Browsing by Subject "Antidepressive agents"

Now showing 1 - 3 of 3
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    Preadmission antidepressant use and bladder cancer: a population-based cohort study of stage at diagnosis, time to surgery, and surgical outcomes
    (Biomed Central, 2018-10-24) Steffensen, Ellen Hollands; Cary, Clint; Jensen, Jørgen Bjerggaard; Larsson, Heidi; Weiner, Michael; Nørgaard, Mette; Urology, School of Medicine
    BACKGROUND: Among cancer patients, prior antidepressant use has been associated with impaired survival. This could be due to differences in stage at diagnosis, in receipt of treatment, or in treatment complications. The purpose of this study was, therefore, to examine if preadmission antidepressant use in patients with bladder cancer is associated with tumor stage at diagnosis, rate of cystectomy, and surgical outcomes, including survival. METHODS: We performed a registry-based cohort study including all patients with incident invasive bladder cancer in Denmark 2005-2015. Exposure was defined as redemption of two or more antidepressant prescriptions one year before cancer diagnosis. We compared tumor stage using logistic regression, postsurgical inpatient length of stay using linear regression, and other outcomes using Cox regression. All results were adjusted for age, sex, comorbidity, and marital status. RESULTS: Among 10,427 bladder cancer patients, 10% were antidepressant users. At diagnosis, 51% of users and 52% of non-users had muscle-invasive disease. However, upon adjustment for age, sex, comorbidity, and marital status, users had lower odds of muscle-invasive disease (adjusted odds ratio 0.86 (95% confidence interval (CI) 0.74-0.99)). Among patients with muscle-invasive disease, fewer users than non-users had surgery within three months (15% vs. 24%, adjusted hazard ratio (aHR) 0.75 (95% CI 0.59-0.95)). Of 2532 patients undergoing surgery, 6% were antidepressant users. Postsurgical inpatient length of stay did not differ between users and non-users. The 30-day cumulative incidence of readmission was higher for users (41% vs. 33%, aHR 1.33 (95% CI 1.05-1.67)), while the 90-day incidence of postoperative procedures was 44% for users and 38% for non-users (aHR 1.18 (95% CI 0.93-1.51)). One-year mortality was comparable in users (15%) and non-users (14%). CONCLUSIONS: Antidepressant use in bladder cancer patients was associated with less advanced stage at diagnosis and lower rate of cystectomy. After cystectomy, users had higher rate of readmission and postoperative procedures than non-users, but we found no difference in length of stay or one-year mortality. The results point to the importance of differentiated clinical care according to individual patient characteristics.
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    Rationale and design for a pragmatic randomized trial to assess gene-based prescribing for SSRIs in the treatment of depression
    (Wiley, 2024) Hines, Lindsay J.; Wilke, Russell A.; Myers, Rachel; Mathews, Carol A.; Liu, Michelle; Baye, Jordan F.; Petry, Natasha; Cicali, Emily J.; Duong, Benjamin Q.; Elwood, Erica; Hulvershorn, Leslie; Nguyen, Khoa; Ramos, Michelle; Sadeghpour, Azita; Wu, R. Ryanne; Williamson, Lloyda; Wiisanen, Kristin; Voora, Deepak; Singh, Rajbir; Blake, Kathryn V.; Murrough, James W.; Volpi, Simona; Ginsburg, Geoffrey S.; Horowitz, Carol R.; Orlando, Lori; Chakraborty, Hrishikesh; Dexter, Paul; Johnson, Julie A.; Skaar, Todd C.; Cavallari, Larisa H.; Van Driest, Sara L.; Peterson, Josh F.; IGNITE Pragmatic Trials Network; Psychiatry, School of Medicine
    Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.
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    Stereoselective Metabolism of Bupropion to Active Metabolites in Cellular Fractions of Human Liver and Intestine
    (American Society for Pharmacology and Experimental Therapeutics (ASPET), 2023) Bamfo, Nadia O.; Lu, Jessica B. L.; Desta, Zeruesenay; Medicine, School of Medicine
    Striking stereoselective disposition of the antidepressant and smoking cessation aid bupropion (BUP) and its active metabolites observed clinically influence patients' response to BUP therapy and its clinically important drug-drug interactions (DDI) with CYP2D6 substrates. However, understanding of the biochemical mechanisms responsible is incomplete. This study comprehensively examined hepatic and extrahepatic stereoselective metabolism of BUP in vitro Racemic-, R-, and S-BUP were incubated separately with pooled cellular fractions of human liver [microsomes (HLMs), S9 fractions (HLS9s), and cytosols (HLCs)] and intestinal [microsomes (HIMs), S9 fractions (HIS9s), and cytosols (HICs)] and cofactors. Formations of diastereomers of 4-hydroxyBUP (OHBUP), threohydroBUP (THBUP), and erythrohydroBUP (EHBUP) were quantified using a novel chiral ultra-high performance liquid chromatography/tandem mass spectrometry method. Racemic BUP (but not R- or S-BUP) was found suitable to determine stereoselective metabolism of BUP; both enantiomers showed complete racemization. Compared with that of RR-THBUP, the in vitro intrinsic clearance (Clint) for the formation of SS-THBUP was 42-, 19-, and 8.3-fold higher in HLMs, HLS9 fractions, and HLCs, respectively; Clint for the formation of SS-OHBUP and RS-EHBUP was also higher (2.7- to 3.9-fold) than their R-derived counterparts. In cellular fractions of human intestine, ≥ 95% of total reduction was accounted by the formation of RR-THBUP. Ours is the first to demonstrate marked stereoselective reduction of BUP in HLCs, HIMs, HIS9 fractions, and HICs, providing the first evidence for tissue- and cellular fraction-dependent stereoselective metabolism of BUP. These data may serve as the first critical step toward understanding factors dictating BUP's stereoselective disposition, effects, and DDI risks. SIGNIFICANCE STATEMENT: This work provides a deeper insight into bupropion (BUP) stereoselective oxidation and reduction to active metabolites in cellular fractions of human liver and intestine tissues. The results demonstrate tissue- and cellular fraction-dependent stereospecific metabolism of BUP. These data may improve prediction of BUP stereoselective disposition and understanding of BUP's effects and CYP2D6-dependent drug-drug interaction in vivo.