BACKGROUND: Depression is prevalent among individuals with multiple sclerosis (MS) yet frequently goes undetected and untreated. Time constraints are a barrier to depression screening in MS clinics. We evaluated the clinical utility, diagnostic accuracy and feasibility of the Two-Question Screening tool (2QS) for routine, in-clinic depression screening. OBJECTIVES: A prospective cross-sectional study of 207 consecutively recruited adults with MS (M = 47.3 ± 12.7, 77.3% female) was conducted at a metropolitan MS Clinic. Clinicians administered the 2QS during in-clinic or telehealth consultations. To assess the sensitivity and specificity of the 2QS in identifying depression, participants underwent a Structured Clinical Interview for (SCID-5) for major depressive disorder (MDD), Patient Health Questionnaire-9 (PHQ-9), and the Depression, Anxiety and Stress Scale-21 (DASS-21). Internal consistency, convergent validity and clinician feasibility were assessed. RESULTS: The 2QS had 100% (95% CI: 71%-100%) sensitivity and 68% (95% CI: 60%-76%) specificity for detecting MDD. Clinician screening adherence was 76%. For the in-clinic subsample, clinician-administered 2QS correlations were SCID-5 MDD,  = 0.39 ( = 0.60 with subthreshold depression symptoms added); PHQ-9,  = 0.73; and DASS-D,  = 0.74. CONCLUSIONS: Clinician-administered 2QS is valid and feasible for routine depression screening at MS clinic appointments. With high sensitivity and acceptable specificity, the clinician-administered 2QS is suitable to improve depression detection in people with MS.

OBJECTIVE: Initial presentations of psychosis require a thorough physical health assessment to identify comorbidities, establish treatment safety and exclude organic causes of psychosis. Despite clinical consensus that these assessments are essential, global guidelines are variable and outdated. This work aimed to synthesise current evidence to inform updated recommendations for physical assessments in psychosis, balancing thorough investigation with practical applicability. METHODS: A scoping review of physical health disorders associated with psychosis was conducted using PubMed, Embase and CINAHL. Separately, a systematic review of international guidelines from 2000 to 2025 was performed, extracting physical health assessment recommendations for schizophrenia spectrum disorders. A narrative analysis evaluated the clinical utility of identified investigations. RESULTS: Eighty-four physical health disorders with potential psychotic presentations were identified, mostly rare and typically associated with other neurological or systemic features. There was significant heterogeneity in investigations advised by the 25 identified guidelines, outside of the common consideration for metabolic screening. The majority of guidelines considered investigations for both the exclusion of organic causes of psychosis and identifying a physical health baseline or comorbidity. There was limited consistency around recommendations for neuroimaging or autoimmune screening. Clinical assessment remains central to determining appropriate investigations. CONCLUSION: Global inconsistency in assessment recommendations reflects the complexity of distinguishing organic psychoses from primary psychiatric disorders. Structured yet individualised assessments, informed by symptomatology and risk factors, are essential. A staged, context-sensitive approach is proposed to optimise diagnostic accuracy and avoid unnecessary testing. Updated, evidence-informed guidelines are critical for improving care for people with psychosis.

OBJECTIVES: Functional connectivity between the dorsolateral prefrontal cortex (DLPFC) and subgenual anterior cingulate cortex (sgACC) has been implicated in the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder (MDD). It remains unclear whether effective connectivity between these regions is associated with remission. We examined adults with MDD who received high-frequency rTMS targeting the left DLPFC. METHODS: This single-centre observational study analysed pre-treatment electroencephalography and clinical data of 30 patients. Directed connectivity between the DLPFC and sgACC in the alpha and theta bands was estimated using isolated effective coherence (iCoh) based on exact low-resolution electromagnetic tomography. RESULTS: Baseline alpha-band iCoh values from the left DLPFC to the sgACC were significantly lower in the remission group ( = 0.010, Cohen's  = 1.05), yielding an area under the curve of 0.75 for discriminating remission. In the multivariable logistic regression, lower alpha-band iCoh independently associated with remission (odds ratio = 0.25,  = 0.02). No significant differences were observed in the theta band. CONCLUSIONS: Lower pre-treatment alpha-band effective connectivity from the left DLPFC to the sgACC was associated with remission following rTMS, suggesting that iCoh-derived measures may be a candidate biomarker for personalised rTMS in depression.

BACKGROUND: Current pharmacological treatments offer only limited benefits in altering the course of Alzheimer's disease (AD). Given these limitations, nonpharmacological interventions have emerged as potential therapeutic strategies. This study investigates the therapeutic effects of 40 Hz light stimulation in AD and analyzes blood biomarkers to explore its potential disease-modifying effects. METHODS: This longitudinal study examined the effects of 40 Hz light stimulation on clinical symptoms and blood biomarkers in AD patients. Fourteen individuals were enrolled, with 11 completing the 3-month light stimulation, and 6 continuing to 6 months for the final blood biomarker analysis, including amyloid beta (Aβ) oligomers, Aβ-40, Aβ-42, tau phosphorylated at threonine 181 (p-tau181) and 217 (p-tau217), and neurofilament light chain. RESULTS: At 3 months, cognitive function remained stable or improved in 63.6% of participants, depressive symptoms improved in 54.5%, caregiver burden decreased in 72.7%, and sleep quality improved in 90.9% ( = .014). At 6 months, cognitive function and neuropsychiatric symptoms remained stable or improved in 33.3% and 66.7% of participants, respectively. Biomarker analysis showed decreased Aβ oligomers, increased Aβ-42 and reduced p-tau, suggesting potential disease-modifying effects. CONCLUSIONS: 40 Hz light stimulation demonstrated short-term benefits in cognitive stability, caregiver burden relief, and sleep improvement, with biomarker findings indicating possible neuroprotective effects.

Previous research found that being left behind was positively associated with increased risks of bullying victimization and depressive symptoms, but few studies were conducted to examine the specific left-behind-related adversity that may mediate these relationships. The present study aims to address this gap by examining the mediating roles of eight types of left-behind-related adversity in the association between left-behind status with bullying victimization and depressive symptoms. A total of 1,130 Chinese adolescents (52.4% female;  = 13.3,  = 0.90) completed measures assessing left-behind-related adversity, bullying victimization, depressive symptoms, and demographic variables. The results indicated that being left-behind was associated with higher levels of all eight types of left-behind-related adversity, bullying victimization, and depressive symptoms. Among these adversities, perceived discrimination emerged as a significant mediator in the relationship between being left-behind and both higher levels of bullying victimization and depressive symptoms. Moreover, lack of communication between children and current primary caregivers was also found to mediate the association between being left-behind and more depressive symptoms. These results suggest that perceived discrimination and lack of communication between children and current primary caregivers may serve as underlying mechanisms contributing to the disparity in bullying victimization and depressive symptoms between left-behind children and their non-left-behind counterparts.

BACKGROUND: Pregnancy is a critical period for safeguarding maternal and foetal health, often involving diagnostic and screening methods to detect risks early. These decisions impact not only the foetus (e.g. abortion) but also the mother (e.g. anxiety, depression), the partner (e.g. family conflict), and society. The prenatal period is especially complex due to the physical, psychological, and social changes it entails. This study aims to explore in depth the psychological and social experiences of women who were informed of a potential foetal anomaly during pregnancy but ultimately gave birth to healthy babies. Rather than focusing solely on the diagnostic process, the study sought to understand how women internally managed the uncertainty and emotional burden. METHOD: This qualitative study used a phenomenological approach and interviewed 18 women who were informed of a potential foetal anomaly but gave birth to healthy babies. A total of 151 pages of transcribed data were thematically analysed using Maxqda software. FINDINGS: Six themes emerged: confronting anomaly suspicion, the socio-psychological state of the pregnant woman, reactions from family and partner, process management, difficulties encountered, and emotions during childbirth. Participants reported significant emotional impact upon learning of a possible foetal anomaly, followed by socio-psychological challenges after the diagnosis. CONCLUSION: The findings demonstrate that prenatal anomaly diagnoses affect women on multiple levels, transcending the clinical domain. Holistic prenatal care that acknowledges emotional, social, and cultural dimensions - alongside medical needs - is essential for supporting women during these experiences.

Residential facilities for eating disorders provide recovery-oriented care in less restrictive home-like treatment environments compared to traditional inpatient hospital treatments. These services also frequently integrate staff members with a lived experience of eating disorder recovery-lived experience practitioners-within their treatment frameworks. However, limited research has examined staff experiences of working in these settings. This study explores employee experiences of an Australian residential eating disorder facility using a fixed mixed-methods approach with an independent convergent parallel design. Sixty-five percent of employees consented to participation, with 50% identifying as lived experience practitioners. Findings highlight employees' strong sense of purpose and critical role as facilitators of recovery. Participant narratives positioned staff as, in the words of one participant, the of the facility. While experiences were predominantly positive, employees also identified ideological challenges, including navigating tensions between standardised, phase-based treatment protocols, and person-centered, recovery-oriented care (e.g. adapting structured approaches to meet individual patient needs). Given the centrality of the clinician-patient relationship in treatment outcomes and the interconnection between staff wellbeing, patient safety, and care quality, further research is needed to explore how residential organizations can balance structured protocols with individualized care and employee wellbeing to sustain a skilled and resilient workforce.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene, which leads to a mutant protein that destroys neurons in the brain. Despite intense effort, there remains no approved disease-modifying therapy for HD. Here we develop a pan-HTT-targeting CRISPR-Cas9 system that, when delivered to the striatum of R6/2 and YAC128 mice by AAV5, lowered mutant HTT mRNA and protein by 55-80% via its induction of frameshift-inducing indel mutations in HTT exon 1. Cas9 targeting improved motor coordination and locomotor activity, decreased anxiety-like deficits, reduced clasping and weight loss, limited striatal atrophy, and decreased the formation of intranuclear inclusions immunoreactive for the mutant HTT protein. In Hu21/21 mice, which carry the wild-type human HTT gene in lieu of the mouse ortholog, Cas9 lowered the HTT protein by 44% but induced no measurable behavioral deficits and had no adverse effect on neuronal viability, though its targeting was associated with neuroinflammation. Altogether, our results demonstrate the ability for a newly developed pan-HTT-targeting Cas9 system to affect HD-related phenotypes across models and provide insights into its tolerability.

BACKGROUND: Major depressive disorder affects more women than men, possibly due to sex-specific biological and environmental factors. Previous studies have shown that Galanin, as well as specific fragments of it, such as Galanin 1-15 [GAL(1-15)], play a crucial role in modulating depression in animal models by acting on brain regions like the hippocampus and dorsal raphe nuclei. Until now, its effects had only been studied in male rats, where GAL(1-15) produces depressive and anxiogenic behaviors in behavioral tests. This study analyzes, for the first time, the effects of GAL(1-15) on female rats and compares the expression of galaninergic and serotonergic genes between males and females to understand sex-dependent mechanisms in depression. METHODS: For this purpose, the effect of GAL(1-15) administered intranasally in female rats was assessed, using validated behavioral tests for depression: the Forced Swim Test (FST) and the Tail Suspension Test (TST), as well as the anxiety behavior test: the Open Field Test (OFT). Furthermore, the expression of galaninergic genes (GAL, GALR1, GALR2, GALR3) and the 5-HT1A receptor was compared in untreated male and female rats using qPCR in key brain regions implicated in depressive disorder: the dorsal raphe nucleus (DR), the dorsal hippocampus, and the prefrontal cortex (PFC). RESULTS: We demonstrated that GAL(1-15) intranasally administered in female rats strongly produced depressive behavior in the FST as well as in the TST. Moreover, in the anxiety test, intranasal GAL(1-15) at high doses produced anxiety behavior in the OFT. In addition, the qPCR study revealed that naïve female rats exhibited increased expression of the galaninergic system and 5-HT1A receptor compared to naïve male rats in the DR, dorsal hippocampus, and PFC, several nuclei implicated in depression. CONCLUSIONS: These results demonstrate the existence of sexual dimorphism in the galangergic system.These findings on sex-specific neurobiological variations are crucial for advancing toward more precise therapies tailored to the specific characteristics of each sex in the treatment of depression.

BACKGROUND: Demoralization and depression are common among breast cancer survivors (BCS) following treatment. Although these conditions may be comorbid, their clinical distinctiveness highlights the need for deeper longitudinal and integrative examination. AIMS: This study examined longitudinal associations of demoralization and depression with selected psychological factors and their expression over time among BCS following treatment. METHODS: A mixed-methods longitudinal design was employed. Quantitatively, 190 BCS completed self-report measures at baseline (1-2 years postdiagnosis) and 6 months later. Linear mixed-effects models examined time-invariant and time-dependent associations. Qualitatively, 20 participants were interviewed in depth at both time points, and deductive, theory-driven thematic analysis was conducted. RESULTS: Quantitative analyses indicated that negative and positive self-compassion were associated with both demoralization and depression across time. Fear of recurrence was associated with demoralization across time, whereas its association with depression was primarily time-dependent. Qualitative findings revealed substantial heterogeneity and temporal complexity. At baseline, demoralization was marked by loss of the familiar self, diminished agency, and existential distress. Over time, participants followed divergent trajectories: Some experienced restoration of agency, meaning, and self-trust despite ongoing fear of recurrence, whereas others showed persistent or worsening depressive states characterized by resignation, isolation, and self-blame. Fear of recurrence was not uniformly destabilizing and became clinically salient primarily when accompanied by depression. CONCLUSIONS: Integrated findings suggest that demoralization and depression reflect distinct yet intersecting processes that vary over time. Differential assessment and interventions are essential. Demoralization may be best addressed through meaning-centered and identity-focused approaches, whereas depression may require mood-focused and behavioral interventions.

The growing burden of mental illness and limited access to evidence-based psychotherapy have increased interest in artificial intelligence (AI)-driven conversational agents as potential supports for mental health care. In this exploratory pilot study, we examined the safety and feasibility of an intelligent virtual agent (IVA) designed to simulate psychotherapeutic interactions, with a focus on high-risk situations involving suicidality and substance use. Two licensed psychotherapists engaged in scripted interactions with the IVA across 12 predefined scenarios addressing suicidality and substance abuse. The IVA was powered by GPT-4omni and embedded in a Unity-based avatar. After each interaction, testers evaluated acceptance, usability, and human-robot interaction. Two independent psychotherapists rated the IVA's responses using a structured scale assessing guideline adherence, risk recognition, help provision, de-escalation, and empathy. No real patients were involved; all interactions were simulated for safety testing purposes. The IVA showed preliminary indications of good usability and generally empathic responses. However, problematic responses occurred in 29% of conversations, with 12.5% rated as highly critical. Responses rated as "critical" or "highly critical" referred to outputs that failed to provide adequate support, showed insufficient risk recognition, or included ethically problematic suggestions. Key concerns included inadequate recognition of risk, normalization of substance use, and insufficient referral to crisis resources, particularly in scenarios involving underage alcohol access and suicide-related inquiries. In this small, expert-based pilot safety evaluation, the findings suggest that although AI-based agents may improve access to mental health support, rigorous safety evaluation, clinical oversight, and robust safeguards are essential prior to clinical deployment. No clinical conclusions can be drawn from this simulated study.

Exposure-based cognitive behavioral therapy (CBT) is the frontline treatment for pediatric obsessive-compulsive disorder (OCD), but not all youth fully respond to this treatment. While multiple factors may influence CBT response, homework adherence in CBT is a modifiable target that can improve treatment outcomes. This report examines the relationship between homework adherence and clinical outcomes in a large sample of youth with OCD who received exposure-based CBT. Here, 137 youth with OCD between 7 and 17 years old (M = 12.42, SD = 2.88) participated in a randomized controlled trial of exposure-based CBT. Homework adherence was monitored weekly, and OCD severity was assessed by independent evaluators masked to treatment condition using gold-standard rating scales. Mixed-effects linear and logistic regression models examined the relationship between homework adherence, reductions in OCD severity, treatment response, and clinical remission at post-treatment. Follow-up investigations explored differences in patterns between early- and late-homework adherence. Finally, baseline clinical predictors of homework adherence were explored. There was a significant predictive relationship between greater homework adherence and reduced OCD severity, greater incidence of treatment response, and greater incidence of clinical remission at post-treatment. Greater homework adherence later in treatment-as opposed to earlier in treatment-was most impactful in predicting positive clinical outcomes in exposure-based CBT. Presence of co-occurring ADHD was a significant predictor of decreased homework adherence. Taken together, findings provide insight into a modifiable therapeutic target that can improve treatment outcomes in exposure-based CBT.

BACKGROUND: Evidence on the associations of intra-familial ACEs and DepS with cardiometabolic multimorbidity (CMM) remains limited. We aimed to evaluate the joint associations of intra-familial ACEs and DepS with CMM and to determine whether DepS mediates the relationship between intra-familial ACEs and CMM. METHODS: The study sample consisted of adults aged 50 years and older enrolled in the China Health and Retirement Longitudinal Study (CHARLS, 2011-2020) and the Health and Retirement Study (HRS, 2012-2020). CMM was defined as the concurrent presence of at least two cardiometabolic conditions, including diabetes, heart disease, and stroke. The associations of intra-familial ACEs and DepS with CMM were estimated using Cox proportional hazards models. We further explored the mediating role of DepS using mediation analysis. RESULTS: Among 14829 participants (CHARLS, n = 7210; HRS, n = 7619), 844 (11.7%) incident CMM cases occurred over a median follow-up of 9.0 years in CHARLS and 698 (9.2%) over 7.8 years in HRS. Participants with coexisting 2 or more intra-familial ACEs and DepS showed the highest CMM risk relative to those with 0 or 1 intra-familial ACE and non-DepS (CHARLS: HR, 2.07; 95% CI, 1.72-2.50; HRS: HR, 2.09; 95% CI, 1.60-2.72). DepS mediated 14.58% (95% CI, 7.69-25.78) of the association between intra-familial ACEs and CMM risk in CHARLS and 11.84% (95% CI, 3.61-31.16) in HRS. CONCLUSION: Intra-familial ACEs and DepS were linked to elevated CMM risk, and the relationship between intra-familial ACEs and CMM was partially mediated by DepS, highlighting the importance of integrated intervention for CMM.

Emerging evidence has highlighted the gut-brain axis as a critical mediator in the pathogenesis of both major depressive disorder (MDD) and autoimmune hepatitis (AIH), where systemic inflammation and gut barrier dysfunction play pivotal roles. This study investigated the therapeutic potential of avanafil (AVA), a selective phosphodiesterase-5 inhibitor (PDE5I), in a lipopolysaccharide (LPS)-induced rat model that mimics inflammation-driven MDD and AIH. LPS administration significantly impaired cognitive behavior, induced depressive-like symptoms, elevated pro-inflammatory cytokines, disrupted gut and blood-brain barrier (BBB) integrity, and caused hepatic dysfunction. AVA treatment markedly improved behavioral performance in the novel object recognition and forced swim test, enhanced zonula occludens-1 (ZO-1) expression, and attenuated LPS-induced elevations of matrix metalloproteinase-9 (MMP-9), interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6). Mechanistically, AVA downregulated the TLR4/NF-κB/IDO pathway, restored serotonin levels, reduced quinolinic acid accumulation, and activated the Nrf2/HO-1 signaling cascade in both hippocampal and liver tissues. These findings suggest that AVA exerts neuroprotective and hepatoprotective effects by modulating intestinal permeability, inflammation, and oxidative stress, making it a promising therapeutic candidate for conditions associated with systemic inflammation such as MDD and AIH.

INTRODUCTION: Postherpetic neuralgia (PHN) frequently coexists with depression and remains associated with poor clinical outcomes despite interventional neuromodulation. Repetitive transcranial magnetic stimulation (rTMS) may lower the incidence of poor prognosis in this population. The aim of this trial was to evaluate the effect of perioperative rTMS in patients with PHN and comorbid depression undergoing neuromodulation. METHODS: This randomized, single-center, sham-controlled trial was conducted at the First Affiliated Hospital of Soochow University in Jiangsu Province from February 2025 to November 2025. A total of 174 participants were randomly assigned, stratified by neuromodulation therapy, to receive either 10 Hz rTMS (n = 87) or sham stimulation (n = 87) targeting the primary motor cortex for five consecutive days. The primary outcome was the incidence of poor prognosis at 3 months. RESULTS: The incidence of poor prognosis was significantly lower in the rTMS group compared with the sham group (27.4% versus 42.7%; odds ratio [OR] 0.51; 95% confidence interval [CI] 0.27-0.97; P = 0.039), corresponding to an absolute risk reduction of 15.3%. After adjusting for potential confounders, patients in the rTMS group were less likely to experience poor prognosis at 3 months than those in the sham group (adjusted OR, 0.47; 95% CI 0.23-0.95; P = 0.036). CONCLUSIONS: In this randomized controlled trial, perioperative rTMS reduced the risk of unfavorable clinical outcomes in patients with PHN and comorbid depression undergoing neuromodulation, without compromising safety. These findings support rTMS as a promising adjunctive therapeutic strategy in this population. TRIAL REGISTRATION: Chinese Clinical Trial Register Identifier: ChiCTR2500096978.

Anxiety is a prevalent non-motor symptom of Parkinson's disease (PD), yet treatment options remain limited. This randomized, double-blind, placebo-controlled trial evaluated the effects of a 12-week probiotic supplement containing nine bacterial strains (Bifidobacterium bifidum W23, Bifidobacterium lactis W51 and W52, Lactobacillus acidophilus W37, Levilactobacillus brevis W63, Lacticaseibacillus casei W56, Ligilactobacillus salivarius W24, and Lactococcus lactis W19 and W58) on anxiety symptoms in 61 individuals with PD and clinically significant anxiety. Both the probiotic (n = 30) and placebo (n = 31) groups showed significant within-group improvements on the Parkinson Anxiety Scale, with no significant between-group differences. The probiotic group showed a statistically significant improvement on the Montreal Cognitive Assessment compared with placebo (adjusted mean difference of 1.1 points; 95% confidence interval: 0.04-2.1; p = 0.043). No treatment effects were seen on other secondary outcomes, including depression, constipation, or motor symptoms. No significant between-group differences in gut microbiota composition or systemic inflammatory markers were observed. While the multi-strain probiotic did not reduce anxiety more than placebo, its potential cognitive effects warrant further investigation in larger trials. This trial was registered on ClinicalTrials.gov (NCT03968133) on May 28, 2019.