Purpose Synaptic density is strongly correlated with cognitive function in many neurological disorders. All synapses contain synaptic vesicle glycoprotein 2 A (SV2A), making it a potential therapeutic target for neurodecline. ABBV-552, a high-affinity positive SV2A modulator, increases neurotransmitter release, improving synaptic efficiency. This Phase 1, open-label, mass balance study examined ABBV-552 safety, pharmacokinetics, metabolism, and elimination. Methods Eight healthy males were orally administered 15 mg [C-14]-ABBV-552. Safety was assessed via treatment-emergent adverse event (TEAE), vital sign, electrocardiogram, and laboratory value monitoring. Serial blood, urine, and fecal samples were collected pre-dose, Days 1-14, and daily until discharge. Sample radioactivity was measured with HPLC and metabolites characterized with mass spectrometry. Results Eight participants (30-49 years old) received 15 mg [C-14]-ABBV-552 (similar to 100 & micro;Ci) and were included in analyses (3 prematurely withdrew [personal reasons]). All TEAEs were Grade 1 in severity; euphoria (25.0%), dizziness (25.0%), and muscular weakness (12.5%) were deemed possibly-related to ABBV-552. No meaningful changes in laboratory values, vital signs, or ECGs were observed. Mean radioactive recovery was 78.8% (urine: 70.9%, feces: 7.83%), with < 1% parent drug in excreta. Parent and one metabolite (M2, mono-oxidized parent) accounted for 84% and 13%, respectively, of circulating drug-related material. M5, M9, and M33 were most prominent in urine (similar to 13%, similar to 17%, similar to 11% of dose, respectively); M2/M36 (coeluted; 1.4% of dose) in feces. Conclusions Orally-administered ABBV-552 was well absorbed and primarily recovered in urine as metabolites. M2 was the only major circulating metabolite. Therefore, ABBV-552 is primarily hepatically metabolized and metabolites are renally eliminated. These findings support further investigation of ABBV-552 in neurodegenerative disorders.
Pharmacovigilance Centres (PVCs) provide independent drug information to healthcare professionals in addition to their pharmacovigilance activities. However, their impact on clinical decision-making has been poorly studied. This study assessed the impact of a French PVC on clinical management in a tertiary university hospital (Toulouse University Hospital). We conducted a retrospective observational study including all drug-related enquiries submitted to the Toulouse PVC during 2024. Impact was evaluated according to three predefined criteria: whether the enquiry was submitted before or after a clinical management decision had been made, concordance between PVC recommendations and subsequent clinical management, and documentation of the advice in the electronic patient record. Based on these criteria, impact was classified as certain, probable, or uncertain for enquiries submitted before clinical management, and as confirmatory (validating an already implemented decision) or uncertain for enquiries submitted after clinical management had already been initiated. A total of 128 enquiries were analysed. Most concerned adverse drug reactions (111/128), involved hospitalised patients (100/128), and originated from a broad range of clinical departments, mainly geriatrics (14/128), gastroenterology (11/128), neurology (11/128), infectious diseases (10/128) and internal medicine (10/128). Overall, clinical management was concordant with PVC recommendations in 87
Purpose To investigate the role of CYP2D6 and its pharmacogenetic variability in the association between anticholinergic burden and cognitive function in older adults.Methods We conducted a cross-sectional analysis of 872 community-dwelling adults >= 65 years from the ActiFE-Ulm cohort. Cognitive performance was assessed using the Mini-Mental State Examination (MMSE). Anticholinergic burden scores deriving from CYP2D6-metabolised drugs (ABS2D6) were calculated for all regularly scheduled medications. CYP2D6 metaboliser status was determined via genotyping and categorised as poor (PM), intermediate (IM), normal (NM), or ultrarapid (UM). The 25th, 50th, and 75th percentiles of the MMSE score distribution were studied using quantile regression to examine the association between ABS2D6 and cognition, including interaction and stratified analyses by metaboliser status.Results ABS2D6 was significantly associated with lower MMSE scores at the 50th and 75th percentiles in early models, but not after additional adjustment for age and sex. A consistent effect modification by IM status was observed at the 75th percentile, with IMs showing a significant negative association between ABS2D6 and MMSE in stratified analyses (beta = -0.34 [95% CI: -0.64, -0.05]). After excluding participants with use of CYP2D6 inhibitors, this effect became more pronounced (beta = -0.50 [95% CI: -0.82, -0.18]). Findings among PMs remained uncertain due to limited subgroup size.Conclusion These exploratory findings suggest that CYP2D6 metaboliser status may contribute to interindividual susceptibility to anticholinergic burden-related lower cognitive performance. If confirmed in larger longitudinal studies, pharmacogenetic information may support more individualised anticholinergic risk assessment and safer prescribing in older adults.
Antipsychotic-related overweight and metabolic dysregulation are highly prevalent among patients with severe mental illness. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated substantial metabolic benefits in the general population, their efficacy and safety in antipsychotic-treated patients remain unclear. This review aimed to systematically evaluate the efficacy and safety of GLP-1RAs in patients with antipsychotic-related overweight and metabolic dysregulation. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating GLP-1RAs in adults receiving antipsychotic treatment. PubMed, Web of Science, Embase, MEDLINE, the Cochrane Library, and ClinicalTrials.gov were searched from inception to September 13, 2026. Primary outcomes included changes in body weight, body mass index (BMI), HbA1c, and total cholesterol. Random-effects models were used to pool mean differences (MDs) and risk ratios (RRs). This study was registered with PROSPERO (CRD420261290294). Eight RCTs involving 535 randomized participants were included. GLP-1RAs treatment was associated with significant reductions in body weight (MD = -6.54 kg, 95
