Contents lists available at ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr Research Paper Childhood trauma and insulin resistance in patients suffering from depressive disorders Carla Nasca a, ⁎ , Kathleen Watson-Lin b , Benedetta Bigio a , Thalia K. Robakis b , Alison Myoraku b , Tonita E. Wroolie b , Bruce S. McEwen a, ⁎ , Natalie Rasgon a,b, ⁎⁎ a Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, USA b Center for Neuroscience in Women's Health, Stanford University, Palo Alto, CA 91304, USA ARTICLE INFO Keywords: Insulin resistance Insulin secretion Childhood stress Emotional abuse Family history of type-2 diabetes Risk factors ABSTRACT Objective: Insulin resistance (IR) is a metabolic dysfunction often co-morbid with major depressive disorder (MDD). The paths to development of MDD remain largely unspecified, highlighting a need for identification of risk factors. Here, we tested whether specific subscales of childhood trauma as well as family history of type-2 diabetes (Fam-Hx-Dm2) are risk factors for development of metabolic dysfunction and severity of depressive symptoms. Research design and methods: We used a sample of 45 adults suffering from MDD that was well-characterized for insulin resistance and sensitivity as assessed by measures of fasting plasma glucose (FPG) plasma insulin (FPI) levels, body mass index (BMI), weight, homeostasis model assessment of insulin sensitivity (HOMA), Matsuda index as well as both glucose and insulin responses to oral glucose challenges. Severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale (HDRS-21). Physical, sexual and emotional abuse as well as physical and emotional neglect were assessed with the Childhood Trauma Questionnaire. First- or second-degree relatives with type-2 diabetes defined fam-Hx-DM2. Results: Individuals reporting higher rates of emotional abuse were more likely to have greater IR as showed by elevated FPI levels and HOMA. No association was found with any of the other subscales of childhood trauma (e.g., physical abuse). Similarly, Fam-Hx-DM2 was associated with greater degree of IR as shown by elevated FPI, HOMA, but also FPG, weight and BMI. Moreover, we report a relationship and interaction between Fam-Hx- DM2 and emotional abuse on severity of depressive symptoms. Specifically, emotional abuse and Fam-HX-DM2 predicted severity of depressive symptoms at HDRS-21. Also, severity of depressive symptoms was greater with higher reported rates of emotional abuse but only in patients with negative Fam-Hx-Dm2. Individuals reporting higher emotional abuse and negative Fam-Hx-Dm2 also showed higher FPG levels. Conversely, individuals re- porting higher emotional abuse and positive Fam-Hx-Dm2 showed higher FPI levels. This data suggest that Fam- Hx-Dm2 may define two different metabolic endophenotypes. Conclusions: Our findings suggest that Fam-HX-DM2 and emotional abuse represent separate risk factors for developing metabolic dysfunction (i.e.: IR) in patients suffering from MDD, and that the effects of emotional abuse on psychiatric illness may depend upon the personal characteristics, including Fam-Hx-DM2. 1. Introduction Major depressive disorder (MDD) is a heterogeneous and complex disorder, increasingly considered as a whole body disease (Rasgon and McEwen, 2016; Nasca et al., 2019). Exposure to stress, including early life adversity (ELA), is a primary risk factor for development of MDD, and causes dysregulation of both peripheral and central systems (McEwen et al., 2015; Nemeroff, 2016; Nasca et al., 2018). Under- standing the biological mechanisms underlying metabolic function in humans with MDD is a critical step to propose personalized medicine interventions for decreasing vulnerability to early life stress, and therefore, reducing risk for developing depressive disorders. Metabolic dysfunction, including insulin resistance (IR) and obesity, is increasingly implicated in the pathophysiology of MDD as well as in https://doi.org/10.1016/j.expneurol.2019.01.005 Received 9 September 2018; Received in revised form 18 December 2018; Accepted 9 January 2019 ⁎ Corresponding authors at: Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, 1230 York Avenue, New York, NY 10065, USA. ⁎⁎ Corresponding author at: Center for Neuroscience in Women's Health, Stanford University, Palo Alto, CA 91304, USA. E-mail addresses: cnasca@rockefeller.edu (C. Nasca), mcewen@rockefeller.edu (B.S. McEwen), nrasgon@stanford.edu (N. Rasgon). Experimental Neurology 315 (2019) 15–20 Available online 11 January 2019 0014-4886/ © 2019 Published by Elsevier Inc. T