Sage

Erratum in JAMA Psychiatry. 2025 Nov 1;82(11):1153. doi: 10.1001/jamapsychiatry.2025.2398. IMPORTANCE: The incidence and nature of discontinuation symptoms following antidepressant cessation remain unclear. OBJECTIVE: To examine the presence of discontinuation symptoms using standardized scales (eg, Discontinuation-Emergent Signs and Symptoms [DESS]) and the incidence of individual discontinuation symptoms in individuals who stop taking antidepressants. DATA SOURCES: The databases Embase, PsycINFO, Ovid MEDLINE, and Cochrane Library were systematically searched from inception until November 7, 2023. STUDY SELECTION: Randomized clinical trials (RCTs) reporting discontinuation symptoms using a standardized scale or individual symptoms (eg, adverse events) following antidepressant cessation were included. DATA EXTRACTION AND SYNTHESIS: Data extracted were cross-checked by 2 reviewers. Additional unpublished data from 11 RCTs were included. A random-effects meta-analysis was conducted to calculate standardized mean difference between individuals who discontinued an antidepressant vs those who continued an antidepressant or discontinued placebo. A proportion and odds ratio (OR) meta-analysis was performed to assess incidence of individual discontinuation symptoms compared to placebo. Subgroup analyses were conducted to compare different antidepressants. Data analysis was conducted between September 2024 and December 2024. MAIN OUTCOMES AND MEASURES: The primary outcomes were incidence and nature of antidepressant discontinuation symptoms measured using standardized or unstandardized scales. RESULTS: A total of 50 studies were included, 49 of which were included in meta-analyses. The 50 studies included 17 828 participants in total, with 66.9% female participants and mean participant age of 44 years. Follow-up was between 1 day and 52 weeks. The DESS meta-analysis indicated increased discontinuation symptoms at 1 week in participants stopping antidepressants (standardized mean difference, 0.31; 95% CI, 0.23-0.39; number of studies [k] = 11; n = 3915 participants) compared to those taking placebo or continuing antidepressants. The effect size was equivalent to 1 more

To assess the effect of Long-acting injectable (LAI) antipsychotics in acutely ill patients, we systematically searched major databases for randomized controlled trials (RCTs) comparing LAIs with other LAIs, oral antipsychotics, or placebo in acutely symptomatic adults with schizophrenia-spectrum disorders. Data were analyzed with a random-effects network meta-analysis. Co-primary outcomes were efficacy (mean change in psychopathology rating scales) and acceptability (all-cause discontinuations) at study endpoint. Of 25 RCTs, 19 studies tested second-generation LAIs (SGA-LAIs) and six first-generation LAIs (FGA-LAIs). Due to a disconnected network, FGA-LAIs were analyzed separately, with poor data quality. The SGA-LAIs network included 8,418 individuals (males=63%, mean age=39.3 years). All SGA-LAIs outperformed placebo in reducing acute symptoms at study endpoint (median follow-up=13 weeks). They were more acceptable than placebo with the only exception of olanzapine, for which no differences with placebo emerged. Additionally, we distinguished between different LAI formulations of the same antipsychotic to explore potential pharmacokinetic differences. Most formulations outperformed placebo in the very short-term (2 weeks or less), regardless of the need for initial oral supplementation. SGA-LAIs are evidence-based treatments in acutely ill individuals with schizophrenia-spectrum disorders. Findings support the use of SGA-LAIs to manage psychopathology and improve adherence right from the acute phases of illness.

Update of Res Sq. 2024 Jan 12:rs.3.rs-3787917. doi: 10.21203/rs.3.rs-3787917/v1. Sub-optimal response in schizophrenia is frequent, warranting augmentation strategies over treatment-as-usual (TAU). We assessed nutraceuticals/phytoceutical augmentation strategies via network meta-analysis. Randomized controlled trials in schizophrenia/schizoaffective disorder were identified via the following databases: PubMed, MEDLINE, EMBASE, Scopus, PsycINFO, CENTRAL, and ClinicalTrials.gov. Change (Standardized Mean Difference = SMD) in total symptomatology and acceptability (Risk Ratio = RR) were co-primary outcomes. Secondary outcomes were positive, negative, cognitive, and depressive symptom changes, general psychopathology, tolerability, and response rates. We conducted subset analyses by disease phase and sensitivity analyses by risk of bias and assessed global/local inconsistency, publication bias, risk of bias, and confidence in the evidence. The systematic review included 49 records documenting 50 studies (n = 2384) documenting 22 interventions. Citicoline (SMD =-1.05,95%CI = -1.85; -0.24), L-lysine (SMD = -1.04,95%CI = -1.84; -0.25), N-acetylcysteine (SMD = -0.87, 95%CI = -1.27; -0.47) and sarcosine (SMD = -0.5,95%CI = -0.87-0.13) outperformed placebo for total symptomatology. High heterogeneity (tau2 = 0.10, I2 = 55.9%) and global inconsistency (Q = 40.79, df = 18, p = 0.002) emerged without publication bias (Egger's test, p = 0.42). Sarcosine improved negative symptoms (SMD = -0.65, 95%CI = -1.10; -0.19). N-acetylcysteine improved negative symptoms (SMD = -0.90, 95%CI = -1.42; -0.39)/general psychopathology (SMD = -0.76, 95%CI = -1.39; -0.13). No compound improved total symptomatology within acute phase studies (k = 7, n = 422). Sarcosine (SMD = -1.26,95%CI = -1.91; -0.60), citicoline (SMD = -1.05,95%CI = -1.65;-0.44), and N-acetylcysteine (SMD = -0.55,95%CI = -0.92,-0.19) outperformed placebo augmentation in clinically stable participants. Sensitivity analyses removing high-risk-of-bias studies confirmed overall findings in all phases and clinically stable samples. In contrast, the acute phase analysis restricted to low risk-of-bias studies showed a superior effe

(R,S)-ketamine (ketamine) and its enantiomer (S)-ketamine (esketamine) can produce rapid and substantial antidepressant effects. However, individual response to ketamine/esketamine is variable, and there are no well-accepted methods to differentiate persons who are more likely to benefit. Numerous potential peripheral biomarkers have been reported, but their current utility is unclear. We conducted a systematic review/meta-analysis examining the association between baseline levels and longitudinal changes in blood-based biomarkers, and response to ketamine/esketamine. Of the 5611 citations identified, 56 manuscripts were included (N = 2801 participants), and 26 were compatible with meta-analytical calculations. Random-effect models were used, and effect sizes were reported as standardized mean differences (SMD). Our assessments revealed that more than 460 individual biomarkers were examined. Frequently studied groups included neurotrophic factors (n = 15), levels of ketamine and ketamine metabolites (n = 13), and inflammatory markers (n = 12). There were no consistent associations between baseline levels of blood-based biomarkers, and response to ketamine. However, in a longitudinal analysis, ketamine responders had statistically significant increases in brain-derived neurotrophic factor (BDNF) when compared to pre-treatment levels (SMD [95% CI] = 0.26 [0.03, 0.48], p = 0.02), whereas non-responders showed no significant changes in BDNF levels (SMD [95% CI] = 0.05 [-0.19, 0.28], p = 0.70). There was no consistent evidence to support any additional longitudinal biomarkers. Findings were inconclusive for esketamine due to the small number of studies (n = 2). Despite a diverse and substantial literature, there is limited evidence that blood-based biomarkers are associated with response to ketamine, and no current evidence of clinical utility. © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

BACKGROUND: There is still no approved medication for the core symptoms of autism spectrum disorder (ASD). This network meta-analysis investigated pharmacological and dietary-supplement treatments for ASD. METHODS: We searched for randomized-controlled-trials (RCTs) with a minimum duration of seven days in ClinicalTrials.gov, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (from inception up to July 8, 2018), CENTRAL and PubMed (up to November 3, 2021). The co-primary outcomes were core symptoms (social-communication difficulties-SCD, repetitive behaviors-RB, overall core symptoms-OCS) measured by validated scales and standardized-mean-differences (SMDs). Associated symptoms, e.g., irritability/aggression and attention-deficit/hyperactivity disorder (ADHD) symptoms, dropouts and important side-effects, were investigated as secondary outcomes. Studies in children/adolescents and adults were analyzed separately in random-effects pairwise and network meta-analyses. RESULTS: We analyzed data for 41 drugs and 17 dietary-supplements, from 125 RCTs (n = 7450 participants) in children/adolescents and 18 RCTs (n = 1104) in adults. The following medications could improve at least one core symptom domain in comparison with placebo: aripiprazole (k = 6 studies in analysis, SCD: SMD = 0.27 95% CI [0.09, 0.44], RB: 0.48 [0.26, 0.70]), atomoxetine (k = 3, RB:0.49 [0.18, 0.80]), bumetanide (k = 4, RB: 0.35 [0.09, 0.62], OCS: 0.61 [0.31, 0.91]), and risperidone (k = 4, SCM: 0.31 [0.06, 0.55], RB: 0.60 [0.29, 0.90]; k = 3, OCS: 1.18 [0.75, 1.61]) in children/adolescents; fluoxetine (k = 1, RB: 1.20 [0.45, 1.96]), fluvoxamine (k = 1, RB: 1.04 [0.27, 1.81]), oxytocin (k = 6, RB:0.41 [0.16, 0.66]) and risperidone (k = 1, RB: 0.97 [0.21,1.74]) in adults. There were some indications of improvement by carnosine, haloperidol, folinic acid, guanfacine, omega-3-fatty-acids, probiotics, sulforaphane, tideglusib and valproate, yet imprecise and not robust. Confidence in these estimates was very low or low, except moderate for oxytocin. Medications differed substantially in improving associated symptoms, and in their side-effect profiles. LIMITATIONS: Most of the studies were inadequately powered (samp

BACKGROUND: To examine the association between self-reported food insecurity and depression in 34,129 individuals aged ≥50 years from six low- and middle-income countries (LMICs) (China, Ghana, India, Mexico, Russia, and South Africa). METHODS: Cross-sectional, community-based, nationally representative data from the WHO Study on global AGEing and adult health (SAGE) were analyzed. Self-reported past 12-month food insecurity was assessed with two questions on frequency of eating less and hunger due to lack of food. Questions based on the World Mental Health Survey version of the Composite International Diagnostic Interview were used for the endorsement of past 12-month DSM-IV depression. Multivariable logistic regression analysis and meta-analysis were conducted to assess associations. RESULTS: In total, 34,129 individuals aged ≥50 years [mean (SD) age, 62.4 (16.0) years; 52.1% females] were included in the analysis. Overall, the prevalence of moderate and severe food insecurity was 6.7% and 5.1%, respectively, while the prevalence of depression was 6.0%. Meta-analyses based on countrywise estimates showed that overall, moderate food insecurity (vs. no food insecurity) is associated with a nonsignificant 1.69 (95% confidence interval [CI] = 0.82-3.48) times higher odds for depression, while severe food insecurity is significantly associated with 2.43 (95% CI = 1.65-3.57) times higher odds for depression. CONCLUSIONS: In this large representative sample of older adults from six LMICs, those with severe food insecurity were over two times more likely to suffer from depression (compared with no food insecurity). Utilizing lay health counselors and psychological interventions may be effective mechanisms to reduce depression among food-insecure populations. Interventions to address food insecurity (e.g., supplemental nutrition programs) may reduce depression at the population level but future longitudinal studies are warranted. © 2021 Wiley Periodicals LLC.

BACKGROUND: Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms. METHODS: We searched ClinicalTrials.gov , CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a random-effects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317 . RESULTS: Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8-12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = - 0.32, 95% CI [- 0.39, - 0.25], in repetitive behaviors - 0.23[- 0.32, - 0.15] and in scales measuring overall core symptoms - 0.36 [- 0.46, - 0.26]. Overall, 19%, 95% CI [16-22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain. LIMITATIONS: About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers. CONCLUSIONS: Placebo response in ASD was substantial and predicted by design- and participant-related factors, wh

OBJECTIVE: Brief non-pharmacologic chronic pain treatments are largely effective and widely recommended for pain self-management. The purpose of this study was to evaluate veteran and provider perceptions of acceptability, appropriateness, and feasibility of Brief Cognitive Behavioral Therapy (Brief CBT-CP) content and materials to inform future implementation efforts in primary care and other integrated settings. DESIGN: Qualitative analysis of data from a pilot randomized controlled trial (RCT). SETTING: Two Veterans Affairs (VA) primary care clinics in the Northeast. SUBJECTS: Veterans (n = 10) who completed Brief CBT-CP treatment, integrated behavioral health providers (IBHPs; n = 3 clinical social workers; n = 4 clinical psychologists), and primary care physicians (PCPs; n = 5). METHOD: Rapid Qualitative Analysis of semi-structured interview data. INTERVENTION: Brief CBT-CP, an adapted intervention for chronic pain intended for use in primary care and other integrated care settings utilizing brief treatment modalities. RESULTS: PCPs and IBHPs described Brief CBT-CP as highly acceptable and clinically useful, particularly in response to its focus on biopsychosocial pain self-management skills. Similarly, veterans pointed to the non-pharmacologic skills as a highly acceptable component of treatment. The intervention was also viewed as highly appropriate by providers who emphasized the treatment's alignment with the tenets of primary care, accessibility, and potential to strengthen stepped care adherence. Some providers suggested minor modifications to the content. Veterans regarded Brief CBT-CP as highly appropriate due to the customizability of the non-pharmacologic skills which helped them achieve their recovery goals while acknowledging that the primary limitation was the intervention's inability to completely eliminate pain. Providers, who viewed the intervention as practical overall, anticipated issues such as patient readiness and logistics as potentially impacting treatment uptake; veterans, however, perceived the intervention as feasible, favoring flexibility with scheduling. CONCLUSIONS: Veterans and providers endorsed Brief CBT-CP as a highly accept

INTRODUCTION: COVID-19 boosters restore waning immunity. After demonstrating non-inferiority of 15 μg versus 30 μg BNT162b2 at 28 days in Mongolian adults, we assessed 24-month immunogenicity and safety. METHODS: In this randomised, controlled trial, adults primed with ChAdOx1-S, BBIBP-CorV, or Gam-COVID-Vac were assigned (1:1) to 15 μg or 30 μg BNT162b2. Anti-spike IgG, surrogate virus neutralisation (sVNT) against Wuhan-Hu-1 and Omicron BA.1, and interferon-gamma (IFN-γ) release assays (Ag1/Ag2) were assessed to 24 months. SARS-CoV-2 infections and serious adverse events (SAEs) were recorded. ClinicalTrials.gov: NCT05265065. RESULTS: Of 601 participants, 520 (86.5%) completed follow-up. IgG and IFN-γ responses were comparable between arms at 24 months (IgG geometric mean ratio (GMR) 1.06 [95% CI 0.95-1.18]; Ag1 GMR 1.17 [95% CI 0.82-1.66]; Ag2 GMR 1.06 [95% CI 0.73-1.54]). Median sVNT inhibition remained high (Wuhan-Hu-1 88% [interquartile range (IQR) 86-90]; Omicron BA.1 85% [IQR 70-88]). Twenty-eight SARS-CoV-2 infections occurred. Fifty-three SAEs were balanced by study arm, and none were vaccine related. DISCUSSION: Equivalent immunity and safety from 15 μg and 30 μg BNT162b2 boosters support fractional dosing as a cost-saving strategy. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT05265065, identifier NCT05265065.

OBJECTIVE: Transcranial magnetic stimulation (TMS) has shown promise in reducing posttraumatic stress disorder (PTSD) symptoms, with varied clinical results. A mechanistic understanding is needed to personalize treatment and improve response rates. The threat neurocircuitry, specifically the right amygdala, has consistently been implicated in PTSD pathophysiology. This neuroscience-informed trial aimed to modulate the threat neurocircuitry using functional MRI (fMRI)-guided TMS to treat PTSD. METHODS: In a double-blind clinical trial, 50 adults with PTSD symptoms were randomized to 10 twice-daily sessions of either 1-Hz TMS or sham TMS. TMS was delivered to an fMRI-guided target within the right dorsolateral prefrontal cortex with the strongest functional connection to the right amygdala. The primary outcomes were right amygdala threat reactivity, assessed by fMRI, and skin conductance reactivity during trauma recall, measured pre- and post-TMS. The secondary outcomes were hyperarousal and total PTSD symptoms (based on the PTSD Checklist for DSM-5), measured pre- and post-TMS and at a follow-up assessment between 3 and 6 months after TMS. RESULTS: Active TMS significantly reduced right amygdala threat reactivity compared with sham TMS. No significant effect of TMS was observed on skin conductance reactivity. From pre- to post-TMS, significant reductions in hyperarousal and total PTSD symptoms were observed across groups, but no significant differences between groups were observed. From pre-TMS to follow-up, active TMS compared with sham TMS significantly reduced hyperarousal and total PTSD symptoms. Clinical findings were found to be robust in sensitivity analyses. CONCLUSIONS: This is the first clinical trial to demonstrate that personalized fMRI-guided TMS targeting the threat neurocircuitry reduces amygdala threat reactivity and improves long-term PTSD symptoms at follow-up. These findings suggest the potential for a personalized approach to neuromodulation in individuals with PTSD.

INTRODUCTION: The contribution of patient support to psilocybin's antidepressant effects remains uncertain. METHODS: Relationships between therapeutic alliance (Scale to Assess Therapeutic Relationship-Patient version; STAR-P), psychedelic experience (Five-Dimensional Altered States of Consciousness Questionnaire and Emotional Breakthrough Inventory; 5D-ASC and EBI) and clinical outcomes (Montgomery-Åsberg Depression Rating Scale; MADRS) were explored using correlation and path analysis for individuals with treatment-resistant depression receiving 25 mg psilocybin with monitoring and support (N = 79). RESULTS: Change from Baseline to Week 3 MADRS scores showed weaker correlations with pre-dosing therapeutic alliance (-0.178) than with measures of the psychedelic experience: EBI (-0.637), Oceanic Boundlessness (-0.508), and Visual Restructuralization (-0.516). Path analysis showed no nominally significant direct effects of therapeutic alliance on Week 3 MADRS scores, but there were nominally significant effects of therapeutic alliance on psychedelic experience (Oceanic Boundlessness (β = 0.28), Visual Restructuralization (β = 0.27), and Auditory Alterations (β = 0.25)). Only one indirect effect of therapeutic alliance on clinical outcome reached nominal significance (via Visual Restructuralization; β = -0.15). Stronger effects were seen on clinical outcomes for psychedelic experience (EBI (β = -0.59), Oceanic Boundlessness (β = -0.53), Visual Restructuralization (β = -0.54), and Auditory Alterations (β = -0.24)). CONCLUSIONS: The therapeutic alliance appeared to facilitate the psychedelic experience, and these experiences in turn had stronger nominally significant direct effects on clinical outcomes. The effects of the alliance itself on therapeutic efficacy were either limited or absent. TRIAL REGISTRATION: EudraCT number: 2017-003288-36; Clinicaltrials.gov identifier: NCT03775200.

OBJECTIVE: To evaluate the efficacy and safety of brexpiprazole in patients with early-episode schizophrenia. METHODS: Data were pooled from four 6-week, randomized, double-blind, placebo-controlled trials in schizophrenia. Three trials (ClinicalTrials.gov identifiers: NCT01396421, NCT01393613, NCT01810380) enrolled adults aged 18-65 years; one trial (NCT03198078) enrolled adolescents aged 13-17 years. Data from participants meeting early-episode criteria (age 13-35 years, ≤5 years illness duration) were pooled for participants randomized to brexpiprazole 2-4 mg or placebo. Efficacy on schizophrenia symptoms was primarily evaluated using the Positive and Negative Syndrome Scale (PANSS; primary endpoint in all trials). Change in functioning was measured using the Personal and Social Performance (PSP) scale in adults and Children's Global Assessment Scale (CGAS) in adolescents. Safety was also assessed. RESULTS: Across 476 participants (brexpiprazole 2-4 mg/day, n = 289; placebo, n = 187), change from baseline to Week 6 was greater with brexpiprazole versus placebo on PANSS total score (least squares [LS] mean difference -3.6; 95% confidence interval [CI] -7.0, -0.1; p = 0.04; Cohen's d 0.19), and a combined PSP/CGAS functioning score (LS mean difference 2.3; 95% CI: 0.1, 4.5; p = 0.04; Cohen's d 0.19). The incidence of treatment-emergent adverse events (TEAEs) was 50.7% with brexpiprazole and 46.3% with placebo. The most common TEAEs with brexpiprazole were insomnia (brexpiprazole, 9.2%; placebo, 9.5%) and akathisia (brexpiprazole, 6.5%; placebo, 2.1%). CONCLUSION: This analysis expands the evidence base for brexpiprazole in schizophrenia by demonstrating efficacy in patients who are early in their disease course. The safety profile of brexpiprazole was consistent with previous clinical trials.

Update of medRxiv. 2026 Jan 27:2026.01.26.26344862. doi: 10.64898/2026.01.26.26344862. Resting-state scalp electroencephalography (EEG) is a promising method for predicting patient outcomes of antidepressant treatments. Machine-learning-based EEG analyses of averaged power features (APF) have predicted antidepressant responders in standalone samples but have not yet significantly impacted clinical care. Here, we applied new approaches for analyzing transient spectral event features (SEF) - single, short-lived increases in non-averaged power - in efforts to improve prediction of antidepressant response and yield novel mechanistic biomarkers of readiness to respond. We analyzed resting-state EEG data from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) trial, fitting linear elastic net models predicting depression score change post-treatment from pre-treatment SEF from frontal channels. We found that a model containing SEF only significantly predicted depression score changes rather than categorical response outcomes, and that its performance was similar to existing published models with APF alone. Additionally, a model including both SEF and APF outperformed both the others, emphasizing the utility of including SEF in models using EEG features for predicting antidepressant response to sertraline. We further investigated the most predictive SEF from the SEF only model, with the objective of revealing channel-level biomarkers to guide mechanistic insight into antidepressant response. We found that pre-treatment frontopolar beta duration was significantly correlated with depression score change, with greater degree of symptom response linked to shorter beta events at baseline. This finding replicates prior work on frontopolar beta duration as a possible biomarker of antidepressant response in rTMS and raises the possibility that beta events may be a cross-modal therapeutic biomarker in antidepressant treatment.

BACKGROUND: Data from randomized controlled trials of vitamin D3 supplementation in modifying the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are sparse. OBJECTIVES: We evaluated the effect of vitamin D3 supplementation on healthcare utilization and other clinical outcomes among adults with coronavirus disease 2019 (COVID-19) and their close contacts. METHODS: We conducted a parallel 2-group randomized controlled double-blinded trial targeting free-living adults in the United States and Mongolia. Index participants with newly diagnosed COVID-19 were cluster-randomized with up to one of their cohabiting contacts either to an oral vitamin D3 loading dose of 9600 IU/d for 2 d followed by 3200 IU/d for 4 wk or to placebo. Participants completed weekly questionnaires on healthcare utilization, disease severity, and long COVID (index participants) or new SARS-CoV-2 infection (household contacts). The primary outcome was ≥1 healthcare visits (including hospitalization) or death within 4 wk among the index participants. RESULTS: Index participants (n = 1747) were a median of 38.0 y old (IQR: 31.1-47.0), 65.6% female/other sex, 4.2% Black non-Hispanic, 4.8% Hispanic/Latinx, 43.2% Asian, 44.3% non-Hispanic White, and 44.9% vitamin D deficient or insufficient (25-hydroxyvitamin D3 <20 ng/mL). Baseline characteristics for the household contacts (n = 277) were similar. The 4-wk cumulative incidence of healthcare utilization in index participants did not significantly differ between the vitamin D3 (n = 863) and placebo (n = 884) groups [cumulative incidences, 0.28 compared with 0.29; odds ratio (OR), 0.97; 95% confidence interval (CI): 0.75, 1.24]. Similar nonsignificant results were observed for the prespecified secondary treatment and prevention outcomes, though per-protocol analyses showed a nonsignificant trend toward benefit of vitamin D3 on the prevalence of long COVID at 8 wk (OR, 0.78; 95% CI: 0.59, 1.03). No safety concerns were identified. CONCLUSIONS: Among adults with newly diagnosed SARS-CoV-2 infections, vitamin D3 supplementation did not significantly change the 4-wk cumulative incidence of healthcare utilization or COVID-1

BACKGROUND: Better-than-chance guessing of treatment assignment raises concerns about unblinding as this opens efficacy estimates up to being influenced by factors other than the true efficacy of the intervention. However, such accuracy does not necessarily indicate that efficacy estimates are biased. OBJECTIVE: To assess whether unblinding was biasing (impacting on efficacy estimates) or non-biasing (not impacting on efficacy estimates) in a sham-controlled trial of a home-use transcranial direct-current stimulation (tDCS) device, in which treatment allocation guesses at endpoint were unbalanced. METHODS: Interrelations between i) treatment allocation, ii) treatment allocation guesses, iii) adverse event reports, and iv) depressive symptom severity, as measured by Hamilton Depression Rating Scale, after ten weeks of treatment were examined using linear regression (n = 149). RESULTS: Receiving tDCS was positively associated with a) guessing that one had received tDCS (p = .01704), b) number of adverse events (beta: 0.69, p = .0046), and c) improvement after ten weeks (beta: -2.39, p = .0049). Guessing that one had received tDCS was positively associated with greater improvement (beta: -3.16, p = .0005), whereas the number of reported adverse events correlated negatively with improvement (beta: 0.68, p = .0186). Moreover, among participants who received tDCS, those who reported any of nine examined adverse events consistently showed numerically worse outcomes than those who did not report the same adverse events. CONCLUSIONS: In this exploratory analysis, adverse events correlated negatively with HDRS-rated improvement. This is not consistent with a pathway where adverse events lead to unblinding and, subsequently, to improvement via expectancy effects and/or biased ratings.

IMPORTANCE: Seltorexant, a selective orexin-2 receptor (OX2R) antagonist, has demonstrated antidepressant effects in major depressive disorder (MDD), particularly among patients with higher baseline insomnia symptoms. OBJECTIVE: To investigate flexibly dosed seltorexant vs flexibly dosed quetiapine extended release (quetiapine-XR) as adjunctive treatment to a selective serotonin (SSRI) or serotonin-norepinephrine (SNRI) reuptake inhibitor. SETTING: Outpatient. DESIGN: Randomized, active-controlled, multicenter, exploratory phase 2 study with screening (≤4 weeks), double-blind treatment (24 weeks), and post-treatment follow-up (2 weeks) phases. PARTICIPANTS: Patients with MDD and inadequate response to 1-3 SSRIs/SNRIs, including an ongoing SSRI/SNRI, in the current depressive episode. INTERVENTIONS: Flexibly dosed seltorexant (20 or 40 mg) or quetiapine-XR (150 or 300 mg, with 2-day initial dosing of 50 mg) once daily as adjunctive therapy to an SSRI/SNRI. Randomization (1:1) was stratified by baseline Insomnia Severity Index total score (≥15 vs <15). Safety, tolerability, and preliminary efficacy were evaluated. MAIN OUTCOMES AND MEASURES: Primary efficacy endpoint was time to all-cause study drug discontinuation. Secondary efficacy endpoints included change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Subgroup analyses included MADRS change by mode dose (MD; most frequent daily dose received by a patient during the study). Safety and tolerability also were assessed. RESULTS: Time to all-cause discontinuation (estimated 25th percentile [80% CI]: seltorexant, 62 [38, 83] days vs quetiapine-XR, 42 [35, 61] days; hazard ratio [80% CI]: 0.83 [0.6, 1.2]) and all-cause discontinuation (seltorexant, 41.2% vs quetiapine-XR, 47.1%; 2-sided P = .5355) did not differ significantly between treatment groups. For the seltorexant 20-mg MD group, MADRS total scores consistently improved over time and reductions were numerically greater at weeks 18 and 24 versus the seltorexant 40-mg MD and the combined quetiapine-XR groups, and patients with higher baseline insomnia symptoms had greater improvement in MADRS total score, consistent with prior studies showing

OBJECTIVE: This post hoc analysis of the CHAMPION-NMOSD trial evaluated the safety and efficacy of ravulizumab in patients with aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) previously exposed or naïve to rituximab (RTX). METHODS: Patients received weight-based intravenous ravulizumab with a loading dose followed by maintenance dosing every 8 weeks. Patients were stratified by prior RTX exposure: no RTX exposure (RTX-naïve) vs RTX exposure > 3 months before initiating ravulizumab (RTX-exposed). Key outcomes included treatment-emergent adverse events (TEAEs), serious TEAEs (TESAEs), relapse rates, and vaccination timing from the last RTX dose. RESULTS: Of the 58 patients enrolled, 89.7% were female, with a mean age of 47.4 years, and 21/58 (36.2%) were RTX-exposed. Relapses occurred in 12/21 (57.1%) RTX-exposed patients between their first RTX dose and study entry. The safety profile of ravulizumab was generally similar between RTX-exposed and RTX-naïve groups. Common TEAEs included COVID-19, headache, urinary tract infection, and upper respiratory tract infection. UTIs were more frequent in RTX-exposed individuals. One patient in each group experienced a meningococcal infection. No adjudicated on-trial relapses were reported while on ravulizumab. CONCLUSIONS: Following initiation of ravulizumab, RTX-exposed and RTX-naïve patients with AQP4-Ab+ NMOSD achieved sustained disease control and demonstrated a manageable safety profile. CLINICAL TRIAL INFORMATION: The CHAMPION-NMOSD Trial; ClinicalTrials.gov identifier: NCT04201262 (registered October 06, 2020).

With the growing variety of pharmacological compounds and the increasing need for polypharmacy, accurately predicting drug-drug interactions (DDIs) is essential to ensure both treatment efficacy and patient safety. Beneficial DDIs can enhance therapeutic outcomes. In contrast, adverse interactions may result in toxicity, reduced efficacy, or even fatality. Thus, the accurate prediction of DDIs is paramount. Building on recent advancements in graph neural network (GNN) architectures, this paper extends prior research, such as the SAGE GNN model, Graph Attention Network model, and Graph Diffusion Network model, by integrating advanced techniques such as skip connections, post-processing layers, and optimized training methods. It start from basic GNN to buld more advanced models such as based on Adaptive Graph Diffusion model. Our experimental results shows based on evaluation on 3 different drug-drug interaction dataset that on some evaluation metric basic models outperforms the advanced ones. We have found that GCN with skip connections, GCN with NGNN and SAGE with NGNN give competent accuracy with other baseline models. The corresponding code and datasets used in this study are available on GitHub for reproducibility at: https://github.com/khushnood/DrugDruginteractionPredictionBasedOnGNN . © 2025. The Author(s).

G protein-coupled receptors (GPCRs) are involved in many physiological and pathophysiological processes. Conventional pharmacological models categorize the typology of pharmacologic ligands as agonists or antagonists. Biased agonism is a relatively newer pharmacodynamic characteristic that has potential to optimize therapeutic efficacy while minimizing adverse effects in psychiatric and neurological treatments. We conducted a narrative literature review of articles obtained from PubMed, Embase, and MEDLINE from inception to April 2025, focusing on pharmacologic antagonism (i.e., competitive, noncompetitive, uncompetitive) and agonism (i.e., full, partial, inverse, superagonism, biased). Primary and secondary articles defining these concepts were included, provided they addressed pharmacologic (rather than chemical) antagonism and agonism. Distinct mechanisms of antagonism and agonism were identified, each contributing nuanced receptor modulation beyond the conventional models. Notably, biased agonism facilitates targeted intracellular signaling (e.g., G protein- versus β-arrestin-mediated). Use cases demonstrate relatively greater efficacy (e.g., incretin receptor agonist, tirzepatide) and improved safety (e.g., serotonergic psychedelics, opioids). Biased agonism provides a potential avenue for future drug development, with emerging preclinical evidence suggesting potential to differentially activate intracellular pathways and thereby improve efficacy and safety profiles of psychopharmacologic agents-pending clinical validation. Future research vistas should aim to rigorously assess the long-term outcomes of biased agonism, explicitly addressing individual variability in receptor signaling and therapeutic response.

Essential oils (EOs) from aromatic and medicinal plants have antioxidant and antibacterial properties and are commonly used as preservatives in the food industry. Combining EOs can produce a synergistic effect, enabling their application as condiments at reduced dosages. Therefore, this study aimed to evaluate the antioxidant and antibacterial activities of the combination of three EOs extracted from Sage (Salvia officinalis), Oregano (Origanum vulgare), and Cumin (Cuminum cyminum). This experiment involved a three-factor simplex lattice design comprising 14 experimental runs with three replications. Gas chromatography-mass spectrometry (GC-MS) analysis identified carvacrol (39.54%) and γ-terpinene (23.22%) as the principal components of the EO from O. vulgare, while cumin aldehyde (24.24%) and lavandulyl acetate (19.56%) and γ-terpinene (18.78%) were dominant in the EO of C. cyminum; additionally, S. officinalis exhibited α-thujene (34.85%) and pinocarvone (18.44%) as its main constituents. The optimal conditions for the independent variables were established at 15.0553% for C. cyminum, 74.0453% for O. vulgare, and 10.90% for S. officinalis. These conditions resulted in notable increases in antioxidant activity, as demonstrated by a DPPH scavenging activity of 88.1% and a FRAP assay value of 11.3 μmol Fe(II)/g dry weight (DW). Additionally, the optimal conditions yielded significant inhibition zones against various bacterial strains, measuring 18.59 mm for Salmonella enterica, 22.97 mm for Escherichia coli, and 19.26 mm for Staphylococcus aureus. The predictive models showed high and statistically significant regression coefficients for all the parameters (p < 0.05). The measured parameters were in close agreement with the predicted values from the quadratic polynomial equation. Correlation analysis tools can effectively identify EOs' synergistic properties and predict active compounds' optimal characteristics. These findings confirm that the antioxidant and antibacterial activities are enhanced through the synergistic combination of EOs, underscoring their potential as effective natural preservatives in industrial applications. © 2025. The Author(s).

BACKGROUND: Zuranolone is an oral, once-daily, 14-day treatment course approved for adults with postpartum depression in the United States. AIMS: To assess cognitive effects, pharmacokinetics, and safety of zuranolone, alone or with alprazolam/ethanol. METHODS: This was a phase 1, two-part, two-period, randomized, double-blind, placebo-controlled crossover trial. Participants received zuranolone 50 mg or placebo once daily for 9 days, and additionally received alprazolam (1 mg, Part A), ethanol (males: 0.7 g/kg; females: 0.6 g/kg, Part B), or corresponding placebo on days 1, 5, and 9. Within each part, participants received all treatment combinations. Cognition was assessed using a computerized test battery; pharmacokinetics and safety were also evaluated. RESULTS: All participants (Part A, N = 24; Part B, N = 25) received ⩾1 dose of zuranolone/placebo. Compared to placebo, zuranolone produced small-to-moderate cognitive decline (Cohen's |d| = 0.126-0.76); effects were larger with alprazolam (Cohen's |d| = 0.523-0.93) and ethanol (Cohen's |d| = 0.345-0.88). Zuranolone coadministration with alprazolam (Cohen's |d| = 0.6-1.227) or ethanol (Cohen's |d| = 0.054-0.5) generally worsened cognitive decline when compared with zuranolone alone. Maximal pharmacodynamic effects occurred at approximately 5 h and were resolved by 12 h postbaseline. No pharmacokinetic interactions were observed. Incidence of adverse events was similar between groups; most events were mild or moderate in severity. CONCLUSION: A general small-to-moderate magnitude decline in cognition occurred with zuranolone alone. Coadministration with alprazolam/ethanol increased the magnitude, but not the duration, of effects compared with single-agent administration. Zuranolone prescribers and patients should be aware of the potential for increased central nervous system-depressant effects if coadministered with GABAergic active compounds such as alprazolam and ethanol.

Cedirogant is an inverse agonist of retinoic acid-related orphan receptor gamma thymus (RORγt) developed for the treatment of moderate to severe chronic plaque psoriasis. Here, we report the results from two phase I studies in which the pharmacokinetics (PK), safety, and efficacy of cedirogant in healthy participants and patients with moderate to severe chronic plaque psoriasis were evaluated. The studies consisted of single (20-750 mg) and multiple (75-375 mg once-daily [q.d.]) ascending dose designs, with effect of food and itraconazole on cedirogant exposure also evaluated. Safety and PK were evaluated for both healthy participants and psoriasis patients, and efficacy was assessed in psoriasis patients. Following single and multiple doses, cedirogant mean terminal half-life ranged from 16 to 28 h and median time to reach maximum plasma concentration ranged from 2 to 5 h across both populations. Cedirogant plasma exposures were dose-proportional after single doses and less than dose-proportional from 75 to 375 mg q.d. doses. Steady-state concentrations were achieved within 12 days. Accumulation ratios ranged from approximately 1.2 to 1.8 across tested doses. Food had minimal effect and itraconazole had limited impact on cedirogant exposure. No discontinuations or serious adverse events due to cedirogant were recorded. Psoriasis Area and Severity Index (PASI) and Self-Assessment of Psoriasis Symptoms (SAPS) assessments demonstrated numerical improvement with treatment of cedirogant 375 mg q.d. compared with placebo. The PK, safety, and efficacy profiles of cedirogant supported advancing it to phase II clinical trial in psoriasis patients. © 2023 AbbVie Inc and The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Certain selective serotonin reuptake inhibitors (SSRIs) have anti-inflammatory effects in preclinical models, and recent clinical studies suggest that fluvoxamine can prevent deterioration in patients with COVID-19, possibly through activating sigma 1 receptors (S1Rs). Here we examined potential mechanisms contributing to these effects of fluvoxamine and other SSRIs using a well-characterized model of pro-inflammatory stress in rat hippocampal slices. When hippocampal slices are exposed acutely to lipopolysaccharide (LPS), a strong pro-inflammatory stimulus, basal synaptic transmission in the CA1 region remains intact, but induction of long-term potentiation (LTP), a form of synaptic plasticity thought to contribute to learning and memory, is completely disrupted. Administration of low micromolar concentrations of fluvoxamine and fluoxetine prior to and during LPS administration overcame this LTP inhibition. Effects of fluvoxamine required both activation of S1Rs and local synthesis of 5-alpha reduced neurosteroids. In contrast, the effects of fluoxetine did not involve S1Rs but required neurosteroid production. The ability of fluvoxamine to modulate LTP and neurosteroid production was mimicked by a selective S1R agonist. Additionally, fluvoxamine and fluoxetine prevented learning impairments induced by LPS in vivo. Sertraline differed from the other SSRIs in blocking LTP in control slices likely via S1R inverse agonism. These results provide strong support for the hypothesis that S1Rs and neurosteroids play key roles in the anti-inflammatory effects of certain SSRIs and that these SSRIs could be beneficial in disorders involving inflammatory stress including psychiatric and neurodegenerative illnesses. © 2023. The Author(s).

Comment in JAMA. 2022 Jul 12;328(2):146-148. doi: 10.1001/jama.2022.10018. IMPORTANCE: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. OBJECTIVE: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. INTERVENTIONS: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). MAIN OUTCOMES AND MEASURES: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. RESULTS: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interact

OBJECTIVE: Drug-related problems (DRPs) could affect patient care and lead to deleterious manifestations, therefore, this investigation aimed to review the recently published studies concerning DRPs to improve their availability to clinical pharmacists, hoping that this information will be supportive and relevant to their practice settings. MATERIALS AND METHODS: A search of Elsevier, Sage, Springer/Nature, and Wiley online libraries on Egyptian Knowledge Bank (EKB) was limited to the cumulative period from 1/1/2015 to 20/10/2020. The abstracts of 156 articles were critically reviewed and 50 articles were included based on relevance while excluding books. The selected articles reported DRPs and different strategies to reduce them. Moreover, drug-drug interactions (DDIs) in various patient populations were confirmed by many articles. Additionally, potential drug-drug interactions (pDDIs) predisposing factors were reported by others. RESULTS: 24 articles (48%) illustrated DDIs, 5 articles (10%) demonstrated ADRs, 4 articles (8%) showed medication errors (MEs), and 25 articles (50%) revealed efforts to reduce DRPs. The psychiatric population is at the utmost risk of pDDIs. Polypharmacy was the furthest recurrently reported risk factor related to DDIs. Adverse drug events (ADEs) increased healthcare costs. Different strategies to avoid DRPs were published through the stated period. CONCLUSIONS: Our findings can be supportive to healthcare professionals in enhancing their patients' quality of care by reducing the exposure to ADEs.

Ethanol is a noncompetitive inhibitor of N-methyl-d-aspartate receptors (NMDARs) and acutely disrupts hippocampal synaptic plasticity and learning. In the present study, we examined the effects of oxysterol positive allosteric modulators (PAMs) of NMDARs on ethanol-mediated inhibition of NMDARs, block of long-term potentiation (LTP) and long-term depression (LTD) in rat hippocampal slices, and defects in one-trial learning in vivo. We found that 24S-hydroxycholesterol and a synthetic oxysterol analog, SGE-301, overcame effects of ethanol on NMDAR-mediated synaptic responses in the CA1 region but did not alter acute effects of ethanol on LTD; the synthetic oxysterol, however, overcame acute inhibition of LTP. In addition, both oxysterols overcame persistent effects of ethanol on LTP in vitro, and the synthetic analog reversed defects in one-trial inhibitory avoidance learning in vivo. These results indicate that effects of ethanol on both LTP and LTD arise by complex mechanisms beyond NMDAR antagonism and that oxysterol NMDAR PAMS may represent a novel approach for preventing and reversing acute ethanol-mediated changes in cognition. SIGNIFICANCE STATEMENT: Ethanol acutely inhibits hippocampal NMDARs, LTP, and learning. This study found that certain oxysterols that are NMDAR-positive allosteric modulators can overcome the acute effects of ethanol on NMDARs, LTP, and learning. Oxysterols differ in their effects from agents that inhibit integrated cellular stress responses.

Zuranolone (SAGE-217) is a novel, synthetic, clinical stage neuroactive steroid GABAA receptor positive allosteric modulator designed with the pharmacokinetic properties to support oral daily dosing. In vitro, zuranolone enhanced GABAA receptor current at nine unique human recombinant receptor subtypes, including representative receptors for both synaptic (γ subunit-containing) and extrasynaptic (δ subunit-containing) configurations. At a representative synaptic subunit configuration, α1β2γ2, zuranolone potentiated GABA currents synergistically with the benzodiazepine diazepam, consistent with the non-competitive activity and distinct binding sites of the two classes of compounds at synaptic receptors. In a brain slice preparation, zuranolone produced a sustained increase in GABA currents consistent with metabotropic trafficking of GABAA receptors to the cell surface. In vivo, zuranolone exhibited potent activity, indicating its ability to modulate GABAA receptors in the central nervous system after oral dosing by protecting against chemo-convulsant seizures in a mouse model and enhancing electroencephalogram β-frequency power in rats. Together, these data establish zuranolone as a potent and efficacious neuroactive steroid GABAA receptor positive allosteric modulator with drug-like properties and CNS exposure in preclinical models. Recent clinical data support the therapeutic promise of neuroactive steroid GABAA receptor positive modulators for treating mood disorders; brexanolone is the first therapeutic approved specifically for the treatment of postpartum depression. Zuranolone is currently under clinical investigation for the treatment of major depressive episodes in major depressive disorder, postpartum depression, and bipolar depression.

BACKGROUND: There are no pharmacotherapies available for cognitive impairment associated with schizophrenia (CIAS). The CONNEX programme investigated the efficacy and safety of iclepertin, a glycine transporter-1 (GlyT1) inhibitor, for the treatment of CIAS. METHODS: CONNEX-1, CONNEX-2, and CONNEX-3 were phase 3, randomised, double-blind, placebo-controlled trials conducted across 338 specialist psychiatric centres in 41 countries. Adults aged 18-50 years with schizophrenia were randomised 1:1 using interactive response technology to oral 10 mg iclepertin or placebo once daily for 26 weeks in combination with standard-of-care antipsychotic therapy. Patients, investigators, and trial personnel were masked to treatment assignment. The primary endpoint was change from baseline at week 26 in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) overall composite T-score. Efficacy analyses included randomly allocated patients, excluding those allocated in error or who discontinued from the trial before receiving treatment. Safety and tolerability assessments included adverse event monitoring in patients who received one or more doses of trial medication. These trials were registered with ClinicalTrials.gov (NCT04846868, NCT04846881, NCT04860830) and are complete. Individuals with lived experience informed the trial designs and selection of outcome measures; they were not involved in the writing process. FINDINGS: Between Sept 8, 2021, and April 24, 2024, 1835 patients were recruited and received at least one dose of trial medication (918 for iclepertin and 917 for placebo); 1602 patients completed treatment. 1207 (66%) of 1836 patients were male and 629 (34%) patients were female. Most patients were either White (903 [49%]) or Asian (558 [30%]), and the majority were not of Hispanic or Latino ethnicity (1238 [67%]). The mean age was 34·7 years (SD 8·8). At week 26, there was no significant difference between treatment groups in the primary endpoint. The adjusted mean difference for iclepertin versus placebo for MCCB overall composite T-score was 0·127 [95% CI -0·396 to 0·650]; p=0·63). On-treatment a

INTRODUCTION: Understanding factors associated with hesitancy about pediatric COVID-19 vaccination is important for identifying strategies to improve vaccination rates. Our objective was to describe beliefs about COVID-19 vaccination among caregivers who had not yet vaccinated their children against COVID-19. METHODS: From July 2022 to February 2023, caregivers of children unvaccinated for COVID-19 across 15 states within the IDeA States Pediatrics Clinical Trial Network were recruited into a randomized, controlled trial of a COVID-19 vaccine communication phone app. Recruitment sites served high numbers of children from rural areas or of backgrounds other than non-Hispanic White. At baseline, caregivers answered questions from the SAGE Vaccine Hesitancy Scale (VHS), and questions about trusted sources of information about COVID-19. We compared responses by rurality, race, and ethnicity using chi-square tests, and used multivariable modeling of a composite outcome of summed VHS scores to identify factors associated with vaccine hesitancy. RESULTS: A total of 725 caregivers were randomized; 512 completed the baseline survey. Many caregivers lived in a rural area (34.9 %) and nearly half were of non-White race (47.3 %). Over 80 % somewhat or strongly agreed that vaccines are important, that childhood vaccines are effective, and that vaccination is a good way to protect children from disease. Rural caregivers were more likely than non-rural caregivers to state that they generally do what their doctor recommends with regard to childhood vaccines (46.93 % vs. 37.00 %, p < .0021). In the multivariable model, the combined group of Asian, Native Hawaiian, Other Pacific Islander or multiracial caregivers, and Black or African American caregivers, had a higher vaccine hesitancy compared to White caregivers (25.25, 25.91, 22.50 respectively) (p < .0001). CONCLUSIONS: As we navigate work to build vaccine confidence, this study provides support for additional directions of study to better understand particular populations and could be further reproduced to look at intentions with other vaccines.

We here present evidence-based guidelines for the pharmacological treatment of migraine. These guidelines, created by the Italian Society for the Study of Headache and the International Headache Society, aim to offer clear, actionable recommendations to healthcare professionals. They incorporate evidence-based recommendations from randomized controlled trials and expert-based opinions. The guidelines follow the GRADE approach for assessing the quality of evidence. The guideline development involved a systematic review of literature across multiple databases, adherence to Cochrane review methods, and a structured framework for data extraction and interpretation. Although the guidelines provide a robust foundation for migraine treatment, they also highlight gaps in current research, such as the paucity of head-to-head drug comparisons and the need for long-term outcome studies. These guidelines serve as a resource to standardize migraine treatment and promote high-quality care across different healthcare settings.