Skip to main content Accessibility help

Sex similarities and differences in risk factors for recurrence of major depression

  • Hanna M. van Loo (a1) (a2), Steven H. Aggen (a1) (a3), Charles O. Gardner (a1) (a3) and Kenneth S. Kendler (a1) (a3) (a4)



Major depression (MD) occurs about twice as often in women as in men, but it is unclear whether sex differences subsist after disease onset. This study aims to elucidate potential sex differences in rates and risk factors for MD recurrence, in order to improve prediction of course of illness and understanding of its underlying mechanisms.


We used prospective data from a general population sample (n = 653) that experienced a recent episode of MD. A diverse set of potential risk factors for recurrence of MD was analyzed using Cox models subject to elastic net regularization for males and females separately. Accuracy of the prediction models was tested in same-sex and opposite-sex test data. Additionally, interactions between sex and each of the risk factors were investigated to identify potential sex differences.


Recurrence rates and the impact of most risk factors were similar for men and women. For both sexes, prediction models were highly multifactorial including risk factors such as comorbid anxiety, early traumas, and family history. Some subtle sex differences were detected: for men, prediction models included more risk factors concerning characteristics of the depressive episode and family history of MD and generalized anxiety, whereas for women, models included more risk factors concerning early and recent adverse life events and socioeconomic problems.


No prominent sex differences in risk factors for recurrence of MD were found, potentially indicating similar disease maintaining mechanisms for both sexes. Course of MD is a multifactorial phenomenon for both males and females.


Corresponding author

Author for correspondence: Hanna M. van Loo, E-mail:


Hide All
Boschloo, L, Schoevers, RA, Beekman, AT, Smit, JH, van Hemert, AM and Penninx, BW (2014) The four-year course of major depressive disorder: the role of staging and risk factor determination. Psychotherapy and Psychosomatics 83(5), 279288.
Bracke, P (1998) Sex differences in the course of depression: evidence from a longitudinal study of a representative sample of the Belgian population. Social Psychiatry and Psychiatric Epidemiology 33(9), 420429.
de Graaf, R, ten Have, M, Tuithof, M and van Dorsselaer, S (2013) First-incidence of DSM-IV mood, anxiety and substance use disorders and its determinants: results from the Netherlands Mental Health Survey and Incidence Study-2. Journal of Affective Disorders 149(1–3), 100107.
Eaton, WW, Shao, H, Nestadt, G, Lee, BH, Bienvenu, OJ and Zandi, P (2008) Population-based study of first onset and chronicity in major depressive disorder. Archives of General Psychiatry 65(5), 513520.
Frank, E, Prien, RF, Jarrett, RB, Keller, MB, Kupfer, DJ, Lavori, PW, Rush, AJ and Weissman, MM (1991) Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence. Archives of General Psychiatry 48(9), 851855.
Friedman, J, Hastie, T and Tibshirani, R (2010) Regularization paths for generalized linear models via coordinate descent. Journal of Statistical Software 33(1), 122.
Gerrits, MM, van Oppen, P, van Marwijk, HW, van der Horst, H and Penninx, BW (2013) The impact of chronic somatic diseases on the course of depressive and anxiety disorders. Psychotherapy and Psychosomatics 82(1), 6466.
Gopinath, S, Katon, WJ, Russo, JE and Ludman, EJ (2007) Clinical factors associated with relapse in primary care patients with chronic or recurrent depression. Journal of Affective Disorders 101(1–3), 5763.
Hardeveld, F, Spijker, J, De Graaf, R, Hendriks, SM, Licht, CM, Nolen, WA, Penninx, BW and Beekman, AT (2013a) Recurrence of major depressive disorder across different treatment settings: results from the NESDA study. Journal of Affective Disorders 147(1–3), 225231.
Hardeveld, F, Spijker, J, De Graaf, R, Nolen, WA and Beekman, AT (2013b) Recurrence of major depressive disorder and its predictors in the general population: results from the Netherlands Mental Health Survey and Incidence Study (NEMESIS). Psychological Medicine 43(1), 3948.
Hastie, T, Tibshirani, R and Friedman, J (2009) The Elements of Statistical Learning: Data Mining, Inference, and Prediction, 2nd edn. New York, NY: Springer.
Heagerty, PJ and Saha-Chaudhuri, P (2013) survivalROC: Time-dependent ROC curve estimation from censured survival data.1.0.3 edn. Available at
Holma, KM, Holma, IAK, Melartin, TK, Rytsälä, HJ and Isometsä, ET (2008) Long-term outcome of major depressive disorder in psychiatric patients is variable. Journal of Clinical Psychiatry 69(2), 196205.
James, G, Witten, D, Hastie, T and Tibshirani, R (2013) An Introduction to Statistical Learning with Applications in R. New York: Springer.
Kendler, KS (2014) The structure of psychiatric science. The American Journal of Psychiatry 171(9), 931938.
Kendler, KS and Gardner, CO (2014) Sex differences in the pathways to major depression: a study of opposite-sex twin pairs. The American Journal of Psychiatry 171(4), 426435.
Kendler, KS and Prescott, CA (2006) Genes, Environment and Psychopathology: Understanding the Causes of Psychiatric and Substance use Disorders. New York: Guilford Press.
Kendler, KS, Thornton, LM and Gardner, CO (2000) Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “kindling” hypothesis. The American Journal of Psychiatry 157(8), 12431251.
Kessing, LV (1998) Recurrence in affective disorder. II. Effect of age and gender. The British Journal of Psychiatry: The Journal of Mental Science 172, 2934.
Kessing, LV, Andersen, PK and Mortensen, PB (1998) Predictors of recurrence in affective disorder. A case register study. Journal of Affective Disorders 49(2), 101108.
Kessler, RC (2003) Epidemiology of women and depression. Journal of Affective Disorders 74(1), 513.
Kessler, RC, McGonagle, KA, Swartz, M, Blazer, DG and Nelson, CB (1993) Sex and depression in the National Comorbidity Survey. I: Lifetime prevalence, chronicity and recurrence. Journal of Affective Disorders 29(2–3), 8596.
Kuehner, C (2017) Why is depression more common among women than among men?. The Lancet Psychiatry 4, 146158.
Mattisson, C, Bogren, M, Horstmann, V, Munk-Jorgensen, P and Nettelbladt, P (2007) The long-term course of depressive disorders in the Lundby Study. Psychological Medicine 37(6), 883891.
Mueller, TI, Leon, AC, Keller, MB, Solomon, DA, Endicott, J, Coryell, W, Warshaw, M and Maser, JD (1999) Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. The American Journal of Psychiatry 156(7), 10001006.
Musliner, KL, Munk-Olsen, T, Laursen, TM, Eaton, WW, Zandi, PP and Mortensen, PB (2016) Heterogeneity in 10-year course trajectories of moderate to severe major depressive disorder: a Danish National Register-Based Study. JAMA Psychiatry 73(4), 346353.
Oldehinkel, AJ and Bouma, EM (2011) Sensitivity to the depressogenic effect of stress and HPA-axis reactivity in adolescence: a review of gender differences. Neuroscience and Biobehavioral Reviews 35(8), 17571770.
Patten, SB, Wang, JL, Williams, JV, Lavorato, DH, Khaled, SM and Bulloch, AG (2010) Predictors of the longitudinal course of major depression in a Canadian population sample. Canadian Journal of Psychiatry. Revue canadienne de psychiatrie 55(10), 669676.
Piccinelli, M and Wilkinson, G (2000) Gender differences in depression. Critical review. The British Journal of Psychiatry: The Journal of Mental Science 177, 486492.
R Core Team (2014) R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria.
Royston, P and Altman, DG (2013) External validation of a Cox prognostic model: principles and methods. BMC Medical Research Methodology 13, 33.
Rutter, M, Caspi, A and Moffitt, TE (2003) Using sex differences in psychopathology to study causal mechanisms: unifying issues and research strategies. Journal of Child Psychology and Psychiatry, and Allied Disciplines 44(8), 10921115.
Schloerke, B, Crowley, J, Cook, D, Hofmann, H, Wickham, H, Briatte, F, Marbach, M and Thoen, E (2014) GGally: Extension to ggplot2., R package version 0.4.7 edn.
Simon, N, Friedman, J, Hastie, T and Tibshirani, R (2011) Regularization paths for cox's proportional hazards model via coordinate descent. Journal of Statistical Software 39(5), 113.
Steyerberg, EW, Vickers, AJ, Cook, NR, Gerds, T, Gonen, M, Obuchowski, N, Pencina, MJ and Kattan, MW (2010) Assessing the performance of prediction models: a framework for traditional and novel measures. Epidemiology (Cambridge, Mass.) 21(1), 128138.
Stroud, CB, Davila, J and Moyer, A (2008) The relationship between stress and depression in first onsets versus recurrences: a meta-analytic review. Journal of Abnormal Psychology 117(1), 206213.
Thernau, T (2014) A Package for Survival Analysis in S. R package. 2.37-7 edn. Available at
van Buuren, S and Groothuis-Oudshoorn, K (2011) Mice: multivariate imputation by chained equations in R. Journal of Statistical Software 45(3), 167.
van Loo, HM, Aggen, SA, Chardner, CO and Kendler, KS (2015) Multiple risk factors predict recurrence of major depressive disorder in women. Journal of Affective Disorders 180, 5261.
van Loo, HM, van den Heuvel, ER, Schoevers, RA, Anselmino, M, Carney, RM, Denollet, J, Doyle, F, Freedland, KE, Grace, SL, Hosseini, SH, Parakh, K, Pilote, L, Rafanelli, C, Roest, AM, Sato, H, Steeds, RP, Kessler, RC and de Jonge, P (2014) Sex dependent risk factors for mortality after myocardial infarction: individual patient data meta-analysis. BMC Medicine 12(1), 242.
Wang, JL, Patten, SB, Currie, S, Sareen, J and Schmitz, N (2012) Predictors of 1-year outcomes of major depressive disorder among individuals with a lifetime diagnosis: a population-based study. Psychological Medicine 42(2), 327334.
Wichers, M, Geschwind, N, van Os, J and Peeters, F (2010) Scars in depression: is a conceptual shift necessary to solve the puzzle? Psychological Medicine 40(3), 359365.
Wu, TT, Chen, YF, Hastie, T, Sobel, E and Lange, K (2009) Genome-wide association analysis by lasso penalized logistic regression. Bioinformatics (Oxford, England) 25(6), 714721.
Xu, H, Caramanis, C and Mannor, S (2012) Sparse algorithms are not stable: a no-free-lunch theorem. IEEE Transactions on Pattern Analysis and Machine Intelligence 34(1), 187193.
Zou, H and Hastie, T (2005) Regularization and variable selection via the elastic net. Journal of the Royal Statistical Society, Series B 67, 301320.


Type Description Title
Supplementary materials

Van Loo et al supplementary material 1
Van Loo et al supplementary material

 Word (96 KB)
96 KB
Supplementary materials

Van Loo et al supplementary material 2
Van Loo et al supplementary material

 PDF (98 KB)
98 KB


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed