Summary: Biological changes that accompany aging may help explain why many older adults with major depression do not fully recover after antidepressant treatment.
Source: UConn
Major depression in older adults is common, causes significant disability, and raises the risk of age-related diseases such as Alzheimer’s disease and other dementias, cardiovascular conditions, and premature mortality. With a growing older population, late-life depression represents an urgent public health concern.
A substantial proportion of older adults with depression—roughly half—do not achieve full remission with standard antidepressant therapy. Persistent depressive symptoms in later life are linked to reduced psychological well-being, greater disability, faster cognitive decline, and accelerated biological aging.
Understanding the biological mechanisms behind poor treatment response is essential for improving care and for identifying which patients are less likely to benefit from conventional antidepressant strategies.
In a study published June 30, 2022, in JAMA Network Open, Breno Diniz, MD, PhD, associate professor of psychiatry at the UConn Center on Aging at UConn Health, and colleagues investigated whether markers of cellular senescence are associated with clinical outcomes in late-life depression.
The researchers evaluated a composite biomarker index known as the senescence-associated secretory phenotype (SASP) index, which reflects interrelated cellular and molecular processes linked to aging and senescence. Their central hypothesis was that age-related biological changes measured by the SASP index might be a mechanism underlying poorer antidepressant response in older adults.
Using clinical data and archived plasma samples from a nonrandomized, open-label trial of venlafaxine extended release (doses 37.5–300 mg daily for up to 12 weeks), the team examined whether higher SASP index scores were associated with a lower likelihood of remission from a major depressive episode in older adults.
The sample included 416 participants with a mean age of 60.02 (SD, 7.13) years; 64% identified as female. Baseline mean Montgomery-Åsberg Depression Rating Scale (MADRS) score was 26.6 (SD, 5.7). Analyses of the biomarker data were completed in 2021.
Results showed that higher SASP index scores were independently associated with a greater chance of nonremission after antidepressant treatment. Specifically, each 1-unit increase in the SASP index raised the odds of nonremission by 19% (adjusted odds ratio, 1.19; 95% CI, 1.05–1.35; P = .006). Notably, no single SASP biomarker alone predicted remission; the composite index captured the interrelated biology most relevant to outcome.
These findings suggest that molecular and cellular senescence—represented by the SASP index—may contribute to treatment resistance in late-life depression. The study highlights the value of combining biological markers into a composite score to better predict antidepressant outcomes in older patients.
Clinical implications include the potential to use SASP biomarker profiles to identify individuals less likely to respond to conventional antidepressants and to guide personalized treatment decisions. The results also open avenues for testing geroscience-guided approaches—such as interventions targeting senescent cells—to determine whether modifying senescence biology can improve remission rates in late-life depression.
Further research is needed to validate the SASP index across diverse cohorts, integrate it with clinical and neuroimaging markers, and evaluate whether targeting senescence directly (for example, with senolytic or senomorphic strategies) can enhance antidepressant response among older adults.
About this aging and depression research news
Author: Press Office
Source: UConn
Contact: Press Office – UConn
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Original Research: Open access.
“Association of Molecular Senescence Markers in Late-Life Depression With Clinical Characteristics and Treatment Outcome” by Breno S. Diniz et al., JAMA Network Open
Abstract
Association of Molecular Senescence Markers in Late-Life Depression With Clinical Characteristics and Treatment Outcome
Importance
Many older adults with depression do not achieve remission with antidepressant treatment. Markers of cellular senescence in late-life depression have been linked to greater depressive severity, executive dysfunction, and higher medical illness burden. Because these clinical features predict poorer remission, molecular and cellular senescence abnormalities may underlie treatment resistance in this population.
Objective
To determine whether a composite measure of senescence-associated secretory phenotype (SASP) biomarkers is associated with the likelihood of remission from a depressive episode in older adults.
Design, Setting, and Participants
A nonrandomized, open-label clinical trial conducted from 2009 to 2014 in Pittsburgh, St. Louis, and Toronto enrolled older adults meeting DSM-IV-TR criteria for a current major depressive episode. Biomarker analyses used archived plasma samples assayed in 2021. Data were analyzed between June and November 2021.
Exposure
Venlafaxine extended release, dosed from 37.5 mg to 300 mg daily for up to 12 weeks.
Main Outcomes and Measures
Association between the SASP composite biomarker index and clinical remission following antidepressant treatment, assessed using clinical data and blood samples.
Results
Among 416 participants (mean [SD] age, 60.02 [7.13] years; 64% female; mean [SD] MADRS score, 26.6 [5.7]), higher SASP index scores were independently associated with increased odds of nonremission. A 1-unit increase in the SASP index raised the odds of nonremission by 19% (adjusted OR, 1.19; 95% CI, 1.05–1.35; P = .006). No individual SASP marker alone was associated with remission.
Conclusions and Relevance
These results indicate that molecular and cellular senescence, as captured by a composite SASP index, is associated with poorer antidepressant treatment outcomes in late-life depression. Integrating this index with other molecular, clinical, and neuroimaging markers may enhance evaluation and prediction of treatment response. The findings support further exploration of geroscience-guided interventions that target senescence to improve remission rates in older adults with depression.
Trial Registration
ClinicalTrials.gov Identifier: NCT00892047