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Sex Differences in the Pathways to Major Depression: A Study of Opposite-Sex Twin Pairs
Kenneth S. Kendler, M.D.; Charles O. Gardner, Ph.D.
Am J Psychiatry 2014;171:426-435. doi:10.1176/appi.ajp.2013.13101375
View Author and Article Information

The authors report no financial relationships with commercial interests.

Supported in part by NIH grant MH49492. The Virginia Twin Registry is supported by grant UL1RR031990.

From the Departments of Psychiatry and Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond.

Address correspondence to Dr. Kendler (kendler@vcu.edu).

Copyright © 2014 by the American Psychiatric Association

Received October 17, 2013; Revised November 19, 2013; Accepted November 25, 2013.

Abstract

Objective  The authors sought to clarify the nature of sex differences in the etiologic pathways to major depression.

Method  Retrospective and prospective assessments of 20 developmentally organized risk factors and the occurrence of past-year major depression were conducted at two waves of personal interviews at least 12 months apart in 1,057 opposite-sex dizygotic twin pairs from a population-based register. Analyses were conducted by structural modeling, examining within-pair differences.

Results  Sixty percent of all paths in the best-fit model exhibited sex differences. Eleven of the 20 risk factors differed across sexes in their impact on liability to major depression. Five had a greater impact in women: parental warmth, neuroticism, divorce, social support, and marital satisfaction. Six had a greater impact in men: childhood sexual abuse, conduct disorder, drug abuse, prior history of major depression, and distal and dependent proximal stressful life events. The life event categories responsible for the stronger effect in males were financial, occupational, and legal in nature.

Conclusions  In a co-twin control design, which matches sisters and brothers on genetic and familial-environmental background, personality and failures in interpersonal relationships played a stronger etiologic role in major depression for women than for men. Externalizing psychopathology, prior depression, and specific “instrumental” classes of acute stressors were more important in the etiologic pathway to major depression for men. The results are consistent with previously proposed typologies of major depression that suggest two subtypes that differ in prevalence in women (deficiencies in caring relationships and interpersonal loss) and men (failures to achieve expected goals, with lowered self-worth).

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FIGURE 1. Path Estimates for Best-Fit Model for Causal Pathways to Major Depression in Femalesa

a Parameters estimated to be equal across sexes, greater in females than males, and greater in males than females are depicted in black, red, and blue, respectively. If a path is not present between two variables, that is because it was estimated to have a zero value. Appendix II in the online data supplement contains the best-fit model estimates for all these paths, along with their statistical significance and the equality or nonequality of that path across sexes. The test of equality across sexes was based on raw path coefficients. However, for ease of interpretation and a consistent measure of effect size, we report standardized path coefficients. Thus, paths that are depicted as equal (using raw coefficients) can differ slightly using standardized paths.

FIGURE 2. Path Estimates for Best-Fit Model for Causal Pathways to Major Depression in Malesa

a Parameters estimated to be equal across sexes, greater in females than males, and greater in males than females are depicted in black, red, and blue, respectively. If a path is not present between two variables, that is because it was estimated to have a zero value. Appendix II in the online data supplement contains the best-fit model estimates for all these paths, along with their statistical significance and the equality or nonequality of that path across sexes. The test of equality across sexes was based on raw path coefficients. However, for ease of interpretation and a consistent measure of effect size, we report standardized path coefficients. Thus, paths that are depicted as equal (using raw coefficients) can differ slightly using standardized paths.

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TABLE 1.Summary of Results From a Model Predicting Sex Differences in the Risk for Major Depression in the Past Year From 20 Risk Factors Organized in a Developmental Cascadea
Table Footer Note

a AUD=alcohol use disorder; CD=conduct disorder; CSA=childhood sexual abuse; DIV=history of divorce; DPSLE=dependent proximal stressful life events; DSLE=distal stressful life events; DUD=drug use disorder; EDU=educational attainment; EOAD=early-onset anxiety disorder; F=female; IPSLE=independent proximal stressful life events; LMS=low marital satisfaction; LSE=low self-esteem; LSS=low social support; LTR=lifetime traumas; M=male; MD=major depression; N=neuroticism; ND=nicotine dependence; PH=past history of major depression; PL=parental loss.

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