Mood disturbance during experimental endotoxemia: Predictors of state anxiety as a psychological component of sickness behavior Julie Lasselin a,b,c , Sigrid Elsenbruch c , Mats Lekander a,b,d , John Axelsson a,b,d , Bianka Karshikoff a,b , Jan-Sebastian Grigoleit c,e , Harald Engler c , Manfred Schedlowski c , Sven Benson c,⇑ a Stockholm University, Stress Research Institute, Stockholm, Sweden b Karolinska Institutet, Department of Clinical Neuroscience, Division of Psychology, Solna, Stockholm, Sweden c Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Germany d Osher Center for Integrative Medicine, Karolinska Institutet, Solna, Stockholm, Sweden e Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA article info Article history: Received 18 September 2015 Received in revised form 12 December 2015 Accepted 10 January 2016 Available online 11 January 2016 Keywords: Lipopolysaccharide Inflammation Cytokines Interleukin-6 Sickness behavior Anxiety Psychological condition STAI HADS Predictor variables abstract Lipopolysaccharide (LPS) administration is a well-established model to assess afferent immune-to-brain communication and behavioral aspects of inflammation. Nevertheless, only few studies in comparatively small samples have assessed state anxiety as a psychological component of sickness behavior despite possible clinical implications for the pathophysiology of neuropsychiatric conditions. Thus, the goal of the present analyses carried out in a large, pooled dataset from two independent study sites was to ana- lyze the state anxiety response to LPS administration and to investigate predictors (i.e., cytokine changes; pre-existing anxiety and depression symptoms assessed with the Hospital Anxiety and Depression Scale) of the LPS-induced state anxiety changes at different time points after LPS administration. Data from 186 healthy volunteers who participated in one of six randomized, placebo-controlled human studies involv- ing intravenous administration of LPS at doses of 0.4–0.8 ng/kg body weight were combined. State anx- iety as well as circulating interleukin (IL)-6, tumor necrosis factor (TNF)-a and IL-10 concentrations were significantly increased 2 h and 3 h after LPS administration, with a peak at 2 h, and returned to baseline 6 h after administration. Greater changes in IL-6 from baseline to 3 h after LPS administration signifi- cantly and independently predicted a more pronounced LPS-induced state anxiety response. In addition, higher pre-existing subclinical anxiety symptoms significantly predicted a lower increase in state anxiety 3 h and 6 h after LPS-administration, which was mediated by TNF-a changes. In conclusion, our findings give additional support for a putative role of inflammatory mechanisms in the pathophysiology of stress- related and anxiety disorders and give new insight on the potential role of pre-existing subclinical affec- tive symptoms. Ó 2016 Elsevier Inc. All rights reserved. 1. Introduction Translational research implementing experimental administra- tion of endotoxin in humans has sparked a growing interest over the past decades (Santos and Wilmore, 1996; Bahador and Cross, 2007). Arguably one of the greatest advantages of experimental endotoxemia as a model lies in the complex set of behavioral and physiological responses that can reliably and safely be induced by the administration of low doses of endotoxin. This transient ‘‘sickness response” encompasses different facets including physi- cal symptoms (e.g., moderate rise in body temperature or fever, nausea, chills, headache, pain) as well as behavioral manifestations (e.g., fatigue, difficulties concentrating, social withdrawal, mood impairments) (DellaGioia and Hannestad, 2010; Schedlowski et al., 2014). As such, it is a unique model to study afferent immune-to-brain communication and behavioral aspects of inflammation. Importantly, the central effects of peripheral pro- inflammatory cytokines during endotoxemia are relevant not only in the context of understanding normal, adaptive brain functions and behavioral changes during acute inflammation, but also to elu- cidate behavioral aspects that play a role in a range of neuropsychi- atric conditions (Miller et al., 2008; Capuron et al., 2014; Castanon et al., 2014; Schedlowski et al., 2014). http://dx.doi.org/10.1016/j.bbi.2016.01.003 0889-1591/Ó 2016 Elsevier Inc. All rights reserved. ⇑ Corresponding author at: Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Hufe- landstr 55, 45147 Essen, Germany. E-mail address: sven.benson@uk-essen.de (S. Benson). Brain, Behavior, and Immunity 57 (2016) 30–37 Contents lists available at ScienceDirect Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi