Pharmacotherapy Trials Research Articles

Recommendations for the Design and Implementation of Alcohol Pharmacotherapy Trials: Perspectives of Women With HIV Participating in the WHAT-IF Study.

Naltrexone for alcohol reduction has been poorly studied in women with HIV (WWH), for whom heavy alcohol use is associated with negative HIV outcomes. This study offers recommendations for researchers conducting alcohol pharmacotherapy trials among PWH as suggested by WWH who participated in an alcohol pharmacotherapy trial in Florida. The WHAT-IF? Study enrolled WWH with a history of heavy alcohol use in Miami, Florida, into a clinical trial where participants were randomized to receive naltrexone or placebo to assess effectiveness among WWH. Twenty participants (mean age, 49 years; 85% Black/African American) completed interviews that included questions about barriers to participation and recommendations for future researchers and WWH. Interviews were analyzed using a reflexive thematic approach. We identified six recommendations: 1) increasing opportunities for study engagement, 2) fostering positive relationships to support change, 3) addressing medication concerns, 4) considering structural barriers to participation, 5) improving alcohol-related education, and 6) preventing fraudulent participation. Positive relationships included both study staff and external support. Medication concerns included cost, accessibility, and adherence. Structural barriers included transportation, substance use, and mental health conditions. Better education included information on the risks of alcohol use and encouraging women to quit. Overall, women reported having positive experiences in the WHAT-IF? trial, and many recommended that the study continue. Future alcohol pharmacotherapy studies could consider these recommendations when working with women from underserved communities, including WWH. Additionally, these recommendations could be applied to increase alcohol pharmacotherapy uptake and adherence in clinical practice.

Tackling Cravings in Medical Weight Management: An Update on Pathophysiology and an Integrated Approach to Treatment

Background/Objectives: Food cravings involve a strong drive to consume palatable foods irrespective of nutritional status. Importantly, cravings contribute substantially to the obesity epidemic. Managing hunger alone is insufficient for weight management as this relates only to homeostatic eating and does not address the complex aetiology of hedonic eating and its crucial role in food cravings. Medical weight management clinics and anti-obesity medication trials do not routinely identify and address food cravings. Methods: We conducted a narrative review of the literature consisting of 115 peer-reviewed articles (original articles and reviews). We included articles focused on food craving pathophysiology, assessment, and management strategies providing contrasts against the current medical model of weight management seen in obesity pharmacotherapy trials as well as the current standard of practise. Results: We outline the neurohormonal and psychological drivers of cravings, which lead to a spectrum of eating behaviours, from comfort food eating to binge eating disorders. We provide an overview of ways of identification and measurement options, including their strengths and weaknesses, and an overview of management strategies and their cravings control efficacy, spanning lifestyle modifications like nutrition and sleep, psychological therapies (i.e., cognitive behavioural therapy [CBT], acceptance-based therapies such as mindfulness) and, last but not least, medications that not only are approved for weight reduction but reduce cravings. Finally, based on these findings, we provide a proposed integrated and iterative model that is able to evolve and adapt to the individual over time in tackling cravings for long-term weight loss maintenance. Conclusions: The findings emphasise the importance of cravings management and provide a synthesis on how cravings can be identified in a medical weight management setting, which can be practically implemented in an integrated iterative model spanning anti-obesity medications that have craving control data to evidence-based lifestyle and psychological interventions.

Considerations for the design and conduct of pediatric obesity pharmacotherapy clinical trials: Proceedings of expert roundtable meetings.

Anti-obesity medications (AOMs) have emerged as one element of comprehensive obesity clinical care intended to improve long-term health outcomes for children and adolescents. The number of pediatric AOM clinical trials has burgeoned in recent years as new pharmacotherapeutics have been developed. Factors related to growth and development in children and adolescents can present unique challenges in terms of designing and conducting clinical trials investigating the safety and efficacy of AOMs. These barriers can delay the AOM development and evaluation process, increase the cost of performing trials, create challenges in the interpretation of results, influence the generalizability of the findings and present ethical dilemmas. In an effort to address these issues and provide guidance to streamline the process of designing and conducting pediatric AOM clinical trials, relevant key stakeholders convened a series of roundtable meetings to discuss, debate and achieve harmonization on design features. Stakeholder participants included a multidisciplinary group of international pediatric obesity experts, patient (parent) representatives and representatives from academic medicine, key regulatory agencies and industry. Topics of discussion included primary efficacy end-points, secondary end-points, eligibility criteria, trial run-in and follow-up phases, use of active comparators and guidelines for down-titration and/or stopping rules for excessive weight reduction. Consensus recommendations were agreed upon. Regarding end-points, emphasis was placed on moving away from BMI z-score as a primary outcome, incorporating multiple alternative BMI-related outcomes and measuring adiposity/body fat as a prominent secondary end-point. Trial eligibility criteria were carefully considered to maximize generalizability while maintaining safety. The limited value of trial run-in phases was discussed. It was also underscored that designing trials with extended follow-up periods after AOM withdrawal should be avoided owing to ethical issues (including possible psychological harm) related to weight regain without providing the opportunity to access other treatments. The panel emphasized the value of the randomized, placebo-controlled trial but recommended the thoughtful consideration of the use of active comparators in addition to, or instead of, placebo to achieve clinical equipoise when appropriate. Finally, the panel recommended that clinical trial protocols should include clear guidance regarding AOM down-titration to avoid excessive weight reduction when applicable.

A framework for assessment of adverse events occurring in psychedelic-assisted therapies.

Despite considerable research examining the efficacy of psychedelic-assisted therapies (PATs) for treating psychiatric disorders, assessment of adverse events (AEs) in PAT research has lagged. Current AE reporting standards in PAT trials are poorly calibrated to features of PAT that distinguish it from other treatments, leaving many potential AEs unassessed. A multidisciplinary working group of experts involved in PAT pooled formally and informally documented AEs observed through research experience and published literature. This information was integrated with (a) current standards and practices for AE reporting in pharmacotherapy and psychotherapy trials and (b) published findings documenting post-acute dosing impacts of psychedelics on subjective states, meaning, and psychosocial health variables, to produce a set of AE constructs important to evaluate in PAT as well as recommended methods and time frames for their assessment and monitoring. Correspondence between identified potential AEs and current standards for AE assessment was examined, including the extent of coverage of identified AE constructs by 25 existing measures used in relevant research. Fifty-four potential AE terms warranting systematized assessment in PAT were identified, defined, and categorized. Existing measures demonstrated substantial gaps in their coverage of identified AE constructs. Recommendations were developed for how to assess PAT AEs (including patient, clinician, and informant reports), and when to assess over preparation, dosing session, integration, and follow-up. Application of this framework is demonstrated in a preliminary assessment protocol (available in the supplement). This assessment framework addresses the need to capture post-acute dosing AEs in PAT, accounting for its pharmacotherapy and psychotherapy components, as well as documented impacts of psychedelics on worldviews and spirituality.

Trajectories of craving in the course of pharmacotherapy trials for methamphetamine use disorder.

The aim of this study was to measure trajectories of craving for methamphetamine during the course of pharmacotherapy trials for methamphetamine use disorder. Craving trajectories were identified using Group-Based Trajectory Modeling. The association of craving trajectories with drug use trajectories was examined using a dual trajectory model. Association of craving trajectories with other health and social outcomes was also examined. The study used pooled data from five randomized controlled pharmacotherapy trials for methamphetamine use disorder. A total of 866 adults with methamphetamine use disorder participated in randomized controlled pharmacotherapy trials. Craving was assessed weekly using the Brief Substance Craving Scale. Drug use was assessed using urine toxicology. Alcohol- and drug-related problems, as well as psychiatric, medical, legal, employment and relationship problems, were measured using the Addiction Severity Index. A three-trajectory model with high, medium and low craving trajectories was selected as the most parsimonious model. Craving trajectories were associated with methamphetamine use trajectories in the course of trial; 88.4% of those in the high craving trajectory group had a consistently high frequency of methamphetamine use compared with 18.7% of those in the low craving group. High craving was also associated with less improvement in most other outcomes and higher rate of dropout from treatment. In turn, low craving was associated with a rapidly decreasing frequency of methamphetamine use, greater improvement in most other outcomes and a lower rate of dropout. Participants on modafinil daily and ondansetron 1 mg twice daily were less likely to be in the high craving group compared with those on placebo. Trajectories of methamphetamine craving in the course of clinical trials for methamphetamine use disorder appear to be both highly variable and strongly associated with greater frequency of drug use, other drug-related outcomes and dropout from trials. Two medications, modafinil daily and ondansetron at a dose of 1 mg two times daily, appear to be associated with greater reduction in craving in the course of treatment compared with placebo. A decrease in methamphetamine craving shows promise as an early indicator of recovery from methamphetamine use disorder.

Endpointsfor Pharmacotherapy Trials for AlcoholUse Disorder.

Alcoholuse disorder (AUD) is a debilitating disorder, yet currently approved pharmacotherapies to treat AUD are under-utilized. The three medications approved by the US Food and Drug Administration (FDA) for the indication of AUD are disulfiram, acamprosate, and naltrexone. The current landscape of pharmacotherapies for AUD suggests opportunities for improvement. Clinical trials investigating novel pharmacotherapies for AUD traditionally use abstinence-based drinking outcomes or no heavy drinking days as trial endpoints to determine the efficacy of pharmacotherapies. These outcomes are typically measured through patient self-report endorsements of their drinking. Apart from these traditional outcomes, there have been recent developments in novel endpoints for AUD pharmacotherapies. These novel endpoints include utilizing the World Health Organization (WHO) riskdrinking level reductions to promote a harm-reduction endpoint rather than an abstinence-based endpoint. Additionally, in contrast to patient self-report measurements, biological markers of alcohol use may serve as objective endpoints in AUD pharmacotherapy trials. Lastly, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) definition of recovery from AUD and patient-oriented outcomes offer new frameworks to consider endpoints associated with more than alcohol consumption itself, such as the provider-patient experiences with novel pharmacotherapies. These recent developments in new endpoints for AUD pharmacotherapies offer promising future opportunities for pharmacotherapy development, so long as validity and reliability measures are demonstrated for the endpoints. A greater breadth of endpoint utilization may better capture the complexity of AUD symptomatology.

Ongoing and Future Clinical Trials of Pharmacotherapy for Heart Failure.

Increasing knowledge of the processes leading to heart failure (HF) has allowed significant developments in therapies for HF over the past few decades. Despite the evolution of HF treatment, it still places a large burden on patients and health care systems across the world.We used clinicaltrials.gov to gather information about clinical trials as of August 2023 studying pharmacotherapy for HF. We included interventional trials that were "active, not recruiting", "recruiting", or looking for participants but "not yet recruiting". In total, 119 studies met our criteria of ongoing clinical trials studying novel as well as currently approved HF pharmacotherapies. The major interventions were novel medications/already approved medications for other diseases 29 % (34 trials), sodium-glucose co-transporter inhibitors 21 % (25 trials), angiotensin receptor blocker-neprilysin inhibitors 10 % (12 trials), diuretics 14 % (17 trials) and mineralocorticoid receptor antagonists 5 % (6 trials). Ongoing research will aid in reducing the impact of HF and we summarize clinical trials leading the way to better HF treatment in this review.

Sleep as an Important Target or Modifier in Alcohol Use Disorder Clinical Treatment: Example From a Recent Gabapentin Randomized Clinical Trial.

Alcohol consumption affects sleep both in healthy populations and in patients with alcohol use disorder (AUD). However, sleep has typically not been considered within AUD pharmacotherapy trials. We used data from a completed gabapentin clinical treatment trial to explore the medication's effect on patient-rated insomnia measured by a standard insomnia rating (Insomnia Severity Index [ISI]) and whether this influenced gabapentin's effects on alcohol consumption. This study included 90 individuals with current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition AUD criteria reporting current or past alcohol withdrawal. Participants were assigned to placebo or gabapentin (up to 1200 mg/day) for a 16-week randomized controlled trial with percent heavy drinking days (PHDD) and percent abstinent days (PDA) as outcomes. Utilizing mixed-effects models, this study assessed medication effects on ISI over the trial. We then examined the interaction of baseline ISI and medication on drinking. Finally, given our previous finding of alcohol withdrawal influencing gabapentin efficacy, we added change in ISI as a potential "moderator" of the interaction of medication effects and alcohol withdrawal on drinking. Sleep (ISI) improved more in those treated with gabapentin (60.6% reduction) compared with placebo (37.8% reduction; P = 0.013). Higher baseline ISI predicted drinking in gabapentin-treated individuals (lower PHDD [ P = 0.026] and higher (PDA [ P = 0.047]). ISI was an independent predictor of PHDD decrease and PDA increase ( P < 0.001; P = 0.002), but this did not significantly moderate gabapentin's effectiveness. Although gabapentin positively impacts both alcohol use and sleep, its effect on drinking is not fully dependent on sleep improvement, implying a direct biological mechanism on alcohol use.

Early life stress is associated with greater negative emotionality and peripheral inflammation in alcohol use disorder

Early life stress (ELS) increases risk for psychiatric illness, including alcohol use disorder (AUD). Researchers have hypothesized that individuals with and without a history of ELS who have the same primary DSM-5 diagnosis are clinically and biologically distinct. While there is strong support for this hypothesis in the context of mood disorders, the hypothesis remains largely untested in the context of AUD. This study investigated the impact of ELS on the neuroclinical phenomenology and inflammatory profile of individuals with AUD. Treatment-seeking adults with AUD (N = 163) completed the Adverse Childhood Experiences (ACE) Questionnaire and phenotypic battery as part of a pharmacotherapy trial for AUD (NCT03594435). Participants were classified as having “no-ELS,” (ACE = 0) “moderate-ELS,” (ACE = 1, 2 or 3) or “high-ELS” (ACE = 4 + ). The Addictions Neuroclinical Assessment domains incentive salience and negative emotionality were derived and used to assess the neuroclinical phenomenology of AUD. We tested (1) cumulative ELS as a predictor of ANA domains and (2) ELS group differences in ANA domains. A subset of participants (N = 98) provided blood samples for a biomarker of peripheral inflammation (C-reactive protein; CRP); analyses were repeated with CRP as the outcome variable. Greater ELS predicted higher negative emotionality and elevated CRP, but not incentive salience. The high-ELS group exhibited greater negative emotionality compared with the no-ELS and moderate-ELS groups, with no difference between the latter two groups. The high-ELS group exhibited elevated CRP compared with the no/moderate-ELS group. Findings suggest that high-ELS exposure is associated with a unique AUD neuroclinical presentation marked by greater negative emotionality, and inflammatory profile characterized by elevated peripheral CRP.

Reductions in World Health Organization Risk Drinking Level Are Associated With Reductions in Alcohol Use Disorder Diagnosis and Criteria: Evidence From an Alcohol Pharmacotherapy Trial.

This study aimed to evaluate the validity of World Health Organization (WHO) risk drinking level reductions as meaningful endpoints for clinical practice and research. This study examined whether such reductions were associated with a lower likelihood of a current alcohol use disorder (AUD) diagnosis and fewer AUD criteria. We conducted a secondary data analysis to address these objectives using data from a multisite randomized controlled trial of gabapentin enacarbil extended release in treating moderate to severe AUD among adults (N = 346). Participants received gabapentin enacarbil extended release or placebo for 6 months. The timeline follow-back was used to assess WHO risk drinking level reductions, and the Mini-International Neuropsychiatric Interview was used to assess Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) AUD diagnosis and criteria at baseline (past year) and end of treatment (past month). Most participants (80.1%) achieved at least a 1-level reduction in the WHO risk drinking levels from baseline to end of treatment, and nearly half of participants (49.8%) achieved at least a 2-level reduction. At least a 1-level reduction or at least a 2-level reduction in WHO risk drinking level predicted lower odds of an active AUD diagnosis (1-level: odds ratio, 0.74 [95% confidence interval (CI), 0.66-0.84]; 2-level: odds ratio, 0.71 [95% CI, 0.64-0.79]) and fewer AUD criteria (1-level: B , -1.66 [95% CI, -2.35 to -0.98]; 2-level: B , -1.76 [95% CI, -2.31 to -1.21]) at end of treatment. World Health Organization risk drinking level reductions correlate with Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) AUD diagnosis and criteria, providing further evidence for their use as endpoints in alcohol intervention trials, which has potential implications for broadening the base of AUD treatment.

Sociodemographic and patient reported outcomes by racial and ethnicity status among participants in a randomized controlled trial for methamphetamine use disorder

BackgroundThere has been a significant increase in methamphetamine use and methamphetamine use disorder (Meth UD) in the United States, with evolving racial and ethnic differences. ObjectivesThis secondary analysis explored racial and ethnic differences in baseline sociodemographic and clinical characteristics as well as treatment effects on a measure of substance use recovery, depression symptoms, and methamphetamine craving among participants in a pharmacotherapy trial for Meth UD. MethodsThe ADAPT-2 trial (ClinicalTrials.gov number, NCT03078075; N=403; 69% male) was a multisite, 12-week randomized, double-blind, trial that employed a two-stage sequential parallel design to evaluate the efficacy of combination naltrexone (NTX) and oral bupropion (BUP) vs. placebo for Meth UD. Treatment effect was calculated as the weighted mean change in outcomes in the NTX-BUP minus placebo group across the two stages of treatment. ResultsOf the 403 participants in the ADAPT-2 trial, the majority (65%) reported non-Hispanic White, while 14%, 11% and 10% reported Hispanic, non-Hispanic Black, and non-Hispanic other racial and ethnic categories respectively. At baseline non-Hispanic Black participants reported less severe indicators of methamphetamine use than non-Hispanic White. Treatment effects for recovery, depression symptoms and methamphetamine cravings did not significantly differ by race and ethnicity. ConclusionsAlthough we found racial and ethnic differences at baseline, our findings did not show racial and ethnic differences in treatment effects of NTX-BUP on recovery, depression symptoms and methamphetamine cravings. However, our findings also highlight the need to expand representation of racial and ethnic minority groups in future trials.

The dosing regimen for 17-hydroxyprogesterone caproate was suboptimal: lessons for future pharmacotherapy for pregnant women

BackgroundMakena (17-hydroxyprogesterone caproate) was FDA approved for prevention of recurrent spontaneous preterm birth in 2011 under the accelerated approval pathway but fundamental pharmacokinetic or pharmacodynamic (phase1 and phase 2) studies were not performed. At the time, there were no dose-response or concentration-response data. The therapeutic concentration was not known. The lack of such data questions whether the dosing regimen for 17-hydroxyprogesterone caproate was optimized. ObjectiveThe purpose of this study was to evaluate the dosing regimen for 17-hydroxyprogesterone by analyzing three data sets that evaluated 17-hydroxyprogesterone caproate pharmacology: the Maternal-Fetal Medicine Omega 3 study, the Obstetric-Fetal Pharmacology Research Units study and the Obstetrical-Fetal Pharmacology Research Centers study. If an inappropriate dosing regimen could be identified, such information could inform future studies of pharmacotherapy in pregnancy. Study DesignData from the Omega 3 study were utilized to determine if plasma concentration was related to spontaneous preterm birth risk and if a threshold concentration could be identified. Data from the Obstetric-Fetal Pharmacology Research Units study were used to determine the half-life of 17-hydroxyprogesterone caproate and to develop a model to simulate drug concentrations with various dosing regimens. Data from the Obstetrical-Fetal Pharmacology Research Centers study were used to determine the relationship between dose and safety outcomes. ResultsAnalysis of the Omega 3 dataset indicated that the risk of spontaneous preterm birth decreased as the log of 17-hydroxyprogesterone caproate increased [odds ratio (95%CI) 0.04 (0.00 - 0.90)]. A steady state concentration> 9 ng/ml (equivalent to > 8 ng/ml at 25-28 weeks) was associated with the lowest risk of spontaneous preterm birth [hazard ratio (95%CI) 0.52 (0.27-0.98, p=0.04)]; this concentration was not achieved in 25% of subjects receiving the 250 mg weekly dose. In the Obstetrical-Fetal Pharmacology Research Units study, the adjusted half-life (median and IQR) of 17-hydroxyprogesterone caproate was 14.0 (11.5-17.2) days. Simulations indicated that with the 250 mg weekly dose, > 5 weekly injections were required to reach the 9 ng/ml target; however, those with the shortest half-life (corresponding to higher clearance), never reached the targeted 9 ng/ml concentration. In 75% of subjects, a loading dose of 500 mg weekly for 2 weeks followed by 250 mg weekly achieved and maintained the 9 ng/ml concentration within two weeks but in those 25% with the shortest half-life, concentrations exceeded the 9 ng/ml target for only 3 weeks. In the Obstetrical-Fetal Pharmacology Research Centers study, all 65 subjects receiving a weekly dose of 500 mg exceeded the 9 ng/ml steady state. ConclusionsThe dosing regimen for 17-hydoxyprogesterone caproate was inadequate. There is a significant inverse relationship between drug concentration and spontaneous preterm birth. Risk is lowest when concentration exceeds 9 ng/ml but 25% of women receiving the 250 mg weekly dose will never reach and maintain this concentration. The drug’s long half-life necessitates a loading dose to achieve therapeutic concentrations rapidly. The omission of basic pharmacologic studies to determine the proper dosing may have compromised the effectiveness of 17-hydroxyprogesterone caproate. Future pharmacotherapy trials in pregnancy must first complete fundamental pharmacology studies.

The reporting quality of randomized controlled trials in pharmacotherapy for pituitary adenomas.

Medical therapy has become an increasingly important intervention owing to improvements in the multidisciplinary care for pituitary adenomas (PAs). This study aimed to assess the reporting quality of randomized controlled trials (RCTs) on PAs pharmacotherapy. RCTs evaluating the efficacy of pharmacotherapy in PAs published in English between January 1, 1974, and December 31, 2022, were searched for and collected from PubMed and MEDLINE. The 2010 Consolidated Standards for Test Reports (CONSORT) statement-based 28 items overall quality score (OQS) was used to evaluate the overall quality of each report. Twenty-seven related RCTs including 1816 patients were retrieved. The median OQS score was 12 (range, 6-19) on a scale of 0 to 28. Important items, such as background, objectives, participants, interventions, and outcomes, were sufficiently reported in 100% (27/27) of the articles. Statistical methods were adequately described in 93% (25/27) of patients. However, RCTs underreported identification as randomized trials in the title (3/27, 11%), sample size, allocation concealment, implementation, ancillary analysis method, and Diagram and Ancillary analyses (1/27, 4%). The OQS of published RCTs has significantly increased since 2010 (P = .012). The multivariate final model showed significant associations between higher OQS and publication since 2010 and enrollment of more than 100 patients. The overall reporting quality of RCTs on pharmacotherapy in PAs was poor, based on the 2010 CONSORT statement. However, we noticed an improvement in the OQS over the years and identified the factors associated with a better report. Increased effort is necessary to raise awareness of these issues among writers, readers, reviewers, and editors.

Abstract TP12: Changes in Plasma Metabolites Reflect Lesional Iron Content and Permeability Imaging as Monitoring Biomarkers of Hemorrhage in Cavernous Angiomas

Background: Increase in mean lesional iron content (≥6%) measurement by QSM and vascular permeability (≥ 40%) assessed by DCEQP MRI have been associated with new bleeding in cavernous angiomas (CA), and are used as monitoring biomarkers in clinical trial of pharmacotherapy in CAs with symptomatic hemorrhage (SH). Plasma metabolites have been associated with CA in unsupervised discovery, and linked mechanistically to the permissive microbiome and angiogenic and inflammatory mechanisms in CAs. To date, their levels change has not been compared to lesional QSM and DCEQP change during prospective monitoring. Methods: Fifty-nine paired plasma samples and MRI sequences were simultaneously acquired in 46 subjects at beginning and end of 1-year epochs in prospective follow-up of cases with CA enrolled in clinical trial after SH. Plasma levels of 14 metabolites previously associated with CA were assayed by liquid-chromatography mass spectrometry, and their changes were compared to changes in mean lesional QSM and DCEQP during the same epochs. Univariate correlations were followed by multivariate analyses combining multiple metabolites levels to minimize Akaike Information Criterion (AIC) or increase R 2 . Accuracy (AUC on receiver operating curves) and sum of squared error (SSE) are reported for associations achieving statistical significance with FDR correction. Results: Aceltyl.L.carnitine absolute change was correlated with QSM absolute change (p=0.01). Highest accuracy for lesional ΔθΣμ ινχρεασε ≥6% was reported for the absolute change of Arachidonic Acid + LPE.18.0 (AUC 99.7%; SD 0.003; p0.01). Relative change of Arachidonic Acid + Hypoxanthine + Piperine, and absolute change of LPE.18.0 + Pipecolic Acid + Piperine had the highest accuracy (AUC 99.1%; SD 0.008 and 98.0%; 0.013) for lesional DCEQP increase of ≥40%. Relative change in Phenylacetylglutamine and LPE.18.0+Piperine reported the lowest SSE (9.77; 438.33) with respective QSM and DCEQP relative change Conclusion: Changes in circulating metabolites accurately reflect changes in lesional iron content and permeability in CASH during yearly follow-up. Results are a proof of concept that blood tests could replace more complex and costly imaging biomarkers in monitoring CA hemorrhage.

Patient Priorities, Decisional Comfort, and Satisfaction with Metformin versus Insulin for the Treatment of Gestational Diabetes Mellitus.

We compared patient priorities, decisional comfort, and satisfaction with treating gestational diabetes mellitus (GDM) with metformin versus insulin among pregnant individuals with GDM requiring pharmacotherapy. We conducted a cross-sectional study of patients' perspectives about GDM pharmacotherapy in an integrated prenatal and diabetes care program from October 19, 2022, to August 24, 2023. The exposure was metformin versus insulin as the initial medication decision. Outcomes included standardized measures of patient priorities, decisional comfort, and satisfaction about their medication decision. Among 144 assessed individuals, 60.4% were prescribed metformin and 39.6% were prescribed insulin. Minoritized individuals were more likely to receive metformin compared with non-Hispanic White individuals (34.9 vs. 17.5%; p = 0.03). Individuals who were willing to participate in a GDM pharmacotherapy clinical trial were more likely to receive insulin than those who were unwilling (30.4 vs. 19.5%; p = 0.02). Individuals receiving metformin were more likely to report prioritizing avoiding injections (62.4 vs. 19.3%; adjusted odds ratio [aOR]: 2.83; 95% confidence interval [CI]: 1.10-7.31), wanting to take a medication no more than twice daily (56.0 vs. 30.4%; aOR: 3.67; 95% CI: 1.56-8.67), and believing that both medications can equally prevent adverse pregnancy outcomes (70.9 vs. 52.6%; aOR: 2.67; 95% CI: 1.19-6.03). Conversely, they were less likely to report prioritizing a medication that crosses the placenta (39.1 vs. 82.5%; aOR: 0.09; 95% CI: 0.03-0.25) and needing supplemental insulin to achieve glycemic control (21.2 vs. 47.4%; aOR: 0.36; 95% CI: 0.15-0.90). Individuals reported similarly high (mean score > 80%) levels of decisional comfort, personal satisfaction with medication decision-making, and satisfaction about their conversation with their provider about their medication decision with metformin and insulin (p ≥ 0.05 for all). Individuals with GDM requiring pharmacotherapy reported high levels of decision comfort and satisfaction with both metformin and insulin, although they expressed different priorities in medication decision-making. These results can inform future patient-centered GDM treatment strategies. · Pregnant individuals with GDM requiring pharmacotherapy expressed a high level of decisional comfort and satisfaction with medication decision making.. · Individuals placed different priorities on deciding to take metformin versus insulin.. · These results can inform interventions aimed at delivering person-centered diabetes care in pregnancy that integrates patient autonomy and knowledge about treatment options..

The dynamic interaction between symptoms and pharmacological treatment in patients with major depressive disorder: the role of network intervention analysis

IntroductionThe Major Depressive Disorder (MDD) is a mental health disorder that affects millions of people worldwide. It is characterized by persistent feelings of sadness, hopelessness, and a loss of interest in activities that were once enjoyable. MDD is a major public health concern and is the leading cause of disability, morbidity, institutionalization, and excess mortality, conferring high suicide risk. Pharmacological treatment with Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin Noradrenaline Reuptake Inhibitors (SNRIs) is often the first choice for their efficacy and tolerability profile. However, a significant percentage of depressive individuals do not achieve remission even after an adequate trial of pharmacotherapy, a condition known as treatment-resistant depression (TRD).MethodsTo better understand the complexity of clinical phenotypes in MDD we propose Network Intervention Analysis (NIA) that can help health psychology in the detection of risky behaviors, in the primary and/or secondary prevention, as well as to monitor the treatment and verify its effectiveness. The paper aims to identify the interaction and changes in network nodes and connections of 14 continuous variables with nodes identified as "Treatment" in a cohort of MDD patients recruited for their recent history of partial response to antidepressant drugs. The study analyzed the network of MDD patients at baseline and after 12 weeks of drug treatment.ResultsAt baseline, the network showed separate dimensions for cognitive and psychosocial-affective symptoms, with cognitive symptoms strongly affecting psychosocial functioning. The MoCA tool was identified as a potential psychometric tool for evaluating cognitive deficits and monitoring treatment response. After drug treatment, the network showed less interconnection between nodes, indicating greater stability, with antidepressants taking a central role in driving the network. Affective symptoms improved at follow-up, with the highest predictability for HDRS and BDI-II nodes being connected to the Antidepressants node.ConclusionNIA allows us to understand not only what symptoms enhance after pharmacological treatment, but especially the role it plays within the network and with which nodes it has stronger connections.

Insights for successful recruitment of people who actively use heroin to a pharmacotherapy trial: a case study

ABSTRACT Background This paper reports on recruiting strategies in a study which aimed to examine the mechanism of intranasal oxytocin on cue-induced opiate craving and attentional bias in males using heroin in addition to substitute opiates from four UK community drug treatment services. Methods Recruitment took place during and post-COVID-19 periods of social distancing and lockdowns. Caseworkers obtained consent to contact from interested service users before an initial telephone screen. People were then scheduled for in-person screens, typically within seven days of the initial telephone call. Subsequent visits took place within 30 days of the previous visit. Each visit lasted one hour and participants received one £20 voucher per completed visit. Results Thirty participants were randomized from 113 referrals. We were unable to contact 36% (n = 41) of people. Of those eligible to start the study (n = 44), 68% (n = 30) agreed to start the study, retaining 82% (n = 24) to completion. Factors which positively influenced recruitment were having a research presence on site, the cultivation of relationships and demonstrating respect and gratitude toward the participants. Conclusions These results support the feasibility of recruiting males currently using heroin in addition to substitute opiates utilizing a person-first approach with service users and staff.

A Review of Therapeutics for Treatment-Resistant Depression in the Older Adult.

One-third of older adults with depression meet criteria for treatment resistance, typically defined as a lack of response to two or more adequate trials of an antidepressant. Treatment resistance contributes to an unfavorable prognosis, compromised medical outcomes, heightened disability, accelerated cognitive decline, and an elevated risk of developing dementia. Despite this significant morbidity, evidence is sparse for how to proceed with treatment in this population. Non-pharmacologic therapy (e.g., diet, psychotherapy) can be utilized as adjunctive therapy, despite little published evidence of benefit, given that the risks are low. Pharmacotherapy trials in the treatment-resistant late-life depression population lack strong methods and external validity; however, the use of venlafaxine as monotherapy and add-on therapy, as well as lithium, bupropion, or aripiprazole as add-on therapy to standard antidepressant therapy, have enough evidence that a trial with appropriate monitoring is a prudent strategy. Electroconvulsive therapy remains a well-studied safe therapy, especially when used as maintenance treatment once an initial cycle is completed but is traditionally underutilized in the treatment-resistant late-life depression population. Ensuring non-pharmacologic and pharmacologic strategies are optimized and given a sufficient trial in those with treatment-resistant late-life depression is the best we can do for this vulnerable population.

Antifibrotic therapy in nonalcoholic steatohepatitis: time for a human-centric approach.

Nonalcoholic steatohepatitis (NASH) might soon become the leading cause of end-stage liver disease and indication for liver transplantation worldwide. Fibrosis severity is the only histological predictor of liver-related morbidity and mortality in NASH identified to date. Moreover, fibrosis regression is associated with improved clinical outcomes. However, despite numerous clinical trials of plausible drug candidates, an approved antifibrotic therapy remains elusive. Increased understanding of NASH susceptibility and pathogenesis, emerging human multiomics profiling, integration of electronic health record data and modern pharmacology techniques hold enormous promise in delivering a paradigm shift in antifibrotic drug development in NASH. There is a strong rationale for drug combinations to boost efficacy, and precision medicine strategies targeting key genetic modifiers of NASH are emerging. In this Perspective, we discuss why antifibrotic effects observed in NASH pharmacotherapy trials have been underwhelming and outline potential approaches to improve the likelihood of future clinical success.

Psychometrics of the Concise Health Risk Tracking Self-Report (CHRT-SR16) Assessment of Suicidality in a Sample of Adults with Moderate to Severe Methamphetamine Use Disorder: Findings from the ADAPT-2 Randomized Trial.

The co-occurrence of suicidality and substance use disorders has been well established, but rating scales to examine suicidal behavior and risk are sparse among participants with substance use disorders. We examined the psychometric properties of the 16-item Concise Health Risk Tracking Scale - Self Report (CHRT-SR16) to measure suicidality among adults with moderate-to-severe methamphetamine use disorder. Participants (n = 403) with moderate-to-severe methamphetamine use disorder completed the CHRT-SR16 as part of a randomized, double-blind, placebo-controlled pharmacotherapy trial. The CHRT-SR16 factor structure was assessed using confirmatory factor analysis (CFA). Internal consistency was estimated with coefficients alpha (α) and omega (ω), test-retest reliability with intraclass correlation coefficient (ICC) and standard error of measurement, and convergent validity using Spearman's ρ rank order correlation coefficient test between CHRT-SR16 factors and the Patient Health Questionnaire (PHQ-9). The analyses utilized baseline and week 1 data (for test-retest reliability only). CFA revealed a seven-factor model of Pessimism, Helplessness, Social Support, Despair, Impulsivity, Irritability, and Suicidal Thoughts as the best-fitting model. The CHRT-SR16 also exhibited strong internal consistency (α = 0.89; ω = 0.89), test-retest reliability (ICC = 0.78) and convergent validity with the PHQ-9 total score (ρ = 0.62). The CHRT-SR16 showed strong psychometric properties in a sample of participants with primary methamphetamine use disorder. NCT03078075.