Association of Molecular Senescence Markers in Late-Life Depression With Clinical Characteristics and Treatment Outcome

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Mulsant reported receiving grants from the National Institute of Mental Health (NIMH) during the conduct of the study, from Brain Canada, from the Canadian Institutes of Health Research, from the Centre for Addiction and Mental Health (CAMH) Foundation, from Patient-Centred Outcomes Research Institute (PCORI), and from the US National Institutes of Health (NIH); use of software from Capital Solutions Design LLC and from HAPPYneuron; serving on the board of trustees for CAMH; serving as an unpaid consultant for Myriad Neuroscience; and receiving compensation from the University of Pittsburgh, Pittsburgh, Pennsylvania. Dr Blumberger reported receiving grants from Canadian Institutes of Health Research, from Brain Canada, and from the NIH; research support from the CAMH Foundation and the Campbell Research Institute; nonfinancial support from Magventure, from Brainsway, and from Indivior outside the submitted work. Dr Karp reported receiving grants from NIMH and grants from PCORI during the conduct of the study; an honorarium from Otsuka and from NightWare Scientific advising; and potential for equity from Aifred Health Scientific outside the submitted work. Dr Lenze reported receiving personal fees from Prodeo, Boehringer-Ingelheim, IngenioRx, and Pritikin outside the submitted work; research support from PCORI, National Institute of Health, COVID Early Treatment Fund, Janssen, and Emergent Venture FastGrants; in addition, Dr Lenze has a patent pending for sigma 1 receptor agonists for COVID-19. No other disclosures were reported.

Figures

Figure 1.. Senescence-Associated Secretory Phenotype (SASP) Index Scores According to Treatment Response, Age of Onset of the Depressive Disorder, and Sex

Dots indicate mean and whiskers indicate 95% CI. EOD indicates early-onset depression; LOD, late-onset depression.

Figure 2.. Scatterplots of the Association Between Senescence-Associated Secretory Phenotype (SASP) Index Scores, Age, Medical Comorbidity Burden and Executive Function Performance

Dots indicate each individual included in the analysis; shaded area indicates 95% CI for the linear trend; line indicates linear trend. CIRS-G indicates Cumulative Illness Rating Scale–Geriatrics.