The interaction between child maltreatment, adult stressful life events and the 5-HTTLPR in major depression Robert A. Power a, * , Lucy Lecky-Thompson a , Helen L. Fisher a , Sarah Cohen-Woods a , Georgina M. Hosang a , Rudolf Uher a, b , Georgia Powell-Smith a , Robert Keers a, c , Maria Tropeano a , Ania Korszun c , Lisa Jones d , Ian Jones e , Michael J. Owen e , Nick Craddock e , Ian W. Craig a , Anne E. Farmer a , Peter McGuffin a a MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London, UK b Department of Psychiatry, Dalhousie University, Halifax, NS, Canada c Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Centre for Psychiatry, London, UK d Department of Psychiatry, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, UK e MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, UK article info Article history: Received 30 December 2012 Received in revised form 26 March 2013 Accepted 27 March 2013 Keywords: Mismatch hypothesis Stressful life events Child maltreatment Major depression Geneeenvironment interaction 5-HTTLPR abstract Both childhood maltreatment and adult stressful life events are established risk factors for the onset of depression in adulthood. However, the interaction between them can be viewed through two conflicting frameworks. Under a mismatch hypothesis stressful childhoods allow ‘adaptive programming’ for a stressful adulthood and so can be protective. Only when childhood and adulthood do not match is there a risk of behavioural problems. Alternatively, under the cumulative stress hypothesis we expect increased risk with each additional stressor. It has also been suggested that an individual’s genetic background may determine the extent they undergo adaptive programming, and so which of these two hypotheses is relevant. In this study we test for an interaction between exposure to childhood maltreatment and adult stressful life events in a retrospective sample of 455 individuals, using major depression as the outcome. We also test whether this interaction differs by genotype at the 5-HTTLPR, a candidate for an individual’s plasticity to adaptive programming. Early maltreatment and stressful life events in adulthood interacted to produce increased risk for depression over each individually (p ¼ 0.055). This supports the cumulative stress hypothesis over the mismatch hypothesis, at least with respect to severe environmental risk factors. This effect was not altered by 5-HTTLPR allele, suggesting there was no difference by genotype in adaptive programming to these events. We suggest that the apparent additional vulnerability to stressful events of those who have experienced maltreatment has clinical relevance, highlighting the importance of providing support beyond the immediate aftermath of maltreatment into adulthood. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction Child maltreatment (such as abuse or neglect) has long been associated with increased risk of psychopathology in adulthood, including depression (Edwards et al., 2003; Mazure, 1998; Windle et al., 1995), and presents a major social burden. Adult stressful life events (e.g. bereavement and divorce) also predict risk for the onset of depression (Brown and Harris, 1989; Monroe et al., 1999; Paykel et al., 1980) and triggering depressive episodes (Hosang et al., 2012). However, the interaction between these two types of adversity is far from simple. In a recent review of the topic, Nederhof and Schmidt (2012) described two conflicting models, the cumulative stress hypothesis and mismatch hypothesis, for explaining the interactions between early and adult stressors, and proposed a study design for differentiating them. The cumulative stress hypothesis states that disease risk in- creases as adversity accumulates through life, the more traditional view for which there is considerable evidence e.g. (Brown et al., 2008; Kendler et al., 2004; McLaughlin et al., 2010). The mismatch hypothesis stipulates that individuals are primed to undergo “adaptive phenotypic programming” during development, in order to best match their adult phenotype with the predicted * Corresponding author. E-mail address: robert.r.power@kcl.ac.uk (R.A. Power). Contents lists available at SciVerse ScienceDirect Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/psychires 0022-3956/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jpsychires.2013.03.017 Journal of Psychiatric Research 47 (2013) 1032e1035