Study links antidepressant use and epigenetic aging to higher mortality risk in postmenopausal women

By Tarun Sai Lomte

In a recent study published in Aging, researchers evaluated the impact of depressive symptoms, use of antidepressants, and epigenetic age acceleration (EAA) on mortality in postmenopausal individuals.

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​​​​​​​Study: Relationships of depression and antidepressant use with epigenetic age acceleration and all-cause mortality among postmenopausal women. Image Credit: Photoroyalty/Shutterstock.com

Background

Depression is the most prevalent mental illness in geriatric populations, contributing to the global burden of diseases. It is a risk factor for chronic conditions, such as cardiovascular disease, metabolic syndrome, and diabetes.

Antidepressants are widely prescribed medicines among older adults. Around 25% of those prescribed antidepressants take them for more than a decade; however, there is limited evidence on the long-term impact of antidepressant use.

While antidepressants have potential health benefits, they are associated with various side effects. Postmenopausal individuals represent a high-risk group for depressive symptoms and antidepressant use. Their vulnerability to age-related conditions may increase with depressive symptoms or antidepressant use.

About the study

In the present study, researchers examined the relationship between elevated depressive symptoms (EDSs), antidepressant use, and EAA or all-cause mortality among postmenopausal individuals.

They used data from the Women’s Health Initiative (WHI), a long-term study that recruited a multiethnic sample during 1993-98 in the United States (US).

At enrolment, participants completed a questionnaire and underwent a clinical examination. The current analysis was restricted to those with DNA methylation data for epigenetic age calculation. An algorithm for depressive symptoms was generated; a score > 0.06 indicated strong evidence of depression.

EDSs were repeatedly evaluated at enrolment and during a three-year follow-up to examine temporal changes. Antidepressant use was similarly examined for temporal changes. EAA was defined using four epigenetic clocks – Hannum, PhenoAge, GrimAge, and Horvath.

Death was ascertained semi-annually or annually by following up with care providers, family, or friends. Participants were followed up until December 31, 2021.

Covariates included sociodemographic, lifestyle, and health factors. The team plotted Kaplan-Meier estimates for survival probabilities against baseline EDSs, antidepressant use, and combined exposure (EDSs and antidepressant use).

Logistic or Cox proportional hazard regression models estimated the odds and hazard ratios. Bivariate associations of baseline health, lifestyle, and socioeconomic characteristics with EAA, EDS/antidepressant use, and all-cause mortality risk.

Besides, the relationship between EAA and EDS, antidepressant use, or both was evaluated. Causal mediation analyses examined moderating or mediating effects of EAA on the association between EDSs/antidepressants and mortality risk.

One model (1) was unadjusted, model 2 was partially adjusted (only socioeconomic factors were controlled for), and model 3 was additionally adjusted for health and lifestyle factors.

Findings

Overall, 1,900 postmenopausal individuals were included in the analyses. The average age at baseline was 64.6; nearly 66% were White, and 32% were Black.

Of these, 11% had EDSs, and 7% used antidepressants at baseline. During a mean follow-up of 20.4 years, 1,161 deaths were recorded. Baseline antidepressant use and the combined exposure were significantly associated with higher all-cause mortality risk.

The odds of EDSs or the combined exposure reduced with age, higher physical activity, education, and income but increased with body mass index and among current smokers. All-cause mortality risks increased with age and were reduced among Black and Hispanic subjects relative to While and non-Hispanic individuals, respectively.

In logistic regression models, only GrimAge acceleration was associated with antidepressant use or the combined exposure in the crude and partially adjusted models.

This association was attenuated when additionally adjusted for health and lifestyle factors. In Cox proportional hazard regression models, PhenoAge and GrimAge acceleration were associated with higher mortality risk.

Besides, an increase in antidepressant use between baseline and three-year follow-up was associated with elevated mortality risk. Changes in EDS status during this time frame had no impact on mortality.

Causal mediation analyses suggested that GrimAge acceleration partially mediated the effects of baseline antidepressant use and the combined exposure on all-cause mortality risk in the partially adjusted model only.

Conclusions

In sum, the study evaluated the impact of antidepressant use, depressive symptoms, and EAA on all-cause mortality in postmenopausal individuals. Baseline use of antidepressants, longitudinal increase in their use, and accelerated epigenetic aging predicted all-cause mortality risks.

GrimAge acceleration partly mediated the effects of baseline antidepressant use and combined EDSs/antidepressant use on mortality risk before adjusting for health and lifestyle factors. Further studies are required in diverse populations.

Journal reference:

Beydoun MA, Beydoun HA, Ashe J, et al. (2024) Relationships of depression and antidepressant use with epigenetic age acceleration and all-cause mortality among postmenopausal women. Aging,. doi: 10.18632/aging.205868. https://www.aging-us.com/article/205868/text