acts on the neuromuscular roots of OSA. Preclinical work demonstrated that pharyngeal dilator tone is suppressed in sleep through withdrawal of noradrenergic excitation and active muscarinic inhibition at the hypoglossal motor nucleus, providing the rationale for combining a noradrenergic agent with an antimuscarinic to augment hypoglossal motor output and preserve upper-airway patency. Building on a series of smaller precursor trials of noradrenergic-antimuscarinic combinations, AD109 has demonstrated consistent efficacy across phase 2 and two large phase 3 trials (SynAIRgy and LunAIRo), with meaningful reductions in the apnea-hypopnea index, improvements in nocturnal oxygenation, and a generally favorable tolerability profile. These findings position AD109 as a promising oral option, particularly for adults with mild to severe OSA who cannot tolerate or decline PAP. However, its effect on long-term cardiovascular, neurocognitive, and mortality outcomes remains to be established. This commentary reviews the mechanism of action and clinical trial evidence for AD109 and related combinations.

ObjectiveThe prevalence of attention-deficit/hyperactivity disorder (ADHD) has risen in recent decades. The objective of this study was to identify trends in prevalence rates of ADHD medication use as well as any patterns of ADHD medication use among individuals aged up to 24 years in Quebec, Canada.MethodWe conducted a repeated cross-sectional study using medico-administrative data between the fiscal years 2000 to 2001 and 2022 to 2023. We estimated crude and age-adjusted prevalence rates along with their 99% confidence intervals according to sex, age (only for crude estimates), material and social deprivation, and ADHD medication type, namely stimulants (amphetamine-based and methylphenidate-based medications) and non stimulants (atomoxetine and guanfacine). We also analyzed prescribing by prescriber type.ResultsAmong the 4,771,183 individuals aged ≤24 years, 7.7% claimed ADHD medications. Age-adjusted prevalence of ADHD medication use increased from 2000 to 2001 (1.9%) until 2017 to 2018 (7.9%) and plateaued afterwards. The analysis highlighted not only variations in medication use over time but also by sex, with males more likely to be prescribed these medications than females. Family physicians have become the primary prescribers, overtaking pediatricians in recent years. Stimulant medications were the most common treatment throughout the study period, though we observed diversification in prescribed ADHD medication types across age groups.ConclusionsThis study emphasizes a significant increase in ADHD medication use from 2000 to 2018 and a stabilization in use afterwards. The expansion of diagnostic criteria in 2013 and heightened awareness may have narrowed the disparity between the condition's prevalence and its management and may explain the increase in use observed in earlier years and the stabilization observed over the more recent years. The disparities between males and females, as well as between age groups, highlight the need for continuous monitoring of prescribing trends and support targeted equity evaluations to inform service planning and improve access where needed.

Pharmacotherapy persistence in adults with attention-deficit/hyperactivity disorder (ADHD) remains concerning; however, evidence describing early treatment changes and discontinuation is limited. This study aimed to describe initial ADHD pharmacotherapy patterns and quantify claims-based initial regimen instability in Japanese adults. Using a Japanese claims database, we assembled a cohort of adults who initiated ADHD medication with methylphenidate, atomoxetine, guanfacine, or polytherapy (combination therapy) at initiation. Initial regimen instability was defined as the first observed regimen modification, including switching, add-on/polytherapy, de-escalation or combination-pattern change among initial polytherapy users, or a temporary drug-free interruption followed by restart after 31-179 d. A sustained medication-free period of ≥180 d without restart was treated as a competing event. We estimated cumulative incidence functions for initial regimen instability, treating the sustained medication-free period as a competing event. Fine-Gray models adjusted for age, sex, and major psychiatric comorbidities were used to compare initial regimens with methylphenidate as a reference. Landmark analysis was used to assess robustness. Among 14814 initiators, 3085, 8517, 3076, and 136 started methylphenidate, atomoxetine, guanfacine, and initial polytherapy, respectively. In the adjusted Fine-Gray model, the subdistribution hazard ratio for initial regimen instability was 0.74 for atomoxetine and 0.72 for guanfacine, whereas it was higher (2.65) for initial polytherapy in the main analysis. However, this estimate was sensitive to the operational definition of regimen instability. Landmark analysis yielded consistent differences between regimens. Initial ADHD pharmacotherapy showed heterogeneity in Japanese adults and included initial polytherapy, with initial regimen instability differing substantially depending on the starting regimen.

2-Aryl oxetanes are valuable strained-ring synthons, yet a broadly useful chemical kinetic resolution of this substrate class has remained largely unavailable. Here we report a dinuclear (salen)titanium-catalyzed radical ring-opening strategy for the kinetic resolution of 2-aryl oxetanes under mild conditions. The reaction accommodates diverse aryl-, heteroaryl-, and drug-conjugated substrates, delivering enantioenriched oxetanes with high regio- and enantioselectivity. The resulting oxetanes serve as versatile chiral platforms and enable concise, modular, and enantio-retentive access to pharmaceutically relevant targets, including (S)-Atomoxetine, (S)-Nisoxetine, and (S)-Fluoxetine. Mechanistic studies reveal distinct stability/reactivity relationships between diastereomeric Ti-oxetane intermediates, differentiated by an unusual ligand-substrate C-H···π interaction, display distinct stability/reactivity relationships during C─O bond homolysis. Beyond establishing a broadly useful kinetic resolution of 2-aryl oxetanes, this work reveals an unusual mode of attractive ligand-substrate recognition in salen-titanium radical catalysis.