BACKGROUND:The DCP (Diuretic Comparison Project), a pragmatic trial, evaluated whether chlorthalidone compared with hydrochlorothiazide would reduce the risk of nonfatal cardiovascular disease or noncancer-related death. The intent-to-treat analysis found no difference in such comparison (hazard ratio, 1.04 [95% CI, 0.94-1.16]). The objective of the current study is to estimate the per-protocol effect of chlorthalidone (12.5/25 mg daily) compared with hydrochlorothiazide (25/50 mg daily) in preventing major adverse cardiovascular events among older patients with hypertension. METHODS:The effect of adhering to treatment strategies was assessed by censoring at first instance of nonadherence, defined as a gap (>90-day gap in drug coverage), switch (switching between study medications), and discontinuation (stop taking chlorthalidone/hydrochlorothiazide altogether for >90 days before the end of the study). The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and noncancer-related death. Using inverse probability weighting, we evaluated the per-protocol effect of chlorthalidone and hydrochlorothiazide using DCP trial data. RESULTS:Nonadherence was found in 5476 (40%) participants; among 8047 (60%) adherents, 3905 (49%) were randomized to chlorthalidone and 4142 (51%) to hydrochlorothiazide. After censoring time when participants deviated from the assigned treatments, the estimated 5-year risk ratio of the composite primary outcome of nonfatal cardiovascular disease and noncancer-related death was 1.36 (95% CI, 0.96-2.12) in chlorthalidone compared with hydrochlorothiazide. CONCLUSIONS:The per-protocol analysis indicated a lower risk with hydrochlorothiazide compared with chlorthalidone in preventing nonfatal cardiovascular disease and noncancer-related death; however, this difference was not statistically significant using dispensation data to identify adherence. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02185417.

Results of a clinical trial may misrepresent the target population. Inappropriate inclusion/exclusion criteria, selective recruitment, and differential participation may restrict the number of patients who consent to join the study. Frequently, they differ from the real-world population in terms of key outcome-related characteristics. Such biased selection may make the therapeutic agent seem more or less effective within a certain stratum. While block randomization and an intent-to-treat design can help to minimize confounding within the trial sample, differences may still exist with respect to the distribution of these variables in the population. To mitigate misleading conclusions, the current manuscript illustrates how to ‘population-adjust’ survival estimates in a clinical trial using the Beckett–Bayes expansion method. In contrast to other population adjustment methods, this novel approach involves substituting the probability of belonging to a specific sample stratum with the corresponding population data (i.e., population borrowing). As a regression-free technique, the method is not susceptible to model misspecification. A large clinical trial focusing on cardiovascular-related deaths in patients with hypertension is used as an example to illustrate the method. The proposed framework is promising and easy to implement when reliable population-level information is available.

Importance Patients with prior myocardial infarction (MI) or stroke have a greater risk of recurrent cardiovascular (CV) events. Objective To evaluate the association of chlorthalidone (CTD) vs hydrochlorothiazide (HCTZ) with CV outcomes and noncancer deaths in participants with and without prior MI or stroke. Design, Setting, and Participants This was a prespecified secondary analysis of the Diuretic Comparison Project (DCP), a pragmatic randomized clinical trial conducted within 72 participating Veterans Affairs health care systems from June 2016 to June 2021, in which patients aged 65 years or older with hypertension taking HCTZ at baseline were randomized to continue HCTZ or switch to CTD at pharmacologically comparable doses. This secondary analysis was performed from January 3, 2023, to February 29, 2024. Exposures Pharmacologically comparable daily dose of HCTZ or CTD and history of MI or stroke. Main Outcomes and Measures Outcome ascertainment was performed from randomization to the end of the study. The primary outcome consisted of a composite of stroke, MI, urgent coronary revascularization because of unstable angina, acute heart failure hospitalization, or noncancer death. Additional outcomes included achieved blood pressure and hypokalemia (potassium level <3.1 mEq/L; to convert to mmol/L, multiply by 1.0). Results The DCP randomized 13 523 participants to CTD or HCTZ, with a mean (SD) study duration of 2.4 (1.4) years. At baseline, median age was 72 years (IQR, 69-75 years), and 96.8% were male. Treatment effect was evaluated in subgroups of participants with (n = 1455) and without (n = 12 068) prior MI or stroke at baseline. There was a significant adjusted interaction between treatment group and history of MI or stroke. Participants with prior MI or stroke randomized to CTD had a lower risk of the primary outcome than those receiving HCTZ (105 of 733 [14.3%] vs 140 of 722 [19.4%]; hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01) compared with participants without prior MI or stroke, among whom incidence of the primary outcome was slightly higher in the CTD arm compared with the HCTZ arm (597 of 6023 [9.9%] vs 535 of 6045 [8.9%]; HR, 1.12; 95% CI, 1.00-1.26; P = .054) (P = .01 for interaction). The incidence of a nadir potassium level less than 3.1 mEq/L and hospitalization for hypokalemia differed among those with and without prior MI or stroke when comparing those randomized to CTD vs HCTZ, with a difference only among those without prior MI or stroke (potassium level <3.1 mEq/L: prior MI or stroke, 43 of 733 [5.9%] vs 37 of 722 [5.1%] [P = .57]; no prior MI or stroke, 292 of 6023 [4.9%] vs 206 of 6045 [3.4%] [P < .001]; hospitalization for hypokalemia: prior MI or stroke, 14 of 733 [1.9%] vs 16 of 722 [2.2%] [P = .72]; no prior MI or stroke: 84 of 6023 [1.4%] vs 57 of 6045 [0.9%] [P = .02]). Conclusions and Relevance Results of this secondary analysis of the DCP trial suggest that CTD may be associated with reduced major adverse CV events and noncancer deaths in patients with prior MI or stroke compared with HCTZ.

Nonracemic amisulpride (SEP-4199) is an investigational 85:15 ratio of aramisulpride to esamisulpride and currently in clinical trials for the treatment of bipolar depression. During testing of SEP-4199, a pharmacokinetic/pharmacodynamic (PK/PD) disconnect was discovered that prompted the development of a controlled-release (CR) formulation with improved therapeutic index for QT prolongation. Observations that supported the development of a CR formulation included (i) plasma concentrations of amisulpride enantiomers were cleared within 24-hours, but brain dopamine D2 receptor (D2R) occupancies, although achieving stable levels during this time, required 5 days to return to baseline; (ii) nonracemic amisulpride administered to non-human primates produced significantly greater D2R occupancies during a gradual 6-hour administration compared with a single bolus; (iii) concentration-occupancy curves were left-shifted in humans when nonracemic amisulpride was gradually administered over 3 and 6 hours compared with immediate delivery; (iv) CR solid oral dose formulations of nonracemic amisulpride were able to slow drug dissolution in vitro and reduce peak plasma exposures in vivo in human subjects. By mathematically solving for a drug distribution step into an effect compartment, and for binding to target receptors, the discovery of a novel PK/PD model (termed here as Distribution Model) accounted for hysteresis between plasma and brain, a lack of receptor saturation, and an absence of accumulation of drug occupancy with daily doses. The PK/PD disconnect solved by the Distribution Model provided model-informed drug development to continue in Phase III using the non-bioequivalent CR formulation with diminished QT prolongation as dose-equivalent to the immediate release (IR) formulation utilized in Phase II.

BACKGROUND:Metabolic syndrome (MetS), which can be induced or exacerbated by the current class of antipsychotic drugs, is highly prevalent in patients with schizophrenia and presents significant challenges to lifetime disease management. Supported by initial clinical results, trace amine-associated receptor 1 (TAAR1) agonists have emerged as potential novel treatments for schizophrenia. Notably, non-clinical studies have also shown weight-lowering and glucoregulatory effects of TAAR1 agonists, including the investigational agent ulotaront. However, the translatability of these findings to humans has not been adequately assessed. Given that delayed gastric emptying (GE) was identified as a potential mechanism contributing to the metabolic benefits of TAAR1 agonists in rodents, the aim of this study was to evaluate the effect of ulotaront on GE in patients with schizophrenia and concurrent MetS with prediabetes. METHODS:Patients with schizophrenia were randomized to receive a single oral dose of ulotaront (150 mg) and their previous antipsychotic (PA) in an open-label, crossover, two-sequence design (NCT05402111). Eligible participants fulfilled at least three of five MetS criteria and had prediabetes defined by elevated glycated haemoglobin (5.7-6.4%) and/or fasting homeostatic model assessment of insulin resistance (i.e. ≥2.22). Following an overnight fast and 4 h post-dose, participants ingested a 99mTc-sulphur colloid radiolabelled egg meal (320 kcal, 30% fat). GE was measured by scintigraphy over 4 h. Endpoints included GE of solids half-time (T1/2) and percentage gastric retention at 1, 2 and 4 h. RESULTS:Thirty-one adults were randomized and 27 completed the study. Ulotaront significantly delayed GE of solids [median GE T1/2 ulotaront at 139 min (119, 182) vs. the participant's PA of 124 min (109, 132), p = .006]. A significant increase in gastric retention was seen in the ulotaront versus the PA group at 1 h (80% vs. 75%, p = .015), 2 h (61% vs. 50%, p = .023) and 4 h (17% vs. 7%, p = .002) post-meal. CONCLUSION:Ulotaront delayed the GE of solids in patients with schizophrenia and concurrent MetS with prediabetes. Additional studies are needed to assess whether treatment with TAAR1 agonists is associated with weight loss and glucoregulatory improvement.

Adverse event (AE) data in randomized controlled trials (RCTs) allow quantification of a drug’s safety risk relative to placebo and comparison across medications. The standard US label for Food and Drug Administration-approved drugs typically lists AEs by MedDRA Preferred Term that occur at ≥ 2

Background: Ulotaront (SEP-363856) is a novel agonist at trace amine-associated receptor 1 and sero-tonin 5-HT1A receptors in clinical development for the treatment of schizophrenia. Previous studies demonstrated ulotaront suppresses rapid eye movement (REM) sleep in both rodents and healthy vol-unteers. We assessed acute and sustained treatments of ulotaront on REM sleep and symptoms of cat-aplexy and alertness in subjects with narcolepsy-cataplexy.Methods: In a multicenter, double-blind, placebo-controlled, randomized, 3-way crossover study, ulo-taront was evaluated in 16 adults with narcolepsy-cataplexy. Two oral doses of ulotaront (25 mg and 50 mg) were administered daily for 2 weeks and compared with matching placebo (6-treatment sequence, 3-period, 3-treatment). Results: Acute treatment with both 25 mg and 50 mg of ulotaront reduced minutes spent in nighttime REM compared to placebo. A sustained 2-week administration of both doses of ulotaront reduced the mean number of short-onset REM periods (SOREMPs) during daytime multiple sleep latency test (MSLT) compared to placebo. Although cataplexy events decreased from the overall mean baseline during the 2-week treatment period, neither dose of ulotaront statistically separated from placebo (p = 0.76, 25 mg; p = 0.82, 50 mg), and no significant improvement in patient and clinician measures of sleepiness from baseline to end of the 2-week treatment period occurred in any treatment group.Conclusions: Acute and sustained treatment with ulotaront reduced nighttime REM duration and day-time SOREMPs, respectively. The effect of ulotaront on suppression of REM did not demonstrate a sta-tistical or clinically meaningful effect in narcolepsy-cataplexy. Registration: ClinicalTrials.gov identifier: NCT05015673.(c) 2023 Published by Elsevier B.V.

PURPOSE:Low-dose naltrexone (LDN) is commonly used to control pain and other symptoms, especially in patients with autoimmune diseases, but with limited evidence. This study tests the efficacy of LDN in reducing chronic pain in patients with osteoarthritis (OA) and inflammatory arthritis (IA), where existing approaches often fail to adequately control pain. METHODS:In this randomized, double-blind, placebo-controlled, crossover clinical trial, each patient received 4.5 mg LDN for 8 weeks and placebo for 8 weeks. Outcome measures were patient reported, using validated questionnaires. The primary outcome was differences in pain interference during the LDN and placebo periods, using the Brief Pain Inventory (scale, 0-70). Secondary outcomes included changes in mean pain severity, fatigue, depression, and multiple domains of health-related quality of life. The painDETECT questionnaire classified pain as nociceptive, neuropathic, or mixed. Data were analyzed using mixed-effects models. FINDINGS:Seventeen patients with OA and 6 with IA completed the pilot study. Most patients described their pain as nociceptive (n = 9) or mixed (n = 8) rather than neuropathic (n = 3). There was no difference in change in pain interference after treatment with LDN (mean [SD], -23 [19.4]) versus placebo (mean [SD], -22 [19.2]; P = 0.90). No significant differences were seen in pain severity, fatigue, depression, or health-related quality of life. IMPLICATIONS:In this small pilot study, findings do not support LDN being efficacious in reducing nociceptive pain due to arthritis. Too few patients were enrolled to rule out modest benefit or to assess inflammatory or neuropathic pain. CLINICALTRIALS:gov identifier: NCT03008590.

BACKGROUND:Intimate partner violence (IPV) is a prevalent social determinant of health. The US Preventive Services Task Force recommends routine IPV screening of women, but uptake remains variable. The Veterans Health Administration (VHA) initiated implementation facilitation (IF) to support integration of IPV screening programs into primary care clinics. An evaluation of IF efforts showed variability in IPV screening rates across sites. The follow-up study presented here used a Matrixed Multiple Case Study (MMCS) approach to examine the multilevel factors impacting IPV screening program implementation across sites with varying levels of implementation success. METHODS:This mixed methods study is part of a larger cluster randomized stepped wedge Hybrid-II program evaluation. In the larger trial, participating sites received 6 months of IF consisting of an external facilitator from VHA's Office of Women's Health working closely with an internal facilitator and key site personnel. Recognizing the heterogeneity in implementation outcomes across sites, the MMCS approach was used to enable interpretation of qualitative and quantitative data within and across sites to help contextualize the primary findings from the larger study. Qualitative data collection was guided by the integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework and included interviews with key informants involved in IPV screening implementation at eight sites. Quantitative data on IPV screening uptake was derived from medical records and surveys completed by key personnel at the same eight sites to understand implementation facilitation activities. RESULTS:Fifteen factors influencing IPV screening implementation spanning all four i-PARIHS domains were identified and categorized into three distinct categories: (1) factors with enabling influence across all sites, (2) factors deemed important to implementation success, and (3) factors differentiating sites with high/medium versus low implementation success. CONCLUSIONS:Understanding the influencing factors across multi-level domains contributing to variable success of IPV screening implementation can inform the tailoring of IF efforts to promote spread and quality of screening. Implementation of IPV screening programs in primary care with IF should consider consistent engagement of internal facilitators with clinic staff involved in implementation, the resourcefulness of external facilitators, and appending resources to IPV screening tools to help key personnel address positive screens. TRIAL REGISTRATION:ClinicalTrials.gov NCT04106193. Registered on September 26, 2019.

TPS4610 Background: Bladder cancer is the tenth most common malignancy and the fourteenth most common cause of cancer death worldwide. Currently, platinum-based chemotherapy followed by avelumab maintenance immunotherapy is the first-line standard of care for advanced bladder cancer (aBC). Even though maintenance avelumab therapy has improved overall survival, its efficacy is still disappointing with a response rate of less than 10% and progression-free survival benefit of 1.7 months. The phosphoinositide 3-kinase (PI3K) pathway harbors more activating alterations than any other growth signaling pathway in aBC. Furthermore, PI3K δ and γ are expressed by immune cells and regulate their function. Activation alterations along the PI3K pathway are putative molecular drivers and can possibly be targeted for the treatment of aBC. In preclinical studies, we found that a pan-PI3K class I inhibitor, copanlisib, potentiates anti-programmed cell death 1 (PD1) antibody in syngeneic bladder cancer mouse models with or without activation alterations along the PI3K pathway (Zhu S, J Immunother Cancer. 2021). We hypothesize that copanlisib potentiates avelumab as maintenance therapy for aBC. Methods: This is a multi-center, single-arm, open-label Phase II trial with a lead-in safety phase to determine the efficacy and toxicity of combination copanlisib and avelumab maintenance therapy in aBC. The major inclusion criteria are patients with aBC without disease progression after platinum-based chemotherapy and no contraindication for avelumab and copanlisib. With a type I error of 5% and power of 80% with a log-rank test, we will need 26 patients for this study. With an attrition rate of 10%, we will enroll 29 patients from four US Department of Veterans Affairs Medical Centers. Copanlisib will be administered through intravenous infusion (IV) at 60 mg on Day 1, 8 and 15, and avelumab will be administered 800 mg IV on Day 1 and 15 of each 4-week treatment cycle for up to 26 cycles. Imaging will be repeated every two cycles during first year of therapy and thereafter every 3 cycles or clinically indicated. The primary endpoint is progression-free survival (PFS). The secondary endpoints include CT or MRI determined radiographic overall response rate, toxicity, overall survival, and molecular correlative studies. Kaplan-Meier estimates will be presented together with median PFS with 2-sided 95% confidence intervals (CI). In particular, the PFS rates at 3, 6, 9, 12 and 15 months will be estimated with corresponding 2-sided 95% CIs. Adverse events will be assessed according to CTCAE v5. Tumor response is determined according to Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1 criteria. This study is currently open for enrollment. Clinical trial information: NCT05687721 .

Background/Aims: The US Department of Veterans Affairs Point of Care Clinical Trial Program conducts studies that utilize informatics infrastructure to integrate clinical trial protocols into routine care delivery. The Diuretic Comparison Project compared hydrochlorothiazide to chlorthalidone in reduction of major cardiovascular events in subjects with hypertension. Here we describe the cultural, technical, regulatory, and logistical challenges and solutions that enabled successful implementation of this large pragmatic comparative effectiveness Point of Care clinical trial. Methods: Patients were recruited from 72 Veterans Affairs Healthcare Systems using centralized processes for subject identification, obtaining informed consent, data collection, safety monitoring, site communication, and endpoint identification with minimal perturbation of the local clinical care ecosystem. Patients continued to be managed exclusively by their clinical care providers without protocol specified study visits, treatment recommendations, or data collection extraneous to routine care. Centralized study processes were operationalized through the application layer of the electronic health record via a data coordinating center staffed by clinical nurses, data scientists, and statisticians without site-based research coordinators. Study data was collected from the Veterans Affairs electronic health record supplemented by Medicare and National Death Index data. Results: The study exceeded its enrolled goal (13,523 subjects) and followed subjects for the 5-year study duration. The key determinant of program success was collaboration between researchers, regulators, clinicians, and administrative staff at the site level to customize study procedures to align with local clinical practice. This flexibility was enabled by designation of the study as minimal risk and determination that clinical care providers were not engaged in research by the Veterans Affairs Central Institutional Review Board. Cultural, regulatory, technical, and logistical problems were identified and solved through iterative collaboration between clinical and research entities. Paramount among these problems was customization of the Veterans Affairs electronic health record and data systems to accommodate study procedures. Conclusions: Leveraging clinical care for large-scale clinical trials is feasible but requires a rethinking of traditional clinical trial design (and regulation) to better meet requirements of clinical care ecosystems. Study designs must accommodate site-specific practice variation to reduce the impact on clinical care. A tradeoff thus exists between designing trial processes tailored to expedite local study implementation versus those to produce a more refined response to the research question. The availability of a uniform and flexible electronic health record in the Department of Veterans Affairs played a major role in the success of the trial. Conducting Point of Care research in other healthcare systems without such research-friendly infrastructure presents a more formidable challenge.

Background: The CSP590 randomized trial was designed to estimate the effect of lithium on suicidality. After a third of the intended number of participants were enrolled, the hazard ratio of suicidality was 1.10 (95% CI: 0.77, 1.55). Based on this, the trial was stopped for futility. However, only 17% of patients adhered to the specified protocol. Aims: The objective was to estimate the per-protocol effect of lithium on suicidality, that is, the effect of adhering to the treatment strategies as specified in the protocol. Methods: We stopped individuals’ follow-up if/when they showed evidence of nonadherence. We then conducted the analysis in the restricted sample, adjusting for prognostic factors that predict adherence via inverse probability weighting. The primary outcome was the 12-month risk of suicidality (including death from suicide, suicide attempt, interrupted attempt, hospitalization specifically to prevent suicide). Results: The estimated 12-month risk of suicidality was 18.8% for lithium, and 24.3% for placebo. The risk ratio was 0.78 (95% CI: 0.43, 1.37) and the risk difference −5.5 percentage points (95% CI: −17.5, 5.5). Results were consistent across sensitivity analyses. Conclusions: With one-third of the targeted sample size, lithium effects (compared with placebo) ranging between a 17.5% reduction and a 5.5% increase in the risk of suicidality were highly compatible with the data. Thus, a protective effect of lithium on suicidality among patients with bipolar disorder or major depressive disorder cannot be ruled out. Trials should incorporate adequate per-protocol analyses into the decision-making processes for stopping trials for futility.

Introduction: The Veterans Health Administration initiated implementation facilitation to inte-grate intimate partner screening programs in primary care. This study investigates implementation facilitation's impact on implementation and clinical effectiveness outcomes.Study design: A cluster randomized, stepped-wedge, hybrid-II implementation-effectiveness trial (January 2021-April 2022) was conducted amidst the COVID-19 pandemic.Setting/participants: Implementation facilitation was applied at 9 Veterans Health Administra-tion facilities, staged across 2 waves.Participants were all women receiving care at participating pri-mary care clinics 3 months before (pre-implementation facilitation n=2,272) and 9 months after initiation of implementation facilitation (implementation facilitation n=5,149).Intervention: Implementation facilitation included an operations-funded external facilitator work-ing for 6 months with a facility-funded internal facilitator from participating clinics. The pre-implementation facilitation period comprised implementation as usual in the Veterans Health Administration.Main outcome measures: Primary outcomes were changes in (1) reach of intimate partner vio-lence (IPV) screening programs among eligible women (i.e., those seen within participating clinics during the assessment period; implementation outcome) and (2) disclosure rates among screened women (effectiveness outcome). Secondary outcomes included disclosure rates among all eligible women and post-screening psychosocial service use. Administrative data were analyzed.Results: For primary outcomes, women seen during the implementation facilitation period were nearly 3 times more likely to be screened for IPV than women seen during the pre-implementation facilitation period (OR=2.70, 95% CI=2.46, 2.97). Women screened during the implementation facilitation period were not more likely to disclose IPV than those screened during the pre implementation facilitation period (OR=1.14, 95% CI=0.86, 1.51). For secondary outcomes, owing to increased reach of screening during implementation facilitation, women seen during the implementation facilitation period were more likely to disclose IPV than those seen during the pre-implementation facilitation period (OR=2.09, 95% CI=1.52, 2.86). Women screened during implementation facilitation were more likely to use post-screening psychosocial services than those screened during pre-implementation facilitation (OR=1.29, 95% CI=1.06, 1.57).Conclusions: Findings indicate that implementation facilitation may be a promising strategy for increasing the reach of IPV screening programs in primary care, thereby increasing IPV detection and strengthening connections to support services among the patient population.Trial registration: This study is registered at www.clinicaltrials.gov NCT04106193.Am J Prev Med 2023;65(2):251-260. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Inhibitors of dopamine transporters (DAT), norepinephrine transporters (NET) and serotonin transporters (SERT) are effective treatments for neuropsychiatric diseases. Dasotraline [(1R,4 S)- 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-1-naphthalenamine, also known as SEP-225289) was evaluated for its inhibitory potency at DAT, NET and SERT using in vitro and in vivo assays. In vitro radiometric functional uptake studies showed preferential inhibition by dasotraline of hDAT (IC50 =3 nM) and hNET (IC50 =4 nM relative to hSERT(IC50 =15 nM). In mouse ex vivo occupancy studies, dasotraline demonstrated total plasma concentration-dependent occupancy at DAT, NET and SERT. Determination of the TO50 (50% transporter occupancy) were 32, 109 and 276 ng/ml, respectively. In SPECT imaging studies in baboons, dasotraline (0.2 mg/kg iv) displaced radiotracer binding to DAT by 87% but only 20% at NET and SERT. Rat microdialysis studies were performed in prefrontal cortex and striatum. Dasotraline produced sustained (>4 h) increases in dopamine and norepinephrine concentrations. Dasotraline was also more potent at increasing synaptic dopamine in the striatum, and norepinephrine in the prefrontal cortex than serotonin in these regions. In summary, dasotraline preferentially inhibits DAT and NET relative to SERT. Together, the occupancy and neurochemical profile of dasotraline provide a mechanistic basis for the treatment of diseases that have an underlying causality involving dopamine and norepinephrine dysfunction.

Importance Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression. Objective To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event. Design, Setting, and Participants This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019. Interventions Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo. Main Outcomes and Measures Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide. Results The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group. Conclusions and Relevance In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities. Trial Registration ClinicalTrials.gov Identifier:NCT01928446

Schizophrenia is a chronic, heterogeneous, severe psychiatric disorder characterized by a spectrum of symptomology and is associated with substantial morbidity and mortality. For the last 70 years, available treatments have shared blockade of dopamine D2 receptors as their primary mechanism of action (MOA), the efficacy of which has been limited by incomplete resolution of all symptoms as well as treatment non-response in a select subset of patients. In addition, antipsychotics are associated with class-related side effects attributed to this primary MOA, including extrapyramidal symptoms (EPS). The need for non-D2 treatment options for patients which offer a novel risk/benefit profile is therefore apparent. There has been substantial investment in the research and development of non-D2 drug candidates. However, none of these programs have received successful regulatory approval by the FDA (as of Oct 2022). In this article, the scale of industry-sponsored clinical trials for D2-based investigational pharmacological treatments in schizophrenia was quantified and compared with investigational compounds with non-D2 MOAs. In a dataset of 545 clinical trials identified in ClinicalTrials.gov from January 2002 to July 2022, total enrollments in trials of non-D2-based compounds for the treatment of schizophrenia summed to approximately 34,000 patients, compared with 27,144 patients for D2-based compounds. These data indicate that there remains substantial and ongoing investment in the development of novel non-D2 options for schizophrenia, with a success rate measured by regulatory approval that is well-below recent benchmarks for the broader category of CNS drugs. Improved trial design, conduct, endpoints, and analyses/methods may influence signal detection and reliability to support development and registration of non-D2 compounds.

Objective Improved biomarkers of current disease activity and prediction of relapse are needed in antineutrophil cytoplasmic antibody–associated vasculitis (AAV). For clinical relevance, biomarkers must perform well longitudinally in patients on treatment and in patients with nonsevere flares. Methods Twenty‐two proteins were measured in 347 serum samples from 74 patients with AAV enrolled in a clinical trial. Samples were collected at Month 6 after remission induction, then every 3 months until Month 18, or at the time of flare. Associations of protein concentrations with concurrent disease activity and with future flare were analyzed using mixed‐effects models, Cox proportional hazards models, and conditional logistic regression. Results Forty‐two patients had flares during the 12‐month follow‐up period, and 32 remained in remission. Twenty‐two patients had severe flares. Six experimental markers (CXCL13, IL‐6, IL‐8, IL‐15, IL‐18BP, and matrix metalloproteinase‐3 [MMP‐3]) and ESR were associated with disease activity using all three methods (P < 0.05, with P < 0.01 in at least one method). A rise in IL‐8, IL‐15, or IL‐18BP was associated temporally with flare. Combining C‐reactive protein (CRP), IL‐18BP, neutrophil gelatinase‐associated lipocalin (NGAL), and sIL‐2Rα improved association with active AAV. CXCL13 and MMP‐3 were increased during treatment with prednisone, independent of disease activity. Marker concentrations during remission were not predictive of future flare. Conclusion Serum biomarkers of inflammation and tissue damage and repair have been previously shown to be strongly associated with severe active AAV were less strongly associated with active AAV in a longitudinal study that included mild flares and varying treatment. Markers rising contemporaneously with flare or with an improved association in combination merit further study.

BACKGROUND:Recent US guidelines recommend chlorthalidone over other thiazide-type diuretics for the treatment of hypertension based on its long half-life and proven ability to reduce CVD events. Despite recommendations most clinicians prescribe hydrochlorothiazide (HCTZ) over chlorthalidone (CTD). No randomized controlled data exist comparing these two diuretics on cardiovascular outcomes. METHODS:The Diuretic Comparison Project (DCP) is a multicenter, two-arm, parallel, Prospective Randomized Open, Blinded End-point (PROBE) trial testing the primary hypothesis that CTD is superior to HCTZ in the prevention of non-fatal CVD events and non-cancer death. Patients with hypertension taking HCTZ 25 or 50 mg were randomly assigned to either continue their current HCTZ or switch to an equipotent dose of CTD. The primary outcome is time to the first occurrence of a composite outcome consisting of a non-fatal CVD event (stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, or hospitalization for acute heart failure) or non-cancer death. The trial randomized 13,523 patients at 72 VA medical centers. The study is conducted by a centralized research team with site procedures embedded in the electronic health record and all data collected through administrative claims data, with no study related visits for participants. The trial will have 90% power to detect an absolute reduction in the composite event rate of 2.4%. RESULTS:Enrollment ended in November 2021. There are 4128 participting primary care providers and 16,595 patients individually consented to participate, 13,523 of whom were randomized. CONCLUSIONS:DCP should provide much needed evidence as to whether CTD is superior to HCTZ in preventing cardiovascular events in hypertensive patients. CLINICAL TRIAL REGISTRATION:NCT02185417 [https://clinicaltrials.gov/ct2/show/NCT02185417].