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Comment & Response |

Estrogen-Based Therapies and Depression in Women Who Naturally Enter Menopause Before Population Average—Reply

Marios K. Georgakis, MD1; Alkistis Skalkidou, MD, PhD2; Eleni Th. Petridou, MD, MPH, PhD1
[+] Author Affiliations
1Department of Hygiene, Epidemiology, and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
2Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
JAMA Psychiatry. 2016;73(8):874-875. doi:10.1001/jamapsychiatry.2016.0953.
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In Reply The letter by Hengartner raised important issues regarding the significance and interpretation of findings in our recent meta-analysis1 on the association of increasing age at menopause and duration of reproductive period with decreased risk for depression in postmenopausal women. While we value the concerns, the following points should be underlined.

Large sample sizes indeed provide the statistical power to yield practically nonsignificant deviations from the null hypothesis; however, in our study, causality criteria were also met. Specifically, our results followed a biologically plausible hypothesis supported by previous epidemiologic and basic research evidence, whereas the lack of heterogeneity in the analysis implies coherence across different populations and study designs. Interestingly, the findings were also replicated in an equally large study (N = 60 114) of primary data from a Korean population2 published after we completed our systematic review. The magnitude of the association in our meta-analysis (2.3% decrease in depression risk for 2-year increase in age at menopause; exact odds ratio, 0.977) is rather comparable with the 2.9% increased risk for 1-year increment of age at menopause reported for breast cancer3 and the 3% decreased risk for 1-year increment for cardiovascular disease.4 Moreover, the association was amplified for severe depression (decreased by 5.1% depression risk for 2-year increase of age at menopause) and the risk actually doubled for women with age at menopause younger than 40 years, indicating a biological gradient of the effect. Last, regarding the comment by Hengartner on the lack of association in the analysis adjusting for past depression, we clearly showed in the eFigure in the Supplement for our article1 that the association reached nominal statistical significance (exact odds ratio, 0.976; exact 95% CI, 0.957-0.996, with upper limit rounded to 1.00; P = .02). An observation attributed to random fluctuation would not be expected to follow such a pattern; yet, because of inherent limitations, detailed in our publication, cautious interpretation of the findings is suggested.


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August 1, 2016
Michael Pascal Hengartner, PhD, MSc
1Department of Applied Psychology, Zurich University of Applied Sciences, Zurich, Switzerland
JAMA Psychiatry. 2016;73(8):874. doi:10.1001/jamapsychiatry.2016.0709.
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