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Association of Molecular Senescence Markers in Late-Life Depression with Clinical Characteristics and Treatment Outcome
Importance: Many older adults with depression do not experience remission with antidepressant treatment, and markers of cellular senescence in late-life depression (LLD) are associated with greater severity of depression, greater executive dysfunction, and higher medical illness burden. Since these clinical characteristics are associated with remission in LLD, molecular and cellular senescence abnormalities could be a possible biological mechanism underlying poor treatment response in this population. Objective: To examine whether the senescence-associated secretory phenotype (SASP) index was associated with the likelihood of remission from a depressive episode in older adults. Design, Setting, and Participants: A nonrandomized, open-label clinical trial was conducted between August 2009 and August 2014 in Pittsburgh, Pennsylvania; St Louis, Missouri; and Toronto, Ontario, Canada, with older adults in a current major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) diagnostic criteria. Data from biomarker analyses were reported according to the clinical trial archived plasma samples run in March 2021. Data were analyzed from June to November 2021. Exposure: Venlafaxine extended release (dose ranging from 37.5 mg to 300 mg daily) for up to 12 weeks. Main Outcomes and Measures: The association between a composite biomarker-based index (SASP index) and treatment remission in older adults with major depression was measured using clinical data and blood samples. Results: There were 416 participants with a mean (SD) age of 60.02 (7.13) years; 64% (265 participants) were self-reported female, and the mean (SD) Montgomery-Asberg Depression Rating Scale score was 26.6 (5.7). Higher SASP index scores were independently associated with higher rates of nonremission, with an increase of 1 unit in the SASP index score increasing the odds of nonremission by 19% (adjusted odds ratio, 1.19; 95% CI, 1.05-1.35; P =.006). In contrast, no individual SASP factors were associated with remission in LLD. Conclusions and Relevance: Using clinical data and blood samples from a nonrandomized clinical trial, the results of this study suggest that molecular and cellular senescence, as measured with the SASP index, is associated with worse treatment outcomes in LLD. Combining this index score reflecting interrelated biological processes with other molecular, clinical, and neuroimaging markers may be useful in evaluating antidepressant treatment outcomes. These findings inform a path forward for geroscience-guided interventions targeting senescence to improve remission rates in LLD. Trial Registration: ClinicalTrials.gov Identifier: NCT00892047. © 2022 American Medical Association. All rights reserved.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
Supplementary Material for: The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis
<p><b><i>Background:</i></b> Antidepressants (ADs) are commonly
prescribed medications, but their long-term health effects are debated.
ADs disrupt multiple adaptive processes regulated by evolutionarily
ancient biochemicals, potentially increasing mortality. However, many
ADs also have anticlotting properties that can be efficacious in
treating cardiovascular disease. We conducted a meta-analysis assessing
the effects of ADs on all-cause mortality and cardiovascular events in
general-population and cardiovascular-patient samples. <b><i>Methods:</i></b>
Two reviewers independently assessed articles from PubMed, EMBASE, and
Google Scholar for AD-related mortality controlling for depression and
other comorbidities. From these articles, we extracted information about
cardiovascular events, cardiovascular risk status, and AD class. We
conducted mixed-effect meta-analyses testing sample type and AD class as
moderators of all-cause mortality and new cardiovascular events. <b><i>Results:</i></b>
Seventeen studies met our search criteria. Sample type consistently
moderated health risks. In general-population samples, AD use increased
the risks of mortality (HR = 1.33, 95% CI: 1.14-1.55) and new
cardiovascular events (HR = 1.14, 95% CI: 1.08-1.21). In cardiovascular
patients, AD use did not significantly affect risks. AD class also
moderated mortality, but the serotonin reuptake inhibitors were not
significantly different from tricyclic ADs (TCAs) (HR = 1.10, 95% CI:
0.93-1.31, <i>p</i> = 0.27). Only “other ADs” were differentiable from
TCAs (HR = 1.35, 95% CI: 1.08-1.69). Mortality risk estimates increased
when we analyzed the subset of studies controlling for premedication
depression, suggesting the absence of confounding by indication. <b><i>Conclusions:</i></b> The results support the hypothesis that ADs are harmful in the general population but less harmful in cardiovascular patients.</p
Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: The protocol of a randomized controlled trial
Background: Lithium is the gold-standard treatment for bipolar disorder, is highly effective in treating major depressive disorder, and has anti-suicidal properties. However, clinicians are increasingly avoiding lithium largely due to fears of renal toxicity. Nephrogenic Diabetes Insipidus (NDI) occurs in 15-20% of lithium users and predicts a 2-3 times increased risk of chronic kidney disease (CKD). We recently found that use of statins is associated with lower NDI risk in a cross-sectional study. In this current paper, we describe the methodology of a randomized controlled trial (RCT) to treat lithium-induced NDI using atorvastatin. Methods: We will conduct a 12-week, double-blind placebo-controlled RCT of atorvastatin for lithium-induced NDI at McGill University, Montreal, Canada. We will recruit 60 current lithium users, aged 18-85, who have indicators of NDI, which we defined as urine osmolality (UOsm) < 600 mOsm/kg after 10-h fluid restriction. We will randomize patients to atorvastatin (20 mg/day) or placebo for 12 weeks. We will examine whether this improves measures of NDI: UOsm and aquaporin (AQP2) excretion at 12-week follow-up, adjusted for baseline. Results: Not applicable. Conclusion: The aim of this clinical trial is to provide preliminary data about the efficacy of atorvastatin in treating NDI. If successful, lithium could theoretically be used more safely in patients with a reduced subsequent risk of CKD, hypernatremia, and acute kidney injury (AKI). If future definitive trials confirm this, this could potentially allow more patients to benefit from lithium, while minimizing renal risk