Obesity and major depressive disorder (MDD) frequently co-occur and confer mutually reinforcing risks, including elevated suicidality. Tirzepatide has demonstrated substantial metabolic benefits, yet its psychiatric safety in high-risk populations with MDD remains uncertain. This study aimed to compare suicidal ideation outcomes among adults with comorbid obesity and MDD initiating tirzepatide versus non–GLP-1RA anti-obesity medications. This retrospective, propensity score–matched cohort study used deidentified electronic health record data from the TriNetX Global Collaborative Network. Adults (≥18 years) with diagnosed obesity and MDD who initiated tirzepatide or non–GLP-1RA anti-obesity medications were included. The primary outcome was suicidal ideation. Secondary outcomes included anxiety disorders, insomnia disorders, all-cause mortality, and emergency department or inpatient encounters. Among 24,103 matched pairs, tirzepatide use was associated with lower risk of suicidal ideation (HR, 0.63; 95% CI, 0.42–0.93), anxiety disorders (HR, 0.83; 95% CI, 0.81–0.86), insomnia disorders (HR, 0.92; 95% CI, 0.86–0.98), all-cause mortality (HR, 0.38; 95% CI, 0.25–0.58), and emergency department visits or hospitalizations (HR, 0.94; 95% CI, 0.89–0.99). Risk reduction was generally consistent across prespecified subgroups. Control outcome analyses supported the internal validity of the findings. In conclusion, this study provides real-world evidence that tirzepatide initiation was associated with a lower recorded risk of suicidal ideation, as well as reduced anxiety, insomnia, all-cause mortality, emergency department visits, and hospitalizations, among adults with comorbid obesity and MDD. This observational association should not be interpreted as evidence of a direct antisuicidal effect. These findings support the potential for tirzepatide to serve as a metabolically favorable treatment option associated with a lower risk of suicidal ideation in this vulnerable, high-risk population.
Metabotropic γ-aminobutyric acid type B receptors (GABABRs) are implicated in alcohol use disorder (AUD) and represent a promising therapeutic target. However, robust biomarkers of GABABRs target engagement and sensitivity in humans are lacking. We examined transcranial magnetic stimulation (TMS)–derived cortical inhibition and growth hormone (GH) release as measures of GABABR function, and whether heavy alcohol use is associated with altered responses to pharmacological GABABR activation. In a randomized, double-blind, placebo-controlled crossover study, 31 healthy volunteers (16 heavy drinkers, 15 light drinkers) received baclofen 30 mg, baclofen 60 mg, or placebo across three sessions. Long-interval intracortical inhibition (LICI), short-interval intracortical inhibition, and intracortical facilitation were assessed with paired-pulse TMS at baseline and ~60 min post-dose. Baclofen blood concentrations and plasma GH levels were measured. Baclofen produced dose-dependent increases in GH release, confirming neuroendocrine GABABR engagement. The LICI response to baclofen differed between groups: In light drinkers, baclofen at 30 mg potentiated LICI, and a similar potentiation was seen at 60 mg, indicating that a plateau may have been reached. In contrast, in heavy drinkers, a potentiation of LICI similar to that in light drinkers was seen at 30 mg baclofen, but was absent at the 60 mg dose despite comparable pharmacokinetics, suggesting altered GABABR function. Effects were selective for GABABR–mediated inhibition, with no consistent modulation of short-interval intracortical inhibition or corticospinal excitability. Acute baclofen administration reveals altered GABABR sensitivity in heavy drinkers, with preserved responses at lower doses but reduced response under stronger agonist stimulation. LICI and GH release provide complementary biomarkers of central and peripheral GABABRs engagement and may support translational development of mechanism-based treatments for AUD.
Oxidative stress plays a key role in bipolar disorder (BD). 8,5’-cyclopurine-2’-deoxynucleosides (cPUs), including R- and S-cdA, are tandem oxidative lesions that distort the DNA helix, impair replication and transcription, and are primarily repaired by the nucleotide excision repair (NER) pathway. To date, cPU levels and NER gene expressions have not yet been studied in BD. This study assessed cPU levels and the expression of NER genes (XPB, XPC, XPD, XPF, ERCC1, and CSB) in individuals with BD (n = 44), their unaffected siblings (n = 37), and healthy controls (HC; n = 46). Urinary cPU levels were quantified using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Expression of NER pathway genes were assessed in peripheral blood samples using quantitative reverse transcription PCR. cPU levels were significantly elevated in both BD and sibling groups compared to HCs, with R-cdA concentrations highest in siblings. NER gene expressions were also increased: XPB, XPF, ERCC1, and CSB were upregulated in siblings, while XPC was elevated in both BD and sibling groups. XPB, XPF, and CSB levels were significantly higher in siblings than in the BD group, whereas XPD expression was increased in the BD group compared to both siblings and HCs. Elevated nucleotide damage and increased NER gene expression in individuals with BD and their unaffected siblings support prior evidence implicating oxidative DNA damage and repair mechanisms in BD pathogenesis. The identification of cPU lesions and distinct NER expression patterns highlights additional molecular markers and suggests a potential familial vulnerability contributing to the development of BD.
Generalized anxiety disorder (GAD) is a prevalent disorder associated with disrupted topological organization of large-scale brain networks. However, the morphological basis for network disruption and its clinical relevance remains unexplored. We constructed single-subject cortical morphological networks for 58 drug-free GAD patients and 86 age- and sex-matched healthy controls (HCs) separately based on cortical thickness, surface area, cortical volume, mean curvature, sulcal depth and local gyrification index. Between-group differences in local morphology and network topology were analyzed using general linear models. Partial correlation analyses were conducted to examine the relationship between brain alterations and clinical characteristics in GAD patients, while controlling for age, sex, education years and intracranial volume. Compared with HCs, GAD patients showed increased thickness in the left middle temporal gyrus and decreased local gyrification index in the left superior frontal gyrus. At the network level, GAD patients exhibited increased local efficiency, normalized clustering coefficient, and small-worldness, alongside decreased characteristic path length in cortical volume-based networks. Local morphology and network topological properties were associated with clinical characteristics such as illness duration, age of onset, anxiety severity, and personality traits. Our findings revealed both region-specific cortical abnormalities and global network reorganization in GAD patients. In particular, the shift toward stronger small-world configurations suggests enhanced local integration and global communication efficiency. These results highlight that GAD is associated not only with focal cortical alterations but also with systemic structural network changes that may underlie excessive anxiety and personality traits associated with the disorder.
Long-acting injectable (LAI) aripiprazole is approved for maintenance treatment of bipolar disorder (BD), but real-world efficacy and safety evidence remains limited. Using the TriNetX Global Collaborative Network, we conducted a target trial emulation among patients with BD who initiated oral aripiprazole between 2017 and 2023. Patients switching to LAI within one month were compared with those continuing oral therapy. After 1:1 propensity score matching on demographics, comorbidities, prior treatments, and laboratory data, hazard ratios (HRs) with 95% confidence intervals (CIs) for nine efficacy and safety outcomes were estimated using Cox proportional hazards models, with prespecified sensitivity and subgroup analyses. After matching, 1814 LAI and 1814 oral aripiprazole users were followed for a mean of 1.6 years. LAI use was associated with reduced all-cause hospitalization (HR 0.77, 95%CI 0.69–0.85) and emergency department visits (0.88, 0.79–0.98), with no difference in suicidal ideation or behavior (0.90, 0.75–1.08) or all-cause mortality (0.86, 0.55–1.37). Risks were higher for obesity (1.17, 1.06–1.29) and extrapyramidal symptoms (2.20, 1.38–3.50), but lower for major adverse cardiovascular events (0.73, 0.55–0.95) and hyperlipidemia (0.83, 0.72–0.97). Efficacy benefits were most pronounced in females and middle-aged or older adults; in adolescents, suicidal ideation or behavior was markedly reduced (0.49, 0.35–0.68). Sensitivity analyses showed similar trends. In BD, LAI aripiprazole was associated with better clinical outcomes without increased mortality compared with continued oral aripiprazole. The favorable benefit–risk profile supports broader consideration of LAI in maintenance care, with active monitoring of obesity and extrapyramidal symptoms.
