Citations

Abstract Background The purpose of this study was to review the association between the SLC6A4 5-HTTLPR polymorphism and antidepressant (AD)-associated treatment emergent mania (TEM) in bipolar disorder alongside starting a discussion on the merits of developing risk stratification models to guide when not to provide AD treatment for bipolar depression. Methods Studies that examined the association between clinical and genetic risk factors, specifically monoaminergic transporter genetic variation, and TEM were identified. A meta-analysis was performed using the odds ratio to estimate the effect size under the Der-Simonian and Laird model. Results Seven studies, referencing the SLC6A4 5-HTTLPR polymorphism and TEM (total N = 1578; TEM+ =594, TEM− = 984), of 142 identified articles were included. The time duration between the start of the AD to emergence of TEM ranged from 4 to 12 weeks. There was a nominally significant association between the s allele of the 5-HTTLPR polymorphism and TEM (odds ratio, 1.434; 95% confidence interval, 1.001–2.055; P = 0.0493; I 2 = 52%). No studies have investigated norepinephrine or dopamine transporters. Conclusion Although the serotonin transporter genetic variation is commercially available in pharmacogenomic decision support tools, greater efforts, more broadly, should focus on complete genome-wide approaches to determine genetic variants that may contribute to TEM. Moreover, these data are exemplary to the merits of developing risk stratification models, which include both clinical and biological risk factors, to guide when not to use ADs in bipolar disorder. Future studies will need to validate new risk models that best inform the development of personalized medicine best practices treating bipolar depression.

Abstract There is increasing interest in individualizing treatment selection for more than 25 regulatory approved treatments for major depressive disorder (MDD). Despite an inconclusive efficacy evidence base, antidepressants (ADs) are prescribed for the depressive phase of bipolar disorder with oftentimes an inadequate treatment response and or clinical concern for mood destabilization. This study explored the relationship between antidepressant response in MDD and antidepressant-associated treatment emergent mania (TEM) in bipolar disorder (BD). We conducted a genome-wide association study (GWAS) and polygenic score analysis of TEM and tested its association with a subset of BD-I patients treated with SSRIs or SNRIs. Our results did not identify any genome-wide significant variants although, we found that a higher polygenic score (PGS) for antidepressant response in MDD was associated with higher odds of TEM in BD. Future studies with larger transdiagnostic cohorts treated with antidepressants are encouraged to identify a neurobiological mechanism associated with a spectrum of depression improvement (response- emergent mania).

Abstract Purpose To report historical patterns of pharmaceutical expenditures, to identify factors that may influence future spending, and to predict growth in drug spending in 2023 in the United States, with a focus on the nonfederal hospital and clinic sectors. Methods Historical patterns were assessed by examining data on drug purchases from manufacturers using the IQVIA National Sales Perspectives database. Factors that may influence drug spending in hospitals and clinics in 2023 were reviewed, including new drug approvals, patent expirations, and potential new policies or legislation. Focused analyses were conducted for biosimilars, cancer drugs, diabetes medications, generics, COVID-19 pandemic influence, and specialty drugs. For nonfederal hospitals, clinics, and overall (all sectors), estimates of growth of pharmaceutical expenditures in 2023 were based on a combination of quantitative analyses and expert opinion. Results In 2022, overall pharmaceutical expenditures in the US grew 9.4% compared to 2021, for a total of $633.5 billion. Utilization (a 5.9% increase), price (a 1.7% increase) and new drugs (a 1.8% increase) drove this increase. Adalimumab was the top-selling drug in 2022, followed by semaglutide and apixaban. Drug expenditures were $37.2 billion (a 5.9% decrease) and $116.9 billion (a 10.4% increase) in nonfederal hospitals and clinics, respectively. In clinics, new products and increased utilization growth drove growth, with a small impact from price changes. In nonfederal hospitals, a drop in utilization led to a decrease in expenditures, with price changes and new drugs contributing to growth in spending. Several new drugs that will influence spending have been or are expected to be approved in 2023. Specialty and cancer drugs will continue to drive expenditures along with the evolution of the COVID-19 pandemic. Conclusion For 2023, we expect overall prescription drug spending to rise by 6.0% to 8.0%, whereas in clinics and hospitals we anticipate increases of 8.0% to 10.0% and 1.0% to 3.0%, respectively, compared to 2022. These national estimates of future pharmaceutical expenditure growth may not be representative of any particular health system because of the myriad of local factors that influence actual spending.

AbstractTo date, bipolar disorder (BD) genetic studies and polygenic risk scores (PRSs) for BD are based primarily on populations of European descent (EUR) and lack representation from other ancestries including Latin American (LAT). Here, we describe a new LAT cohort from the Mayo Clinic Bipolar Biobank (MCBB), a multisite collaboration with recruitment sites in the United States (EUR; 1,443 cases and 777 controls) and Mexico and Chile (LAT; 211 cases and 161 controls) and use the sample to explore the performance of a BD‐PRS in a LAT population. Using results from the largest genome‐wide association study of BD in EUR individuals, PRSice2 and LDpred2 were used to compute BD‐PRSs in the LAT and EUR samples from the MCBB. PRSs explained up to 1.4% (PRSice) and 4% (LDpred2) of the phenotypic variance on the liability scale in the LAT sample compared to 3.8% (PRSice2) and 3.4% (LDpred2) in the EUR samples. Future larger studies should further explore the differential performance of different PRS approaches across ancestries. International multisite studies, such as this one, have the potential to address diversity‐related limitations of prior genomic studies and ultimately contribute to the reduction of health disparities.

Lithium has been a cornerstone treatment for bipolar disorder (BD). Despite descriptions in the literature regarding associations between long-term lithium therapy (LTLT) and development of a thyroid disorder (overt/subclinical hypo/hyperthyroidism, thyroid nodule, and goiter) in BD, factors such as time to onset of thyroid abnormalities and impact on clinical outcomes in the course of illness have not been fully characterized. In this study we aimed to compare clinical characteristics of adult BD patients with and without thyroid disorders who were on LTLT. We aimed to identify the incidence of thyroid disorders in patients with BD on LTLT and response to lithium between patients with and without thyroid disorders in BD. The Cox proportional model was used to find the median time to the development of a thyroid disorder. Our results showed that up to 32% of patients with BD on LTLT developed a thyroid disorder, of which 79% developed hypothyroidism, which was corrected with thyroid hormone replacement. We did not find significant differences in lithium response between patients with or without thyroid disorders in BD. Findings from this study suggest that patients with BD and comorbid thyroid disorders when adequately treated have a response to lithium similar to patients with BD and no thyroid disorders.

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

91 Background: Most screening clinical trials are not representative of the populations susceptible to disparities in breast cancer outcomes. Strategies are needed to address known structural barriers to clinical trial participation. We partnered with a federally qualified health center to provide no-cost ride-share services as a strategy to facilitate enrollment of uninsured, Hispanic women in Maricopa County, Arizona into a national trial offering no-cost mammography screening. Objective: This pilot survey study explored the feasibility and experiences of uninsured, Hispanic women with a no-cost ride share program as part of the National Cancer Institute funded ECOG-ACRIN clinical trial, TMIST, studying mammography screening at the Mayo Clinic Arizona in Phoenix. Methods: Participants completed a validated survey by phone and interview-style. Survey items assessed women’s use of and experiences with the ride share service including barriers, benefits, and if the ride share service facilitated their participation in the screening trial. Descriptive statistics were calculated using SAS. Results: A total of 30 women completed the survey (response rate = 30/33). All women first-time Mayo Clinic trial participants and 90% lived at least 30 minutes away from trial facility. The mean age of women was X years, 90% had a high school degree or less, and 97% were Spanish speaking. Most women (73.7%) said that travel distance was a barrier to participation in prior clinical trials. A large proportion of women (73%) reported using ride share services for this trial and all agreed that the ride service made it easier for them to attend their trial visit. Nearly 1/3 (64%) said that they were uncertain or would not have been able to participate without the ride-share as an option. Among women using the ride share service, the main benefits of the program included at-home pick up and the service being of no-cost. Other benefits included flexible timing (86%) and one-on-one service (86%). The primary barrier of the program was the driver not speaking the dominant native language (27.3%). Conclusions: Despite lengthy travel distances, women reported overwhelming positive experiences with the no-cost ride share program and agreed that the service helped facilitate their participation in the clinical trial. Thus, no-cost ride share programs are a promising and feasible strategy to reduce barriers to clinical trial participation among historically underserved populations. Future studies should continue to explore the benefits and sustainability of ride-share programs, including benefits to clinical trial retention.

Background The Woven EndoBridge (WEB) device is a novel intrasaccular flow disruptor tailored for bifurcation aneurysms. We aim to describe the degree of aneurysm occlusion at the latest follow-up, and the rate of complications of aneurysms treated with the WEB device stratified according to rupture status. Methods Our data were taken from the WorldWideWeb Consortium, an international multicenter cohort including patients treated with the WEB device. Aneurysms were classified into two groups: ruptured and unruptured. We compared clinical and radiologic outcomes of both groups. Propensity score matching (PSM) was done to match according to age, gender, bifurcation, location, prior treatment, neck, height, dome width, daughter sac, incorporated branch, pretreatment antiplatelets, and last imaging follow-up. Results The study included 676 patients with 691 intracranial aneurysms (529 unruptured and 162 ruptured) treated with the WEB device. The PSM analysis had 55 pairs. In both the unmatched (85.8% vs 84.3%, p=0.692) and matched (94.4% vs 83.3%, p=0.066) cohorts there was no significant difference in the adequate occlusion rate at the last follow-up. Likewise, there were no significant differences in both ischemic and hemorrhagic complications between the two groups. There was no documented aneurysm rebleeding after WEB device implantation. Conclusion There was no significant difference in both the radiologic outcomes and complications between unruptured and ruptured aneurysms. Our findings support the feasibility of treatment of ruptured aneurysms with the WEB device.

Abstract Purpose Recognizing the negative impact that antipsychotic-induced movement disorders have on the quality of life and treatment outcomes in bipolar disorder (BD), this study aimed to assess clinical correlates and antipsychotic use patterns of tardive dyskinesia (TD+) in BD. Materials and Methods Participants with and without TD were included. Clinical variables were compared using t-test and χ2 test. Antipsychotic use patterns in TD+, including number of trials, mean doses, and estimated cumulative exposure, were assessed in a case-only analysis. Results The prevalence rate of TD was 5.1%. In comparison to the TD− group (n = 1074), TD+ participants (n = 58) were older, more likely to be female and have type I bipolar illness. There were 60.3% of the TD+ group that continued using antipsychotics at study entry and had a mean cumulative exposure to antipsychotics of 18.2 ± 15.6 years. Average dose, in haloperidol equivalents, was 5.9 ± 3.5 mg and 77.7% of the trials were second-generation antipsychotics. Conclusions This study confirms previously identified TD risk factors, such as age, sex, and bipolar subtype in a large BD cohort. Limitations included a cross-sectional design and the lack of tardive illness severity assessment. As atypical antipsychotics continue to be primary mood stabilization treatment, attempting to harmonize large data sets to identify additional biomarkers of tardive risk will optimize individualized care for patients with BD.