bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using Patient iPSC-Derived Neurons to Uncover Mechanisms Associated with Response to Antidepressant Drugs: A Framework for Precision Medicine in Depression
Authors: Kugel Aleksandra , Kroitorou Dana , Albeldas Claudia , Solal Talia Cohen , Laifenfeld Daphna 
Published: January 2025

IntroductionDepression is a leading cause of disability worldwide affecting over 300 million individuals globally. Despite the abundance of approved antidepressants, the majority of depressed patients do not respond to their first prescribed antidepressant, with over 30% not responding to subsequent drugs. This is largely attributed to individual differences in the underlying pathophysiology of the disease, which make some medications efficacious for some patients while ineffective for others. Multiple studies have been conducted with the aim of identifying patient subgroups associated with drug response, with a large focus on variations in genetic and gene expression levels that may underlie response to specific drugs. However, these studies yielded mostly inconsistent results, with robust genetic effects largely related to drug pharmacokinetics and gene expression level associations poorly reproducible. In this study, we assessed gene expression levels in iPSC-derived neurons from depressed patients with a known response profile to various medications, alongside genetic variations. iPSC-derived neurons have the potential to unravel mechanisms that are neuronal specific and thus not observed in patient whole blood molecular analysis.MethodsPatient-derived lymphoblastoid cell lines from the Sequenced Treatment Alternatives to Relieve Depression (STARD) study with known response to Citalopram or Bupropion were reprogrammed and then differentiated to cortical neurons. Analysis of genetic variants and differential gene expression was performed on the derived neurons to identify variants and gene expression levels that are associated with drug response.ResultsSignificant differential gene expression was shown between Bupropion responders and non-responders as well as between Citalopram responders and non-responders. Functional enrichment analysis revealed biologically relevant pathways that differ between responders and non-responders in Bupropion and in Citalopram. In addition, we found an interplay between genetics and neuronal gene expression, that is associated with patient drug response. This was specifically observed in genes implicated in drug mechanism of action, including COMT and BDNF.ConclusionsPatient-derived neurons have utility in mechanistic disease and drug modeling, and can elucidate mechanisms that cannot be read out from systemic whole blood analysis. In addition, combining genetics and target organ gene expression levels has the potential to be used as biomarkers for drug response. Together, these findings support a novel framework for precision medicine in depression.FundingGenetika+
A Review of the Delivery Technologies used in Attention-Deficit/Hyperactivity Disorder Stimulant Medications
Authors: Cutler Andrew J , Hanaie Jacob 
Published: January 2025

IntroductionMultiple pharmaceutical technologies have been developed over the years and applied in the Attention-Deficit/Hyperactivity Disorder (ADHD) treatment space. While the base drugs are either the same or similar, these technologies lead to differences in the medications’ properties – including mechanism of release, timing of active drug release, and pharmacokinetic profiles. The technology differences also bring up clinical considerations applicable to patients, including delayed- or extended-release properties so that once daily dosing can be achieved.This review seeks to make side-by-side comparisons of the technical features of the different technologies used in ADHD medications, not an efficacy comparison. The publication will focus on stimulant medications that use methylphenidate or amphetamine formulations. Gaining an understanding of the technologies’ properties and their implications will help clinicians to make more informed decisions when developing their patients’ treatment plans to fit their individual needs, and potentially improve adherence.MethodsSources including published literature, company websites, filed patents, and prescribing information were reviewed to extract data on the technology used for different ADHD medications. The comparison of the technology in ADHD medications included the drug delivery system, mechanism of drug release, and technology components such as use of resins, beads, complexes, coating or layers. Special considerations that come from these properties were elucidated and framed into a broader clinical context.ResultsAlthough the medications evaluated were all stimulants containing methylphenidate or amphetamine as the active ingredient, they vary significantly in the technology used to deliver medication to patients. Differences in the technologies used to deliver the stimulants are significant and provide the platform to meet individual patient needs. This side-by-side comparison, describing the specific features and benefits of each technology, will better inform prescribers, leading to better treatment of patients’ ADHD.ConclusionsClarifying the technologies available among ADHD pharmacotherapies and discussing their implications on patient care may help healthcare professionals better understand the treatment landscape and assist them in clinical decision-making for appropriate ADHD treatment. Knowledge of the mechanism of the technology could improve patients’ medication adherence. Additionally, understanding the applications of the technology could also benefit research and clinical programs.FundingTris Pharma
Drug-Drug Interactions with Vesicular Monoamine Transporter 2 Inhibitors: Population Estimate of Patients With Tardive Dyskinesia at Risk in Real-World Clinical Practice
Authors: Mychaskiw Marko , Ghibellini Giulia , Dotiwala Zenobia , Konings Martijn , Gandhi Pooja , Casciano Julian 
Published: January 2025

IntroductionValbenazine and deutetrabenazine (vesicular monoamine transporter 2 inhibitors) are approved for tardive dyskinesia (TD) treatment in adults. To prevent potential drug-drug interactions (DDIs), valbenazine labeling recommends doses 40 mg/day when taking strong CYP3A4 or CYP2D6 inhibitors and avoidance of strong CYP3A4 inducers and monoamine oxidase inhibitors (MAOIs). Deutetrabenazine labeling recommends doses ≤36-mg/day when taking strong CYP2D6 inhibitors and avoidance of MAOIs. This study estimated proportions of patients with TD at risk of DDIs with valbenazine/deutetrabenazine in real-world practice.MethodsPatients aged ≥18 years with TD and ≥1 antipsychotic claim(s) and no valbenazine/ deutetrabenazine claims ≥3 months prior and ≥12 months after diagnosis were identified in the Symphony Health Sciences database (US-based medical, hospital, and pharmacy claims database). Proportions of patients meeting valbenazine/deutetrabenazine concomitant medication labeling restrictions were summarized descriptively.Results14,264/66,046 patients with TD met inclusion criteria. Proportions of patients at potential risk of DDIs were lower with deutetrabenazine ≤36 mg/day (0.2%) and >36 mg/day (21%) versus valbenazine 40 mg/day (4.4%; 22-times difference) and >40 mg/day (28%; 1.3-times difference). Across age groups, underlying conditions (major depressive, mood, and bipolar disorders; schizophrenia), and payer types, proportions of patients at potential risk of DDIs were lower with deutetrabenazine ≤36 mg/day (0.0%– 0.5%) and >36 mg/day (14%– 30%) versus valbenazine 40 mg/day (3%– 5%; 8.0- to >40.0times difference) and >40 mg/day (22%– 35%; 1.2- to >1.5-times difference).ConclusionsEstimated proportions of patients with TD at potential risk of DDIs was lower with deutetrabenazine versus valbenazine overall and across age, underlying conditions, and payer types.FundingTeva Branded Pharmaceutical Products R&D, Inc.
d-Amphetamine Transdermal System (d-ATS) in Treatment of Children and Adolescents With ADHD: SKAMP Score Analysis From a Pivotal Trial
Authors: Cutler Andrew J. , Komaroff Marina , Castelli Mariacristina , Meeves Suzanne , Balakrishnan Kanan , Khan Mawish 
Published: January 2025

BackgroundThe dextroamphetamine transdermal system (d-ATS) was developed as an alternative to current oral formulations of amphetamine, which is a first-line treatment for ADHD. In a randomized controlled trial of d-ATS in children and adolescents with ADHD, the primary endpoint (SKAMP total score) and secondary endpoints were met. This analysis evaluated the efficacy of d-ATS using SKAMP total score by optimized dose, gender, age group, ADHD type, and baseline ADHD severity.MethodsThis study comprised a 5-week, open-label dose-optimization period (DOP) followed by a 2-week, randomized, cross-over double-blind treatment period (DBP). All eligible patients received d-ATS 5 mg/9hr, with weekly evaluation for dose increase to 10 mg/9hr, 15 mg/9hr, and 20 mg/9hr. Once reached, the optimal dose was maintained for the DOP and used during the DBP. Preplanned subgroup analyses of mean SKAMP total score by optimized dose, gender, age group, ADHD type, and baseline ADHD severity were conducted. Efficacy was assessed by difference (d-ATS vs placebo) in least-squares (LS) mean SKAMP total score from a mixed-model repeated-measures (MMRM) analysis and is reported throughout as LS mean (95% confidence interval [CI]).ResultsIn total, 110 patients were enrolled in the DOP, and 106 patients were randomized in the DBP. During the DOP, three patients reported 3 TEAEs that led to study discontinuation (irritability, appetite loss, abdominal pain). The difference (d-ATS vs placebo) in LS mean SKAMP total score was -5.9 (-6.8, -5.0), with differences in attention, deportment, and quality of work sub-scores of -1.4 (-1.7, -1.1), -1.9 (-2.2, -1.5), and -1.3 (-1.5, -1.0), respectively. Patients receiving d-ATS at each optimized dose demonstrated improvements vs placebo in LS mean SKAMP total score (-7.3 [-10.8, -3.7], -4.5 [-6.0, -3.0], -5.9 [-7.4, -4.5], -7.6 [-9.6, -5.6] at 5, 10, 15, and 20 mg/9hr, respectively). Both male and female patients experienced improvements vs placebo in SKAMP total score. The observed difference was greater in males (-6.3 [-7.3, -5.2]) vs females (-5.0 [-6.6, -3.4]). Similarly, improvements vs placebo were seen in patients with combined type ADHD and in those with predominantly inattentive type ADHD, with an observed LS mean difference of -8.0 (-9.2, -6.8) for the combined type and -3.3 (-4.6, -2.1) for the inattentive type. In addition, patients demonstrated improvement during the DBP regardless of baseline ADHD severity. The difference in LS mean SKAMP total score was -4.5 (-5.9, -3.1) for patients with a baseline SKAMP total score of 0-36 and -6.7 (-7.9, -5.6) for those with a baseline SKAMP score of 37-54.Conclusionsd-ATS was effective and generally well-tolerated in treating ADHD in children and adolescents regardless of optimized dose, gender, age group, ADHD type, or baseline ADHD severity.FundingNoven Pharmaceuticals, Inc.
Assessment of Underdiagnosis of Tardive Dyskinesia by Geographic Region, Social Determinants, and Other Patient Characteristics
Authors: Gandhi Pooja , Zhang Su , Patel Ayush , Ayyagari Rajeev 
Published: January 2025

IntroductionTardive dyskinesia (TD) is a hyperkinetic movement disorder associated with antipsychotics (APs).ObjectiveTo estimate TD diagnosis rates across geographic regions of the United States (US) among adults who use APs.MethodsIn this retrospective cohort study, patients with ≥1 AP claim (≥30-day supply) followed by TD diagnosis (index date) aged ≥18 years at index date with ≥12 months of continuous insurance eligibility after index date and geographic location information were identified in the IBM MarketScan© commercial insurance database (2012– 2019). Additional information was collected from the US census, the Internal Revenue Service, and the Centers for Medicare & Medicaid Services. . Observed TD diagnosis rates were estimated by metropolitan statistical area (MSA; ie, a major city and surrounding geographic areas linked by socioeconomic factors with ≥50,000 individuals). A weighted multivariable linear regression model was used to calculate expected TD diagnosis rates per 1000 patients with an AP prescription at the MSA level. Estimated and expected TD diagnosis rates were aggregated at the state level. Underdiagnosis of TD was defined as the observed TD diagnosis rate being lower than the expected TD diagnosis rate.ResultsAmong 572,314 people who met inclusion criteria, the mean observed TD diagnosis rate across 341 MSAs was 3.10 per 1000 patients with an AP prescription; 86 (25.2%) MSAs had no patients with a TD diagnosis. Over 50% of MSAs and states had an underdiagnosis of TD. MSAs with the highest expected TD diagnosis rates were Missoula, MT (5.47), Billings, MT (5.39), and Madison, WI (5.16). MSAs with the highest observed TD rates were Chambersburg-Waynesboro, PA (18.52), Napa, CA (13.70), and San Angelo, TX (13.07). MSAs with the largest negative differences between observed and expected TD diagnosis rates (ie, highest underdiagnosis rates) were Missoula, MT (−5.47), Billings, MT (−5.39), and Gainesville, FL (−4.39). States with the highest expected TD rates were Montana (5.28), Idaho (4.52), and Alaska (4.32). States with the highest observed TD rates were North Dakota (7.09), Idaho (5.85), and New Mexico (5.67). States with the highest underdiagnosis rates were South Dakota (−3.72), Vermont (−3.57), and Montana (−3.21).ConclusionsOverall, this study showed that TD was underdiagnosed in >50% of US geographic regions. This research highlights opportunities for improved TD recognition in areas with TD underdiagnosis.FundingTeva Branded Pharmaceutical Products R&D, Inc.
Valbenazine Improves Tardive Dyskinesia with or Without Concomitant Antipsychotic Therapy: A Meta-Analysis of Three Long-Term Valbenazine Trials
Authors: Dunayevich Eduardo , Marder Stephen R. , Hinton Sean C. , Factor Stewart A. , Watanabe Yumi , Nakanishi Arline 
Published: January 2025

IntroductionValbenazine is a highly selective vesicular monoamine transporter 2 inhibitor indicated for tardive dyskinesia (TD), a persistent and potentially debilitating movement disorder associated with prolonged antipsychotic exposure. Given the paucity of data regarding the course of TD in patients no longer taking antipsychotics, a meta-analysis of 3 long-term valbenazine studies was conducted in subgroups with and without concomitant antipsychotic use at baseline.MethodsKINECTTM-3 (NCT02274558), KINECTTM-4 (NCT02405091), and JKINECT (NCT03176771) data were analyzed in study completers taking antipsychotics at baseline (AP+) and those who were not (AP-). The Abnormal Involuntary Movement Scale (AIMS) total score was used to measure TD severity at baseline, Wk48 (end of valbenazine treatment), and Wk52 (4 weeks after valbenazine withdrawal). The meta-analysis implemented a random-effects model that weighted each study based on inverse variance, adjusted for between-study variance.ResultsOf 576 enrolled patients, 336 (58.3%) were study completers and included for analysis: AP+ (n=269); AP- (n=67). Mean baseline AIMS scores ranged from 7.9–14.9 (AP+) and 10.9–14.5 (AP-). Mean changes from baseline in AIMS scores indicated substantial TD improvements with valbenazine at Wk48 (AP+, 6.1; AP-, -6.5) and return towards baseline severity at Wk52 (AP+, -2.1; AP-, -1.4).ConclusionsOnce-daily valbenazine treatment resulted in substantial and sustained TD improvement through Wk48, with no meaningful differences between AP+ and AP- subgroups. The return towards baseline severity after valbenazine withdrawal shows TD is chronic and often irreversible, even in patients no longer taking antipsychotics. Continuous treatment with valbenazine may be warranted irrespective of antipsychotic therapy.FundingNeurocrine Biosciences, Inc.
Safety and Tolerability of KarXT (Xanomeline Trospium): Pooled Results From the Randomized, Double-Blind, Placebo-Controlled EMERGENT Trials
Authors: Brannan Stephen K. , Cutler Andrew J. , Sawchak Sharon , Kando Judith , Miller Andrew C. , Claxton Amy , Paul Steven M. , Kaul Inder 
Published: January 2025

IntroductionIn prior studies, the dual M1/M4 preferring muscarinic receptor agonist xanomeline demonstrated antipsychotic activity in people with schizophrenia and Alzheimer’s disease, but its further clinical development was limited primarily by gastrointestinal side effects. KarXT combines xanomeline and the peripherally restricted muscarinic receptor antagonist trospium chloride. KarXT is designed to preserve xanomeline’s beneficial central nervous system effects while mitigating adverse events (AEs) due to peripheral muscarinic receptor activation. The efficacy and safety of KarXT in schizophrenia was demonstrated in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials.MethodsThe EMERGENT trials enrolled people with a recent worsening of positive symptoms warranting hospitalization, Positive and Negative Syndrome Scale total score ≥80, and Clinical Global Impression–Severity score ≥4. Eligible participants were randomized 1:1 to KarXT or placebo. KarXT dosing (xanomeline/trospium) started at 50 mg/20 mg twice daily (BID) and increased to a maximum of 125 mg/30 mg BID. Safety was assessed by monitoring for spontaneous AEs after administration of the first dose of trial drug until the time of discharge on day 35. Data from the EMERGENT trials were pooled, and all safety analyses were conducted in the safety population, defined as all participants who received ≥1 dose of trial drug.ResultsA total of 683 participants (KarXT, n=340; placebo, n=343) were included in the pooled safety analyses. Across the EMERGENT trials, 51.8% of people in the KarXT group compared with 29.4% in the placebo group reported ≥1 treatment-related AE. The most common treatment-relatedAEs occurring in ≥5% of participants receiving KarXT and at a rate at least twice that observed in the placebo group were nausea (17.1% vs 3.2%), constipation (15.0% vs 5.2%), dyspepsia (11.5% vs 2.3%), vomiting (10.9% vs 0.9%), and dry mouth (5.0% vs 1.5%). The most common treatment-related AEs in the KarXT group were all mild or moderate in severity.ConclusionsIn pooled analyses from the EMERGENT trials, KarXT was generally well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the efficacy results showing a clinically meaningful reduction in the symptoms of schizophrenia, support the potential of KarXT to be the first in a new class of antipsychotic medications based on muscarinic receptor agonism and a well-tolerated alternative to currently available antipsychotics.FundingKaruna Therapeutics
Long-Acting Injectable Antipsychotic Treatment: Calculating Cost Offsets From Real-World Data
Authors: Kane John M. , Hollenbeak Christopher S. , Kotak Sameer , Thompson Stephen 
Published: January 2025

BackgroundLong-acting injectable antipsychotics (LAIs) have demonstrated better rates of adherence among patients with schizophrenia than oral antipsychotics (OAs). While LAIs often cost more than OAs, better adherence can lead to cost offsets in other areas.ObjectiveThe purpose of this LAI Cost-Offset Value Calculator (LCVC) model is to provide an evidence-based model that estimates total costs and total cost offsets for a hypothetical population of adult patients with schizophrenia treated with atypical LAIs relative to second-generation oral antipsychotics (SGOAs) in the United States.MethodsThe model was derived based on studies included in a recent meta-analysis of patients who relapsed while taking an SGOA and were either switched to an atypical LAI or continued an SGOA. User inputs to the model include population size and payer archetype. The model then estimates the difference in adherence rates, relapse rates, hospitalizations, hospital days, hospital costs, emergency department (ED) visits, ED costs, and pharmacy costs, as well as cost offsets overall and by source (ie, hospitalization, ED, pharmacy).ResultsIn the base case, representing a hypothetical cohort of 1000 adult patients with schizophrenia in the United States and a composite payer archetype, 1-year pharmacy costs were higher for patients who switched to an LAI relative to patients who continued taking an SGOA ($14,561,971 vs $7,203,142). However, cost offsets were observed for other dimensions of direct costs, including lower ED costs ($1,664,808 vs $2,241,483) and substantially lower hospital costs ($23,623,612 vs $44,195,100) due to fewer relapses (409 vs 508). For some payer archetypes (ie, Medicare and Veteran Affairs), the cost offsets completely covered the higher pharmacy costs for LAIs; for others (ie, Commercial and Medicaid), the cost offsets partially covered the higher pharmacy costs for LAIs, though sometimes substantially.ConclusionDespite potential higher pharmacy costs for LAIs, this model supports the conclusion that those costs could be mitigated by cost offsets in other areas, with varying results depending on payer archetype. The LCVC model, parameterized using real-world data extracted from a recent systematic review and meta-analysis, may be helpful for payers in understanding the potential cost offsets of switching patients with schizophrenia who have relapsed while taking OAs to LAIs. To our knowledge, there are no similar studies for schizophrenia that calculate cost offsets based solely on empirical evidence of patients who failed on OAs.FundingTeva Branded Pharmaceutical Products R&D, Inc.
Capital Backed Funding Arrangements
Authors: Steeden Derek , Aponte Adolfo , Barnett David , Carr Vicky , Pearce Iain , Reid Andrew , Repp Jonathan , Stone Ben , van Rees Claire , Vigneswaran Ragulan , Xu Kelvin 
Published: January 2025

Abstract
The rise in interest rates globally in 2022–23 led to improved scheme funding for many defined-benefit pension schemes. Many schemes in the UK now find themselves closer to, or at, a fully funded position on a low-risk basis (annuity buyout or self-sufficiency). Finishing the journey while managing the risk of losses on that journey is highly desirable, but may be difficult to achieve in practice.
However many schemes are not yet sufficiently funded to buy out liabilities in full with an insurer. Others may not wish to, and many who can afford to do so are not yet able to for investment reasons (such as holding illiquid assets) or operational reasons (such as the time needed to resolve member data issues). For schemes that instead look to adopt self-sufficient ongoing management with low dependency on the sponsoring employer, this may be difficult to maintain in practice. In short, there remains a risk that benefits will not be secured in full, which with hindsight could have been avoided.
The addition of capital to pension scheme assets has long been deployed to enhance the security of member benefits e.g., capital from insurers in the case of a buyout or capital from sponsors in the form of contingent assets.
More recently, providers have developed a diverse set of arrangements that draw on external capital to aid trustees and corporates to meet scheme funding ambitions. Capital Backed Funding Arrangements (“CBFA”) are in this context an additional tool in the trustee toolkit for delivering funding strategies.
This paper focusses on the UK-defined benefit market but the dynamics are applicable to other jurisdictions, with CBFAs being developed for wider markets (e.g., Ireland).
In this paper we:

survey the current scheme funding landscape and consider the need in this environment for arrangements to support scheme funding journeys to deliver benefits in full

summarise the key features of arrangements in the market that may support these objectives

set out considerations for trustees and sponsoring companies when assessing these arrangements.

The aim of this paper is educational – to increase awareness of the key issues and potential solutions. Professional advice will always be required prior to any transaction. We welcome feedback from readers on further material that would be beneficial to support consideration of these arrangements.