Multi-omics driven predictions of response to acute phase combination antidepressant therapy: a machine learning approach with cross-trial replication

Combination antidepressant pharmacotherapies are frequently used to treat major depressive disorder (MDD). However, there is no evidence that machine learning approaches combining multi-omics measures (e.g., genomics and plasma metabolomics) can achieve clinically meaningful predictions of outcomes to combination pharmacotherapy. This study examined data from 264 MDD outpatients treated with citalopram or escitalopram in the Mayo Clinic Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) and 111 MDD outpatients treated with combination pharmacotherapies in the Combined Medications to Enhance Outcomes of Antidepressant Therapy (CO-MED) study to predict response to combination antidepressant therapies. To assess whether metabolomics with functionally validated single-nucleotide polymorphisms (SNPs) improves predictability over metabolomics alone, models were trained/tested with and without SNPs. Models trained with PGRN-AMPS’ and CO-MED’s escitalopram/citalopram patients predicted response in CO-MED’s combination pharmacotherapy patients with accuracies of 76.6% (p < 0.01; AUC: 0.85) without and 77.5% (p < 0.01; AUC: 0.86) with SNPs. Then, models trained solely with PGRN-AMPS’ escitalopram/citalopram patients predicted response in CO-MED’s combination pharmacotherapy patients with accuracies of 75.3% (p < 0.05; AUC: 0.84) without and 77.5% (p < 0.01; AUC: 0.86) with SNPs, demonstrating cross-trial replication of predictions. Plasma hydroxylated sphingomyelins were prominent predictors of treatment outcomes. To explore the relationship between SNPs and hydroxylated sphingomyelins, we conducted multi-omics integration network analysis. Sphingomyelins clustered with SNPs and metabolites related to monoamine neurotransmission, suggesting a potential functional relationship. These results suggest that integrating specific metabolites and SNPs achieves accurate predictions of treatment response across classes of antidepressants. Finally, these results motivate functional investigation into how sphingomyelins might influence MDD pathophysiology, antidepressant response, or both.

The use of Mono- and Combination Pharmacotherapy in Men and Women with Lower Urinary Tract Symptoms (LUTS) in the UK: A Retrospective Observational Study

Background: Combination pharmacotherapy for lower urinary tract symptoms (LUTS) is beneficial to selected patients and recommended by guidelines. Patterns of real-world LUTS drug use, especially combination pharmacotherapy, have not been studied extensively. Moreover, further understanding of the recent landscape is required following the introduction of the beta-3-adrenoceptor agonist mirabegron in the UK in 2013 for overactive bladder (OAB). The objective was to describe mono- and combination pharmacotherapy use for LUTS in patients in UK clinical practice. Methods: This was a retrospective, descriptive, observational database study using UK Clinical Practice Research Datalink GOLD and linked databases. Men and women ≥ 18 years with a first prescription for any LUTS drug from 2014–2016 with ≥ 12 months continuous enrolment pre- and post-index date were included. Primary endpoints were mono- or combination pharmacotherapy use for LUTS in male and female cohorts. Secondary endpoints were description of treatment prescribed, treatment persistence and patient demographics. Data were analyzed descriptively. Sub-cohorts were defined by drugs prescribed at index date.Results: 79,472 patients (61.3% male) were included, based on index treatments. Of all men, 82.5% received any benign prostatic obstruction (BPO) drug, 25.4% any OAB drug, and 7.9% any BPO drug plus any OAB drug. As either mono- or combination pharmacotherapy, 77.1% received an alpha-blocker, 18.9% a 5-alpha reductase inhibitor, 23.9% an antimuscarinic agent, and 2.1% mirabegron. Of all women, 94.5% received any OAB drug, 6.0% duloxetine, and 0.5% any OAB drug plus duloxetine. As either mono- or combination pharmacotherapy, 87.7% received an antimuscarinic, and 9.7% mirabegron. In men or women receiving OAB treatment, approximately 2.5% received combination pharmacotherapy with an antimuscarinic agent and mirabegron. For OAB drug monopharmacotherapies, mirabegron had the highest persistence in both male and female cohorts. Conclusions: This study provides a better understanding of the recent landscape of LUTS drug use in UK clinical practice. It highlights potential undertreatment of storage symptoms in men and the low use of combination OAB treatments.

Association Between Optimal Combination Pharmacotherapy and Survival After Stroke: A Registry and Pharmaceutical Dispensing Study

IntroductionTo prevent further vascular events, prescribing of multiple classes of medications (antihypertensive, antithrombotic and lipid-lowering) is recommended in national clinical guidelines following ischaemic stroke. Objectives and ApproachUsing real-world data, we determined the association between optimal combination pharmacotherapy (supply of all three classes, “optimal pharmacotherapy”) and survival after stroke. We linked a cohort of patients with first-ever ischaemic stroke from the Australian Stroke Clinical Registry (2010-2014) with national pharmaceutical dispensing and national mortality data. Cox regression was used to determine associations between pharmacotherapy in the first 30 days of stroke with 1-year (from day 31 to 395) all-cause mortality. All analyses were adjusted for socio-demographic (age, sex) and clinical characteristics (stroke severity, discharge destination). ResultsAmong 6684 patients discharged following first-ever ischaemic stroke (median length-of-stay 5 days), 6466 patients who survived to 30 days were included (44% female, median age 74 years). During the first 30 days from discharge, 71.4% received ≥1 medication class, and 32.9% (n=2125) received optimal pharmacotherapy. Patients with optimal pharmacotherapy were older (≥75 years 50.3% vs <75 years 44.5%; p<0.001), discharged directly home (home 58.5% vs other 40.3%; p<0.001) and experienced a less severe stroke (able to walk on admission 46.9% vs 36.4%; p<0.001), than those without optimal pharmacotherapy. Between day 31 and 395, there were 667 deaths; 530 related to cardiovascular disease. Compared to no medication, treatment with two medications was associated with a 42% lower risk of death (hazard ratio [HR]: 0.58; 95%CI: 0.45-0.73); and optimal pharmacotherapy had a 62% lower risk of death (HR: 0.38; 95% CI: 0.31-0.47). Survival was similar between those with one or no medication. Conclusion / ImplicationsPatients with ischaemic stroke who received optimal pharmacotherapy within 30-days of admission had greater one-year-survival. Further research is required to understand reasons for sub-optimal pharmacotherapy in these patients.

Abstract 13214: Underuse of Combination Pharmacotherapy for Management of Dyslipidemia versus Diabetes and Hypertension Among Patients With Atherosclerotic Cardiovascular Disease (ascvd): Insights From the Getting to an Improved Understanding of Low-density Lipoprotein-cholesterol and Dyslipidemia Management (gould) Registry

Introduction: Cardiovascular disease prevention entails treatment of multiple risk factors, including diabetes (DM), hypertension (HTN), and hyperlipidemia (HLD), based on guidelines that promote the use of combination therapy when monotherapy does not achieve treatment goals. The purpose of this study is to determine how frequently combination pharmacotherapy is employed to manage these disorders among patients with atherosclerotic cardiovascular disease (ASCVD), based on the GOULD registry. Methods: The multicenter, observational GOULD registry describes low-density lipoprotein cholesterol (LDL-C) treatment patterns over time in adults with clinical ASCVD in the United States. Patients were enrolled into 3 cohorts: 1) Currently on PCSK9 inhibitor (PCSK9i), or not on PCSK9i with 2) LDL-C 70-99 mg/dL, or 3) LDL-C ≥100 mg/dL. We determined the prevalence of DM and HTN within this registry, the classes of medications used to treat these disorders, and how frequently patients were on two or more medications to treat these disorders at baseline, 6, 12, 18, and 24 months, respectively. Results: Among 5,006 patients in this cohort on lipid-lowering therapy (LLT), 35.2% had DM and 86.0% had HTN at baseline. Of those receiving treatment, 47.6% and 71% were receiving two or more medications for management of DM and HTN, respectively. In contrast, only 19.5% of patients were receiving two or more LLT medications (51.9% among PCSK9i subjects, 15.4% among LDL-C subjects) (Figure). There was a modest increase in combination lipid therapy from 19.5% at baseline to 25.6% at 24 months. Conclusions: Despite recent guidelines supporting the use of combination therapy in patients with high risk ASCVD with an LDL-C above threshold after statin therapy, this high-risk group continues to be managed mostly with statin monotherapy in contrast to the widespread use of combination therapy for the treatment of DM and HTN.