Objective:The Wnt/β-catenin pathway plays a critical role in neuroplasticity and neurogenesis. The present study aimed to investigate whether circulating regulators of the Wnt/β-catenin pathway-Porcupine, Notum, and Dickkopf-1-differ in adolescents diagnosed with suicidal behavior disorder (SBD) and nonsuicidal self-injury disorder (NSSID) compared with control group. Methods:This case-control study included adolescents aged 12 to 18 years: SBD (n = 41), NSSID (n = 40), and control group (n = 40). Diagnoses were established according to DSM-5 Section III criteria, and psychiatric comorbidities were assessed using the K-SADS-PL. Serum concentrations of Porcupine, Notum, and Dickkopf-1 were measured by ELISA. The Revised Child Anxiety and Depression Scale was used to evaluate the severity of psychiatric symptoms. Results:Serum Porcupine and Notum levels were significantly higher in both the SBD and NSSID groups than in control group, and these differences remained significant after adjusting for age and sex. In contrast, Dickkopf-1 levels did not differ between groups. When patients were reclassified according to psychotropic medication use, Porcupine and Notum levels remained elevated compared with control group in both medication users and non-users. Within the patient groups, no significant correlations were observed between biomarker levels and symptom scores. Conclusion:Elevated serum Porcupine and Notum levels-modulators of the Wnt/β-catenin pathway-characterize adolescents with SBD and NSSID and are consistent with a potential shared biological substrate across self-harm phenotypes. Longitudinal, multicenter studies integrating central and peripheral measures are needed to clarify causality and clinical utility.
Objective:To determine whether newly diagnosed pediatric tic disorder is associated with white-matter microstructural alterations on diffusion tensor imaging (DTI) relative to healthy controls, and whether these changes relate to tic severity and circulating pro-inflammatory cytokines. Methods:Twenty-one medication-naïve children with tic disorder and 26 healthy controls underwent 3T DTI and blood sampling. Voxel-wise group differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity (RD) were examined using tract-based spatial statistics. In the tic group, correlations between DTI metrics, tic severity (Yale Global Tic Severity Scale scores), and cytokine levels were tested, followed by mediation analysis. Results:Patients showed lower FA and higher MD and RD across multiple tracts, including the corpus callosum, corticospinal tract, inferior longitudinal fasciculus (ILF), and inferior fronto-occipital fasciculus (IFOF). Elevated RD in the left ILF correlated with greater tic severity (ρ = 0.61, p = 0.004). Cytokine-DTI associations were region-specific: higher interleukin-1β was linked to lower FA in the left corticospinal tract and higher MD in the right IFOF, whereas higher tumor necrosis factor-α was associated with lower RD in the right IFOF. Conclusion:Medication-naïve pediatric tic disorder is characterized by widespread white-matter abnormalities that relate to both clinical severity and peripheral inflammation. Integrating DTI and immune measures may facilitate biomarker development and guide neuroinflammation-targeted interventions in pediatric tic disorders.
Bupropion is an antidepressant commonly considered to have a relatively low risk of inducing manic switch in the treatment of bipolar depression. However, in certain cases-particularly at higher doses and in the presence of psychotic features-manic switching may occur. In this report, we present a male patient with bipolar I disorder who developed a psychotic manic episode following an increase in bupropion XL dose from 150 mg to 300 mg/day while receiving lithium treatment. This case highlights that, despite its reputation as a relatively safe antidepressant in bipolar depression, bupropion may precipitate dose-related manic and psychotic switches. Based on the clinical findings observed in this patient, cautious dose titration beyond 150 mg/day may be considered in individuals with bipolar disorder with psychotic features, with particular attention to close clinical monitoring following any dose escalation.
Postpartum depression (PPD) is a highly prevalent but under-reported and undertreated disorder that affects mothers and infants alike. The management of PPD has to be thoughtfully catered to limit the exposure of infants to harmful drugs. This network meta-analysis (NMA) was conducted to assess the efficacy of pharmacological interventions for the prevention and treatment of PPD. We searched PubMed/MEDLINE, EMBASE, Scopus, Google Scholar, Cochrane databases and clinical trial registries to find studies to be included, and data were extracted. Random effects Bayesian NMA was performed using Markov chain Monte Carlo simulations. A network graph was built, the rank probability of each treatment was determined, and the surface under the cumulative rank probability curve was calculated. The risk of bias assessment, including publication bias, was assessed. Data from 54 studies, including 7,438 participants, were included for this NMA. No pharmacological intervention demonstrated robust superiority over placebo for the treatment of PPD, though wide credible intervals (CrI) and limited sample sizes preclude definitive conclusions. Trazodone (-1.6; 95% CrI: -2.7 to -0.41) and diphenhydramine (-1.4; 95% CrI: -2.5 to -0.20) are the two treatments that showed an efficacy superior to placebo in the prevention of PPD as seen by symptom severity scores. There was no publication bias, as observed by the funnel plot and Egger's regression test. Based on single small trials, trazodone and diphenhydramine showed statistically superior efficacy to placebo in preventing PPD. Safety considerations in the perinatal and breastfeeding context must be carefully evaluated before these agents are considered in clinical practice.
Objective:Long-acting injectable (LAI) antipsychotics improve adherence and reduce relapse, yet short-term cardiac effects during the initial dosing window remain insufficiently characterized. We examined early corrected QT (QTc) changes within 7-14 days after first LAI dose in psychiatric inpatients and tested whether changes vary by LAI type and common clinical modifiers. Methods:We conducted a retrospective chart review of psychiatric inpatients who received their first LAI antipsychotic during admission. Electrocardiograms (ECG) obtained before LAI initiation and again 7-14 days after injection were analyzed. QTc intervals were calculated using Bazett's formula. The primary outcome was the within-patient QTc change (ΔQTc). Prespecified subgroup analyses examined differences across clinical subgroups. Results:Sixty-three patients had paired ECG recordings. Baseline QTc values were comparable across subgroups. Overall, QTc change after LAI injection was small and not statistically significant (418.7 ± 22.8 ms vs. 421.0 ± 25.0 ms; p = 0.323), and no patient exceeded QTc ≥ 500 ms. Modest QTc increases were observed with second-generation LAIs (p = 0.008), particularly paliperidone palmitate (p = 0.046), as well as with concomitant anticholinergic use (p = 0.024) and medical comorbidity (p = 0.034); however, absolute changes remained < 10 ms. In regression analysis (R2 = 0.565), baseline QTc was the only independent predictor of post-injection QTc (β = 0.687, p < 0.001). Conclusion:Early QTc changes after LAI initiation were small and not clinically meaningful. Post-injection QTc was mainly determined by baseline QTc, supporting guideline-concordant ECG monitoring without routine intensified cardiac surveillance in low-risk patients.
Objective:Benzodiazepines (BZPs) continue to be widely prescribed in non-psychiatric settings, despite clinical guideline recommendations favouring selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) for the treatment of anxiety and depressive disorders. Long-term, hospital-based evidence comparing these prescribing patterns in Japan remains limited. The study aim was to evaluate long-term trends in BZP prescribing relative to SSRI/SNRI use and to identify factors associated with anxiolytic BZP versus SSRI/SNRI prescriptions. Methods:We conducted a database study of all 16,886,524 prescriptions issued between April 2001 and March 2022 at a tertiary university hospital in Japan. Anxiolytic and hypnotic BZPs, SSRIs, SNRIs, and related antidepressants were identified. The ratio of anxiolytic BZP to SSRI/SNRI prescriptions (B/S ratio) was calculated according to department group. Factors associated with anxiolytic BZP versus SSRI/SNRI prescribing were examined using multiple logistic regression analysis. Results:Anxiolytic BZP prescriptions accounted for 2.3% of all prescriptions and declined over time, whereas SSRI/SNRI prescriptions (1.4%) remained largely stable throughout the study period. The B/S ratio was consistently higher in internal medicine than in psychiatry, although a gradual reduction was observed over time. Multivariable analysis demonstrated that anxiolytic BZP prescribing was independently associated with the internal medicine department, female sex, outpatient status, younger age, and earlier calendar years. Conclusion:Despite a temporal decline, anxiolytic BZPs continue to be preferentially prescribed over SSRIs/SNRIs in non-psychiatric settings. These findings underscore persistent gaps between evidence-based recommendations and clinical practice and highlight the need for targeted educational and policy interventions to optimise psychotropic prescribing.
Objective:Obesity is a global health concern linked to neuroinflammation, cognitive decline, and depression. Tumor necrosis factor-α (TNF-α) is a key mediator of these effects, and its inhibition may offer therapeutic benefits. This study investigated whether etanercept (ETN), a TNF-α inhibitor, prevents neurobehavioral alterations induced by a cafeteria (CAF) diet in rats. Methods:Male rats were assigned to control, CAF, or CAF + ETN groups for 12 weeks. Cognitive and affective behaviors were assessed by the Morris water maze, passive avoidance, forced swimming, and sucrose preference tests. Hippocampal TNF-α, interleukin-1β, and brain-derived neurotrophic factor (BDNF) levels were measured. Results:CAF-fed rats developed obesity, memory impairment, and depression-like behaviors, accompanied by increased proinflammatory cytokines and reduced BDNF immunoreactivity. ETN attenuated weight gain and improved cognitive and emotional performance with normalized hippocampal proinflammatory cytokines levels. After ETN treatment, BDNF levels significantly increased compared to the CAF group but still remained lower than the controls. Conclusion:The results of the study indicate that TNF-α inhibition alleviates obesity-induced neuroinflammation and rescues cognitive and emotional behavioral impairments, while only partially restoring hippocampal BDNF levels. These results suggest a potential link between TNF-α inhibition and the mitigation of obesity-associated neurobehavioral dysfunction through the suppression of hippocampal neuroinflammation.
Objective:We aimed to investigate whether LGALS9 contributes to the effects of repetitive transcranial magnetic stimulation (rTMS) in the treatment of ischemic stroke (IS) in rats. Methods:The model of cerebral ischemia in rats was established via middle cerebral artery occlusion (MCAO). After being injected with LGALS9 siRNA prior to MCAO surgery and undergoing rTMS intervention postoperatively, the rats were evaluated for neurological function using the modified neurological severity score (mNSS) and for behavioral function through the foot-fault test and Rotarod test. Brain tissues were collected, and pathological changes were observed. Levels of IL-1β, IL-6, and IL-18 were assessed using ELISA. Immunohistochemistry was employed to detect CD86 expression, while RT-qPCR and Western blot were used to detect LGALS9 expression. Results:MCAO rats showed higher mNSS scores, more foot-fault errors, shorter Rotarod duration, elevated IL-6, IL-18, and IL-1β levels, decreased LGALS9 expression, increased CD86 expression, severe brain damage with increased apoptotic neurons, and elevated neuropathological injury scores. rTMS intervention improved the neurological function of MCAO rats and alleviated the inflammatory response in brain tissues, and LGALS9 enhanced the improvement effects induced by the rTMS intervention. Conclusion:rTMS can improve neurological function, reduce inflammatory responses, and protect brain tissue in rats with IS, effects for which LGALS9 is required to achieve the full benefit. The molecular mechanisms of the rTMS‑LGALS9 pathway remain unclear, as its downstream signaling and effects on neurological function and inflammation are not fully elucidated. Moreover, findings from animal models require further validation for human disease relevance and clinical translation.
Type 2 diabetes mellitus is a major contributor to cognitive dysfunction and neurodegeneration, driven by complex metabolic, vascular, and inflammatory disturbances. Although conventional antidiabetic therapies primarily focus on glycemic control, few effectively preserve the integrity of the neurovascular unit (NVU), a critical determinant of brain health. This review examines the neuroprotective potential of dipeptidyl peptidase-4 (DPP-4) inhibitors, highlighting their unique ability to link metabolic regulation with neural and vascular preservation. A literature search was conducted in PubMed and Google Scholar for English-language articles published up to December 2025, using keywords related to cognitive dysfunction, DPP-4 inhibitors, incretins, glucagon-like peptide-1, and the nervous system. Eligible studies included original research, randomized trials, meta-analyses, animal studies, reviews, and mechanistic investigations addressing the effects of DPP-4 inhibitors on NVU stability. Editorials and studies lacking relevance to diabetes-related cognitive impairment or clear biological mechanisms were excluded. Evidence indicates that DPP-4 inhibitors exert dual neuroprotective actions by enhancing incretin signaling (GLP-1/GIP), which supports synaptic plasticity and attenuates neuroinflammation, and by preserving stromal cell-derived factor-1α, thereby activating the CXCR4 pathway to promote endothelial repair. Additional benefits include modulation of the Nrf2/GPX4 axis, reducing oxidative stress and ferroptosis in neural tissue. Comparative analyses suggest potential advantages over other antidiabetic classes, although clinical data on dementia risk remain heterogeneous. Overall, DPP-4 inhibitors emerge as promising agents for stabilizing the NVU beyond glucose lowering, supporting their repositioning in the management of diabetes-associated cognitive dysfunction.
